Clinical trial NCT04150913
Conditions: Non Hodgkin Lymphoma Refractory Non-Hodgkin Lymphoma Relapsed Non Hodgkin Lymphoma Neurotoxicity Neurotoxicity Syndromes Cytokine Release Syndrome
Keywords: Non Hodgkin Lymphoma Refractory Non-Hodgkin Lymphoma Relapsed Non Hodgkin Lymphoma Neurotoxicity Neurotoxicity Syndromes Cytokine Release Syndrome
Sponsor: Marcela V. Maus, M.D.,Ph.D.
Start date: 2020-10-01; Completion date: 2024-10-31
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying the combination of anakinra and axicabtagene ciloleucel to reduce the occurrence of the side effects Cytokine Release Syndrome (CRS) and neurologic toxicities with relapsed or refractory Non-Hodgkin lymphoma (NHL).

* Relapsed NHL is the condition of returned Non-Hodgkin lymphoma.
* Refractory NHL is the condition of previous treatment resistant Non-Hodgkin lymphoma.
* Cytokine Release Syndrome (CRS) is a group of side effect symptoms that can include nausea, headache, rapid heartbeat, shortness of breath, kidney damage, and rash.
* Neurologic toxicity is nervous system disorder characterized by confusion

This research study involves two drugs:

* Anakinra
* Axicabtagene Ciloleucel.

Detailed description:
This Phase 2, single center, open-label research study is studying the combination of Anakinra and Axicabtagene Ciloleucel to reduce the occurrence of the side effects Cytokine Release Syndrome (CRS) and neurologic toxicities in people with relapsed or refractory Non-Hodgkin lymphoma (NHL).

The research study procedures include screening for eligibility and study treatment including evaluations and follow up visits.

* This research study involves two drugs:

  * Anakinra
  * Axicabtagene Ciloleucel
* A total of 20 participants are anticipated to be enrolled to this trial
* The U.S. Food and Drug Administration (FDA) has not approved anakinra for use in treatment of Non-Hodgkin lymphoma (NHL).

Arms: arm 1: Patients who meet eligibility criteria for the study will subsequently be enrolled for treatment.

* Screening
* Enrollment/Leukapheresis period
* Bridging therapy (if applicable)
* Lymphodepleting chemotherapy period
* Investigational Product (IP) treatment period

  * Anakinra
  * Axicabtagene Ciloleucel
* Post treatment assessment period
* Long term follow-up period
Interventions: intervention 1: Anakinra intervention 2: Axicabtagene Ciloleucel
Intervention descriptions: intervention 1: Subcutaneous, dosage per protocol. Day 0 through Day 6. intervention 2: Once, intravenous infusion, dosage per protocol

Protocol documents:
Prot_SAP_000.pdf: 
Page 1
NCI Protocol #:
N/A
DF/HCC Protocol #: 19-348
TITLE:  A Phase 2 trial of anakinra for the prevention of CAR-T cell mediated neurotoxicity.
Coordinating Center:
Massachusetts General Hospital (MGH)
*Principal Investigator (PI):
Matthew J. Frigault, MD
MGH Cancer Center
mfrigault@mgh.harvard.edu
IND #:  146073
IND Sponsor:  
Marcela V. Maus, MD, PhD
MGH Cancer Center
Statistician:
Study Coordinator: 
Nora Horick
Jami Brown, MS, CCRP
Massachusetts General Hospital
Massachusetts General Hospital
nhorick@mgh.harvard.edu
jbrown56@mgh.harvard.edu
Responsible Research Nurse:
Responsible Data Manager: 
      Betsy Valles
      Natascha Nolet
Massachusetts General Hospital
Massachusetts General Hospital
55 Fruit St, Boston, MA 02114
nnolet@mgh.harvard.edu
617-643-9072
617-726-0054
bvalles@mgh.harvard.edu
Other Agent(s):  MGH is the sponsor of this study, working in close collaboration with Kite, a 
Gilead company, to fund, develop and conduct this protocol. 
Protocol Type / Version # / Version Date: Original/Version #7/26AUG2021
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NCT04150913


NCI Protocol #: N/A
DF/HCC Protocol #: 19-348
Protocol Version Date: 26AUG2021
2
CLINICAL STUDY PROTOCOL SYNOPSIS
Name of Sponsor/Company:
Marcela V. Maus, MD, PhD, Massachusetts General Hospital (MGH) 
Name of Investigational Product:
Anakinra
Title of Study (Protocol Title): 
A Phase 2 trial of anakinra for the prevention of CAR-T cell mediated neurotoxicity.
Protocol Number: 19-348
Study center(s): MGH Cancer Center
Principal Investigator: Matthew J. Frigault, MD
Investigator: 
Studied period (years): 2
Estimated date first patient enrolled: quarter IV, 2019
Estimated date last patient completed: quarter IV, 2021
Phase of development: 2
Objectives:
Primary Objective

To assess the impact of anakinra as preventative management of CAR-T related neurotoxicity. 
Secondary Objective:

To assess the impact of anakinra as preventative management of CAR-T related CRS. 

To evaluate the efficacy of axicabtagene ciloleucel in combination with preventative anakinra 
in terms of DOR, ORR, PFS, and OS
Exploratory Objective:

To assess the function, expansion and phenotype of axicabtagene ciloleucel in patients 
receiving preventative anakinra. 

To assess mechanisms of tumor resistance and escape. 

To compare CRS/Neurotox grading used in Zuma-1 to new ASBMT guidelines (Lee 2018).
Route and Regimen:
Investigational Product:

Anakinra treatments consists of sub-cutaneous injection at a target weight base dose of 
100mg for subjects <50kg and 200mg for subjects ≥50 kg. Refer to Section 6.4.3 for 
treatment details. 
Bridging Therapy (in between leukapheresis and lymphodepleting chemotherapy)

At the discretion of the investigator, bridging therapy may be considered for subjects at the 
investigator’s discretion
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NCI Protocol #: N/A
DF/HCC Protocol #: 19-348
Protocol Version Date: 26AUG2021
3

For subjects receiving bridging therapy, refer to Section 6 for bridging therapy details.
Lymphodepleting Chemotherapy

Axicabtagene ciloleucel is administered after a lymphodepleting 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.
Procedures:
At specific time points as outlined in the schedule of assessments, subjects will undergo the following 
assessments/procedures: collection of informed consent, general medical history including previous 
treatments for NHL, physical exam including vital signs and performance status, neurologic 
assessments, blood draws for complete blood count (CBC), chemistry panels, cytokines, C-reactive 
protein, lymphocyte subsets, anti-axicabtagene ciloleucel antibodies, replication-competent retrovirus 
(RCR) and anti-CD19 CAR T cell analysis. Women of childbearing potential will undergo a urine or 
serum pregnancy test. 
Subjects will also undergo a baseline electrocