Clinical trial NCT02926833
Conditions: Refractory Diffuse Large B Cell Lymphoma
Sponsor: Kite, A Gilead Company
Start date: 2016-09-29; Completion date: 2023-01-12
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens.

The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in participants with refractory diffuse large B-cell lymphoma (DLBCL).

Participants 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 (NCT05041309).

Detailed description:

Arms: arm 1: Participants received conditioning chemotherapy consisting of 30 mg/m\^2 fludarabine and 500 mg/m\^2 cyclophosphamide intravenous (IV) infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10\^6 anti-CD19 chimeric antigen receptor (CAR) T cells/kg followed by 4 doses of atezolizumab (ATZ) (1200 mg/dose) IV infusion every 21 days, beginning 21 days following KTE-C19. arm 2: Participants received conditioning chemotherapy consisting of 30 mg/m\^2 fludarabine and 500 mg/m\^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 14 days following KTE-C19. arm 3: Participants received conditioning chemotherapy consisting of 30 mg/m\^2 fludarabine and 500 mg/m\^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19. arm 4: Participants received conditioning chemotherapy consisting of 30 mg/m\^2 fludarabine and 500 mg/m\^2 cyclophosphamide IV infusion per day for 3 days followed by KTE-C19 IV infusion at a target dose of 2 x 10\^6 anti-CD19 CAR T cells/kg followed by 4 doses of ATZ (1200 mg/dose) IV infusion every 21 days, beginning 1 day following KTE-C19.
Interventions: intervention 1: KTE-C19 intervention 2: Atezolizumab intervention 3: Cyclophosphamide intervention 4: Fludarabine
Intervention descriptions: intervention 1: A single infusion of KTE-C19 CAR-T cells administered intravenously intervention 2: Administered intravenously intervention 3: Administered intravenously intervention 4: Administered intravenously

Protocol documents:
SAP_004.pdf: 
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Prot_002.pdf: 





























































































































































































SAP_003.pdf: 
KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 1 of 29 
 
 
 
Sponsor: 
Kite Pharma, Inc. 
2400 Broadway   
Santa Monica, CA 90404 
United States of America 
Company Code: 
KTE-C19 
NCT Number: 
NCT02926833 
USAN Name: 
axicabtagene ciloleucel 
Product Name: 
axicabtagene ciloleucel (with atezolizumab) 
Protocol: 
A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of 
KTE-C19 in Combination with Atezolizumab in Subjects with Refractory 
Diffuse Large B-Cell Lymphoma (DLBCL) 
Version Number: 
1.0 
Release Date: 
25JUN2018  
Replaces Previous Version(s): 
NA 
Date: 
25JUN2018  
 
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. 
 
 
 
 
 
 
 
 
 
 


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 2 of 29 
 
TABLE OF CONTENTS 
LIST OF TABLES..................................................................................................................... 3 
LIST OF FIGURES ................................................................................................................... 3 
LIST OF ABBREVIATIONS.................................................................................................... 4 
1. 
INTRODUCTION ............................................................................................................. 6 
2. 
OBJECTIVES .................................................................................................................... 6 
3. 
STUDY DESIGN ............................................................................................................... 6 
3.1. 
Study Overview ............................................................................................................. 6 
3.2. 
Hypothesis ..................................................................................................................... 8 
3.3. 
Sample Size Considerations .......................................................................................... 8 
3.4. 
Replacement of Subjects ............................................................................................... 8 
3.5. 
Study Duration .............................................................................................................. 9 
3.5.1. Study Duration for Individual Subjects .................................................................. 9 
3.5.2. Completion of Study ................................................................................................ 9 
3.5.3. Subject Eligibility ..................................................................................................... 9 
3.6. 
Protocol Planned Study Treatments ............................................................................. 9 
3.6.1. Conditioning Chemotherapy ................................................................................... 9 
3.6.2. Study Treatment ...................................................................................................... 9 
3.6.3. Dosage Modification .............................................................................................. 10 
4. 
STUDY ENDPOINTS AND COVARIATES .................................................................. 10 
4.1. 
Primary Endpoints...................................................................................................... 10 
4.2. 
Secondary Endpoints .................................................................................................. 10 
4.3. 
Exploratory Endpoints ............................................................................................... 11 
4.4. 
Subgroups and Covariates .......................................................................................... 11 
5. 
DEFINITIONS ................................................................................................................. 11 
5.1. 
General ........................................................................................................................ 11 
5.2. 
Safety ........................................................................................................................... 12 
5.3. 
Efficacy ........................................................................................................................ 15 
6. 
ANALYSIS SETS ............................................................................................................ 16 
6.1. 
Full Analysis Set .......................................................................................................... 16 
6.2. 
Modified Intent-to-treat Set ........................................................................................ 16 
6.3. 
Safety Analysis Set ...................................................................................................... 16 
6.4. 
DLT Evaluable Set (Phase 1 only) .............................................................................. 16 
6.5. 
Safety Retreatment Analysis Set................................................................................. 16 
6.6. 
mITT Retreatment Analysis Set ................................................................................. 16 
7. 
SAFETY INTERIM ANALYSIS..................................................................................... 17 
8. 
HANDLING OF MISSING AND INCOMPLETE DATA ............................................. 17 
8.1. 
Efficacy Data ............................................................................................................... 17 
8.2. 
Safety Data .................................................................................................................. 17 
8.3. 
Detection of Bias ......................................................................................................... 17 
8.4. 
Outliers ........................................................................................................................ 17 
9. 
STATISTICAL METHODS OF ANALYSIS ................................................................. 17 
9.1. 
Overview of Analysis .................................................................................................. 17 
9.2. 
Subject Accountability ................................................................................................ 18 
9.3. 
Important Protocol Deviations ................................................................................... 18 
9.4. 
Demographic and Baseline Characteristics................................................................ 18 
9.5. 
Medical and Surgical History ..................................................................................... 19 
9.6. 
Prior Therapy for Primary Study Disease and Prior Radiotherapy ......................... 19 
9.7. 
Efficacy Analyses ........................................................................................................ 19 


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 3 of 29 
 
9.7.1. Complete Response and Objective Response ........................................................ 20 
9.7.2. Duration of Response ............................................................................................. 20 
9.7.3. Progression-free Survival ...................................................................................... 20 
9.7.4. Overall Survival ..................................................................................................... 21 
9.7.5. Tumor Burden ....................................................................................................... 21 
9.8. 
Safety Analyses ........................................................................................................... 21 
9.8.1. Adverse Events ....................................................................................................... 21 
9.8.2. Laboratory Test Results ........................................................................................ 22 
9.8.3. Anti-axicabtagene Ciloleucel Antibodies ............................................................... 22 
9.8.4. Anti-therapeutic Antibodies to Atezolizumab ....................................................... 22 
9.8.5. Replication-competent Retrovirus......................................................................... 22 
9.8.6. Exposure to Study Treatment and Product Characteristics ................................. 22 
9.8.7. Exposure to Concomitant Medications and Procedures ....................................... 23 
9.8.8. Subsequent Anti-cancer Therapy .......................................................................... 23 
9.8.9. Duration of Study Treatment ................................................................................ 23 
9.9. 
Pharmacokinetics ........................................................................................................ 23 
10. REFERENCES ................................................................................................................ 24 
11. APPENDICES .................................................................................................................. 25 
11.1. Appendix 1:  Conventions for Clinical Data that Require Imputation for Partial or 
Missing Dates .............................................................................................................. 25 
11.1.1. Imputation Rules for Partial or Missing Death Dates .......................................... 25 
11.2. Appendix 2:  Derivation of Time to Event Endpoints ................................................ 26 
11.2.1. Duration of Response ............................................................................................. 26 
11.2.2. Progression-free Survival ...................................................................................... 27 
11.2.3. Overall Survival ..................................................................................................... 28 
11.3. Appendix 3:  Derivation of Last Date Known to be Alive .......................................... 28 
 
LIST OF TABLES 
Table 1. 
Two-sided 95% and 80% Exact Confidence Intervals Corresponding to 
Observed CR Rate Following Treatment of 25 Subjects with Axicabtagene 
Ciloleucel and Atezolizumab .................................................................................. 8 
Table 2. 
Imputation Rules for Partial or Missing Start Dates ........................................... 25 
Table 3. 
Primary Analysis of DOR ..................................................................................... 26 
Table 4. 
Sensitivity Analysis of DOR ................................................................................. 27 
Table 5. 
Primary Analysis of PFS ...................................................................................... 27 
Table 6. 
Sensitivity Analysis of PFS ................................................................................... 28 
Table 7. 
Imputation Rule of OS Event/Censoring Date ..................................................... 28 
 
LIST OF FIGURES 
Figure 1. Study Schema.......................................................................................................... 7 
 
 


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 4 of 29 
 
LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
AE 
Adverse event 
ASCT 
Autologous stem cell transplant 
ATC 
Anatomical therapeutic chemical 
BCL 
B-cell lymphoma 
BSA 
Body surface area 
CAR 
Chimeric antigen receptor 
CR 
Complete response 
CRF 
Case report form 
CRR 
Complete response rate 
CRS 
Cytokine release syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLBCL 
Diffuse large B-cell lymphoma 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
EBV 
Epstein-Barr virus 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full analysis set 
GBC 
Germinal Center B Cell-like 
KTE-C19 
Company code for axicabtagene ciloleucel 
HLGT 
High-level group term 
IPD 
Important protocol deviation 
IPI 
International Prognostic Index 
IWG 
International Working Group  
LTFU 
Long Term Follow-up 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mITT 
Modified intent-to-treat 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin lymphoma 
ORR 
Objective response rate 


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 5 of 29 
 
Abbreviation  
Definition 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetics 
PR 
Partial response 
PT 
Preferred term 
RCR 
Replication-competent retrovirus 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCT 
Stem cell transplant 
SD 
Stable disease 
SIA 
Systemic immune activation 
SOC 
System organ class 
SPD 
Sum of the product of the diameter 
SOA 
Schedule of Assessments 
SRT 
Safety review team 
TEAE 
Treatment-emergent adverse event 
WHODrug 
World Health Organization Drug Dictionary 
 
 
 


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 6 of 29 
 
1. INTRODUCTION 
This statistical analysis plan (SAP) sets forth prospectively the details of statistical analyses that are 
outlined in protocol KTE-C19-106 entitled “A Phase 1–2 Multi-Center Study Evaluating the Safety and 
Efficacy of KTE-C19 in Combination with Atezolizumab in Subjects with Refractory Diffuse Large B-
Cell Lymphoma (DLBCL),” dated 21 Sep 2017.  The scope of this SAP includes all the statistical 
analyses that are outlined in the protocol. 
2. OBJECTIVES 
This study is organized into 2 phases:  Phase 1 and Phase 2. 
The primary objective of Phase 1 is to evaluate the safety of axicabtagene ciloleucel and atezolizumab 
combination regimens. 
The primary objective of Phase 2 is to evaluate the efficacy of axicabtagene ciloleucel infusion followed 
by atezolizumab, as measured by the complete response (CR) rate in subjects with refractory DLBCL.  
Secondary objectives will include assessing the safety and tolerability of axicabtagene ciloleucel followed 
by atezolizumab treatment as well as secondary endpoints efficacy, biomarker, pharmacokinetics (PK), 
and anti-therapeutic antibody endpoints listed in Section 4. 
3. STUDY DESIGN 
3.1. Study Overview  
This is a Phase 1-2, open-label study evaluating the safety and efficacy of axicabtagene ciloleucel 
followed by atezolizumab in subjects with refractory DLBCL.  The trial will be separated into 2 distinct 
phases designated as Phase 1 and Phase 2.  
Phase 1:  Approximately 3–9 subjects with refractory DLBCL will be enrolled in up to 3 cohorts to 
evaluate the safety of axicabtagene ciloleucel followed by atezolizumab regimen.  A safety review team 
(SRT), internal to the study sponsors and Phase 1 investigators, will review safety data after subjects in 
Phase 1 have completed the dose-limiting toxicities (DLT) part of the study.  The SRT will make 
recommendations on further study conduct of Phase 1 and progression to Phase 2 as depicted in Figure 1. 


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 7 of 29 
 
Figure 1. 
Study Schema 
 
Abbreviations:  DLT, dose-limiting toxicity. 
*During Phase 1, cohorts will be enrolled sequentially, beginning with Cohort 1.  After each Phase 1 cohort has completed 
enrollment and subjects have cleared the DLT window, the SRT will meet and review the overall benefit/risk profile of the 
dosing schedule tested in that cohort.  SRT recommendations for further study conduct may include addition of subjects to a 
cohort prior to opening a subsequent cohort, advancement to a subsequent cohort, exploration of alternative conditioning 
chemotherapy or KTE-C19 doses, advancement to Phase 2, or study termination. 
 
Phase 2:  Approximately 22 subjects will be enrolled to receive treatment with axicabtagene ciloleucel 
followed by atezolizumab based on the dose and schedule selected to move forward from the Phase 1 
portion of the study as recommended by the SRT.  
Independent of the cohort or phase of the study, each subject will proceed through the following study 
periods:  
• 
Screening  
• 
Enrollment/Leukapheresis  
• 
Conditioning chemotherapy  
• 
Investigational treatment (axicabtagene ciloleucel followed by atezolizumab)  
• 
Post-treatment assessment  
• 
Long-term follow-up  
Details on the study requirements during each study period are presented in Section 7 of the study 
protocol. 
   
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
  
 
  
 
 
   
 






KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 10 of 29 
 
3.6.2.2. 
Atezolizumab Dosing and Administration 
Atezolizumab is infused intravenously 
 
  
 
  
 
  
 
 
3.6.3. Dosage Modification  
No reduction or modification of the atezolizumab dose is planned.  
4. STUDY ENDPOINTS AND COVARIATES  
4.1. Primary Endpoints  
Phase 1:  the incidence of DLT.  
Phase 2:  CR rate per the revised International Working Group (IWG) Response Criteria for Malignant 
Lymphoma (Cheson et al, 2007) as determined by study investigators.  
4.2. Secondary Endpoints  
Phase 1 and Phase 2: 
• 
Objective response rate (ORR; CR + partial response [PR]) per the revised IWG Response 
Criteria for Malignant Lymphoma (Cheson et al, 2007) determined by study investigators 
• 
Duration of response (DOR) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
• 
Incidence of adverse events (AEs) and clinically significant changes in safety lab values 
• 
Levels of axicabtagene ciloleucel in blood  
• 
Incidence of anti-axicabtagene ciloleucel antibodies 
• 
Atezolizumab PK 
• 
Incidence of anti-atezolizumab antibodies in serum 
• 
Levels of cytokines in serum 
CCI


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 11 of 29 
 
4.3. Exploratory Endpoints 
  
 
 
  
4.4. Subgroups and Covariates 
The following variables may be used to examine efficacy results in subgroups or covariate analyses, as 
well as safety analyses. Analyses might be subject to restrictions due to small sample size. 
• 
Eastern Cooperative Oncology Group (ECOG) performance status (0, 1) 
• 
Age at baseline ( < 65, ≥ 65)  
• 
Histologically proven DLBCL type   
• 
Tumor Epstein-Barr virus (EBV) status (EBV+, EBV-, or unknown) 
• 
Molecular subgroups (GBC, ABC, or unknown) 
• 
Disease stage at study entry (I–II, III–IV) 
• 
International Prognostic Index (IPI) total score at baseline (0–1, 2–3, 4–5) 
• 
Prior transplant (autologous stem cell transplant [ASCT])(Y/N) 
• 
Refractory subgroup (primary refractory, refractory to second line or greater, relapse post ASCT) 
• 
Expression of CD19 in tumor tissue prior to treatment  
• 
Expression of PD-L1 in tumor tissue prior to treatment 
• 
Baseline bone marrow involvement 
• 
Tumor burden at baseline, as measured by the sum of the product of the diameters (SPD) of target 
lesions at baseline (≤ median vs > median value) 
• 
Total CAR T cells of the product infused (≤ median vs > median) 
• 
Prior platinum   
5. DEFINITIONS 
5.1. General 
Study enrollment:  Subjects are considered enrolled in the study after the leukapheresis procedure is 
initiated. 
Study Day 0:  Defined as the day the subject received axicabtagene ciloleucel infusion.  The day prior to 
study Day 0 will be study Day –1.  Any days prior to study Day 0 will be sequential and negative integer-
valued.  
CCI


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 12 of 29 
 
Baseline:  Defined as the last non-missing value measured on or prior to conditioning chemotherapy, 
unless otherwise specified.   
Baseline of retreatment:  If the subject is eligible for retreatment with axicabtagene ciloleucel, the last 
records on or prior to conditioning chemotherapy retreatment will be considered the baseline of 
retreatment, unless otherwise specified.    
Refractory subgroup at baseline:  Chemotherapy-refractory disease is defined as one or more of the 
following: 
• 
Primary refractory:  A subject is considered to be primary refractory if the subject experienced 
disease progression as best response to first-line therapy or had stable disease after at least 
4 cycles of first-line therapy with duration of stable disease no longer than 6 months from the last 
dose of therapy.  
• 
Refractory to second- or greater-line therapy:  A subject is considered to be refractory to second- 
or greater-line therapy if the subject experienced progressive disease (PD) as best response to the 
most recent therapy regimen or experienced stable disease after at least 2 cycles of therapy with 
duration of stable disease no longer than 6 months.  
• 
Relapse post-ASCT:  A subject is considered to be relapsed post-ASCT if the subject experienced 
PD or relapse ≤ 12 months after ASCT.  
In case a subject may meet the criteria for multiple refractory subgroups, this subject will be assigned to 
the subgroup based on the hierarchy of priority of relapse post-ASCT > Refractory to second- or greater-
line of therapy > primary refractory.   
5.2. Safety 
Treatment-emergent adverse event (TEAE):  Any worsening of a pre-existing medical condition that 
occurs on or after axicabtagene ciloleucel infusion or any AE with onset on or after axicabtagene 
ciloleucel infusion.  
Investigational treatment period:  Beginning from the date axicabtagene ciloleucel infusion through 
30 days after completing the final dose of atezolizumab or 3 months after the axicabtagene ciloleucel 
infusion, whichever is longer. 
Investigational retreatment period:  Beginning from the date of the axicabtagene ciloleucel retreatment 
infusion through 30 days after completing the final dose of atezolizumab retreatment or 3 months after the 
axicabtagene ciloleucel infusion in retreatment, whichever is longer. 
Deaths:  Any death occurring on or after the first dose of conditioning chemotherapy up through the end 
of study.  
Adverse events of interest:  The following AEs are of interest for the treatment of axicabtagene 
ciloleucel followed by atezolizumab.   


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 13 of 29 
 
Identified risks:  
• 
Cytokine-release syndrome (CRS)  
• 
Neurologic events  
• 
Prolonged cytopenias    
• 
Infections 
• 
Hypogammaglobulinemia 
Potential risks:  
• 
Secondary malignancies  
• 
Tumor lysis syndrome  
• 
Immunogenicity (anti-axicabtagene ciloleucel or anti-atezolizumab antibodies)  
• 
Replication-competent retrovirus (RCR) 
• 
Systemic immune activation (SIA) 
CRS:  CRS is identified via collection of the syndrome on a case report from (CRF) specifically designed 
to collect CRS.  Specific individual symptoms of CRS (eg, fever) collected on the AE log are coded using 
Medical Dictionary for Drug Regulatory Activities (MedDRA) and linked to the corresponding CRS 
episode.  Individual symptoms of CRS are graded per National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03, and CRS as a syndrome is graded per 
modified Lee criteria (Lee et al, 2014).  In the modified grading scale, neurologic AEs are not reported as 
part of the CRS syndrome because they will be reported separately with the neurologic events category 
and graded per CTCAE version 4.03. 
Neurologic events:  Neurologic AEs are identified with a search strategy based on known neurologic 
toxicities associated with anti-CD19 immunotherapy (Topp et al, 2015).  The search strategy focuses on 
central nervous system toxicity, without regard to temporal relationship or concomitant conditions (eg, 
CRS).  Neurologic events will be reported separately from CRS. 
Cytopenias:  Cytopenias (neutropenia, anemia, and thrombocytopenia) are identified as the following:  
• 
Neutropenia is identified using the following MedDRA preferred terms:  febrile neutropenia, 
neutropenia, neutrophil count decreased. 
• 
Anemia is identified using the standardized MedDRA query (SMQ) haematopoietic erythropenia 
(broad). 
• 
Thrombocytopenia is identified using the SMQ haematopoietic thrombocytopenia (narrow). 
Cytopenias present after 30 days from the axicabtagene ciloleucel infusion will be summarized as 
prolonged cytopenias.  


KTE-C19-106 
Kite Pharma, Inc. 
Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
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Infections:  Infections are identified as AEs within the MedDRA system organ class (SOC) of Infections 
and Infestations that occur after treatment with anti-CD19 CAR T cells.  Subtypes of infections are 
identified using MedDRA high-level group terms (HLGT) that capture events of:  
• 
Bacterial infection, encompassing the MedDRA HLGTs of:  
o Bacterial infectious disorders  
o Chlamydial infectious disorders 
• 
Viral infection, encompassing the MedDRA HLGT of viral infectious disorders 
• 
Opportunistic infections, encompassing the MedDRA HLGTs of:  
o Fungal infectious disorders 
o Mycobacterial infectious disorders 
• 
Other infections, encompassing the MedDRA HLGT of Infections – pathogen unspecified  
Hypogammaglobulinemia:  Hypogammaglobulinemia is identified as AE coded as MedDRA preferred 
terms of hypogammaglobulinemia, blood immunoglobulin D decreased, and blood immunoglobulin G 
decreased. 
Secondary malignancy:  Secondary malignancies are identified via collection on a CRF in which the 
investigator classifies the event as a secondary malignancy.  Additionally, AEs that are coded into the 
SOC of Neoplasms benign, malignant, and unspecified (including cysts and polyps) with the exception of 
preferred terms containing “B-cell” or “B cell” and “Lymphoma” will be reviewed to identify other 
potential events.   
Tumor lysis syndrome:  Tumor lysis syndrome is identified as events with MedDRA preferred terms in 
the Tumor Lysis Syndrome SMQ (MedDRA).  The narrow version of this SMQ will be used. 
Study day of onset of event/syndrome:  Study day of onset of an event/syndrome is defined as the study 
day of the first occurrence of the event/syndrome.  Study day of onset of Grade 3 or higher 
events/syndromes are defined in the same way, but restricted to Grade 3 or higher events/syndromes. 
Study day of resolution of an event/syndrome:  Study day of resolution of an event/syndrome is the last 
study day the event is present.  If multiple events occur after axicabtagene ciloleucel infusion, the study 
day of resolution is the last day of the multiple events presented.  Study day of resolution will not be 
calculated for events that are ongoing at the time of the data cutoff date or death.   
Duration of an AE of interest:  The duration of an AE of interest may be derived only among subjects 
for whom all events of the class have resolved by the analysis data cutoff date.  The duration is defined as 
the stop day of the last AE in the event class—the start day of the first AE in the event class + 1. 


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5.3. Efficacy 
Complete response rate (CRR):  The proportion of subjects with a CR while on study.  Subjects who do 
not meet the criteria for CR by the analysis cutoff date will be considered non-CR.  The derivation of this 
endpoint will only include response assessments obtained after at least 1 dose of atezolizumab 
administration and prior to any subsequent therapies for non-Hodgkin lymphoma (NHL) (including SCT 
and retreatment with axicabtagene ciloleucel and atezolizumab).  Responses will be assessed per the 
revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) as determined by study 
investigators. 
Objective response rate (ORR):  The proportion of subjects with a CR or PR while on study.  Subjects 
who do not meet the criteria for objective response by the analysis cutoff date will be considered non-
responders.  The derivation of this endpoint will only include response assessments obtained after at least 
1 dose of atezolizumab administration and prior to any subsequent therapies for NHL (including stem cell 
transplant [SCT] and retreatment with axicabtagene ciloleucel and atezolizumab).  Responses will be 
assessed per the revised IWG Response Criteria for Malignant Lymphoma (Cheson et al, 2007) as 
determined by study investigators.  
Duration of response (DOR):  DOR is defined only for subjects who experience an objective response 
(CR or PR) and is the time from the first objective response to disease progression per the revised IWG 
Response Criteria for Malignant Lymphoma (Cheson et al, 2007) or death due to any reason.  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.  DOR will be derived using disease assessments obtained on study 
prior to any subsequent therapies for NHL (including SCT and retreatment with axicabtagene ciloleucel 
and atezolizumab).  The DOR for subjects who undergo SCT while in an axicabtagene ciloleucel-induced 
response will be censored at the last evaluable disease assessment prior to SCT.  A sensitivity analysis 
will be conducted in which disease assessments obtained after SCT are included in the derivation of 
DOR. Additional details on the derivation of DOR are provided in Section 11.2, Appendix 2.  
Progression-free survival (PFS):  PFS is defined as the time from the axicabtagene ciloleucel infusion 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.  PFS will be derived using 
disease assessments obtained on study prior to any subsequent therapies for NHL (including SCT and 
retreatment with axicabtagene ciloleucel and atezolizumab).  The PFS for subjects who undergo SCT 
while in an axicabtagene ciloleucel-induced response will be censored at the last evaluable disease 
assessment prior to the SCT.  A sensitivity analysis will be conducted in which disease assessments 
obtained after SCT will be included in the derivation of disease assessment.  Additional details on the 
derivation of PFS are provided in Section 11.2, Appendix 2. 
Overall survival (OS):  OS is defined as the time from the 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 date 
known to be alive or the data cutoff date, whichever is earlier.  Further details on the derivation of OS and 




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7. SAFETY INTERIM ANALYSIS 
The SRT will review safety data during Phase 1 of the study and will make recommendations on further 
study conduct in Phase 1 and progression to Phase 2 based on the incidence of axicabtagene ciloleucel-
related DLTs and review of serious adverse events (SAEs).  
The SRT will also meet once during the Phase 2 portion of the study when 6 subjects have completed 
their 1-month disease assessment.  The SRT will review safety and efficacy data and is empowered to 
make trial conduct recommendations based on an analysis of risk vs benefit.  The SRT may meet more 
often as needed. 
8. HANDLING OF MISSING AND INCOMPLETE DATA 
8.1. Efficacy Data 
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 algorithms discussed in Section 11.2, Appendix 2 will 
be used. 
8.2. Safety Data 
Partial AE start dates will be imputed.  If dates are missing or incomplete for AE start dates, the algorithm 
defined in Section 11.1, Appendix 1 will be used.  Completely missing death dates or death dates with 
only a year reported will not be imputed. 
8.3. Detection of Bias 
A listing of subject incidence of important protocol deviations (IPD) will be generated.  The deviations 
included in this list will include 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 IPD.  
High rates of IPD may indicate bias.  
8.4. 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. 
9. STATISTICAL METHODS OF ANALYSIS 
9.1. Overview of Analysis   
Analyses of the Phase 1 and Phase 2 portions of the study will be presented separately, unless otherwise 
specified.  Within the Phase 1 summaries, each dose cohort will be presented separately.   


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The primary efficacy analysis will be performed when the last treated subject in the mITT set has had the 
opportunity to be evaluated for response 6 months after the axicabtagene ciloleucel infusion.  The final 
analysis will occur when all subjects have completed the study.   
9.2. Subject Accountability 
The number of subjects screened, leukapheresed, treated with conditioning chemotherapy, treated with 
axicabtagene ciloleucel and atezolizumab, or retreated with axicabtagene ciloleucel and atezolizumab will 
be summarized.  The reasons for discontinuing treatment and discontinuing study will be summarized.  
Summaries of actual follow-up time will be provided.  The number of subjects enrolled by site will be 
summarized.  The number of subjects in each analysis set along with reasons for exclusion (if any) will be 
provided. 
9.3. Important Protocol Deviations 
The clinical study team will define IPD categories and review all potential deviations at a minimum, prior 
to the database snapshot for the primary efficacy analysis.  IPDs will be categorized by deviation type (eg, 
entry/eligibility, use of excluded medication).  The subject incidence of IPDs will be summarized overall 
and by category. 
9.4. Demographic and Baseline Characteristics  
Summary statistics and frequencies for the following demographic and baseline characteristics will be 
tabulated:  
• 
Age at baseline and by category (< 65, ≥ 65)  
• 
Sex  
• 
Ethnicity 
• 
Race  
• 
Height 
• 
Weight  
• 
ECOG performance status at baseline 
• 
Histologically proven DLBCL type  
• 
Tumor EBV Status (EBV+, EBV-, or unknown)  
• 
Molecular subgroups (GCB, ABC, or unknown)  
• 
For subjects with cytogenetics testing performed: 
o BCL-2 alternations/over-expressions (Y/N) 
o BCL-6 alternations/over-expressions (Y/N) 
o C-MYC alternations/over-expressions (Y/N) 


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• 
Disease stage (I, II, III, IV) and extent (presence of B symptoms, splenic involvement, extra-
nodal disease, bulky disease, bone marrow involvement)  
• 
IPI risk category  
• 
Refractory subgroup (primary refractory, second line or greater, relapse post-ASCT) 
• 
Prior ASCT  
• 
Lines of prior therapy for primary study disease 
• 
Tumor burden at baseline, as measured by the SPD of target lesions at baseline  
• 
CD19 expression in tumor intensity at baseline   
• 
PD-L1 expression in tumor intensity and immune infiltrate tumor intensity at baseline 
• 
Baseline bone marrow involvement 
• 
Best response to prior anti-cancer therapy  
• 
Prior radiotherapy information (Y/N) 
• 
Best response to prior transplant  
• 
Prior anti-CD20 
• 
Prior anthracycline 
• 
Prior platinum 
9.5. Medical and Surgical History  
Medical and surgical history will be coded using the latest version of MedDRA.  The numbers and 
percentages of subjects with medical history will be reported by SOC and preferred term (PT). 
9.6. Prior Therapy for Primary Study Disease and Prior Radiotherapy 
Prior therapy for DLBCL will be coded by anatomical therapeutic chemical (ATC) code and PT using the 
latest version of World Health Organization Drug Dictionary (WHODrug) and will be summarized in 
frequency tabulations (subject counts and percentages) by PT.   
Intent of prior radiotherapy and body site to receive the radiotherapy will be summarized in frequency 
tabulations (subject counts and percentages). 
9.7. Efficacy Analyses 
Efficacy analyses will be conducted on the mITT analysis set and will use investigator assessment of 
disease status per (Cheson et al, 2007).  
For subjects retreated with axicabtagene ciloleucel and atezolizumab, disease assessments obtained prior 
to retreatment will be included in the primary summaries of objective and best response, DOR, PFS, and 
summaries of change in tumor burden.  For such subjects, disease assessments obtained after retreatment 


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will be included in the summaries of objective and best response to retreatment with axicabtagene 
ciloleucel and atezolizumab and DOR after retreatment with axicabtagene ciloleucel and atezolizumab.  
The subject’s OS time will be derived from the last date known alive regardless of retreatment time.  
9.7.1. Complete Response and Objective Response 
9.7.1.1. 
Analyses of Response Rate 
The subject incidence of CR and objective response (CR + PR) will be calculated (Cheson et al, 2007).  
Two-sided 95% confidence intervals will be generated using the Clopper-Pearson (an exact interval) 
method. 
The number and percentage of subjects who initially do not attain CR and who subsequently attain a CR 
will be summarized.  
9.7.1.2. 
Subgroup Analyses  
The response rates and exact 2-sided 95% confidence intervals will be generated for subgroups of the 
mITT analysis set based on, but not limited to, the covariates defined in Section 4.4.  A forest plot of the 
proportion of responders for each of these groups will be generated. 
9.7.2. Duration of Response 
The Kaplan-Meier approach will be used to estimate DOR.  The number of subjects censored and the 
reasons for censoring will be summarized.  The reverse Kaplan-Meier approach (Schemper and Smith 
1996) will be used to estimate the follow-up time for DOR.     
A sensitivity analysis of DOR will be conducted in which disease assessments obtained after SCT (for 
subjects who undergo SCT while in an axicabtagene ciloleucel-induced response) are used in the 
derivation of DOR. 
DOR may be summarized in subgroups defined by the best response attained on study. 
9.7.3. Progression-free Survival  
Kaplan-Meier plots, estimates, and 2-sided 95% confidence intervals will be generated for PFS.  
Estimates of the proportion of subjects alive and progression-free at 3-month intervals will be provided.  
The number of subjects censored or having events, and the reasons for censoring or type of events (PD or 
death), will be summarized.  The reverse Kaplan-Meier approach (Schemper and Smith 1996) will be 
used to estimate the follow up time for PFS. 
A sensitivity analysis of PFS will be conducted in which the disease assessments obtained after ASCT 
will be included in the derivation of disease assessment.  Subgroup analyses of the PFS rate at 6 months 
may be generated in subgroups defined by the covariates in Section 4.4. 
PFS may be summarized in subgroups defined by the best response attained on study. 


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9.7.4. Overall Survival 
The analysis of OS will use the same methods as the analysis of PFS.  The reverse Kaplan-Meier 
approach (Schemper and Smith 1996) will be used to estimate the follow-up time for overall survival.  OS 
may be summarized in subgroups defined by the best response attained on study. 
9.7.5. Tumor Burden 
The change in tumor burden, as measured by the SPD of the selected lesions, from baseline to post-
baseline nadir will be summarized in absolute numbers (mm2) and percentages.  A graphical summary of 
this change will be presented in a vertical bar chart with each subject’s change from baseline to nadir 
displayed as a vertical bar, with color coding that indicates best response attained (“waterfall” plot).  
Summary statistics will be provided for this change.  Data collected after new anti-cancer therapy or SCT 
will not be included for the analyses.   
9.8. Safety Analyses  
Safety analyses will be conducted on the SAS.  The primary analysis of safety data will summarize all 
TEAEs and laboratory values.  For subjects who undergo retreatment with axicabtagene ciloleucel and 
atezolizumab, AEs occurring in this period may be summarized in an additional separate summary or 
listing that presents only the AEs occurring during the retreatment period.  
AEs will be coded with the latest version of MedDRA.  The severity of AEs will be graded using the NCI 
CTCAE version 4.03.  The incidence and severity of CRS will be graded using a revised CRS grading 
scale developed by Lee and colleagues (Lee et al, 2014).  Individual symptoms associated with CRS will 
be graded per CTCAE version 4.03. 
Subjects enrolled, but not dosed with the study combination treatment, will be followed for AEs for 
30 days after the last study procedure.  AEs reported in these subjects will be archived in the study 
database and available in study data tabulation model (SDTM) and analysis data model (ADaM) datasets, 
but will not be tabulated in AE summaries.  
9.8.1. Adverse Events  
The subject incidence of the following TEAEs will be tabulated by SOC and PT:  
• 
Summary of AEs (any, worst severity, serious, related)  
• 
All AEs  
• 
All SAEs  
• 
All axicabtagene ciloleucel and/or atezolizumab related AEs  
• 
All axicabtagene ciloleucel and/or atezolizumab related SAEs  
• 
All Grade 3 or higher AEs  
• 
All Grade 3 or higher axicabtagene ciloleucel and/or atezolizumab related AEs  


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• 
The most common AEs    
• 
The most common Grade 3 or higher AEs    
• 
AEs of interest, including identified risks (CRS, neurological event, infections, cytopenias, 
hypogammaglobulinemia), and potential risks (secondary malignancies, tumor lysis syndrome, 
SIA, and immunogenicity)  
• 
Other clinically important adverse reactions  
• 
Death (through the long-term follow-up and treatment-related SAEs) 
Summary statistics for the study day of onset, the study day of resolution, and the duration of AEs of 
interest will be provided.  A subject listing of deaths and SAEs (including narratives) will be provided by 
overall and by treatment period.  
Subgroup analyses of AEs may be generated using the covariates listed in Section 4.4 if applicable.  
9.8.2. Laboratory Test Results  
Laboratory results will be graded according CTCAE (version 4.03).  Laboratory data collected at baseline 
and through the treatment and follow-up periods will be summarized.  Shifts from baseline to minimum 
post-baseline and/or maximum post-baseline will be presented for selected analytes.  The incidence of 
worst grade CTCAE shift for selected analytes will be provided. 
9.8.3. Anti-axicabtagene Ciloleucel Antibodies  
The subject incidence of any anti-axicabtagene ciloleucel antibodies will be tabulated.  For subjects 
testing positive for antibodies, the persistence of the antibody over time will be summarized. 
9.8.4. Anti-therapeutic Antibodies to Atezolizumab 
Atezolizumab PK and incidence of anti-therapeutic antibodies (ATA) in serum will be tabulated.  For 
subjects testing positive for antibodies, the persistence of the antibody over time will be summarized. 
9.8.5. Replication-competent Retrovirus  
The subject incidence of RCR detected in blood samples will be tabulated overall and by assessment time.  
The persistence of RCR over time will be summarized.  
9.8.6. Exposure to Study Treatment and Product Characteristics  
Summary statistics and subject listings will be provided for the following: 
• 
Total body surface area (BSA)-adjusted dose of cyclophosphamide  
• 
Total BSA-adjusted dose of fludarabine  
• 
Weight-adjusted dose of axicabtagene ciloleucel    


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• 
Total CAR T cells of the axicabtagene ciloleucel infusion  
• 
Total T cells of the axicabtagene ciloleucel infusion  
• 
Transduction percentage  
• 
Ratio of CD4 and CD8 T cells  
• 
Percentages of T-cell memory phenotypes  
• 
Interferon gamma (IFN-γ) production in co-cultures of axicabtagene ciloleucel product  
• 
Summary of atezolizumab infusion  
Separate summaries will be presented for retreated subjects if applicable. 
9.8.7. Exposure to Concomitant Medications and Procedures  
The subject incidence of concomitant medications will be provided and summarized by medication 
category (general, immunosuppressive, anti-infective, vasopressor, corticosteroid, and tocilizumab) and 
WHODrug coded term.  The subject incidence of procedures will be tabulated.  
9.8.8. Subsequent Anti-cancer Therapy  
The incidence and type (by WHODrug coded term and categories) of subsequent anti-cancer therapy and 
stem cell transplant (autologous, allogeneic) will be summarized.  
9.8.9. Duration of Study Treatment 
Summary statistics will be provided for the following durations: 
• 
Days from screening to commencement of leukapheresis 
• 
Days from screening to administration of axicabtagene ciloleucel  
• 
Days from leukapheresis to commencement of conditioning chemotherapy 
• 
Days from leukapheresis to receipt of axicabtagene ciloleucel at the study site 
• 
Days from leukapheresis to the administration of axicabtagene ciloleucel 
• 
Days from conditioning chemotherapy to administration of axicabtagene ciloleucel 
• 
Duration of hospitalization for the axicabtagene ciloleucel infusion 
9.9. Pharmacokinetics 
Refer to PK/pharmacodynamics SAP. 
 
 


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10. REFERENCES   
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. 
 
Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. 
Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 
2014;124(2):188-95. 
 
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin 
Trials. 1996;17(4):343-6. 
 
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. 
 
 
 


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11. APPENDICES 
11.1. Appendix 1:  Conventions for Clinical Data that Require Imputation for Partial or Missing 
Dates  
The following data will be imputed using the algorithm shown in Table 2: 
• 
Adverse event (AE) start dates  
• 
Deaths (refer to exceptions in Section 11.1.1)  
• 
Concomitant start dates 
Table 2. 
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 
Abbreviations:  n/a, not available. 
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. 
11.1.1. Imputation Rules for Partial or Missing Death Dates 
• 
If death year and month are available, but day is missing: 
o If mmyyyy for the last contact date = mmyyyy for death date, set death date to the day after 
the last date known to be alive. 
o 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. 


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o If mmyyyy for last date known to be alive > mmyyyy for death date, data error and do not 
impute. 
• 
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. 
Imputation rules for subsequent anti-cancer therapy start dates: 
• 
If year and month are available, but day is missing: 
o If the year and month are the same as last no-serious AE start date, then set the day as no-
serious AE start date + 1 
o If the year or month is after the last no-serious AE start date, then set the day as the first day 
of the month. 
• 
If year is available, and month and day are missing: 
o If the year is same as last no-serious AE start year, then set the date as AE start date + 1 
o If the year is after the last no-serious AE start year, then set January 1 as the date. 
• 
If the date is completely missing, then set the date as last no-serious AE start date + 1. 
11.2. Appendix 2:  Derivation of Time to Event Endpoints  
The derivations of duration of response (DOR), progression-free survival (PFS), and overall survival (OS) 
are provided in Table 3, Table 4, Table 5, Table 6, and Table 7.  Duration of response to retreatment will 
follow the same imputation rules as DOR. 
11.2.1. Duration of Response  
Table 3. 
Primary Analysis of DOR 
Circumstance 
Event/Censored 
Date of Event/Censoring 
Disease progression prior to initiation of new anti-
cancer therapy (including SCT) and prior to data 
cutoff for analysis  
Event 
Progression date 
Death without disease progression and without new 
anti-cancer therapy (including SCT) prior to data 
cutoff for analysis 
Event 
Death date 
New anti-cancer therapy (including SCT) started 
before disease progression or death and prior to data 
cutoff for analysis 
Censored 
Date of last evaluable disease 
assessment prior to initiation of 
new therapy or SCT, whichever 
is earlier 
Disease progression or death documented after data 
cutoff for analysis  
Censored 
Date of last evaluable disease 
assessment prior to data cutoff 
for analysis 


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Circumstance 
Event/Censored 
Date of Event/Censoring 
Remain in response without new anti-cancer therapy 
(including SCT) through the discontinuation of study 
and prior to data cutoff for analysis  
Censored 
Date of last evaluable disease 
assessment prior to the 
discontinuation of study or prior 
to data cutoff for analysis, 
whichever is earlier 
Abbreviations:  SCT, stem cell transplant. 
 
Table 4. 
Sensitivity Analysis of DOR 
Circumstance* 
Event/Censored 
Date of Event/Censoring 
Disease progression after initiation of SCT, but prior 
to other new anti-cancer therapy  
Event 
Progression date 
Death after SCT without disease progression or other 
new anti-cancer therapy  
Event 
Death date 
Remain in response after SCT without other new 
anti-cancer therapy   
Censored 
Last evaluable disease 
assessment date 
Remain in response after SCT prior to other initiated 
new anti-cancer therapy 
Censored 
last evaluable disease 
assessment prior to other 
initiated new anti-cancer 
therapy 
Death without disease progression and without new 
anti-cancer therapy (including SCT) prior to data 
cutoff for analysis  
Censored 
Last evaluable disease 
assessment date before death 
date 
Abbreviations:  SCT, stem cell transplant. 
*For all the other circumstances, follow the imputation rules described in Table 3. 
 
11.2.2. Progression-free Survival   
Table 5. 
Primary Analysis of PFS 
Circumstance 
Event/Censored 
Date of Event/Censoring 
Disease progression prior to initiation of 
new anti-cancer therapy (including SCT) or 
prior to the data cutoff for analysis  
Event 
Progression date 
Death without disease progression and 
without new anti-cancer therapy (including 
SCT) prior to the data cutoff for analysis 
Event 
Death date 
New anti-cancer therapy (including SCT) 
started before disease progression or death 
or prior to the data cutoff for analysis  
Censored 
Date of last evaluable disease assessment 
prior to initiation of new therapy or SCT, 
whichever is earlier 
Disease progression or death documented 
after data cutoff for analysis 
Censored 
Date of last evaluable disease assessment 
prior to data cutoff for analysis 


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Circumstance 
Event/Censored 
Date of Event/Censoring 
No disease progression through the 
discontinuation of study or prior to data 
cutoff for analysis  
Censored 
Date of last evaluable disease assessment 
prior to the discontinuation of study or 
prior to data cutoff for analysis, whichever 
is earlier 
No disease assessment done after 
axicabtagene ciloleucel infusion by the 
cutoff date 
Censored  
Axicabtagene ciloleucel infusion date 
Abbreviations:  SCT, stem cell transplant. 
 
Table 6. 
Sensitivity Analysis of PFS 
Circumstance* 
Event/Censored 
Date of Event/Censoring 
Disease progression after initiation of SCT, 
but prior to other new anti-cancer therapy  
Event 
Progression date 
Death after SCT without disease progression 
or other new anti-cancer therapy  
Event 
Death date 
Remain no disease progression after SCT 
without other new anti-cancer therapy   
Censored 
Last evaluable disease assessment date 
Remain no disease progression after SCT 
prior to other initiated new anti-cancer 
therapy 
Censored 
Last evaluable disease assessment prior to 
other initiated new anti-cancer therapy 
Abbreviations:  SCT, stem cell transplant. 
*For data from SCT after axicabtagene ciloleucel infusion.  For all the other circumstances, follow the imputation rules described 
in Table 5. 
 
11.2.3. Overall Survival 
Table 7. 
Imputation Rule of OS Event/Censoring Date 
Circumstance 
Event/Censored 
Date of Event/Censoring 
Death before data cutoff date for analysis 
Event 
Date of death 
Death after data cutoff date for analysis 
Censored 
Data cutoff date 
Known to be alive after data cutoff date for 
analysis 
Censored 
Data cutoff date 
Alive up through the discontinuation of 
study or data cutoff date, and no further 
information available afterward    
Censored 
Last date known to be alive, date up 
through the date of discontinuation of 
study, or data cutoff date, whichever is 
earlier 
 
11.3. Appendix 3:  Derivation of Last Date Known to be Alive 
The last date known to be alive will be derived by obtaining the maximum complete date among the 
following data modules: 


KTE-C19-106 
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Statistical Analysis Plan 
25 JUN 2018 
 
 
 
Confidential 
Page 29 of 29 
 
• 
Start date of AE (including targeted AE) 
• 
Leukapheresis date 
• 
Conditioning chemotherapy administration date 
• 
Axicabtagene ciloleucel infusion date 
• 
Atezolizumab infusion date 
• 
Computed tomography (CT) scan date 
• 
Positron emission tomography (PET) scan date 
• 
Target lesion assessment date 
• 
Non-target lesion assessment date 
• 
New lesion assessment date 
• 
Disease response assessment date 
• 
Long-term follow-up subject status date where status = “alive” 
• 
End of treatment disposition where status is not equal to death or lost to follow-up 
• 
End of post-treatment assessment period where status is not equal to death or lost to follow-up 
• 
End of study data where end of study reason is not equal to death or lost to follow-up 
 

Prot_000.pdf: 
Protocol KTE-C19-106 Amendment #1 
21 Sep 2017 
.
Kite 
A GILEAu Company 
Kite Phanna Inc. 
PROTOCOL TITLE: A PHASE 1-2 MULTI-CENTER STUDY EVALUATING 1HE SAFETY 
AND EFFICACY OF KTE-C19 IN COMBINATION WITH ATEZOLIZUMAB IN SUBJECTS 
WITH REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL) 
Protocol Number: 
Clinical Study Sponsor: 
Key Sponsor Contacts: 
Date: 
KTE-C19-106 (ZUMA-6) 
Kite Pharma, Inc. 
2225 Colorado Avenue 
Santa Monica, CA 90404 
United States of America 
[PPD 
Sr. D ... i.-r-e-ct,_o-r,--c finicafDeve opment 
Kite Pharma, Inc. 
[PPD 
Plione: PPD 
Email:[PPD 
PPD 
d 
lVlanager, C ~ ical Operations 
Kite Pharma, Inc. 
PPD 
Phone: i.P.P lJ 
Email: lP.PlJ 
21 Sep 2017 
Confidentiality Notice 
This document contains confidential information of Kite Phanna 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. 
Confidential 
Page 1 of93 


Protocol KTE-C19-106 Amendment #1 
21 Sep 2017 
INVESTIGATORS AGREEMENT 
Kite Phanna Inc. 
A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C 19 in Combination with 
Atezolizumab in Subjects with Refracto1y Diffose Large B-Cell Lymphoma (DLBCL) (ZUMA-6) dated 
21 Sep 2017 and agree to abide by all provisions set f01th therein. 
I agree to comply with the International Conference on Ha1monization Tripa1tite 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 strut of the study and for up to one year after the study is completed. 
I agree to ensure that the confidential info1mation contained in this document will not be used for any 
purpose other than the conduct of the clinical investigation without p1ior written consent from Kite 
Pha1ma Inc. 
Signature 
Name of investigator 
Date 
Confidential 
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Protocol KTE-C19-106 Amendment #1
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PROTOCOL SYNOPSIS
TITLE 
A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 in Combination with
Atezolizumab in Subjects with Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
INDICATION
Treatment refractory DLBCL in adult subjects.
STUDY DESIGN
This is a phase 1-2, open-label study evaluating the safety and efficacy of axicabtagene ciloleucel in 
combination with atezolizumab in subjects with refractory DLBCL. The trial will be separated into two 
distinct phases designated as phase 1 and phase 2.  
During phase 1, approximately 3-9 subjects with refractory DLBCL will be enrolled in up to 3 cohorts to
evaluate the safety of axicabtagene ciloleucel and atezolizumab combination regimens. A safety review 
team (SRT) that is internal to the study sponsor and phase 1 investigators, will review safety data after all 
subjects in each phase 1 cohort have had the opportunity complete the dose-limiting toxicities (DLT)
window.  The SRT will make recommendations on further study conduct of phase 1 and progression to 
phase 2 as depicted in Figure 3 and outlined in Section 9.6.  
In phase 2, approximately 22 subjects will be enrolled to receive combination treatment with
axicabtagene ciloleucel and atezolizumab based on the dose and schedule selected to move forward from 
the phase 1 portion of the study as recommended by the SRT. 
Independent of the cohort or phase of the study, each subject will proceed through the following study 
periods:

Screening

Enrollment/Leukapheresis

Conditioning chemotherapy

Combination treatment (axicabtagene ciloleucel and atezolizumab)

Post treatment assessment

Long term follow-up
For study requirements assigned to each study period, please refer to Section 7 for details.
STUDY OBJECTIVES 
The primary objective of phase 1 is to evaluate the safety of axicabtagene ciloleucel and atezolizumab 
combination regimens.  


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The primary objective of phase 2 is to evaluate the efficacy of axicabtagene ciloleucel and atezolizumab, 
as measured by complete response rate in subjects with refractory DLBCL. Secondary objectives will 
include assessing the safety and tolerability of axicabtagene ciloleucel and atezolizumab and additional 
efficacy, biomarker, pharmacokinetic, and anti-therapeutic antibody endpoints.
HYPOTHESIS 
No formal hypothesis will be tested in this study.  The phase 2 portion of the study is designed to estimate 
the true CR rate in patients with refractory DLBCL treated with the axicabtagene ciloleucel followed by
atezolizumab. 
PRIMARY ENDPOINT

Phase 1: Incidence of dose-limiting toxicities (DLT)

Phase 2: Complete response rate (complete response [CR] per the revised International Working 
Group [IWG]) Response Criteria for Malignant Lymphoma (Cheson 2007) as determined by 
study investigators.
SECONDARY ENDPOINT(S) FOR PHASE 1 AND 2

Objective Response Rate (CR + PR) per the revised IWG Response Criteria for Malignant 
Lymphoma (Cheson, 2007)

Duration of Response

Progression Free Survival

Overall Survival 

Incidence of adverse events and clinically significant changes in safety lab values

Levels of axicabtagene ciloleucel in blood and incidence of anti-KTE-C19 antibodies

Atezolizumab pharmacokinetics and incidence of anti- atezolizumab antibodies in serum

Levels of cytokines and other markers in serum
EXPLORATORY ENDPOINT(S) FOR PHASE 1 AND 2
SAMPLE SIZE 
Approximately 3-31 subjects
Phase 1: approximately 3-9 subjects
PPD


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Phase 2: approximately 22 subjects
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
Conditioning Chemotherapy Treatment:

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.
Investigational Product(s):

Axicabtagene ciloleucel treatment consists of a single infusion of CAR transduced autologous T 
cells administered intravenously 
. Subjects 
will be considered evaluable in 
the efficacy set. 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 7.12.8 for retreatment details.

Atezolizumab treatment 
 
 
 
Additional axicabtagene ciloleucel and atezolizumab schedules or regimens may be explored in phase 1.
The axicabtagene ciloleucel and atezolizumab treatment in phase 2 will follow the dosing schedule with 
the best overall benefit/risk profile tested in phase 1 as determined by the safety review team (see Figure 
3).
PROCEDURES
At specific time points as outlined in the schedule of assessments, subjects will undergo the following 
procedures: collection of informed consent, general medical history including previous treatments for 
NHL, physical exam (including neurological assessment) including vital signs and performance status.  
Subjects will also undergo blood draws for complete blood count (CBC), chemistry panels, cytokines, C-
reactive protein, lymphocyte subsets, anti-KTE-C19 antibodies, anti-atezolizumab antibodies, replication 
competent retrovirus (RCR) and anti-CD19 CAR T cell analysis. Women of child-bearing 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), and 
leukapheresis.
PPD
PPD
PPD


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Routinely throughout the conduct of the study, subjects will be asked to report concomitant medications 
and adverse events and will have their disease assessed.
SAFETY REVIEW TEAM
A safety review team (SRT), internal to the study sponsor and phase 1 investigators, will review the 
safety data following each phase 1 cohort and make recommendations on further study conduct of phase 1 
and progression to phase 2.  
The SRT will also meet 1 time during the phase 2 portion of the study when 6 subjects have had the 
opportunity to complete their 1 month disease assessment. The SRT will review safety and efficacy data 
and be chartered to make trial conduct recommendations based on an analysis of risk vs. benefit. The SRT 
may meet more often as needed. Refer to Section 9.6.
STATISTICAL CONSIDERATIONS
The primary endpoint for the phase 1 portion of the study is the incidence of DLT.
The primary endpoint for the phase 2 portion of the study is complete response rate per the revised IWG 
Response Criteria for Malignant Lymphoma (Cheson 2007) as determined by the study investigators. 
This study uses a single-arm design to estimate the true complete response rate in patients with DLBCL 
treated with the combination of axicabtagene ciloleucel and atezolizumab at the dosing schedule closest to 
concomitant administration tested in phase 1 and deemed safe by the SRT. With a total sample size of 25 
patients at a given dosing schedule, of which at least 3 will have been treated in the phase 1 portion, an 
observed CR rate of 70% will yield 95% confidence that estimate of the true CR rate is between 51% and 
88%.  Refer to Section 10 for additional discussion. 


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STUDY GLOSSARY
Abbreviation or Term
Definition/Explanation
AE
adverse event
ALL
acute lymphoblastic leukemia
ANC
absolute neutrophil count
ASCT
autologous stem cell transplant
ATAs
anti-therapeutic antibodies
AUC
area under the curve
Axicabtagene 
ciloleucel / KTE-C19
autologous T cells transduced with retroviral vector containing anti-CD19 CD28/CD3 
zeta chimeric antigen receptor
CAR
chimeric antigen receptor 
CBC
complete blood count
CLL
chronic lymphocytic leukemia
CMV
cytomegalovirus
CNS
central nervous system
CPF
central processing facility
CR
complete response / Complete Remission
CRF
case report form
CRS
cytokine release syndrome
CSF
cerebrospinal fluid
CTCAE
common terminology criteria for adverse events
DLBCL
diffuse large B cell lymphoma
DLT
dose-limiting toxicity
eACT™
engineered autologous cell therapy 
EBV
epstein-Barr virus
ECHO
Echocardiogram
ECG
Electrocardiogram
ECOG
eastern cooperative oncology group
End of Study for 
individual subject
Defined as when the last day that protocol specified assessments are conducted for an 
individual subject
End of Study (primary 
completion)
Defined as when the last subject is assessed or received an intervention for the 
purposes of final collection of data for the primary endpoint at Month 6


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Abbreviation or Term
Definition/Explanation
End of Study (end of 
trial)
Defined as when the last subject is assessed or received an intervention for evaluation 
in the study, including survival assessments 
FAS
full analysis set
FL
follicular lymphoma 
HAMA
human anti-mouse antibodies 
HLH
hemophagocytic lymphohistiocytosis
ICF
informed consent form
ICU
intensive care unit
IP
investigational product
IRB/IEC
institutional review board/independent ethics committee
IWG
International working group 
LMWH
low-molecular-weight heparin
LTFU
long term follow-up
mITT
modified intend 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
OS
overall survival
PET-CT
positron emission tomography–computed tomography
PBMC
peripheral blood mononuclear cells
PMBCL
primary mediastinal B cell lymphoma 
PD
progressive disease
PK
pharmacokinetic
PR
partial response / Partial Remission
RCR 
replication competent retrovirus
scFv
single chain variable fragment
SOA
schedule of assessments


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Abbreviation or Term
Definition/Explanation
SD
stable disease
SRT
safety review team
SUSAR
suspected unexpected serious adverse reactions
Study day 0
Defined as the first day that axicabtagene ciloleucel is administered to the subject
TEAEs
treatment emergent adverse events
TFL
transformed follicular lymphoma
ULN
upper limit of normal


Protocol KTE-Cl9-106 Amendment #1 
21 Sep 2017 
Figure l. 
Study Schema (Phase 1 and Phase 2) 
Tnvestigational Product 
.. 
(IP) Treatment Period 
V) 
:>. 
·;;; 
0.. 
* Axicabtagene Ciloleucel 
(1) 
Treatment 
;... 
(1) 
(1) 
(DayO) 
.a 
.a 
0.. 
... 
oO -+ 
-+ 
0 
--+ 
Subject is hospitalized 
s 
C: 
prior to treatment with 
..... 
(1) 
c:: 
..c: 
axicabtagene ciloleucel 
(1) 
....J 
CJ 
(1) 
;... 
00 
(.) 
{/') 
c:: 
c:: 
(1) 
·a 
E 
.Q 
0 
.--=: 
;... 
'O 
c:: 
0 
CJ 
Investigational Product 
(Ip) Treatment Period 
... 
-
PPD 
5 
E 
V) 
V) 
(1) 
-+ 
-+ 
V) -+ 
V) < ... 
5 s 
(1) 
;... 
f-.. ... 
V) 
0 
/:1., 
* Axicabtagene ciloleucel is administered after a conditioning chemotherapy regimen consisting of fludarabine 
PPD 
· and cyclophosphamide 
PPD 
. Refer to Section 6 for chemotherapy treatment details. 
* Axicabtagene ciloleucel treatment consists of a single infusion of CAR transduc,ed autologous T cells administered intravenously on Day 0 
Kite Phanna Inc. 
-0 
0 li 
/:1., 
0. 
:::s 
I 
2 
0 
µ.. 
E 
5) r 
Of. 
c:: 
0 
....J 
PIii) 
1Atezolizumab treatment PPD 
adininistered in 3 cohorts: 
. In the phase 1 portion, the first dose of atezolizumab will be 
• 
PPD 
-----------------~----------
0 0 
Atezolizumab treatment in phase 2 will follow the dosing schedule from phase 1 agreed upon by the study sponsors and the SRT. 
Confidential 
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TABLE OF CONTENTS
STUDY GLOSSARY..................................................................................................................... 7
LIST OF TABLES....................................................................................................................... 14
LIST OF FIGURES..................................................................................................................... 15
1.
OBJECTIVES ...................................................................................................................... 16
2.
DISEASE BACKGROUND AND RATIONALE.............................................................. 16
2.1.
Anti-CD19 CAR T cell Product..................................................................................... 17
2.2.
Anti-CD19 chimeric antigen receptor (CAR) T cells................................................... 19
2.2.1.
CD19 and Expression ................................................................................................ 19
2.2.2.
Prior experience with axicabtagene ciloleucel and other anti-CD19 CAR T cells19
2.3.
Atezolizumab................................................................................................................... 19
2.3.1.
Summary of Nonclinical Studies for Atezolizumab................................................ 19
2.3.2.
Summary of Clinical Studies for Atezolizumab...................................................... 20
2.4.
Rationale for Combination Therapy............................................................................. 24
3.
STUDY DESIGN.................................................................................................................. 24
3.1.
General Study Design ..................................................................................................... 24
3.2.
Participating Sites........................................................................................................... 26
3.3.
Number of Subjects......................................................................................................... 26
3.4.
Replacement of Subjects................................................................................................. 26
3.5.
Study Duration................................................................................................................ 27
3.5.1.
Study Duration for Individual Subjects................................................................... 27
3.5.2.
Completion of Study.................................................................................................. 27
4.
SUBJECT SCREENING AND ENROLLMENT.............................................................. 27
5.
SUBJECT ELIGIBILITY ................................................................................................... 27
5.1.
Inclusion Criteria............................................................................................................ 27
5.2.
Exclusion Criteria........................................................................................................... 28
6.
PROTOCOL TREATMENT.............................................................................................. 30
6.1.
Treatment Terminology ................................................................................................. 30
6.2.
Study Treatment ............................................................................................................. 30
6.2.1.
Conditioning Chemotherapy .................................................................................... 30
6.2.2.
Axicabtagene Ciloleucel ............................................................................................ 31
6.2.3.
Atezolizumab.............................................................................................................. 31
6.2.4.
Concomitant Therapy ............................................................................................... 32
6.2.5.
Excluded Medications ............................................................................................... 32
6.2.6.
Subsequent Therapy.................................................................................................. 33
6.3.
Rationale for Study Treatment dosing.......................................................................... 33
6.3.1.
Rationale for Conditioning Chemotherapy and Axicabtagene Ciloleucel Dose .. 33
6.3.2.
Rationale for Atezolizumab Dose and Schedule:.................................................... 34
6.3.3.
Rationale for Dosing schedule .................................................................................. 35
6.3.4.
Rationale for Pharmacokinetic and ATA Sample Collection................................ 36
6.4.
Study Treatment Schedule and Administration .......................................................... 36
6.4.1.
Leukapheresis ............................................................................................................ 36
6.4.2.
Cyclophosphamide and Fludarabine (Days -5 through -3 before infusion of 
axicabtagene ciloleucel)............................................................................................. 36
6.4.3.
Axicabtagene Ciloleucel (Day 0): ............................................................................. 37
6.4.4.
Atezolizumab Dosing and Administration Instructions (Day 21, Day 14 or Day 1 
after Axicabtagene Ciloleucel Administration and every 21 days thereafter for 3 
additional (4 total) doses).......................................................................................... 38


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6.5.
Axicabtagene Ciloleucel Toxicity Management ........................................................... 40
6.6.
Atezolizumab Toxicity Management............................................................................. 40
6.6.1.
Safety Plan.................................................................................................................. 40
6.6.2.
Risks Associated with Atezolizumab........................................................................ 40
6.6.3.
Management of Patients Who Experience Atezolizumab-Specific Adverse Events41
6.6.4.
Systemic Immune Activation.................................................................................... 41
7.
STUDY PROCEDURES...................................................................................................... 44
7.1.
Informed Consent ........................................................................................................... 44
7.2.
Demographic Data .......................................................................................................... 44
7.3.
Medical and Treatment History .................................................................................... 44
7.4.
Physical Exam, Vital Signs and Performance Status................................................... 45
7.5.
Cardiac Function ............................................................................................................ 45
7.6.
Magnetic Resonance Imaging........................................................................................ 45
7.7.
Toxicity Evaluation......................................................................................................... 46
7.8.
Bone Marrow Biopsy...................................................................................................... 46
7.9.
Disease Response Assessment ........................................................................................ 46
7.10. Laboratory....................................................................................................................... 47
7.11. Biomarkers ...................................................................................................................... 48
7.12. Description of Study Periods.......................................................................................... 49
7.12.1. Screening .................................................................................................................... 50
7.12.2. Rescreening ................................................................................................................ 51
7.12.3. Enrollment/Leukapheresis........................................................................................ 51
7.12.4. Conditioning Chemotherapy Period........................................................................ 52
7.12.5. Investigational Product Treatment Period.............................................................. 53
7.12.6. Post Treatment Assessment Period.......................................................................... 55
7.12.7. Long Term Follow-up Period ................................................................................... 56
7.12.8. Retreatment................................................................................................................ 57
8.
SUBJECT WITHDRAWAL ............................................................................................... 66
8.1.
Reasons for Removal from Treatment.......................................................................... 66
8.2.
Reasons for Removal from Study.................................................................................. 67
9.
SAFETY REPORTING....................................................................................................... 67
9.1.
Adverse Events................................................................................................................ 67
9.2.
Reporting of Adverse Events ......................................................................................... 68
9.3.
Definition of Serious Adverse Events............................................................................ 69
9.4.
Reporting of Serious Adverse Events and Non-Serious CRS events grade ≥ 3......... 69
9.5.
Pregnancy and Lactation ............................................................................................... 70
9.6.
Safety Review Team and Dose-Limiting Toxicity........................................................ 71
9.7.
Criteria to Pause Enrollment......................................................................................... 72
10. STATISTICAL CONSIDERATIONS ............................................................................... 73
10.1. Hypothesis........................................................................................................................ 73
10.2. Study Endpoints.............................................................................................................. 73
10.2.1. Primary Endpoints .................................................................................................... 73
10.2.2. Secondary Endpoints................................................................................................. 73
10.2.3. Exploratory Endpoints.............................................................................................. 74
10.3. Sample Size Considerations ........................................................................................... 74
10.4. Analysis Subsets.............................................................................................................. 75
10.5. Access to Individual Subject Treatment Assignments................................................. 76
10.6. Interim Analysis.............................................................................................................. 76
10.6.1. Safety Interim Analysis............................................................................................. 76


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10.7. Planned Method of Analysis .......................................................................................... 76
10.7.1. Complete Response Rate........................................................................................... 76
10.7.2. Progression Free Survival......................................................................................... 76
10.7.3. Overall Survival......................................................................................................... 76
10.7.4. Safety........................................................................................................................... 76
10.7.5. Long Term Data Analysis ......................................................................................... 77
10.7.6. Pharmacokinetic Analyses........................................................................................ 77
10.7.7. Immunogenicity Analyses ......................................................................................... 77
11. REGULATORY OBLIGATIONS...................................................................................... 77
11.1. Independent Review Board /Independent Ethics Committee..................................... 77
11.2. Subject Confidentiality................................................................................................... 78
11.3. Investigator Signatory Obligations ............................................................................... 78
12. PROTOCOL AMENDMENTS AND TERMINATION................................................... 78
13. STUDY DOCUMENTATION AND ARCHIVE............................................................... 79
14. STUDY MONITORING AND DATA COLLECTION.................................................... 79
15. PUBLICATION ................................................................................................................... 80
16. COMPENSATION............................................................................................................... 80
17. REFERENCES..................................................................................................................... 81
18. APPENDIX A - REVISED IWG RESPONSE CRITERIA FOR MALIGNANT 
LYMPHOMA (CHESON 2007).......................................................................................... 86
19. APPENDIX B: ATEZOLIZUMAB ANAPHYLAXIS PRECAUTIONS........................ 88
SUMMARY OF CHANGES....................................................................................................... 89


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LIST OF TABLES
Table 1.
Historical Responses in Refractory NHL (SD or PD to Last Line of Therapy).. 17
Table 2.
Study PCD4989g:  Adverse Events with Frequency > 10% of Patients for All 
Grades ....................................................................................................................... 21
Table 3.
Diagnostic Criteria and Recommended Management for Systemic Immune 
Activation (SIA)........................................................................................................ 43
Table 4.
Schedule of Assessments (Cohort 1)* ..................................................................... 59
Table 5.
Schedule of Assessments (Cohort 2)* ..................................................................... 61
Table 6.
Schedule of Assessments (Cohort 3)* ..................................................................... 63
Table 7.
Schedule of Assessments (Long-Term Follow-up Period) .................................... 65
Table 8.
95% and 80% exact confidence intervals corresponding to observed CR rate 
following treatment of 25 patients with axicabtagene ciloleucel and atezolizumab75


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LIST OF FIGURES
Figure 1.
Study Schema (Phase 1 and Phase 2)...................................................................... 10
Figure 2.
Anti-CD19 Chimeric Antigen Receptor Construct and Mechanism of Action... 18
Figure 3.
Study Schema............................................................................................................ 26


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1.
OBJECTIVES
The primary objective of phase 1 is to evaluate the safety of axicabtagene ciloleucel and atezolizumab 
combination regimens.  
The primary objective of phase 2 is to evaluate the efficacy of axicabtagene ciloleucel and atezolizumab, 
as measured by complete response rate in subjects with refractory diffuse large B-cell lymphoma 
(DLBCL). Secondary objectives will include assessing the safety and tolerability of axicabtagene 
ciloleucel and atezolizumab and additional efficacy, biomarker, pharmacokinetic, and anti-therapeutic 
antibody endpoints.
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 (SEER 2014).
Diffuse large B cell lymphoma (DLBCL) is the most common subtype of NHL, 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 that do not respond to first 
line combination chemotherapy (typically R-CHOP) or do not respond to their most recent 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%) 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 aggressive NHL, and 9 patients with transformed follicular lymphoma 
(TFL) that 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
     Phillip et al 1995 (n=28)
ORR 21%
     Josting et al 2000 (n=64)
ORR 15%, median OS 6 mos
     Ardeshna et al 2005 (n=5)
ORR 0%
    Hitz et al 2010 (n=33)
Proceeded to ASCT 9%, 3% survived > 1 year
     Telio et al 2012 (n = 111)
ORR 23%, median OS 10 mos
     Matasar et al 2013 (n=10)
ORR 10%
    
Refractory to 2nd line
     Moskowitz et al 1999 (n=55)
Median OS 5 mos
     Ardeshna et al 2005 (n=28)
ORR 18%, median OS (aggressive NHL) <6 mos
    Seshadri et al 2008 (n=73)
ORR 14%
Relapsed post ASCT
    Nagle et al 2013 (N=45)
Median OS 8 mos
These results suggest that once a patient with DLBCL has become refractory to cytotoxic 
chemoimmunotherapy, the likelihood of achieving a response of any significant duration with subsequent 
lines of chemotherapy is low.  New treatment paradigms are therefore needed in these refractory patients.  
Immunotherapy is an emerging category of cancer therapy that employs the patient’s own immune system 
to combat his or her cancer.  Two distinct immunotherapeutic approaches to the care of patients with 
chemo-refractory lymphoma, engineered T cell therapy and immune checkpoint blockade have shown 
promise in pilot trials (Kochenderfer 2015, Lesokhin 2014).  
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.  
2.1.
Anti-CD19 CAR T cell Product
Anti-CD19 chimeric antigen receptor (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. 


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An anti-CD19 CAR vector constmct has been designed, optimized and initially tested at the Surgery 
Branch of the National Cancer hlstitute (NCI, IND 13871) (Figure 2); Kochende1fer 2009, 2010a). The 
scFv is derived from the va1iable region of the anti-CD19 monoclonal antibody FMC63 (Nicholson 
1997). A po11ion of the CD28 costimulato1y molecule is added, as murine models suggest this is 
important for the anti-tumor effect and persistence of anti-CD19 CART cells (Kowolik 2006). The 
signaling domain of the CD3-zeta chain is essential for T cell activation. These fragments were cloned 
into the mmine stem cell vims-based (MSGVl) vector, utilized to genetically engineer the autologous T 
cells. Treatment with anti-CD19 CART cells was administered to subjects with CD19+ B cell 
malignancies in NCI protocol (09-C-0082; IND 13871) and in several Kite-sponsored clinical trials. 
The same CAR vector constmct will be used in this study. 
The CAR constmct is inse11ed into the T cells' genome by retro viral vector transduction. 
. 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. 
Figure 2. 
Confidential 
Anti-CD19 Chimeric Antigen Receptor Construct and Mechanism of Action 
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Page 18 of93 


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2.2.
Anti-CD19 chimeric antigen receptor (CAR) T cells
2.2.1.
CD19 and Expression
CD19 is a 95 kD 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 2011) with the exception of multiple myeloma.
2.2.2.
Prior experience with axicabtagene ciloleucel and other anti-CD19 CAR T cells
The design and rationale of this study is in part derived from prior experience with axicabtagene 
ciloleucel on another Kite-sponsored study, ZUMA-1, and on a single-center study conducted at the 
National Cancer Institute.  Please see the most current axicabtagene ciloleucel/KTE-C19
investigator’s brochure for details.
2.3.
Atezolizumab
Atezolizumab is a humanized IgG1 monoclonal antibody that targets PD-L1 and inhibits the 
interaction between PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which 
function as inhibitory receptors expressed on T cells. Therapeutic blockade of PD-L1 binding by 
atezolizumab has been shown to enhance the magnitude and quality of tumor-specific T-cell 
responses, resulting in improved anti-tumor activity (Fehrenbacher et al. 2016; Rosenberg et al. 
2016). Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable Fc-effector 
function and associated antibody-mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and in cancer patients, and is 
being investigated as a potential therapy in a wide variety of malignancies. Atezolizumab is being 
studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as in 
combination with chemotherapy, targeted therapy, and cancer immunotherapy.
Atezolizumab is approved for the treatment of urothelial carcinoma and for the treatment of 
non−small cell lung cancer.
Refer to the Atezolizumab Investigator's Brochure for details on nonclinical and clinical studies.
2.3.1.
Summary of Nonclinical Studies for Atezolizumab
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and in vivo activity, to 
determine in vivo pharmacokinetic (PK) behavior, to evaluate the safety profile, and to identify a Phase I 
starting dose.  Comprehensive pharmacology, PK, and toxicology evaluations were performed with 
atezolizumab.


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The safety, PK, and toxicokinetics of atezolizumab were investigated in mice and cynomolgus monkeys 
to support IV administration and to aid in projecting the appropriate starting dose in humans.  Given the 
similar binding of atezolizumab for cynomolgus monkey and human PD-L1, the cynomolgus monkey 
was selected as the primary and relevant nonclinical model for understanding the safety, 
pharmacokinetics, and toxicokinetics of atezolizumab. 
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab supported entry into clinical 
studies, including providing adequate safety factors for the proposed Phase I starting doses.  The results of 
the toxicology program were consistent with the anticipated pharmacologic activity of downmodulating 
the PD-L1/PD-1 pathway; heightened immune responses and the potential to increase immune-associated 
inflammatory lesions were identified as possible safety risks in patients.
Refer to the Atezolizumab IB for details on the nonclinical studies.
2.3.2.
Summary of Clinical Studies for Atezolizumab
For information on the additional ongoing studies, see the latest version of the Atezolizumab IB.
2.3.2.1.
Clinical Safety for Atezolizumab
Single-Agent Clinical Safety in Study PCD4989g
Study PCD4989g, in which atezolizumab is being used as a single agent in subjects with locally advanced 
or metastatic solid tumors or hematologic malignancies, provides the majority of data (with 558 safety-
evaluable patients as of the data extraction date of 11 May 2015) for the safety profile of atezolizumab as 
monotherapy.
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no clear 
dose-related trends in the incidence of adverse events have been determined.
The safety profile of atezolizumab as a single agent is observed to be consistent across different 
indications.  The most common cancer types for these patients include NSCLC, urothelial bladder cancer, 
melanoma, and renal cell carcinoma.  Safety data for NSCLC are also derived from Studies GO28625 
(FIR) and GO28753 (POPLAR).
Adverse Events
Of the 558 patients, 520 patients (93.2%) experienced at least one adverse event, including 376 patients 
(67.4%) who experienced one treatment-related adverse event.  Commonly reported events (reported 
in > 10% of all patients) included fatigue, decreased appetite, nausea, pyrexia, constipation, and cough
(see Table 2).


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Table 2.
Study PCD4989g:  Adverse Events with Frequency > 10% of Patients for All Grades
Preferred Term
All Grades
n (%)
All Grades Related
n (%)
Grade 3/4
n (%)
Grade 3/4 Related
n (%)
Any adverse event
520 (93.2)
376 (67.4)
239 (42.8)
66 (11.8)
Fatigue
192 (34.4)
115 (20.6)
13 (2.3)
6 (1.1)
Decreased Appetite
142 (25.4)
62 (11.1)
4 (0.7)
0 (0.0)
Nausea
136 (24.4)
65 (11.6)
5 (0.9)
2 (0.4)
Pyrexia
117 (21.0)
63 (11.3)
2 (0.4)
0 (0.0)
Constipation
116 (20.8)
8 (1.4)
2 (0.4)
0 (0.0)
Cough
113 (20.3)
11 (2.0)
1 (0.2)
1 (0.2)
Dyspnea
112 (20.1)
18 (3.2)
18 (3.2)
4 (0.7)
Diarrhea
110 (19.7)
53 (9.5)
2 (0.4)
1 (0.2)
Anemia
104 (18.6)
26 (4.7)
23 (4.1)
5 (0.9)
Vomiting
96 (17.2)
28 (5.0)
3 (0.5)
2 (0.4)
Asthenia
88 (15.8)
53 (9.5)
8 (1.4)
4 (0.7)
Back Pain
85 (15.2)
9 (1.6)
8 (1.4)
1 (0.2)
Headache
83 (14.9)
32 (5.7)
2 (0.4)
1 (0.2)
Arthralgia
79 (14.2)
35 (6.3)
2 (0.4)
0 (0.0)
Pruritus
75 (13.4)
55 (9.9)
0 (0.0)
0 (0.0)
Rash
73 (13.1)
53 (9.5)
0 (0.0)
0 (0.0)
Abdominal Pain
63 (11.3)
12 (2.2)
8 (1.4)
0 (0.0)
Insomnia
62 (11.1)
7 (1.3)
1 (0.2)
0 (0.0)
Peripheral edema
59 (10.6)
7 (1.3)
-
-
Chills
57 (10.2)
31 (5.6)
0 (0.0)
0 (0.0)
1 Note:  ‘-‘ refers to missing Common Terminology Criteria grade.
Grade 3/4 adverse events (on the basis of National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0) were reported in 239 patients (42.8%), of which 66 
(11.8%) were considered related.  Grade 3 and 4 adverse events considered related by the investigator 
included  dyspnea, pneumonitis, increased ALT, increased AST, increased gamma-glutamyl transferase 
(GGT), lymphocyte count decreased, cardiac tamponade, asthenia, autoimmune hepatitis, pneumonia, 
influenza, and hypoxia.
Refer to the Atezolizumab IB for details on adverse events observed in patients treated with atezolizumab.


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Immune-Mediated Adverse Events
Given the mechanism of action of atezolizumab, events associated with inflammation and/or immune-
mediated adverse events have been closely monitored during the atezolizumab clinical program.  These 
include potential dermatologic, hepatic, endocrine, gastrointestinal, and respiratory events.  
Refer to the Atezolizumab IB for details on immune-mediated adverse events that were observed in 
patients treated with atezolizumab.  Guidelines for the management of immune-mediated adverse events 
are described in the Atezolizumab IB. 
For additional information, refer to the Atezolizumab IB.
Single-Agent Clinical Safety in Patients with NSCLC in the POPLAR Study
The Phase II POPLAR study interim analysis, as of the 30 January 2015 data cutoff, included data from 
142 patients treated with atezolizumab
 
.  The frequency of patients in the POPLAR study who 
reported any adverse event regardless of attribution was 96.5% for the atezolizumab arm and 95.6% for 
the docetaxel arm.  A higher number of Grade ≥3 adverse events were observed in the docetaxel arm
(55.6% vs. 43.0%), explained primarily by the difference in adverse events due to bone marrow 
suppression.
For additional information, refer to the Atezolizumab IB.
Clinical Safety in Combination with Bevacizumab or Platinum-Based Doublet Chemotherapy
Study GP28328 is a Phase Ib study of atezolizumab in combination with bevacizumab or cytotoxic 
chemotherapy in patients with multiple tumor types including NSCLC, TNBC, and colorectal cancer.  As 
of 10 February 2015, 144 patients had been enrolled in this study:  39 in Arm A 
(atezolizumab, bevacizumab), 36 in Arm B (atezolizumab, bevacizumab, and FOLFOX), 14 in Arm C 
(atezolizumab, carboplatin, and paclitaxel), 24 in Arm D (atezolizumab + carboplatin and pemetrexed), 
20 in Arm E (atezolizumab, carboplatin, and nab-paclitaxel), and 11 in Arm F (atezolizumab + nab-
paclitaxel).  The treatment combinations have been generally well tolerated.  No DLTs have been 
reported during the dose-escalation stage in any study arm.  Patients are being enrolled in safety and 
biopsy expansion cohorts in Arms A and B as well as in additional arms testing atezolizumab in 
combination with commonly used NSCLC chemotherapy doublets.  
A total of 141 of 144 patients (97.9%) reported at least one adverse event while receiving study drug.  
The majority of these events were Grade 2 and 3 in severity.  The five most commonly reported adverse 
events across the study arms (>10% of patients) included fatigue, nausea, diarrhea, decreased appetite, 
and pyrexia.  The adverse events were consistent with the known safety profile of each agent 
(atezolizumab monotherapy and chemotherapy).  No additive effects were observed when atezolizumab 
was administered with chemotherapy.
PPD


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All 39 patients who were enrolled in Arm A reported one or more adverse event.  The five most 
frequently reported events were consistent with the overall population and included fatigue, nausea, 
diarrhea, decreased appetite, and pyrexia.  There were 36 patients enrolled in Arm B, and 97% of patients 
reported at least one adverse event.  The most frequently reported adverse events (> 20% of patients) 
included fatigue, pyrexia, peripheral neuropathy, neutropenia, anemia, diarrhea, decreased appetite, 
temperature intolerance, constipation, vomiting, and nausea.  
All patients who were enrolled in Arms C and D experienced an adverse event; 95% of patients who were 
enrolled in Arm E experienced an adverse event, and 83.3 % of patients enrolled in Arm F experienced an 
adverse event.  The adverse events commonly reported in 2 or more patients in Arms C, D, and E 
included anemia, decreased appetite, hypomagnesemia, nausea, neutropenia, constipation, vomiting, 
fatigue, rash, cough, and diarrhea.  Adverse events commonly reported in 2 or more patients in Arm F 
included dermatitis, upper respiratory infection, alopecia, peripheral sensory neuropathy, fever, 
constipation, neutrophil count decreased, anemia, diarrhea, headache, nausea, and fatigue.
2.3.2.2.
Clinical Activity for Atezolizumab
As of May 10, 2015 relevant clinical data for atezolizumab are mainly available from seven clinical trials 
in patients with solid tumors and hematologic malignancies. For all of these studies, treatment and/or 
analyses are ongoing. These include:

Monotherapy: One Phase Ia (Study PCD4989g) and two Phase II studies (Studies GO28625[FIR] 
and GO28753 [POPLAR])

Combination Therapy: Three Phase Ib studies (Studies GP28328, GP28363 and GP28384), and 
one Phase II (WO29074 [IMmotion150]) study. 
Additional safety information is also gleaned from the entire development program from atezolizumab. 
Further details of all ongoing and planned studies with atezolizumab can be found in the Atezolizumab 
Investigator’s Brochure. 
2.3.2.3.
Clinical Pharmacokinetics and Immunogenicity
On the basis of available preliminary PK data (0.03-20 mg/kg), atezolizumab appeared to show linear PK 
at doses
.  For the 
, the mean apparent clearance (CL) and 
the mean volume of distribution at steady state (Vss) had a range of 3.11 to 4.14 mL/kg and 48.1 to 67.0 
mL/kg, respectively, which is consistent with the expected profile of an IgG1 antibody in humans.
The development of anti-therapeutic antibodies (ATAs) to atezolizumab has been observed in patients in 
all dose cohorts and was associated with changes in PK for some patients in the lower dose cohorts (
 
  The development of detectable ATAs has not had a significant impact on 
pharmacokinetics for doses from 
.  Patients dosed at the
 
levels have maintained the expected target trough levels of drug despite the detection of ATAs.  To date, 
no clear relationship between detection of ATAs and adverse events or infusion reactions has been 
observed.
PPD
PPD
PPD
PPD
PPD
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For additional information on atezolizumab please refer to the Investigator’s Brochure.
2.4.
Rationale for Combination Therapy 
Preclinical and translational results have suggested that T cells that have been engineered to express anti-
CD19 chimeric antigen receptors, such as axicabtagene ciloleucel, rapidly upregulate markers of 
activation, including programmed cell death-1 (PD-1) (Perez 2015), upon target engagement.  Signaling 
through PD-1 is known to deliver a suppressive stimulus on the activated T-cells, giving rise to a 
phenotype commonly referred to as T-cell “exhaustion.” Exhausted T cells have diminished proliferative 
and cytolytic capacity (John 2013).  Therefore, PD-1 expression and signaling on CAR T cells may lead 
to reduced clinical activity. 
Conversely, a growing body of literature suggests that PD-L1 is expressed on a variety of human cancers
and tumor-infiltrating immune cells, including in DLBCL (Herbst 2014, Kiyasu 2015, Chen 2013). 
Furthermore, PD-L1 expression on DLBCL tends to associate with known markers of poor prognosis
including activated B cell (ABC) phenotype and has been shown in retrospective series to be associated 
with shortened survival (Chen 2013, Kiyasu 2015).  Early results of PD-1 blockade with a monoclonal 
antibody, nivolumab, suggests that inhibition of this signaling cascade yields clinical responses in 
lymphoma (Lesokhin 2014), although with limited OR (36%) and CR (9%) rates.  The expression of PD-
L1 on tumor cells and within the tumor microenvironment coupled with the activation-dependent 
expression of PD-1 on engineered T cells given to patients with refractory DLBCL led to the hypothesis 
that blockade of PD-1 ligation would augment the activation, proliferation, and cytolytic activity of CAR 
T cells.  
As an additional safeguard against the potential of added toxicity in patients treated with the combination 
of anti-CD19 CAR T cells and atezolizumab, we have adopted a 3+3 “schedule compression” phase 1 
run-in in this study design.  By staggering the doses of axicabtagene ciloleucel and atezolizumab, we aim 
to mitigate the potential additive or synergistic toxicities related to the combination.  
3.
STUDY DESIGN
3.1.
General Study Design
This is a phase 1-2, open-label study evaluating the safety and efficacy of axicabtagene ciloleucel in 
combination with atezolizumab in subjects with refractory DLBCL. The trial will be separated into two 
distinct phases designated as phase 1 and phase 2.  
During phase 1, approximately 3-9 subjects with refractory DLBCL will be enrolled in up to 3 cohorts to
evaluate the safety of axicabtagene ciloleucel and atezolizumab combination regimens. A SRT that is
internal to the study sponsor and phase 1 investigators, will review safety data after all subjects in each 
phase 1 cohort have had the opportunity complete the DLT window.  The SRT will make 
recommendations on further study conduct of phase 1 and progression to phase 2 as depicted in Figure 3
and outlined in Section 9.6.  


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In phase 2, approximately 22 subjects will be enrolled to receive combination treatment with
axicabtagene ciloleucel and atezolizumab based on the dose and schedule selected to move forward from 
the phase 1 portion of the study as recommended by the SRT. 
Independent of the phase of the study, each subject will proceed through the following study periods:

Screening

Enrollment/Leukapheresis

Conditioning chemotherapy

Combination treatment (axicabtagene ciloleucel and atezolizumab)

Post treatment assessment 

Long term follow-up 
The SRT will also meet 1 time during the phase 2 portion of the study when 6 subjects have had the 
opportunity to complete their 1 month disease assessment. The SRT will review safety and efficacy data 
and be chartered to make trial conduct recommendations based on an analysis of risk vs. benefit. The SRT 
may meet more often as needed. Refer to Section 9.6.
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 in Figure 1.


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Figure 3. 
Study Schema 
Kite Phanna Inc. 
Study Day 
-Sto -1 
0 
21 
42 
Cohort 1 
i,.;.
I 
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*During phase 1, cohorts will be enrolled sequentially, beginning with cohort 1. After each phase 1 cohort has completed enrollment and all subjects 
have cleared the DLT window, the SRT will meet and review the overall benefit/risk profile of the dosing schedule tested in that cohort. SRT 
recommendations for further study conduct may include addition of patients to a cohort prior to opening a subsequent cohort, advancement to a 
subsequent cohort, exploration of alternative conditioning chemotherapy or KTE-Cl 9 doses, advancement to phase 2, or study termination. 
3.2. Participating Sites 
Approximately 5-10 centers located in No1th America will participate in this study. During the conduct 
of the study, additional sites, regions, or countlies may be added as necessaiy. 
3.3. Number of Subjects 
Participants in this trial will be refened to as "subjects". It is anticipated that approximately 3-31 subjects 
will be enrolled into this study as defined below: 
Phase 1: approximately 3-9 subjects 
Phase 2: approximately 22 subjects 
It should be noted that the study sponsor may choose to close enrollment at any time. Please refer to the 
statistical considerations section of the protocol for sample size estimations. 
3.4. Replacement of Subjects 
Subjects will be replaced and continue to be enrolled until the specified number of subjects are attained in 
the DLT evaluable (phase 1) and mITT sets (phase 2). See Section 10.4 for additional infom1ation. 
Subjects who receive PD 
and who receive at least one 
dose of atezolizumab will be considered evaluable in the efficacy set. Subjects who have not received a 
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axicabtagene ciloleucel cell dose in this range  or have not received at least one dose of atezolizumab will 
be retained in the analyses of disposition and safety, where appropriate (Section 10.4).
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 5 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 5 year follow-up is based on the potential persistence of gene transfer vectors in 
treated subjects.
3.5.2.
Completion of 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 all subjects for the overall study population have completed the 6 month disease 
response assessment, are lost to follow-up, withdraw from the study, or die, whichever occurs first.
4.
SUBJECT SCREENING AND ENROLLMENT
All subjects must sign and date the 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 will receive a unique subject identification number. This 
number will be used to identify the subject throughout the study and must be used on all study 
documentation related to the subject.  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.
Subjects are considered enrolled in the study once the leukapheresis procedure is initiated.
5.
SUBJECT ELIGIBILITY
5.1.
Inclusion Criteria
101.
Histologically proven DLBCL including the following types defined by WHO 2008:
o
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;
102.
Chemotherapy-refractory disease, defined as one or more of the following: 
o
No response to first-line therapy (primary refractory disease); subjects who are intolerant 
to first-line therapy chemotherapy are excluded

PD as best response to first-line therapy 


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
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 
o
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
o
Refractory post-ASCT 

Disease progression or relapsed ≤12 months after 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 
103.
Subjects must have received adequate prior therapy including at a minimum: 
o
anti-CD20 monoclonal antibody unless investigator determines that tumor is CD20 
negative, and 
o
an anthracycline containing chemotherapy regimen; 
104.
At least 1 measurable lesion according to the revised 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
105.
MRI of the brain showing no evidence of 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
107.
Age 18 years or older at the time of informed consent
108.
Eastern cooperative oncology group (ECOG) performance status of 0 or 1
109.
Adequate bone marrow, renal, hepatic, pulmonary and cardiac function defined as:
o
ANC ≥1000/uL
o
Platelet count ≥75,000/uL
o
Absolute lymphocyte count ≥100/uL
o
Creatinine clearance (as estimated by Cockcroft Gault) ≥60 mL/min
o
Serum ALT/AST ≤2.5 ULN 
o
Total bilirubin ≤1.5 mg/dl, except in subjects with Gilbert’s syndrome.
o
Cardiac ejection fraction ≥ 50%, no evidence of pericardial effusion as determined by an 
ECHO, and no clinically significant ECG findings
o
No clinically significant pleural effusion
o
Baseline oxygen saturation >92% on room air
110.
Females of childbearing potential must have a negative serum or urine pregnancy test  (females 
who have undergone surgical sterilization or who have been postmenopausal for at least 2 
years are not considered to be of childbearing potential)
5.2.
Exclusion Criteria
201.
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. cervix, 
bladder, breast) unless disease free for at least 3 years 
202.
History of Richter’s transformation of CLL or DLBCL that has arisen (transformed) from 
another histology (e.g. transformed follicular lymphoma)
203.
Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel infusion
204.
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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 treatment with PD-L1 inhibitor, PD-1 inhibitor, anti-CTLA4, anti-CD137, anti-OX40 or 
other immune checkpoint blockade or activator therapy with the exception of subjects who 
received atezolizumab in this study and are eligible for re-treatment
207.
Treatment with systemic immunostimulatory agents (including but not limited to interferon and 
IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to the first 
atezolizumab dose.
208.
Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
209.
History of severe, immediate hypersensitivity reaction attributed to aminoglycosides 
210.
Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring IV 
antimicrobials for management. Simple urinary tract infection (UTI) and uncomplicated 
bacterial pharyngitis are permitted if responding to active treatment.  
211.
History of HIV infection or acute or chronic active hepatitis B or hepatitis C infection. 
Subjects with history of Hep B or Hep C infection must have cleared their infection as 
determined by standard serological and genetic testing per current Infectious Diseases 
Society of America (IDSA) guidelines.
212.
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.
213.
Subjects with detectable cerebrospinal fluid malignant cells or known brain metastases, or with 
a history of cerebrospinal fluid malignant cells or brain metastases.
214.
History or presence of non-malignant CNS disorder such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS 
involvement.
215.
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement.
216.
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, New York 
Heart Association Class II or greater congestive heart failure, or other clinically significant 
cardiac disease within 12 months of enrollment.
217.
Expected or possible requirement for urgent therapy within 6 weeks after leukapheresis
due to ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis 
syndrome).
218.
History of autoimmune disease. Patients with a history of autoimmune-related hypothyroidism 
on a stable dose of thyroid replacement hormone and patients with controlled type 1 diabetes 
mellitus on a stable insulin regimen may be eligible for this study.  
219.
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), 
drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest 
CT scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is 
allowed. 
220.
History of deep vein thrombosis or pulmonary embolism within 6 months of enrollment
221.
Any medical condition likely to interfere with assessment of safety or efficacy of study 
treatment
222.
History of severe immediate hypersensitivity reaction to any of the agents used in this study 
223.
Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment, 
or anticipation of need for such a vaccine during the course of the study
224.
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 
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225.
Subjects of either sex who are not willing to practice birth control from the time of consent 
through 5 months after the last dose of completion of atezolizumab and at least 6 months 
since axicabtagene ciloleucel infusion
226.
In the investigators 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
6.
PROTOCOL TREATMENT 
6.1.
Treatment Terminology
The following terms will be used to describe and define protocol treatment: 

The conditioning chemotherapy regimen used for this study will be fludarabine and 
cyclophosphamide.

The investigational products for this study are named axicabtagene ciloleucel and atezolizumab.

The term study treatment refers to all protocol required therapies.
6.2.
Study Treatment
6.2.1.
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.
6.2.1.1.
Fludarabine 
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides in that 
the sugar moiety is arabinose instead of ribose or deoxyribose.  Fludarabine is a purine antagonist 
antimetabolite.
Refer to the most recent version of the package insert for specific details surrounding the administration 
of fludarabine.
6.2.1.2.
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 
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6.2.1.3.
Mesna
Mesna is a detoxifying agent used to inhibit the hemorrhagic cystitis induced by chemotherapy. The 
active ingredient 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.
6.2.2.
Axicabtagene Ciloleucel
This section contains general information and is not intended to provide specific instructions.  Refer to 
Section 6.4.3.2 and the Investigational Product Manual for details and instruction on storage, thawing, 
and administration of axicabtagene ciloleucel.  
Axicabtagene ciloleucel is supplied cryopreserved in cryostorage bags.  The product in the bag is 
 
.  The cryostorage bags containing axicabtagene ciloleucel arrive 
.  The bags must be stored 
 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 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.  
To date, over 65 subjects have received doses of anti-CD19 CAR T cells made using the vector construct 
used in this study at doses
.  There have been no 
instances of accidental overdose of subjects in this program.  In case of accidental overdose, treatment 
should be supportive.  
 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 (e.g., cryostorage bags, subject identification labels) required in this study are 
identified, please log on to kitepharma.com to report the complaint.
6.2.3.
Atezolizumab
Formulation, Packaging, and Handling
The atezolizumab drug product is provided in a single-use, 20-cc USP/Ph. Eur. Type 1 glass vial as a 
colorless-to-slightly yellow, sterile, preservative-free clear liquid solution intended for dilution in 0.9% 
aqueous sodium chloride solution for IV infusion.  The vial is designed to deliver 20 mL (1200 mg) of 
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atezolizumab solution but may contain more than the stated volume to enable delivery of the entire 20 mL 
volume.  The atezolizumab drug product is formulated as 60 mg/mL atezolizumab in 20 mM histidine 
acetate, 120 mM sucrose, 0.04% polysorbate 20, pH 5.8.
Atezolizumab must be refrigerated at 2°C - 8°C (36°F -46°F) upon receipt until use.  Atezolizumab vials 
should not be used beyond the expiration date provided by the manufacturer.  No preservative is used in 
the atezolizumab drug product; therefore, each vial is intended for single use only.  Vial contents should 
not be frozen or shaken and should be protected from direct sunlight.
For detailed information and instructions, see the Atezolizumab Pharmaceutical Instructions and IB.
6.2.4.
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 the excluded 
medication Section 6.2.5.
All concurrent therapies, including medications, intubation, dialysis, and blood products, will be recorded 
from the date of the informed consent through 30 days after completing the final dose of atezolizumab, or 
3 months after the axicabtagene ciloleucel infusion, whichever is longer. Once this follow up period has 
been completed, only targeted concomitant medication will be collected including gammaglobulin, 
immunosuppressive drugs, anti-infective drugs, and vaccinations, for 24 months or until disease 
progression, whichever occurs first.  
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.
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 last procedure (e.g., 
leukapheresis, conditioning chemotherapy).  
For subjects who are enrolled and receive axicabtagene ciloleucel but do not receive atezolizumab, all 
concurrent therapies will be collected through 3 months post-treatment of axicabtagene ciloleucel.  
Targeted concomitant medication will be collected including gammaglobulin, immunosuppressive drugs, 
anti-infective drugs, and vaccinations, until 24 months following treatment with axicabtagene ciloleucel
or until disease progression, whichever occurs first.  
Specific concomitant medication collection requirements and instructions are included in the case report 
form (CRF) completion guidelines.
6.2.5.
Excluded Medications
Corticosteroid therapy at a pharmacologic dose 
 
) and other immunosuppressive drugs must be avoided for 7 days prior to leukapheresis, 
and 5 days prior to axicabtagene ciloleucel administration. 
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Systemic corticosteroids may not be administered as premedication to patients for whom CT scans with 
contrast are contraindicated (i.e., patients with contrast allergy or impaired renal clearance).  Such patients 
should undergo non-contrast CT scans instead. 
Corticosteroids and other immunosuppressive drugs should also be avoided for 6 months after 
axicabtagene ciloleucel administration, unless used to manage axicabtagene ciloleucel related or 
atezolizumab toxicities. Other medications that might interfere with the evaluation of axicabtagene 
ciloleucel, 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 corticosteroids, other than defined/allowed in this protocol, and other investigational agents are 
prohibited, except as needed for treatment of disease progression after axicabtagene ciloleucel and 
atezolizumab administration.
Denosumab (a RANKL inhibitor) is prohibited during the study because it could potentially alter the 
efficacy and safety of atezolizumab.  Patients who are receiving denosumab prior to enrollment must be 
willing and eligible to receive a bisphosphonate instead while in the study.  Any experimental products 
other than those being investigated in this trial are excluded.
Traditional herbal medicines are prohibited during the study because the ingredients of many herbal 
medicines are not fully studied and their use may result in unanticipated drug-drug interactions that may 
cause or confound assessment of toxicity.
If permissibility of a specific medication/treatment is in question, please contact the Kite Pharma Medical 
Monitor.
6.2.6.
Subsequent Therapy
Subsequent therapy administered after axicabtagene ciloleucel and atezolizumab necessary to treat a 
subjects’ 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. 
Regarding allogeneic stem cell transplantation following exposure to atezolizumab, treating investigators 
are strongly cautioned and are referred to recent data reporting higher than expected rates of severe and 
fatal acute toxicities in patients recently treated with PD-1 inhibitors followed by allogeneic HCST 
(Merryman 2015).
6.3.
Rationale for Study Treatment dosing
6.3.1.
Rationale for Conditioning Chemotherapy and Axicabtagene Ciloleucel Dose
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 


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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.  
To improve the depth and duration of lymphocyte depletion, the conditioning chemotherapy dose will be 
cyclophosphamide (
) and fludarabine (
.  
Cyclophosphamide (
) and fludarabine (
 
 
 
.  
The rationale for the axicabtagene ciloleucel dose in this study is based on aggregate safety and efficacy 
data compiled from the ZUMA-1 study as outlined in in the current axicabtagene ciloleucel 
investigator’s brochure.
6.3.2.
Rationale for Atezolizumab Dose and Schedule:
 
.
The target exposure for atezolizumab was projected on the basis of clinical and nonclinical parameters, 
including nonclinical tissue distribution data in tumor-bearing mice, target-receptor occupancy in the 
tumor, and observed atezolizumab interim pharmacokinetics in humans.  The target trough concentration 
(Ctrough) was projected to be 6 g/mL on the basis of several assumptions, including the following:  
1) 95% tumor-receptor saturation is needed for efficacy and 2) the tumor interstitial concentrationto-
plasma ratio is 0.30 on the basis of tissue distribution data in tumor-bearing mice.
In Study PCD4989g, the first-in-human study in patients with advanced solid tumors and hematologic 
malignancies, 30 patients were treated with atezolizumab at doses ranging from 
 
during the dose-escalation stage and 247 patients were treated with atezolizumab at doses of 
 
 during the dose-expansion stage.  Anti-tumor activity has been observed across doses 
ranging from 1 mg/kg to 20 mg/kg.  There was no evidence of dose-dependent toxicity in 
Study PCD4989g.  The MTD of atezolizumab was not reached, and no dose-limiting toxicities were 
observed at any dose.  ATAs to atezolizumab were associated with changes in pharmacokinetics for some 
patients in the lower dose cohorts (
), but patients treated at 
 
maintained the expected target trough levels of drug despite the detection of ATAs.  To date, no 
relationship has been observed between the development of measurable ATAs and safety or efficacy.  
After review of available PK and ATA data for a range of doses, 
 was identified as the 
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lowest atezolizumab dosing regimen that would maintain Ctrough at 6 g/mL while further 
safeguarding against interpatient variability and the potential for ATAs to lead to subtherapeutic levels of 
atezolizumab.
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in exposure following a 
fixed dose compared with a body weight-adjusted dose.  Therefore, patients in this study will be treated 
Q3W at a fixed dose of 
6.3.3.
Rationale for Dosing schedule
PD-1 is an activation/exhaustion marker of cytolytic T cells and its expression is upregulated on the 
surface of CAR T cells beginning prior to infusion and is further enhanced during in vitro exposure to 
CD19-expressing target cells (Bot 2015).  PD-1 surface expression is also increased following CAR T 
cell infusion (Perez 2015). The capacity for cell division and cytolytic activity of the infused CAR T cells 
is therefore likely inhibited by ligation of PD-1 on the T cell surface beginning at the time of infusion.  
Furthermore, emerging evidence suggests that a primary biomarker of CAR T efficacy in lymphoma is 
the peak level of CAR T cells in peripheral circulation, which occurs in patients treated on NCI study 09-
C-0082 and in ZUMA-1 at approximately day 7-15 after infusion (Kochenderfer 2015, Neelapu 2015).  
Thus, a core translational objective of this study is to augment the initial expansion of CAR T cells 
measurable in circulation.  
For this reason, blocking PD-1 receptor ligation on the surface of CAR T cells using an anti-PD-L1 
monoclonal antibody such as atezolizumab as early and as completely as possible is the most rational goal 
with the combination strategy.  However, insofar as the acute toxicity following anti-CD19 CAR T cell 
infusion is related to the initial axicabtagene ciloleucel expansion, disinhibition of this process with PD-
L1 blockade may potentiate acute toxicity.  Therefore, we have adopted a 3+3 “schedule compression” 
phase 1 run-in in the study design.  By staggering the doses of axicabtagene ciloleucel and atezolizumab, 
we aim to mitigate the potential additive or synergistic toxicities related to the combination.  Patients will 
be enrolled and treated one at a time during the phase 1 portion of the study. The first cohort of 3 patients 
will be dosed with atezolizumab 21 days following infusion of axicabtagene ciloleucel at which point the 
great majority of patients will have passed the window of acute axicabtagene ciloleucel-related toxicities 
such as CRS and neurologic events.  The patients will be closely monitored for recrudescence of CRS and 
neurologic events following administration of atezolizumab, as well as for atezolizumab-specific toxicity.  
If these patients pass the DLT window and the regimen is viewed as safe by the SRT, a second cohort of 3 
patients will be dosed with atezolizumab 14 days after their axicabtagene ciloleucel infusion and 
monitored for DLT.  At 14 days following axicabtagene ciloleucel infusion, most patients will have 
cleared the acute toxicity window and the majority of patients axicabtagene ciloleucel related toxicities 
will have resolved to grade 1 or less; for patients that continue to experience grade ≥ 2 CRS- or 
neurologic event-related adverse events, atezolizumab infusion will be delayed per Section 6.4.4. Safety 
review of cohorts 1 and 2 will indicate whether addition of atezolizumab can potentiate CAR T-related 
toxicity.  If the rate and severity of immune activation is tolerable, a third and final cohort of 3 patients 
will be enrolled who will receive atezolizumab 1 day after axicabtagene ciloleucel, before onset of CRS. 
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6.3.4.
Rationale for Pharmacokinetic and ATA Sample Collection
The proposed PK and ATA sampling for atezolizumab will contribute to the characterization of the 
pharmacokinetics of the atezolizumab when given in combination with axicabtagene ciloleucel and 
conditioning chemotherapy in subjects with DLBCL.   The atezolizumab concentration and atezolizumab 
ATA results may be compared with available data from other clinical studies to assess for a potential 
pharmacokinetic and/or pharmacodynamic interaction between study treatments, and/or explore 
correlations with any clinical activity and safety events.  Sparse sampling was employed to minimize 
inconvenience to the patient while providing a sufficient number of samples to allow characterization of 
atezolizumab concentrations, and ATA formation, after a single atezolizumab dose and at steady state. 
6.4.
Study Treatment Schedule and Administration
6.4.1.
Leukapheresis
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) over night 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 (
 
).  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 
.  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 SOPs. Once the product has passed certain release tests, it will be 
shipped back to the treating facility.  Following completion of each subjects’ conditioning chemotherapy 
regimen, subjects will receive their respective axicabtagene ciloleucel infusion.  
6.4.2.
Cyclophosphamide and Fludarabine (
 
)
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 
 before the receiving axicabtagene 
ciloleucel. The 3 day conditioning chemotherapy regimen will be administered in an outpatient setting. 
The 3 day conditioning regimen of fludarabine and cyclophosphamide will be administered in accordance 
with the below daily dosing instructions.

IV hydration with 1L of 0.9% NaCl given prior to cyclophosphamide on the day of infusion 
followed by:
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
Cyclophosphamide 
 followed by:

Fludarabine 
 followed by: 

An additional 1L of 0.9% NaCl at the completion of the cyclophosphamide infusion 

Add Mesna per institutional guidelines 
Subjects should be instructed to drink plenty of liquids during and for 24 hours following the 
chemotherapy (approximately 2 liters/24 hours). In general subjects should be kept well-hydrated but 
closely monitored to prevent fluid overload. 
6.4.3.
Axicabtagene Ciloleucel (Day 0):
All subjects will be hospitalized to receive treatment with axicabtagene ciloleucel followed by an 
observation period. Subjects will remain in the hospital at a minimum through day 7 post treatment with 
axicabtagene ciloleucel.  
Subjects should not be discharged from the hospital until all axicabtagene ciloleucel-related non-
hematological toxicities return to ≤ grade 1 or 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 hospitalized for ongoing axicabtagene ciloleucel-
related fever, hypotension, hypoxia, or ongoing central neurological toxicity > Grade 1, or if deemed 
necessary by the treating investigator. 
6.4.3.1.
Axicabtagene Ciloleucel Premedication Dosing
The following pre axicabtagene ciloleucel infusion medications should be administered approximately 1 
hour prior to infusion.  Alternatives to the recommendations below should be discussed with the 
medical monitor.

Tylenol 650 mg PO

Benadryl 12.5-25 mg IV or PO
6.4.3.2.
Axicabtagene Ciloleucel Dosing
Central venous access such as a port or a peripherally inserted central catheter is required for the 
administration of axicabtagene ciloleucel and for the hospitalization treatment period.  Catheter care, per 
institutional guidelines, should be followed.  Materials and instructions for the thawing, timing and 
administration of axicabtagene ciloleucel are outlined in the Investigational Product Manual (IPM). The 
IPM must be reviewed prior to administration of axicabtagene ciloleucel.  
Research sites should follow institutional guidelines for the infusion of cell products.  
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6.4.4.
Atezolizumab Dosing and Administration Instructions (Day 21, Day 14 or Day 1 after 
Axicabtagene Ciloleucel Administration and every 21 days thereafter for 3 additional (4 
total) doses)
Atezolizumab treatment
 
 In the phase 1 portion, the first dose of atezolizumab 
will be administered in 3 cohorts:  

Cohort 1: 
 

Cohort 2: 
 

Cohort 3: 
  
A safety review team (SRT), internal to the study sponsor and phase 1 investigators, will review the 
safety data following each phase 1 cohort and make recommendations on further study conduct of phase 1 
and progression to phase 2.  
For more detailed information regarding administration, refer to the Atezolizumab Pharmacy Instructions 
and IB.
Dosage, Administration, and Compliance
Administration of atezolizumab will be performed in a setting with emergency medical facilities and staff 
who are trained to monitor for and respond to medical emergencies.  For more detailed information 
regarding administration, refer to the IB and Pharmacy Manual.
The initial dose of atezolizumab will be delivered over 60 (±15) minutes.  If the first infusion is tolerated 
without infusion-associated adverse events, the second infusion may be delivered over 30 (±10) minutes.  
If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (±10) 
minutes.  For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressure, 
oxygen saturation, and temperature) should be determined within 60 minutes before, during (every 
15 [±5] minutes), and 30 (±10) minutes and 2 hours (±15 minutes) after the infusion.  For subsequent 
infusions, vital signs will be collected within 60 minutes before the infusion, during the infusion if 
clinically indicated or if symptoms occurred in the prior infusion, and 1 hour (±10 minutes) after the 
infusion.
No premedication will be allowed for the first dose of atezolizumab.  Premedication may be administered 
for subsequent infusions at the discretion of the treating physician after consultation with the Medical
Monitor.  The management of infusion-related events will be according to severity as follows:

In the event that a patient experiences a mild (NCI CTCAE Grade 1) infusion-related event, the 
infusion rate should be reduced to half the rate being given at the time of event onset.  After the 
event has resolved, the investigator should wait for 30 minutes while delivering the infusion at the 
reduced rate.  If tolerated, the infusion rate may then be increased to the original rate. 
PPD
PPD
PPD
PPD


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
In the event that a patient experiences a moderate infusion-related event (NCI CTCAE Grade 2) 
or flushing, fever, or throat pain, the patient should have his or her infusion immediately 
interrupted and should receive aggressive symptomatic treatment.  The infusion should be 
restarted only after the symptoms have adequately resolved to baseline grade.  The infusion rate 
at restart should be half of the infusion rate that was in progress at the time of the onset of the 
infusion-related event.

For severe or life-threatening infusion-related events (NCI CTCAE Grade 3 or 4), the infusion 
should be stopped immediately and aggressive resuscitation and supportive measures should be 
initiated.  Patients experiencing severe or life-threatening infusion-related events will not receive 
further infusion and will be further managed as clinically indicated until the event resolves.
For anaphylaxis precautions, see Appendix B.
Any overdose or incorrect administration of study drug should be noted on the Study Drug 
Administration eCRF.  Adverse events associated with an overdose or incorrect administration of study 
drug should be recorded on the Adverse Event eCRF.
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and administration.
Dosage Modification
No reduction or modification of the atezolizumab dose will be allowed.  Any toxicity associated or 
possibly associated with atezolizumab treatment should be managed according to standard medical 
practice.  Additional tests, such as autoimmune serology or biopsies, may be used to determine a possible 
immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory agents have been 
mild and self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications.  Discontinuation of atezolizumab may not have an immediate therapeutic effect, and 
there is no antidote for atezolizumab. In severe cases, immune-mediated toxicities may require acute 
management with topical corticosteroids, systemic corticosteroids, or other immunosuppressive agents.
See the Atezolizumab IB for the management of gastrointestinal, dermatologic, endocrine, pulmonary 
toxicity, hepatotoxicity, potential pancreatic or eye toxicity, and other immune-mediated adverse events, 
as these have been observed with exposure to atezolizumab and are potentially immune mediated.  See 
Appendix B for precautions for anaphylaxis
Atezolizumab may be withheld for up to 42 days.  If atezolizumab has to be withheld for > 42 days due to 
drug-related events without appropriate resolution, despite appropriate management, then atezolizumab 
should be discontinued.  However, if in the investigator’s judgment, the patient is likely to derive benefit 
from resuming atezolizumab after a 42-day delay, atezolizumab may be restarted with the approval of the 
Medical Monitor.  


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Discontinuation of atezolizumab may not have immediate therapeutic effect, and there is no available 
antidote for atezolizumab.  In severe cases, immune-mediated toxicities may be acutely managed with 
topical corticosteroids, systemic corticosteroids, tocilizumab, or TNF-alpha inhibitors.
Atezolizumab dosing will be delayed for ongoing grade ≥2 CRS or neurologic events.  The delayed dose 
will be given upon resolution of CRS- and neurologic events to grade 1 or less. If a dose is held greater 
than 7 days beyond the scheduled administration, it will not be given.  Should an atezolizumab dose be 
delayed less than 7 days, the remaining 3 doses should be administered every 21 days from the onset date 
of first dose.  Likewise all protocol required procedures should follow the same schedule as outlined in 
the schedule of assessments beginning on the onset date of the first dose.
6.5.
Axicabtagene Ciloleucel Toxicity Management
To date, the following important risks have been identified with axicabtagene ciloleucel: CRS, 
neurologic events, infections, and cytopenias.  Please refer to Section 6 of the current Investigator’s 
Brochure 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 that you 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.
6.6.
Atezolizumab Toxicity Management
6.6.1.
Safety Plan
Administration of atezolizumab will be performed in a setting with emergency medical facilities and staff 
who are trained to monitor for and respond to medical emergencies.  All adverse events and serious 
adverse events will be recorded as outlined in Section 9.
6.6.2.
Risks Associated with Atezolizumab
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase the 
risk of immune-mediated adverse events, specifically the induction or enhancement of autoimmune 
conditions or systemic immune activation.  Adverse events with potentially immune-mediated causes, 
including rash, hypothyroidism, hepatitis or elevated transaminase, pneumonitis, colitis, myositis, and 
myasthenia gravis have been observed in patients treated with atezolizumab. For further details 
regarding clinical safety and a more comprehensive list of observed adverse events with atezolizumab, 
see the Atezolizumab IB.


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6.6.3.
Management of Patients Who Experience Atezolizumab-Specific Adverse Events
Toxicities associated or possibly associated with atezolizumab treatment should be managed according to 
standard medical practice.  Additional tests, such as autoimmune serology or biopsies, should be used to 
determine a possible immunogenic etiology.
Although most immune-mediated adverse events observed with immunomodulatory agents have been 
mild and self-limiting, such events should be recognized early and treated promptly to avoid potential 
major complications.  Discontinuation of atezolizumab may not have an immediate therapeutic effect and, 
in severe cases, immune-mediated toxicities may require acute management with topical corticosteroids, 
systemic corticosteroids or other immunosuppressive therapy. 
The investigator should consider the benefit-risk balance a given patient may be experiencing prior 
to further administration of atezolizumab.  
Guidelines for management of adverse events associated with atezolizumab can be found in the 
Atezolizumab IB.  
6.6.4.
Systemic Immune Activation
Systemic immune activation (SIA) is a rare condition characterized by an excessive immune response.  
Given the mechanism of action of atezolizumab, SIA is considered a potential risk when given in 
combination with other immunomodulating agents.
Because of the significant overlap of clinical symptoms and laboratory manifestations of SIA with those 
of CRS and neurologic events, as described in the current axicabtagene ciloleucel investigator’s 
brochure, investigators are advised to consider these syndromes as pathophysiologically interrelated and 
possibly only distinguishable by the timing of their onset and their duration.
As such, it is recommended that the following diagnostic and management strategies be utilized for 
symptoms with onset after the second dose of atezolizumab.  For those symptoms that occur prior to the 
second dose of atezolizumab, please refer to the current axicabtagene ciloleucel investigator’s 
brochure for information regarding axicabtagene ciloleucel-related toxicities.
Recommendations regarding early identification and management of SIA are provided below.  Early 
communication with the Medical Monitor is essential and is strongly encouraged. As for severe CRS, 
neurologic events, or HLH, in the event of suspected SIA, atezolizumab should be withheld and the 
Medical Monitor should be contacted immediately for additional guidance.
Early disease recognition is critical, and SIA should be suspected if, in the absence of an alternative 
etiology, the patient meets two or more of the following criteria:

Hypotension that is refractory to aggressive IV fluid challenge
o
Vasopressor support may be required.


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
Respiratory distress that requires aggressive supportive care
o
Supplemental oxygen and intubation may be required.

Fever 38.5C

Acute renal or hepatic failure

Bleeding from coagulopathy

Any of the following unexplained laboratory abnormalities (change from baseline)
o
Cytopenias (in two or more lineages)
o
Significant transaminitis
o
Coagulopathy

For patients with suspected SIA, an initial evaluation should include the following:
o
CBC with peripheral smear
o
PT, PTT, fibrinogen, and D-dimer
o
Ferritin
o
Triglycerides
o
AST, ALT, and total bilirubin
o
LDH
o
Complete neurologic and abdominal examination (assess for hepatosplenomegaly)
Laboratory tests with normal results should be repeated frequently in patients for whom a high clinical 
suspicion of SIA exists.
If cytopenias are present (Grade  2 in two or more lineages) or ferritin is 3000 ng/mL, the following 
evaluations should also be performed:  

Bone marrow biopsy and aspirate (assess for evidence of hemophagocytosis)

Soluble interleukin 2 (IL-2) receptor (sCD25)

Natural killer cell activity

Cytomegalovirus, Epstein-Barr virus, and herpes-simplex virus evaluation (for reactivated or 
active disease)
Diagnostic criteria and recommended management for SIA are provided in Table 3. The diagnostic 
criteria apply only when alternative etiologies have been excluded.


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Table 3. 
Diagnostic Criteria and Recommended Management for Systemic Immune Activation 
(SIA) 
Systemic Immune Activation Diagnostic Criteria 
(applicable only when alternative etiologies have been excluded) 
Major Criteria 
Minor· Cl'itel'ia 
• 
Fever 
38.5°C on more than one occasion 
• 
Splenomegaly 
• 
Ferritin 
3000 ng/mL 
• 
Cytopenias (Grade 
2 in two or more 
lineages) 
• 
Hemophagocytosis in bone man-ow, spleen, or 
lymph nodes 
• 
Elevated GGT or LFTs (AST, ALT, or total 
• 
Age-adjusted soluble IL-2 receptor elevated 
by 
2 standard deviations 
bili.mbin) 
• 
Elevated triglycerides 
• 
Severe dysfunction in two or more organs 
• 
Elevated LOH 
• 
Decreased fibrinogen 
• 
Decreased natural killer cell activity 
Diagnosis and Management of Systemic Immune Activation 
Number of Criteria 
4 major criteria 
3 major criteria 
OR 
2 major plus 
3 minor 
criteria 
Diagnosis 
Consistent with 
SIA 
Probable SIA 
2 major plus :-:; 2 minor Possible SIA 
criteria 
OR 
Action to Be Taken 
• 
Permanently discontinue atezolizumab. 
• 
Consider treatment with an immunosuppressive agent 
(i.e., anti-IL-6 agent, infliximab, cyclosporine A, or etoposide) 
and IV corticosteroids (i.e., methylprednisolone 1 g once daily 
or equivalent). 
• 
Contact the Medical Monitor for additional recommendations. 
• 
Consider HLH-94 protocol ifthere is no clinical improvement. 
• 
Depending on clinical severity, follow guidelines for 
"Consistent with SIA" or "Possible SIA" diagnosis. 
• 
The Medical Monitor may be contacted for reconnnendations. 
• 
Withhold atezolizumab. 
• 
Consider treatment with IV c011icosteroids. 
• 
The Medical Monitor may be contacted for additional 
1 major plus~ 4 minor 
recommendations. 
criteria 
• 
Follow guidelines for "Consistent with SIA" diagnosis if there 
is no clinical improvement or if clinical worsening occurs. 
• 
If clinical improvement occurs, atezolizumab may be resumed 
following a benefit-risk assessment by the Medical Monitor.* 
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GGT -glutamyl transpeptidase; IL-2 interleukin-2; IV intravenous; LFT liver function test; 
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria in the positive diagnosis of 
hemophagocytic syndrome in adult patients (Hejblum et al. 2014).  
Case reports and recommendations have been published for cytokine-release syndrome (Teachey et al. 2013; Lee et al. 
2014; Maude et al. 2014), and, on the basis of etiologic similarities, these practices have been incorporated into the above 
treatment recommendations.
These recommendations do not replace clinical judgment and are intended as suggested guidance.
*Resumption of atezolizumab may be considered in patients who are deriving benefit, as assessed by the Investigator, and have 
fully recovered from the immune-related event. These patients can only be re-challenged with atezolizumab after approval has 
been documented by both the Study Chair and the Medical Monitor. 
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 7.12. 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 as per country and local regulations and guidelines. Where applicable, 
demographic data will include sex, date of birth, 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.


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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 and Performance Status
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/hospitalization, vital signs including blood pressure, heart rate, respiratory rate, 
oxygen saturation, and temperature will be monitored before and after the axicabtagene ciloleucel
infusion and then routinely (every 4-6 hours) while hospitalized. If the subject has a fever (temperature
38.3oC or greater) at any time during hospitalization, vital signs will be monitored more frequently as 
clinically indicated.
For the first infusion of atezolizumab, the patient’s vital signs (blood pressure, heart rate, respiratory rate, 
oxygen saturation, and temperature) should be determined within 60 minutes before, during (every 
15 [±5] minutes), and 30 (±10) minutes and 2 hours (±15 minutes) after the infusion.  For subsequent 
atezolizumab infusions, vital signs will be collected within 60 minutes before the infusion, during the 
infusion if clinically indicated or if symptoms occurred in the prior infusion, and 1 hour (±10 minutes) 
after the infusion.
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.
7.5.
Cardiac Function 
Each subject’s cardiac function, as measured by Left Ventricular Ejection Fraction (LVEF), will be 
assessed during the screening period to confirm study eligibility. No evidence of clinically significant
pericardial effusion as required by eligibility will also be confirmed. Both 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.
A 12-lead ECG will also be performed during the screening period.
7.6.
Magnetic Resonance Imaging
Each subject will undergo a screening brain MRI to rule out CNS metastasis during the screening period 
of the study.


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7.7.
Toxicity Evaluation
Following axicabtagene ciloleucel dosing, an additional lumbar puncture for collection of CSF should be 
performed at first appearance of grade 2 or greater neurological symptoms or as medically indicated.  
Additional evaluations of the CSF should be performed per institutional standard of care.  CSF samples 
(i.e., baseline and collected on study to assess neurological symptoms) will be submitted to the central 
laboratory.
7.8.
Bone Marrow Biopsy
For subjects with a potential complete response to axicabtagene ciloleucel and atezolizumab, a follow-up 
bone marrow aspirate and 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 7.9 and 
Appendix A for treatment response assessment requirements per the revised IWG Response Criteria for 
Malignant Lymphoma (Cheson 2007).
7.9.
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 2007). Flow cytometric, molecular or cytogenetic studies will not be used to determine 
response.
Baseline 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 have their first post axicabtagene ciloleucel infusion 
planned PET-CT tumor assessment 6 weeks following the axicabtagene ciloleucel infusion and at regular 
intervals as highlighted in the SOA during the post treatment and long term follow-up portion of the 
study. 
Post 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 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.  


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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.
7.10. Laboratory
The below samples will be collected at the time points indicated in the SOA.  Additional samples (e.g., 
blood, urine, CSF, tissue, etc) may be collected as needed for further safety testing. Please refer to the 
Laboratory Manual for additional detail and information on collection requirements. 
Local lab analysis:

Sodium (Na), Potassium (K), Chloride (Cl), Total CO2 (bicarbonate), Creatinine, Glucose, Blood 
Urea nitrogen (BUN), Albumin, Calcium total, Magnesium total (Mg), Inorganic Phosphorus, 
Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin, LDH, Uric Acid

C-reactive protein (CRP)

Complete Blood Count 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. 
Central lab analysis:

Blood draws for lymphocyte subsets, cytokine levels, RCR and tracking of anti-CD19 CAR T 
cells by qPCR analysis will be performed at intervals outlined in the SOA. Mid cycle 
assessments one week after the first cycle of atezolizumab are mandatory. Thereafter, repeated 
mid cycle assessments one week after doses 2-4 of atezolizumab will be at the discretion of the 
investigator unless the patient is admitted to the hospital in which case the assessments will be 
mandatory. 

For Phase 2 only, a PBMC sample will be collected and CBC with differential will be done 2
to 3 days after the first 2 doses of atezolizumab as described in the Schedule of Assessments.

Serum samples will also be evaluated for anti-KTE-C19 antibodies and human anti-mouse
antibodies
o
For serum samples that demonstrate increased anti-KTE-C19 human anti-mouse (HAMA) at 
the Post-Treatment Assessment 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.

Serum samples for analysis of anti-atezolizumab antibodies and PK will be sent to and held at the 
central laboratory until distribution to a sponsor-designated bioanalytical laboratory or to the 
sponsor for analysis


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
 
 
 
 
 
 
7.11. Biomarkers
Biomarker analysis will be performed on blood and tumor samples to evaluate predictive and 
pharmacodynamic markers for axicabtagene ciloleucel in conjunction with PD-L1 blockade. Prognostic 
markers specific for aggressive NHL and related to the tumor immune environment may also be 
evaluated. 
The presence, expansion, persistence, and immunophenotype of transduced anti-CD19 CAR T prior to 
and after atezolizumab treatment cells will be monitored in the blood primarily by PCR analysis, 
complemented by flow cytometry.
Levels of serum cytokines will also be evaluated in the blood.
 
 
 
  
Cerebral spinal fluid (CSF), and additional subject samples (e.g., pleural fluid), may be harvested from 
subjects who develop neurologic events 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.   
As axicabtagene ciloleucel comprises retroviral vector transduced T cells, the presence of replication-
competent-retrovirus (RCR) in the blood of treated subjects will be monitored until Month 12.  If there 
are not positive results, samples will be collected and held for up to 15 years.  
In addition, baseline leukapheresis and final axicabtagene ciloleucel samples will be banked and may be 
analyzed by immunophenotyping, qPCR, and/or gene expression profiling.   
 
Archived tumor tissue will be collected for central path review. Additional analysis will include CD19 
and PD-L1 expression (immunohistochemistry), gene expression profiling, and analysis of DNA 
alterations for sub-classification of DLBCL.
 
.
 
PPD
PPD
PPD
PPD
PPD


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For subjects who withdraw consent, any samples that were not requested to be returned or destroyed will 
remain with the sponsor and any data that may be generated will be entered in the study database. 
Pharmacokinetic and Anti-Therapeutic Antibody Assays
Instruction manuals and supply kits will be provided for all samples sent to the central laboratory. The 
following samples will be sent to the central laboratory, and then to a sponsor-designated bioanalytical 
laboratory or to the sponsor for analysis:

Serum samples will be assayed for the presence of ATAs to atezolizumab with the use of 
validated immunoassays.

Serum samples will be assayed for atezolizumab concentrations with the use of a validated 
immunoassay.  
 
 
7.12. 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.
PPD
PPD
PPD


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7.12.1. Screening
The screening period begins on the date the subject signs the IRB/IEC approved ICF and continues 
through commencement of leukapheresis (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
o
Subjects with symptoms of central nervous system malignancy such as new onset severe 
headaches, neck stiffness, seizures, encephalopathy, cranial nerve deficits, 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, respiratory rate, oxygen saturation, and 
temperature

ECOG performance status 

Neurological examination

ECG

ECHO for LVEF and pericardial effusion assessment
o
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
o
Brain MRI 
o
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. 


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
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 PET-CT scan must be repeated to establish a new baseline.  PET CT 
should be performed as close to enrollment as possible. 

Labs 
o
Chemistry panel
o
CBC with differential
o
β-HCG pregnancy test (serum or urine) on all women of child-bearing potential

Lumbar puncture for subjects with new or suspicious neurological findings suggestive of CNS 
involvement.

Serious Adverse Event reporting (refer to Section 9 for safety reporting guidelines)

Concomitant medications documentation and previous cancer treatment history

 
7.12.2. Rescreening
Subjects who are unable to complete the screening assessments or do not 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 initial signing of the informed consent, only the procedure(s)/assessment(s) that did 
not originally meet the eligibility criteria need 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 initial informed consent, subjects must be 
reconsented and repeat all screening procedures/assessments.
7.12.3. 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.
Additionally, the investigator must review the last CBC with differential and chemistry panel 
drawn prior to the start of leukapheresis to confirm that Inclusion 109 (eg, creatinine clearance, 
serum ALT/AST, total bilirubin) continues to be met (see Section 5.1).
Before leukapheresis commences, the below criteria must be met.  If criteria are not met, 
leukapheresis, cell collection 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 of 
PPD


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the 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 pharmacological dose 
 
) and other immunosuppressive drugs must be avoided for 7 
days prior to leukapheresis
If leukapheresis is delayed beyond 28 days from the Screening Visit, screening procedures will be 
repeated to confirm that the subject remains eligible for enrollment (see Section 7.12.1).
Leukapheresis should occur within approximately 5 days of eligibility confirmation.
Once a subject commences leukapheresis, the subject will be considered enrolled into the study.  
The following procedures/requirements will occur on the leukapheresis collection day and as outlined in 
the SOA:

Vital signs including blood pressure, heart rate, respiratory rate, oxygen saturation, and 
temperature

Height and weight

Labs (to be drawn prior to leukapheresis on the day of or day before leukapheresis)
o
Chemistry panel
o
CBC with differential
o
C-reactive protein (CRP)
o
Cytokine levels
o
Anti-KTE-C19 
o
PBMCs including (Anti-CD19 CAR T cells and Lymphocyte subsets)

Leukapheresis

Adverse/Serious Adverse Event reporting 

Concomitant medications documentation 
7.12.4. Conditioning Chemotherapy Period
Before conditioning chemotherapy commences, the following criteria must be met.  If these criteria 
are not met, then conditioning chemotherapy must be delayed until these events resolve.

No evidence or suspicion of infection. 
PPD


Protocol KTE-C19-106 Amendment #1
21 Sep 2017
Kite Pharma Inc.
Confidential 
Page 53 of 93

No clinically evident changes in bone marrow, renal, hepatic, pulmonary or cardiac 
function since screening

Creatinine clearance is at or above limits set in eligibility criteria (Section 5)

No acute neurological toxicity > Grade 1 (with the exception of peripheral neuropathy)
In addition, if any of the following are known to occur, a delay in conditioning chemotherapy may 
be required. Contact the Kite Medical Monitor before conditioning chemotherapy commences for 
guidance.

WBC count of ≥ 20,000/μL within 48 hours prior to conditioning chemotherapy 

CRP is ≥100 mg/L 

Temperature is ≥ 38.0° C within 48 hours prior to conditioning chemotherapy. Unexplained 
fever requires pan-culture, respiratory viral panel, chest CT and any additional symptom-
directed workup to rule out occult infection. 

If any other screening assessments or procedures are repeated between enrollment and the 
start of conditioning chemotherapy and results are outside the eligibility criteria (Section 5)
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, respiratory rate, oxygen saturation, and 
temperature

Labs (to be drawn prior to chemotherapy)
o
Chemistry Panel 
o
CBC with differential

Fludarabine and cyclophosphamide administration

Adverse/Serious Adverse Event reporting 

Concomitant medications documentation 
7.12.5. Investigational Product Treatment Period
Before axicabtagene ciloleucel infusion commences, the following criteria must be met.  If these 
criteria are not met, then axicabtagene ciloleucel infusion must be delayed until these events 
resolve.  

No evidence or suspicion of infection. Subject must not be receiving systemic anti-microbials 
for the treatment of an active infection within 48 hours prior to axicabtagene ciloleucel 
infusion (prophylactic use of anti-microbials is allowed).


Protocol KTE-C19-106 Amendment #1
21 Sep 2017
Kite Pharma Inc.
Confidential 
Page 54 of 93

No clinically evident changes in bone marrow, renal, hepatic, pulmonary or cardiac function 
since screening

Creatinine clearance is at or above limits set in eligibility criteria (see Section 5)

No acute neurological toxicity > grade 1 (with the exception of peripheral neuropathy)
In addition, if any of the following are known to occur, the axicabtagene ciloleucel infusion may 
need to be delayed. Contact the Kite Medical Monitor before axicabtagene ciloleucel infusion 
commences for guidance:

CRP is ≥100 mg/L

Temperature is ≥ 38.0°C within 48 hours prior to axicabtagene ciloleucel infusion. 
Unexplained fever requires pan-culture, respiratory viral panel, chest CT scan and any 
additional symptom-directed workup to rule out occult infection.

WBC count of ≥ 20,000/μL within 48 hours prior to axicabtagene ciloleucel infusion

If any other screening assessments or procedures are repeated between leukapheresis and 
the axicabtagene ciloleucel infusion and results are outside the eligibility criteria (Section 5; 
with the exception of conditioning chemotherapy-induced cytopenias)
If the axicabtagene ciloleucel infusion is delayed > 2 weeks, conditioning chemotherapy must be 
repeated.  In all cases of axicabtagene ciloleucel infusion delays, contact the Kite Medical Monitor for 
guidance. 
Subjects will be hospitalized to receive treatment with axicabtagene ciloleucel followed by an observation 
period lasting through Day 7 post treatment with axicabtagene ciloleucel. Subjects should not be 
discharged from the hospital until all axicabtagene ciloleucel-related non-hematological toxicities return 
to ≤ Grade 1. 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 hospitalized for ongoing axicabtagene ciloleucel-related fever, hypotension, hypoxia, or ongoing 
central neurological toxicity >grade 1, or if deemed necessary by the treating investigator.
Given the possibility that a subject could develop CRS or neurologic events after discharge from the 
hospital or after treatment with atezolizumab, subjects and their family members/caregivers should be 
educated on potential symptoms such as fever, dyspnea, confusion, aphasia, dysphasia, somnolence, 
encephalopathy, ataxia, or tremor. If subjects develop these symptoms, they should be instructed to 
immediately contact the principal investigator or seek immediate medical attention. 
During this period, the following procedures will be completed at the time points outlined in the SOA:

Physical exam with vital signs including blood pressure, heart rate, respiratory rate, oxygen 
saturation, and temperature

Labs (before axicabtagene ciloleucel infusion, as described in the SOA)


Protocol KTE-C19-106 Amendment #1
21 Sep 2017
Kite Pharma Inc.
Confidential 
Page 55 of 93
o
Chemistry Panel 
o
CBC with differential
o
Cytokine levels 
o
PBMCs including (Anti-CD19 CAR T cells, Lymphocyte subsets and RCRs)

Infusion of axicabtagene ciloleucel

Atezolizumab PK and ATA samples

For Phase 2 only, CBC with differential and PBMC sample collection will be done 2 to 3
days after the first 2 doses of atezolizumab as noted in the SOA.

Infusion of atezolizumab x 4, according to the subject’s assigned cohort in phase 1 or to the 
selected dosing schedule for phase 2

Lumbar puncture and CSF examination as deemed clinically appropriate by the investigator, in
subjects with new onset grade ≥ 2 neurologic symptoms after axicabtagene ciloleucel infusion

 
 

PET-CT +/- bone marrow biopsy and aspirate (Cheson 2007) for disease assessment: If the PET-
CT is not of high enough resolution, the scan must be repeated within 7 days. 

Adverse/Serious Adverse Event reporting (refer to Section 9 for safety reporting guidelines)

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 event/SIA.  It is, therefore, 
recommended that CRP, ferritin, and LDH (if elevated at baseline) be monitored daily starting at Day 0 
and continuing through hospitalization. 
7.12.6. Post Treatment Assessment Period
After completing study treatment all subjects will return to the clinic 30 days following the final dose of 
atezolizumab for post treatment assessment.   The following procedure will be completed for subjects as 
outlined in the SOA:

PET-CT +/- bone marrow biopsy and aspirate (Cheson 2007) for disease assessment: If the PET-
CT is not of high enough resolution for accurate disease assessment, the scan must be repeated
within 7 days. 

Physical exam with vital signs including blood pressure, heart rate, respiratory rate, oxygen 
saturation, and temperature

Labs
o
Chemistry Panel 
PPD


Protocol KTE-C19-106 Amendment #1
21 Sep 2017
Kite Pharma Inc.
Confidential 
Page 56 of 93
o
CBC with differential
o
β-HCG pregnancy test (serum or urine) on all women of child-bearing potential
o
Anti-KTE-C19 
o
Cytokine levels
o
PBMCs including (Anti-CD19 CAR T cells, Lymphocyte subsets and RCRs)

Adverse/Serious Adverse Event reporting (refer to Section 9 for safety reporting guidelines)

Concomitant medications documentation
If a subject is subsequently re-admitted to the hospital with any axicabtagene ciloleucel or atezolizumab-
related adverse events, the following procedures will be performed as outlined in the SOA:

The labs below will be collected on the day of hospital re-admission then weekly through 
and including the day of discharge.
o
PBMCs (Anti-CD19 CAR+ T cells)
o
Cytokines
At any time during the treatment period, if a subject did not respond to treatment (i.e., did not achieve a 
CR or PR) or progresses following a response, the subject will proceed directly to the post treatment 
assessment visit and be followed for survival and disease outcomes in the long term follow-up period.
7.12.7. 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 beginning at month 6 following 
axicabtagene ciloleucel infusion:

Every 3 months (± 2 weeks) beginning with Month 6 through and including Month 18

Every 6 months (± 1 month) beginning with Month 18 through and including Month 60
The following procedures will be completed for subjects who are enrolled and receive axicabtagene 
ciloleucel and atezolizumab, at the time points outlined in the SOA:

Physical exam

PET-CT/ Disease assessment through 60 months or until disease progression, whichever occurs 
first.  

Survival status

Labs
o
CBC with differential
o
Anti-KTE-C19 


Protocol KTE-C19-106 Amendment #1
21 Sep 2017
Kite Pharma Inc.
Confidential 
Page 57 of 93
o
PBMCs including (Anti-CD19 CAR T cells, Lymphocyte subsets and RCRs)

Atezolizumab PK and ATA samples.

Targeted Adverse/Serious Adverse Event reporting (for 24 months or until disease progression
whichever occurs first)
o
Including neurological, hematological, infections, autoimmune disorders, and secondary 
malignancies until disease progression.  

Targeted concomitant medication documentation (for 24 months or until disease progression 
whichever occurs first)
o
Including gammaglobulin, immunosuppressive drugs, anti-infective, and vaccinations

Subsequent therapy for the treatment of NHL 
Subjects may also be contacted by telephone to confirm survival status and report targeted concomitant 
medication use. Should a subject require lab collection, labs may be collected at the clinic or at an 
outside facility to reduce the subject burden.
The following procedures/assessments will be completed for subjects who are enrolled but do not receive 
investigational product, at the time points outlined in the SOA:

Subsequent therapy for the treatment of NHL

Survival status

Disease assessment per standard of care

Adverse/Serious Adverse Event reporting 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.
 
 
 
 
 
 
 
 
 
PPD


Protocol KTE-C19-106 Amendment #1
21 Sep 2017
Kite Pharma Inc.
Confidential 
Page 58 of 93
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD


(lendment #1 
Kite Pharma Inc. 
le of Assessments (Cohort l)* 
Conditioning 
Post 
Eorolbneot/ 
IP T1·eahnent Period 
Ti: 
Screening 
Leukapbe1·esis 
Chemotherapy 
(each ,,isit <calculated from Day 0) 
Follow-
Period 
up 
Within 28 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
days of 
-5 
-4 
-3 
0 
1-7 
14 
21 
28 
42 
49h 
63 
70h 
84 
91 h 
114 
(±2 
(±2 
(±2 
(±2 
(±2 
(±2 
(±2 
(±2 
(±2 
(± 1 
enrollment 
davs) 
davs) 
davs) 
davs) 
davs) 
davs) 
davs) 
davs) 
davs) 
week) 
X 
X 
X 
X 
X 
between Day 7 & Day 30 
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 
Xh 
X 
Xh 
X 
X" 
X 
X 
X 
X 
X 
X 
X 
with new onset grade e'. 2 neutologic symptoms as clinically indicated d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X" 
X 
Xh 
X 
X" 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X' 
X 
X' 
X" 
X 
X" 
X 
X" 
X 
X 
X 
X 
Xi 
Xi 
Xi 
Xk 
Xk 
Xi 
Xi 
Xk 
X 
X 
Q3D' 
X 
X 
X 
X 
Xh 
Xh 
X" 
X 
X 
X 
Day7 
X 
X' 
X 
X' 
X" 
X 
X" 
X 
Xh 
X 
X 
X 
X 
X 


Protocol KTE-Cl9-106 Amendment #1 
21 Sep 2017 
Proc.ednres 
Screening 
Axicabtagene ciloleucel N 
infusion 
Atezolizumab N infusion 
Adverse events/ Concomitant 
X 
medication 
Enrollment/ 
Leukapher·esis 
Schedule of Assessments (Footnotes Cohort 1) 
Conditioning 
IP Treatment Period 
Chemotherapy 
( each °1'isit calculated from Day 0) 
Period 
X 
X 
X 
X 
*If cohort I is selected to serve as the dosing model for phase 2 of the study, then this schedule of assessments will apply for all patients enrolled in phase 2 
Kite Phanna Inc. 
Post 
Tx 
Follow-
up 
X 
. 
• Archival tmnor sample: Either FFPE tumor block or up to 20 unstained slides. ___ PD ________________________________ _ 
Archived andPPD 
(if applicable) will be submitted to central laboratory after eligibility has been confumed and prior to strut of conditioning chemotherapy. 
D 
b PET-CT pe1fon11ed following the subjects last line of therapy and prior to signing the consent may be used for confumation of eligibility. If PET CT is perfom1ed > 28 days 
prior to the initiation of conditioning chemotherapy or if subject receives any anti-cancer therapy betwe,en screening and conditioning chemotherapy, the scans must be repeated 
to establish a new baseline. PET CT should be pe1fon11ed as close to enrollment as possible. Patients with known bone mall'ow involvement will undergo bone mall'ow biopsy 
and aspirate as part of restaging (Ches on 2007). 
c Refer to Section 7.4 for the frequency of vital sign collection following axicabtagene ciloleucel and atezolizumab infosions 
d Lumbar Puncture: subjects with symptoms of CNS malignancy (eg, new onset severe headaches, neck stiffness, or focal neurological fuidings) will have lumbar puncture 
pe1fon11ed at screening to assess cerebral spinal fluid for possible CNS involvement. Subjects with new onset grade~ 2 neurologic symptoms post axicabtagene ciloleucel 
infusion will have lumbar puncture perfonned to assess cerebral spinal fluid as clinically appropriate. PPD 
-
• Blood draw for Anti-KTE-C19: Baseline antibody samples to be collected prior to start of leukapheresis. Refer to Section 7 .10 for fi.irther details. 
f Cytokines: prior to axicabtagene ciloleucel infosion on Day 0, then on Day 1 and then eve1y third day th.rough hospitalization 
g PBMCs Blood draw for PBMCs include the analysis oflymphocytes prior to axicabtagene ciloleucel infosion and lymphocytes, anti KTE•Cl9 CART cells, and RCR after 
axicabtagene ciloleucel infusion. 
h 
D 
i Take a sample prior to the atezolizumab infosion for the initial c,ourse of treatment and dm·ing the retreatment period (if applicable). For the initial course of treatment only, 
take a sample at 30 min+/- IO 1nin after the end of the atezolizumab infusion 
i Take sample prior to the atezolizumab infusion. TI1is sample is NOT required dmmg the retreatment period. 
k Take sample prior to the atezolizumab infusion for the initial com·se of treatment and dm111g the retreatment period (if applicable). 
1 For Phase 2 only, CBC nith differential and blood draw for PBMCs will be done 2 to 3 days afte1· each of the first 2 doses of atezolizumab. 
Confidential 
Page 60 of93 


Protocol KTE-C19-106 Amendment #1 
21 Sep 2017 
Table 5. 
Schedule of Assessments (Cohort 2)* 
Enrollment/ 
Conditioning 
Procedures 
Screening 
Leukapheresis 
Chemotherapy 
Period 
Within28 
Day 
days of 
-5 
-4 
-3 
emollment 
Medical history & disease 
X 
assessment 
ECOG Performance Status 
X 
ECG 
X 
ECHO 
X 
Archival/Fcesh tumor to central 
X 
lab• 
Brain MRI 
X 
PET-CT/ disease assessment b 
X 
Physical exam 
X 
Vital signs (BP, HR. RR 0 2 sat. 
X 
X 
X 
X 
X 
temp)' 
Height & Weight 
X 
X 
Neurological assessment 
X 
Pregnancy test (serum or urine) 
X 
Lumbar Punctured 
X 
Blood draw for Chemistry panel 
X 
X 
X 
X 
X 
Blood draw for CBC 
X 
X 
X 
X 
X 
w/differential 
Blood dtaw for C-reactive protein 
X 
(CRP) 
Blood dtaw for Anti-KTE-C19 • 
X 
Blood dtaw for Atezolizumab PK 
Blood draw for Atezolizumab 
ATA 
Blood draw for Cytokines r 
X 
Blood dtaw for PBMCs g 
X 
Leulrapheresis 
X 
Fludarabine/Cyclophosphamide 
X 
X 
X 
Confidential 
0 
1 - 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Q3Dr 
X 
Day7 
Kite Phaima Inc. 
IP Treatment Pe1iod 
Post 
(each visit calculated from Day 0) 
Tx 
Ph l: Day 
Ph l: 
Day 
17 
Day21 
Day 
Day 
Day 
Day 
Day 
Day 
Day 
14 
Ph2:Day 
Ph 2: 
35 
42 
56 
63 h 
77 
g4h 
107 
(±2 
16· 
Day28• 
(±2 
(±2 
(±2 
(± 2 
(±2 
(±2 
(± 1 
days) 
(±2 
(±2 
days) 
days) 
days) 
days) 
days) 
days) 
week) 
davs) 
davs) 
between Day 7 & Day 30 
X 
X 
X 
X 
X 
X 
X1' 
X 
Xb 
X 
X1' 
X 
X 
X 
X 
X 
X1' 
X 
X1' 
X 
Xh 
X 
X 
with new onset grade ::: 2 neurologic symptoms as clinically indicated d 
X 
X 
X 
X1' 
X 
X1' 
X 
Xh 
X 
X 
X1 
X 
X1 
Xh 
X 
X1' 
X 
X1' 
X 
X 
Jr 
Xi 
Xi 
xi. 
Xk 
Xi 
Xi 
xi. 
X 
X 
X 
X1' 
X1' 
X1' 
X 
X 
X1 
X 
X1 
X1' 
X 
X1' 
X 
Xh 
X 
Page 61 of93 


Protocol KTE-Cl9-106 Amendment #1 
21 Sep 2017 
Procedures 
Screening 
Within 28 
Day 
days of 
enrollment 
Axicabtagene ciloleucel IV 
infusion 
Atezolizumab IV infusion 
Adverse event~ Concomitant 
X 
medication 
Enrollment/ 
Leukapheresis 
Schedule of Assessments (Footnotes Cohort 2) * 
Conditioning 
Chemotherapy 
Period 
Day 
-5 
-4 
-3 
0 
1 - 7 
14 
(± 2 
days) 
X 
X 
IP Treatment Period 
( each visit c-alculated from Day 0) 
Ph 1: Day 
Ph 1: 
17 
Day21 
Day 
Day 
Day 
Day 
Ph 2: Day 
Ph 2: 
35 
42 
56 
63 b 
16· 
Day 2s• 
(± 2 
(± 2 
(± 2 
(±2 
(±2 
(±2 
days) 
days) 
days) 
days) 
davs) 
davs) 
X 
X 
•If cohort 2 is selected to serve as the dosing model for phase 2 of the study, then this schedule of assessments will apply for all patients enrolled in phase 2 
Kite Phanna Inc. 
Post 
Tx 
Day 
Day 
Day 
77 
84b 
107 
(± 2 
(± 2 
(± 1 
days) 
days) 
week) 
X 
-
• Archival tumor sample: Either FFPE tumor block or up to 20 unstained slides. PD 
Archived and fresh ttuuor samples (if applicable) will be submitted to central l'·a;-bo-1-·a7to_1_y_a-;ft:-e-r-e-;-:li-gi".';.b""'.'il;-ity
~ l:""1a-s-;b-e_e_n_c-.o-n-;::fi-m1-e-;d-an-;d-p-n:-. o-r7to- sta:-rt:--o-:f::-c-,o-n-:d::-'.it7'io-nn
-:-.-1g- ch;-e-m- o-;th-e_ra_p_y_. ~ D..----, 
b PET-CT (Ne,ck-Chest-Abdomen-Pelvis): If PET-CT pe1fon11ed > 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. Patients with known bone 
mai1·ow involvement will undergo bone mai1·ow biopsy and aspirate as pait of restaging (Cheson 2007). 
c Refer to Section 7.4 for the frequency of vital sigi1 collection following axicabtagene ciloleucel and atezolizumab infusions. 
d Lumbar Puncture: subjects with symptoms of CNS malignancy ( eg, new onset severe headaches, neck stiffness, or focal 11eu10logical findings) will have hm1bar ptmcttu·e perfonued at 
screening to assess cerebral spinal fluid for possible CNS involvement. Subjects with new onset grade :C:: 2 netu·ologic symptoms post axicabtagene ciloleucel infusion will have 
lumbar ptmcttu·e pe1fon11ed to assess cerebral spinal fluid as clinically app10priate. 
D 
-
e Blood draw for Anti-KTE-C19: Baseline antibody samples to be collected prior to sta1t ofleukapheresis. Refer to Section 7.10 for fi.uther details. 
f Cytokines: prior to axicabtagene ciloleucel infusion on Day 0, then on Day 1 and then eve1y third day through hospitalization. 
g PBMCs Blood draw for PBMCs include the aI1alysis of lymphocytes prior to axicabtagene ciloleucel infusion aI1d lymphocytes, anti KTE-C19 CART cells, and RCR after 
axicabtagene ciloleucel infusion. 
b 
D 
Take a saI11ple prior to the atezolizmnab infusion for the initial course of treatment and during the retreatment period (if applicable). For the initial cotu-se of treatment only, take a 
sample at 30 min+/- 10 min after the end of the atezoliztm1ab infusion. 
i Take saiuple prior to the atezoliztm1ab infusion. This sample is NOT required during the retreatment period. 
k Take saiuple prior to the atezoliztunab infusion for the initial cotu-se of treatment and dtumg the retreatment period (if applicable). 
1 For Phase 2 only, CBC with differential and blood draw for PBMCs will be done 2 to 3 days afte1· each of the first 2 doses ofatezolizumab. 
m For Phase 2 only If the Cohort 2 schedule is selected as the dosing model for Phase 2: Visit Day 17 will be Visit Day 16, and Visit Day 21 will be Visit. Day 28 (Phase 2 only). 
Confidential 
Page 62 of93 


Protocol KTE-C19-106 Amendment #1 
21 Sep 2017 
Table 6. 
Schedule of Assessments (Cohort 3)* 
Enrollment/ 
Conditioning 
Procedures 
Screening 
Leokapberesis 
Chemotherapy 
Period 
Within28 
Day 
days of 
-5 
-4 
-3 
enrollment 
Medical history & disease assessment 
X 
ECOG Performance Status 
X 
ECG 
X 
ECHO 
X 
Archival/Fresh tumor to central lab • 
X 
Brain MRI 
X 
PET-CT/ disease assessment b 
X 
Physical exam 
X 
Vital signs (BP, HR, RR, Oi sat, 
X 
X 
X 
X 
X 
temp) C 
Height & Weight 
X 
X 
Neurological assessment 
X 
Pregnancy test (serum or ucioe) 
X 
Lumbar Puncture• 
X 
Blood draw for Chemistry panel 
X 
X 
X 
X 
X 
Blood draw for CBC w/differential 
X 
X 
X 
X 
X 
Blood draw for C-reactive protein 
X 
(CRP) 
Blood draw for Anti-KTE-C19 • 
X 
Blood draw for Atezolizumab PK 
Blood draw for Atezolizumab ATA 
Blood draw for Cytokines f 
X 
Blood draw for PBMCs • 
X 
Leu.kapheresis 
X 
Fludarabine/Cyclophosphamide 
X 
X 
X 
Axicabtagene ciloleucel IV infusion 
Confidential 
0 
X 
X 
X 
X 
X 
X 
X 
Kite Phaima Inc. 
IP Administration Period 
PostTx 
(each vi.sit calculated from Day 0) 
FoUow-up 
Pb I: Day 
Day 
Day 
35h 
Day 
Day 
Day 
Day 
1-7 
14 
22 
Ph 2: Day 
43 
4gb 
64 
69h 
Day94 
(±2 
(±2 
28'" 
(± 2 
(±2 
(±2 
(±2 
(± I week) 
days) 
days) 
(± 2 
days) 
days) 
days) 
days) 
days) 
between Day 7 & Day 30 
X 
X 
X 
X 
X 
x_h 
X 
Xb 
X 
Xb 
X 
X 
X 
X 
x_h 
X 
Xb 
X 
Xb 
X 
X 
with new onset grade 2: 2 neurologic symptoms as clinically indicated • 
X 
X 
X 
x_h 
X 
Xb 
X 
Xb 
X 
X1 
X 
X1 
Xb 
X 
Xb 
X 
Xb 
X 
X 
X1 
Xi 
Xi 
X" 
X" 
Xi 
Xi 
xt 
Q3Dr 
X 
X 
x• 
Xb 
Xb 
X 
Day 
X 
X1 
Xb 
X 
Xb 
X 
Xb 
X 
71 
Page 63 of93 


Protocol KTE-Cl9-106 Amendment #1 
21 Sep 2017 
Procedures 
Screening 
Atezolizumab IV infusion 
Adverse events/ Concomitant 
medication 
Em·ollment/ 
Leukapheresis 
Schedule of Assessments (Footnotes Cohort 3) 
Conditioning 
Chemother·apy 
Period 
I 
I 
I 
IP Administration Period 
(each vi.sit calculated from Day 0) 
X I 
I X I 
I 
X 
I 
I 
X 
I 
*If cohort 3 is selected to serve as the dosing model for phase 2 of the study, then this schedule of assessments will apply for all patients elll'olled in phase 2 
Kite Phanna Inc. 
PostTx 
Follow-up 
• Archival tumor sample: Either FFPE tmnor block or up to 20 unstained slides. __ 
PD _________________________________ _ 
Archived and fresh tumor samples (if applicable) will be submitted to centrnl laboratory after eligibility has been confinued and prior to start of conditioning chemotherapy. 
D 
b PET-CT (Neck-Chest-Abdomen-Pelvis): 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 elll'ollment as possible. Patients with 
known bone marrow involvement will undergo bone mai1·ow biopsy and aspirate as part of restaging (Cheson 2007). 
c Refer to Section 7.4 for the frequency of vital sign collection following axicabtagene ciloleucel and atezolizumab infusions. 
d Lumbar Prn1cttu·e: subjects with symptoms of CNS malignancy (eg, new onset severe headaches, neck stiffness, or focal neurological findings) will have hm1bai· puncttu·e 
performed at screening to assess cerebral spinal fluid for possible CNS involvement. Subjects with new onset grade c::: 2 nern·ologic symptoms post axicabtagene ciloleucel 
infusion will have lrnnbar p1mcttrre perfom1ed to assess cerebral spinal fluid as clinically appropriate. 
D 
--
• Blood draw for Anti-KTE-C19: Baseline antibody satuples to be collected prior to sta1t ofleukapheresis. Refer to Section 7.10 for fi.uther details. 
f Cytokines: prior to axicabtagene ciloleucel infosion on Day 0, then on Day 1 and then every third day through hospitalization. 
g PBMCs Blood draw for PBMCs include the analysis of lymphocytes prior to axicabtagene ciloleucel infusion and lymphocytes, anti KTE-Cl 9 CART cells, and RCR after 
axicabtagene ciloleucel infusion. 
h 
D 
i Take a sample prior to the atezolinmiab infosion for the initial comse of treatment and during the retreatment period (if applicable). For the initial comse of treatment only, take 
a sample at 30 min +/- 10 min after the end of the atezoli.ztunab infusion. 
i Take sample prior to the atezoli.ztuuab infosion. This sample is NOT required during the retreatment period. 
k Take sample prior to the atezoli.ztuuab infosion for the initial course of treatment and dllfing the retreatment period (if applicable). 
1 For Phase 2 only. CBC with differential and blood draw for PBMCs will be done 2 to 3 days after each of the frrst 2 doses of atezoli.ztuuab. 
m If the Cohort 3 schedule is selected as the dosing model for Phase 2, Visit Day 35 will be Visit Day 28 (Phase 2 only) . 
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Table 7. 
Schedule of Assessments (Long-Term Follow-up Pe1iod) 
Loni Term Follow-up Period 
P1·ocedure 
(Each ,isit calculated from Day 0) 
Visit Frequency 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
Month 
6 
9 
12 
15 
18 
24 
30 
36 
Physical exam' 
X 
X 
X 
X 
X 
X 
X 
PET-CT (Neck-Chest-Abdomen-Pelvis}" 
X 
X 
X 
X 
X 
X 
Disease assessment 
X 
X 
X 
X 
X 
X 
Smvival Status 
X 
X 
X 
X 
X 
X 
X 
X 
Blood draw for CBC w/differential c 
X 
X 
X 
X 
X 
X 
Blood draw for Anti-KTE-Cl9 d 
Blood draw for Atezolizumab PK 
>90 days after the last dose of atezolizumab i 
Blood draw for Atezolizumab ATA 
>90 davs after the last dose of atezolizumab i 
Blood draw for PBMCs c • • 
X 
X 
X 
X 
X 
X 
Targeted AE/SAEs f 
X 
X 
X 
X 
X 
X 
Targeted concomitant medication 
X 
X 
X 
X 
X 
X 
X 
Subsequent therapy for NHI,h 
X 
X 
X 
X 
X 
X 
X 
• Physical exams \Ntll contmue through Month 24 
h PET Scans CTs will continue through Month 60 or until disease progression, whichever comes first 
c Subjects ·will continue to prmride samples for CBC w/diffs, lymphocyte subsets and anti-CD19 CART cells through Month 24 
d Anti-KTE-Cl9 antibody samples, refer to Section 7.10 
X 
X 
X 
Kite Phaima Inc. 
Month 
Month 
Month 
Month 
42 
48 
54 
60 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
e RCR samples, harvest and measured at the Post Treatment Assessment Visit, 6 and 12; then collect yearly for up to 15 years and measure only if positive at the Post Treatment 
Assessment, Visit, 6, or 12. 
f Targeted AEs/SAEs will be collected for 24 months or until disease progression (whichever occurs first) 
g Targeted concomitant medications will be collected for 24 months or until disease progression, whichever occurs first 
h Subsequent therapy administered after axicabtagene ciloleucel infusion for a subje-cts' 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 tem1 follow up period, is considered lost to follow up, withdraws consent, or dies. 
T alee a single time point sample 2'. 90 days after the last atezolizumab infusion for the initial course of therapy and another single time point sample after the retreatment period (if 
applicable). 
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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, publically available data (death records) can be included after withdrawal of 
consent (Guidance for Sponsors, Clinical Investigators, and IRBs Data Retention When Subjects 
Withdraw from FDA-Regulated Clinical Trials, 2008). The investigator is to discuss with the subject 
appropriate procedures for withdrawal from the study.
As part of the study, investigative 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. Investigative 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/non-compliance

Product not available

Lost to Follow-up


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
Death

Decision by sponsor
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
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., DLBCL). 
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 
post-treatment follow up visit of the SOA. 


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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.
Reporting of Adverse Events
The investigator is responsible for ensuring that all adverse events observed by the investigator or 
reported by the subject that occur from enrollment (i.e., commencement of leukapheresis) through 30 
days after completing the final dose of Atezolizumab, or 3 months after the axicabtagene ciloleucel
infusion, whichever is longer.  Once this follow up period has been completed, only targeted adverse 
events including neurological, hematological, infections, autoimmune disorders, and secondary 
malignancies for 24 months or until disease progression, whichever occurs first.
For subjects who are enrolled but do not receive axicabtagene ciloleucel and/or atezolizumab, the 
reporting period ends 30 days after the last procedure (e.g., leukapheresis, conditioning chemotherapy, 
investigational product).
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 the most recent version of the KTE-C19 / axicabtagene ciloleucel IB.
In reviewing adverse events, investigators must assess whether the adverse event is possibly related to 1) 
the investigational product (axicabtagene ciloleucel or atezolizumab), 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 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. Abnormal laboratory findings without clinical significance (based on investigators assessment) 
are not to be recorded as adverse events. Where applicable, clinical sequelae (not the laboratory 
abnormality) are to be recorded as the adverse event.


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The investigator is expected to follow reported adverse events until stabilization or resolution.
9.3.
Definition 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 30 days after completing the final 
dose of atezolizumab, or 3 months after the axicabtagene ciloleucel infusion, whichever is longer. Once 
this follow up period has been completed, 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 or until disease progression,
whichever occurs first.   For subjects who screen fail or are enrolled but do not receive axicabtagene 
ciloleucel and/or atezolizumab, the reporting period ends 30 days after the last procedure (e.g., screen 
procedure, leukapheresis, conditioning chemotherapy, investigational product).  
Serious events which the Investigator assesses as related to axicabtagene ciloleucel or atezolizumab 
should be reported regardless of the time period.
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 health care facility (e.g., 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 
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.” 
9.4.
Reporting of Serious Adverse Events and Non-Serious CRS events grade ≥ 3
All serious adverse events and non-serious CRS events grade ≥ 3 (Lee 2014) must be submitted to Kite
within 24 hours following the investigator’s knowledge of the event. SAEs and non-serious CRS events 
grade ≥ 3 will be reported through the electronic data capture (EDC) system.  This is called eSAE 


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reporting.  If the eSAE system is unavailable, reports will be submitted by email to
Kite_PV@ubc.com (UBC safety mailbox).
Subsequently, all serious adverse events will be reported to the FDA per 21 CFR312.32.
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 event. If the 
malignancy has a fatal outcome within 3 months of the last day of the conditioning therapy, axicabtagene 
ciloleucel or atezolizumab infusion then the event leading to death must be recorded as a serious adverse 
event with CTC 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 
30 days following the final dose of atezolizumab or 3 months following the axicabtagene ciloleucel
infusion, whichever is longer, regardless of attribution to treatment, requires expedited reporting within 
24 hours. Any death occurring greater than 30 days following the final dose of atezolizumab or 3 months
following the axicabtagene ciloleucel infusion, whichever is longer, requires expedited reporting within 
24 hours only if it is considered related to treatment.
9.5.
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 child bearing potential must have a 
negative pregnancy test prior to enrollment because of the potentially dangerous effects of the preparative 
chemotherapy on the fetus.  This experimental therapy should not be administered to pregnant women or 
women who are breastfeeding.
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 axicabtagene ciloleucel infusion, the pregnancy must be reported to the 
sponsor contact.  If a pregnancy occurs in a female subject enrolled into the study or in a female 
partner of a male subject within 5 months of the last dose of atezolizumab, the pregnancy must be 
reported to the sponsor.  Information regarding the pregnancy and/or the outcome may be requested by 
the sponsor.
In addition to reporting any pregnancies occurring during the study, investigators should monitor for 
pregnancies that occur through 6 months after the last dose of axicabtagene ciloleucel and through 5 
months after the last dose of atezolizumab
The pregnancy should be reported to the sponsor within 24 hours of the investigators 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.
9.6.
Safety Review Team and Dose-Limiting Toxicity
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 or atezolizumab related events 
with an onset from immediately after and through 21 days following the first atezolizumab infusion:

Grade 4 hematologic toxicity lasting more than 30 days (except lymphopenia or B-cell aplasia) 

All axicabtagene ciloleucel- or atezolizumab-related grade 3 non-hematologic toxicities lasting 
for > 7 days and all axicabtagene ciloleucel- or atezolizumab-related grade 4 non-hematologic 
toxicities regardless of duration are considered DLTs, with the exception of the following which 
are not considered DLTs:
o
Aphasia/dysphasia or confusion/cognitive disturbance which resolves to at worst grade 2
within 2 weeks, to grade 1 within 4 weeks, and baseline within 6 weeks.
o
Fever
o
Immediate IP-related hypersensitivity reactions occurring within 2 hours of cell or 
atezolizumab infusion that are reversible to a grade 2 or less within 24 hours of 
administration with standard therapy
o
Renal toxicity which requires dialysis for ≤ 7 days
o
Intubation for airway protection if ≤ 7 days
o
Tumor lysis syndrome (TLS) including associated manifestations attributable to TLS (e.g., 
electrolyte abnormalities, renal function, hyperuricemia)
o
Grade 3 transaminase, alkaline phosphatase, bilirubin or other liver function test elevation, 
provided there is resolution to ≤ grade 2 within 14 days
o
Grade 4 transient serum hepatic enzyme abnormalities provided there is resolution to ≤ grade 
3 within < 72 hours
o
Hypogammaglobulinemia grade 3 or 4
o
Grade 3 nausea and/or anorexia
CRS will be graded according to a revised grading system (Lee 2014) as described in the current 
axicabtagene ciloleucel investigator’s brochure.  Adverse events attributed to CRS will be mapped to 


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the overall CRS grading assessment for the determination of DLT.  If grade 3 or 4 CRS per Lee is due to 
one of the exceptions above, the event will not be considered a DLT.
During phase 1, approximately 3-9 subjects with DLBCL will be enrolled to evaluate the safety of 
axicabtagene ciloleucel and atezolizumab schedules/regimens.  
Subjects in each cohort will be evaluated for DLTs within the first 21 days following the completion of 
their first dose of atezolizumab.  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 and atezolizumab regimen.  If the subject incidence of DLT is ≤ 1 of 
3 subjects, the study will proceed to the next cohort, or if specific to cohort 3, proceeding to phase 2 of the 
trial. This decision will be based on overall benefit/risk and available biomarker data.
However, if ≥ 2 of the 3 enrolled subjects within any cohort present with a protocol defined DLT during 
phase 1, the SRT may recommend enrolling an additional set of 3 subjects (up to 6 subjects in total) at the 
same dose and schedule that was administered in the first 3 subjects in that cohort.  In this scenario, 
progression to the next cohort or to phase 2 of the study will proceed if ≤2 of the first 6 subjects present 
with a DLT. 
If the subject incidence of DLT is > 2/6, other axicabtagene ciloleucel regimens, including reduced cell 
dose of axicabtagene ciloleucel and/or reduced conditioning chemotherapy may be explored in 
collaboration with the SRT in an additional 3-6 subjects (Figure 3).   The same DLT rules apply as above.
9.7.
Criteria to Pause Enrollment
As part of its oversight of the study, the SRT also will assess criteria to pause enrollment after 6 subjects 
have been treated with axicabtagene ciloleucel and atezolizumab in the Phase 2 portion of the study and 
have had the opportunity to be followed for 30 days from the first atezolizumab dose.  Enrollment will be 
paused if any of the following criteria is met:
1.
Subject incidence of grade 5 axicabtagene ciloleucel or atezolizumab related adverse events 
within 30 days from atezolizumab infusion is ≥ 20%.
OR
2.
Subject incidence of the following grade 4 axicabtagene ciloleucel-related adverse events lasting 
more than 7 days is ≥40%:
o
Neurologic Events
o
CRS (per Lee 2014 criteria)
o
Other non-hematological serious adverse event
o
Infection (treatment-related)


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10. STATISTICAL CONSIDERATIONS
10.1. Hypothesis
No formal hypothesis will be tested in this study.  The phase 2 portion of the study is designed to estimate 
the true CR rate in patients with refractory DLBCL treated with the combination of axicabtagene 
ciloleucel and atezolizumab. 
10.2. Study Endpoints
10.2.1. Primary Endpoints

Phase 1: Incidence of dose-limiting toxicities (DLT)

Phase 2: Complete response rate (complete response [CR] per the revised International Working 
Group [IWG]) Response Criteria for Malignant Lymphoma (Cheson 2007) as determined by 
study investigators.
10.2.2. Secondary Endpoints
Phase 1 and 2:

Objective Response Rate (CR + PR) per the revised IWG Response Criteria for Malignant 
Lymphoma (Cheson, 2007)

Duration of Response

Progression Free Survival

Overall Survival 

Incidence of adverse events and clinically significant changes in safety lab values

Levels of axicabtagene ciloleucel in blood and Incidence of anti-KTE-C19 antibodies

Atezolizumab pharmacokinetics and incidence of anti- atezolizumab antibodies in serum

Levels of cytokines and other markers in serum
Objective Response Rate: ORR is 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 that do not meet the criteria for an objective response by the 
analysis cutoff date will be considered non-responders. 
Duration of Response: DOR for subjects who experience an objective response 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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Progression Free Survival: PFS is defined as the time from the KTE-C19 infusion date to the date of 
disease progression per the revised IWG Response Criteria for Malignant Lymphoma (Cheson 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.  
Overall Survival: OS is defined as the time from KTE-C19 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-KTE-C19 antibodies and levels of anti-CD19 CAR T cells in blood and levels of 
cytokines and other markers in serum will be summarized.
Incidence of anti-atezolizumab antibodies and levels of atezolizumab in serum will be analyzed as 
described in Section 7.10.
10.2.3. Exploratory Endpoints
10.3. Sample Size Considerations
The anticipated enrollment in this study is approximately 3-31 subjects. 
Phase 1 will enroll approximately 3-9 subjects. If the study proceeds to phase 2, total of up to 22
additional subjects would be enrolled.
This study uses a single-arm design to estimate the true complete response rate in patients with DLBCL 
treated with the combination of atezolizumab and axicabtagene ciloleucel at the dosing schedule closest to 
concomitant administration tested in phase 1 and deemed safe by the SRT. With a total sample size of 25 
patients at a given dosing schedule, of which at least 3 will have been treated in the phase 1 portion, an 
observed CR rate of 70% will yield 95% confidence that estimate of the true CR rate is between 51% and 
88%.
Additional assumptions and corresponding two-sided 95% and 80% exact confidence intervals are seen in 
Table 8.
PPD


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Table 8.
95% and 80% exact confidence intervals corresponding to observed CR rate following 
treatment of 25 patients with axicabtagene ciloleucel and atezolizumab
Observed CR Rate
95% Confidence Interval
80% Confidence Interval
40%
[21%, 61%]
[27%, 55%]
45%
[28%, 69%]
[34%, 62%]
50%
[31%, 72%]
[38%, 66%]
55%
[35%, 76%]
[41%, 70%]
60%
[39%, 79%]
[45%, 73%]
65%
[47%, 85%]
[53%, 80%]
70%
[51%, 88%]
[57%, 84%]
75%
[55%, 91%]
[62%, 87%]
80%
[59%, 93%]
[66%, 90%]
10.4. Analysis Subsets  
Full Analysis Set: the full analysis set will consist of all enrolled subjects and will be used for summaries 
of subject disposition.
Modified Intent to Treat Set (mITT): the modified intent to treat set will consist of all subjects enrolled 
and treated with the target dose of axicabtagene ciloleucel, 
 
) and at least one dose of atezolizumab as determined upon completion of the phase 1 
and phase 2 portions of the study. This analysis set will be used for all efficacy analyses.
The DLT evaluable set will include all subjects in each phase 1 cohort treated with axicabtagene 
ciloleucel and at least one dose of atezolizumab who either:
Received the target axicabtagene ciloleucel dose and were followed for at least 21 days after the first 
atezolizumab infusion; or
Received a dose of anti-CD19 CAR T cells lower than the target for that cohort and a subsequent 
atezolizumab infusion and experienced a DLT during the 21 day post-atezolizumab infusion period.
For the phase 1 portion of the study and the evaluation of DLT, the target dose is 
).
If needed, more subjects will be enrolled and treated to achieve 3 DLT evaluable subjects at the target 
dose.
Safety analysis set: the safety set is defined as all subjects treated with any dose of axicabtagene 
ciloleucel.
PPD
PPD


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10.5. 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 and Trial Integrity Document.
10.6. Interim Analysis
10.6.1. Safety Interim Analysis
An 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.
The SRT will review accumulating safety data during the phase 2 portion of the study. Refer to
Section 3.1.
10.7. Planned Method of Analysis
The primary analysis will be performed when the last treated subject in the mITT set has had the 
opportunity to be evaluated for response 6 months after the axicabtagene ciloleucel infusion. The final 
analysis will occur when all subjects have completed the study (defined in Section 3.5.2).
10.7.1. Complete Response Rate
The incidence of complete response and exact 2-sided 95% confidence intervals will be generated.  
10.7.2. 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.
10.7.3. 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.
10.7.4. 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 vital signs will be summarized with 
descriptive statistics. The incidence of concomitant medications will be summarized.
Tables and/or narratives of deaths though the long term follow-up and treatment related SAEs will be 
provided.


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10.7.5. Long Term Data Analysis
All subjects will be followed for survival for up to approximately 5 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.
10.7.6. Pharmacokinetic Analyses
As appropriate, serum concentrations of atezolizumab will be tabulated, summarized, and plotted after 
appropriate grouping.   Additional PK and PK/PD analyses (e.g., population modelling, including pooled 
analyses across studies) may also be performed as appropriate. If done, these additional analyses may be 
reported separately from the Clinical Study Report, and may include additional PK parameters as 
appropriate (e.g., AUC, time-to-maximum concentration, maximum concentration, and half-life).  
10.7.7. Immunogenicity Analyses
The immunogenicity analyses will include patients with at least one pre-dose and one post-dose ATA 
assessment, with patients grouped as appropriate.  The numbers and proportions of ATA-positive patients 
and ATA-negative patients during both the treatment and follow-up periods will be summarized after 
appropriate grouping.
Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA 
response following study drug administration (treatment-induced ATA response), or if they are ATA 
positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 
titer units) than the titer of the baseline sample (treatment-enhanced ATA response). Patients are 
considered to be ATA negative if they are ATA negative at baseline and all post-baseline samples are 
negative, or if they are ATA positive at baseline but do not have any post-baseline samples with a titer 
that is at least 4-fold greater than the titer of the baseline sample (treatment unaffected).
The relationship between ATA status and safety, efficacy, PK, and biomarker endpoints will be analyzed 
and reported descriptively via subgroup analyses.
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 


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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 will be reported according with local laws and regulations

Age at the time of enrollment
For reporting of serious adverse events, subjects will be identified by their respective subject 
identification number, initials and data of birth (as per their local reporting requirements for both initials 
and date of birth)
Per federal regulations and ICH/GCP guidelines, investigators and institutions are required to permit 
authorization to the sponsor, 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
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
Kite Pharma reserves the right to terminate the study at any time. Both Kite pharma and the investigator 
reserve the right to terminate the investigators 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.


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Kite Pharma reserves the unilateral right, at is sole discretion, to determine whether to manufacture 
axicabtagene ciloleucel and provide it to sites and subjects after the completion of the study and before 
treatment becomes commercially available.
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 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. Example 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. Case report form 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 centralize 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, investigator brochure, 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.
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.


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By signing the investigator 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.
15. PUBLICATION
Authorship of publications from data generated in this study 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
o
Substantial contributions to the conception or design of the work, acquisition of data,
analysis, or interpretation of data for the work; AND
o
Drafting the article or revising it critically for important intellectual content; AND
o
Final approval of the version to be published; AND
o
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 individuals who 
accept direct responsibility for the manuscript. This individual should fully meet the criteria for 
authorship defined above.
Funding, collection of data or general supervision of the research alone or in combination does not qualify 
an individual for authorship.
Any publication, in any form, that is derived from this study must be submitted to Kite 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.
16. COMPENSATION
The study sponsor (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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response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 
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Davila ML et al. Efficacy and Toxicity Management of 1928z CAR T Cell Therapy in B Cell Acute 
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a patient with macrophage activation syndrome: potential implications for diagnostics and treatment. Acta 
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Cancer J Clin. 2010; 60; 393-408
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(CAR) T Cells. 2014 ASH Meeting and Exposition: Abstract 2296.
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Rheumatol. 2010;6(4):232-241.
Gattinoni L, Finkelstein SE, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances 
the efficacy of adoptively transferred tumor-specific CD8+ T cells. JEM. October 2005; 202(7): 907-912.
Guidance for Sponsors, Clinical Investigators, and IRBs Data Retention When Subjects Withdraw from
FDA-Regulated Clinical Trials, 2008 http://www.fda.gov/Drugs/default.htm Published October 2008,
Accessed June 27, 2014.
Hejblum G, Lambotte O, Galicier L, Coppo P, Marzac C, et al. (2014) A Web-Based Delphi Study for
Eliciting Helpful Criteria in the Positive Diagnosis of Hemophagocytic Syndrome in Adult Patients. PLoS
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Herbst RS, Soria JC, Kowanetz M, et al Predictive correlates of response to the anti-PD-L1 antibody
MPDL3280A in cancer patients. Nature. 2014 Nov 27;515(7528):563-7.
Hitz F,  Connors JM, Gascoyne RD, 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
John LB, Devaud C, Duong CPM, et al. Anti-PD-1 Antibody Therapy Potently Enhances the Eradication 
of Established Tumors By Gene-Modified T Cells. Clin Canc Res. October 15, 2013. 19(20). 5636-5646.
Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophagocytic lymphohistiocytosis.  Blood 2011 
(Oct);118(15):4041-4052.
Josting A, et al. Prognostic factors and treatment outcome in primary progressive Hodgkins Lymphoma:  
a report from the German Hodgkin study group; Blood 2000 August 15; 96: 1280-1286.
Kiyasu J, Miyoshi H, Hirata A, et al. Expression of programmed cell death ligand 1 is associated with 
poor overall survival in patients with diffuse large B-cell lymphoma. Blood. 2015 Nov 5;126(19):2193-
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Klebanoff CA, Knong HT, et al. Sinks, supressors and antigen presenters: how lymphodepletion enhances 
T cell-mediated tumor immunotherapy. Trends Immunol. February 2005; 26(2): 111-117
Kochenderfer et al. Chemotherapy-Refractory Large-cell and Indolent B-cell Malignancies Can Be
Effectively Treated with Autologous T Cells Expressing Anti-CD19 Chimeric Antigen Receptor. J Clin
Oncol. 2015 Feb 20;33(6):540-9
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that recognizes murine CD19 can eradicate lymphoma and normal B cells. Blood. Nov 11, 2010a;
116(19): 3875–3886.
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toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor–transduced T cells. Blood. 2012 
119:2709-2720.
Kochenderfer JN et al. Construction and Pre-clinical Evaluation of an Anti-CD19 Chimeric Antigen
Receptor. J Immunother. 2009 September; 32(7): 689–702.
Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, Maric I, Raffeld
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lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood.
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chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T 
cells. Cancer Res 66(22):10995-11004, 2006
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Hematology 2015;190-196
Lackner H, Urban C, Sovinz P, et al.  Hemophagocytic lymphohistiocytosis as severe adverse event of 
antineoplastic treatment in children.  Haematologica. 2008;93(2):291-294.
Lee DW, Gardner R, Porter DL, et al. How I treat: current concepts in the diagnosis and management of 
cytokine release syndrome. Blood. 2014 May 29. pii: blood-2014-05-552729.
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Lyman, GH et al 2015. Venous Thromboemolism Prophylaxix and Treatment in Patients With Cancer: 
American Society of Clinical Oncology Clinical Practice Guideline Update 2014. J Clin Oncol. 59: 7351
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acute lymphoblastic leukemia. Blood. 2015 (June);125(26):4017-4023
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meeting, Orlando FL. Abstract 2018.
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Subjects with Refractory Aggressive Non-Hodgkin Lymphoma. Proc ASH 2015; Abstract
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Porter DL, Hwang W, Frey NV, et al.  Chimeric antigen receptor T cells persist and induce sustained 
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APPENDICES
18. APPENDIX A - 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.   

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 


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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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19. APPENDIX B: ATEZOLIZUMAB ANAPHYLAXIS PRECAUTIONS
Equipment Needed:

Tourniquet

Oxygen

Epinephrine for subcutaneous, intravenous (IV), and/or endotracheal use in accordance with 
standard practice 

Antihistamines

Corticosteroids

IV infusion solutions, tubing, catheters, and tape
Procedures
In the event of a suspected anaphylactic reaction during study drug infusion, the following procedures 
should be performed:
1.
Stop the study drug infusion.
2.
Apply a tourniquet proximal to the injection site to slow systemic absorption of study drug.  Do 
not obstruct arterial flow in the limb.
3.
Maintain an adequate airway.
4.
Administer glucocorticoids, antihistamines, epinephrine, or other medications as required by 
patient status and directed by the physician in charge.
5.
Continue to observe the patient and document observations.


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SUMMARY OF CHANGES
Protocol Version
Protocol Section
Description
v.2.0, Amendment 
#1, 21-Sep-2017
2.2.2, Anti CD19 CAR 
T cell Study Designs 
and Results
Removed anti-CD19 CAR T cell study results and added a 
reference to the axicabtagene ciloleucel IB.
v.2.0, Amendment 
#1, 21-Sep-2017
2.3, Atezolizumab
Updated language to align with the current atezolizumab 
protocol template.
v.2.0, Amendment 
#1, 21-Sep-2017
4, Subject Screening 
and Enrollment
Added language to clarify that subjects are considered enrolled 
when leukapheresis is initiated.
v.2.0, Amendment 
#1, 21-Sep-2017
4, Subject Screening 
and Enrollment
Revised language to clarify that the subject ID number is 
assigned after the subject has consented (entered screening) 
and not prior to consent.
v.2.0, Amendment 
#1, 21-Sep-2017
5.1, Exclusion Criteria
Revised language for the refractory subgroups (no response to 
1st line or 2nd or greater line of therapy) to clarify SD as best 
response after the last line of therapy with SD duration no 
longer than 6 months from last dose of therapy.
v.2.0, Amendment 
#1, 21-Sep-2017
5.2, Exclusion Criteria
EXC 202 updated to add exclusion for history of DLBCL that 
has transformed from another histology.
v.2.0, Amendment 
#1, 21-Sep-2017
5.2, Exclusion Criteria
EXC 211 updated to specify exclusion of active acute or 
chronic hepatitis B or C infection and to clarify that history of 
such infection must be cleared by IDSA guidelines.
v.2.0, Amendment 
#1, 21-Sep-2017
5.2, Exclusion Criteria
EXC 213. Active tuberculosis removed as a standalone 
exclusion criteria as this is covered by EXC 211.
v.2.0, Amendment 
#1, 21-Sep-2017
5.2, Exclusion Criteria
EXC 217 (EXC 218 in the original protocol version) updated to 
specify a timeframe for which the requirement for urgent 
therapy is exclusionary (within 6 weeks are leukapheresis).
v.2.0, Amendment 
#1, 21-Sep-2017
5.2, Exclusion Criteria
EXC 225 (EXC 226 in the original protocol version) updated to 
clarify birth control practice from 6 months after axicabtagene 
ciloleucel administration and 5 months after atezolizumab 
administration to align with the atezolizumab IB.
v.2.0, Amendment 
#1, 21-Sep-2017
6.3.1, Rationale for 
Conditioning 
Chemotherapy and 
Axicabtagene 
Ciloleucel Dose
Updated rationale for the axicabtagene ciloleucel dose by 
adding reference to the axicabtagene ciloleucel IB for safety 
and efficacy from the ZUMA-1 study.
v.2.0, Amendment 
#1, 21-Sep-2017
6.4.3.1, Axicabtagene 
Ciloleucel 
Premedication Dosing
Added range for Benadryl dose and clarified that alternatives 
for the administration of pre-medication drugs should be 
discussed with the medical monitor.


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#1, 21-Sep-2017
6.4.3.2, Axicabtagene 
Ciloleucel Dosing
Axicabtagene ciloleucel administration guidelines removed 
from the protocol and reference is added to the Investigational 
Product Manual.
v.2.0, Amendment 
#1, 21-Sep-2017
6.5, KTE-C19 Toxicity 
Management
Replaced toxicity management guidelines with a reference to 
the axicabtagene ciloleucel IB for CRS, neurologic events, 
infections, and cytopenias and management guidance.
v.2.0, Amendment 
#1, 21-Sep-2017
6.6.3, Management of 
Patients Who 
Experience 
Atezolizumab - Specific 
Adverse Events
Removed list of AEs considered associated with atezolizumab 
as a comprehensive list (and guidelines for management of 
these AEs) as these are referenced in the atezolizumab IB.
v.2.0, Amendment 
#1, 21-Sep-2017
6.6.4, Systemic Immune 
Activation
Added reference to the axicabtagene ciloleucel IB for 
information on CRS, neurologic events, and other toxicities 
related to axicabtagene ciloleucel.
v.2.0, Amendment 
#1, 21-Sep-2017
7.5, Cardiac Function
Specified "clinically significant” pericardial effusion to be 
exclusionary.
v.2.0, Amendment 
#1, 21-Sep-2017
7.10, Laboratory
For Phase 2, added requirement for hematology and sample 
collection for PBMCs 2 to 3 days after each dose of 
atezolizumab.
v.2.0, Amendment 
#1, 21-Sep-2017
7.10, Laboratory
Removed sample collection requirements for anti-BSA.
v.2.0, Amendment 
#1, 21-Sep-2017
7.11, Biomarkers
Clarified that RCR is tested up to Month 12.  If there are no 
positive tests, samples will be collected and held for up to 15 
years.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.1, Screening
Clarified screening period to start at the time of informed 
consent through the commencement of leukapheresis.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.2, Rescreening
Rescreening language updated to clarify expectations for 
rescreening within and outside of 28 days after informed 
consent.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.3, Enrollment / 
Leukapheresis
Pre-requisites for initiating leukapheresis reworded for clarity.  
Expectations for timing of leukapheresis is clarified as within 
approximately 5 days from eligibility confirmation.


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#1, 21-Sep-2017
7.12.3, Enrollment / 
Leukapheresis
Removed requirement to contact the Kite Medical Monitor for 
CRP >/= 100 mg/L.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.4, Conditioning 
Chemotherapy Period
Pre-requisites for initiating conditioning chemotherapy updated 
and reworded for clarity.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.5, Investigational 
Product Treatment 
Period
Pre-requisites for initiating axicabtagene ciloleucel 
administration updated and reworded for clarity.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.5, Investigational 
Product Treatment 
Period
For Phase 2, added requirement for hematology and sample 
collection for PBMCs 2 to 3 days after each dose of 
atezolizumab.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.7   Long Term 
Follow-up Period
Clarified that Disease Assessment will continue through Month 
60 or until disease progression.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.8, Retreatment
Clarified that screening assessments may be repeated if 
clinically indicated, as determined by the investigator, to 
confirm eligibility for retreatment.
v.2.0, Amendment 
#1, 21-Sep-2017
7.12.8, Retreatment
Revised criteria regarding CD19 tumor expression for clarity.
v.2.0, Amendment 
#1, 21-Sep-2017
9.3, Definition of 
Serious Adverse Events
Added examples of serious targeted AEs for clarity.
v.2.0, Amendment 
#1, 21-Sep-2017
9.3, Definition of 
Serious Adverse Events
Added language to clarify that all SAEs, which are assessed to 
be related to axicabtagene ciloleucel or atezolizumab, are to be 
reported regardless of the time period.
v.2.0, Amendment 
#1, 21-Sep-2017
9.4, Reporting of 
Serious Adverse Events 
and Non-Serious CRS 
events grade ≥ 3
Added method for reporting SAEs and CRS >/= Grade 3 
electronically through the EDC system.
v.2.0, Amendment 
#1, 21-Sep-2017
9.4, Reporting of 
Serious Adverse Events 
and Non-Serious CRS 
events grade ≥ 3
Updated email address for SAE and/or CRS >/= Grade 3 
reporting to Kite_PV@ubc.com due to transition of case 
handling responsibility from the CRO to Kite.
v.2.0, Amendment 
#1, 21-Sep-2017
9.5, Pregnancy and 
Lactation
Updated to clarify the pregnancy reporting time period to be 5 
months after the last dose of atezolizumab and 6 months after 
the last dose of axicabtagene ciloleucel.


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#1, 21-Sep-2017
9.6, Safety Review 
Team and Dose-
Limiting Toxicity
Corrected to specify that the DLT window is from the first 
dose of atezolizumab through 21 days after the first dose of 
atezolizumab.
v.2.0, Amendment 
#1, 21-Sep-2017
10.2, End Points
Replaced current text describing the end points with the text 
from the synopsis section for consistency.
v.2.0, Amendment 
#1, 21-Sep-2017
10.2.3, Exploratory 
Endpoints
Replaced current text describing the end points with the text
from the synopsis section for consistency.
v.2.0, Amendment 
#1, 21-Sep-2017
16, Compensation
Removed Roche as a study sponsor.
v.2.0, Amendment 
#1, 21-Sep-2017
References
Added reference for Fehrenbacher et al. 2016.
v.2.0, Amendment 
#1, 21-Sep-2017
References
Added reference for Rosenberg et al. 2016.
v.2.0, Amendment 
#1, 21-Sep-2017
References
Removed reference for Butte et al. 2007.
v.2.0, Amendment 
#1, 21-Sep-2017
Synopsis
Removed ORR as determined by Cheson 2014 as a Secondary 
Endpoint for phase 1 and phase 2.
v.2.0, Amendment 
#1, 21-Sep-2017
Study Glossary 
Added Axicabtagene Ciloleucel to the KTE-C19 definition.
v.2.0, Amendment 
#1, 21-Sep-2017
Study Glossary 
Added Complete Remission to the CR definition.
v.2.0, Amendment 
#1, 21-Sep-2017
Study Glossary 
Added Partial Remission to the PR definition.
v.2.0, Amendment 
#1, 21-Sep-2017
Schedule of Assessment 
(Cohort 1, 2, and 3)
For Phase 2, added footnote to state that CBC w/ differential 
and blood draw for PBMCs will be done 2 to 3 days after the 
first 2 doses of atezolizumab.  
v.2.0, Amendment 
#1, 21-Sep-2017
Schedule of Assessment 
(Cohort 2)
For Phase 2, Day 17 study procedures will be done on Day 16 
and Day 21 study procedures will be done on Day 28.
v.2.0, Amendment 
#1, 21-Sep-2017
Schedule of Assessment 
(Cohort 3)
For Phase 2, Day 35 study procedures will be done on Day 28.
v.2.0, Amendment 
#1, 21-Sep-2017
Schedule of Assessment 
(Cohort 3)
.
v.2.0, Amendment 
#1, 21-Sep-2017
Schedule of Assessment 
(LTFU), 
Corrected to remove Disease Assessment from Month 15, 30, 
42, and 54.
PPD


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Description
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#1, 21-Sep-2017
Schedule of Assessment 
(LTFU)
Corrected to add corresponding PET-CT scans wherever 
Disease Assessment is done.
v.2.0, Amendment 
#1, 21-Sep-2017
Throughout 
Updated name of investigational product from KTE-C19 to 
axicabtagene ciloleucel.
v.2.0, Amendment 
#1, 21-Sep-2017
Throughout
Protocol format converted to Global Submit template.
v.2.0, Amendment 
#1, 21-Sep-2017
Title
Updated medical monitor title and address.
v.2.0, Amendment 
#1, 21-Sep-2017
Title
Updated study manager Information.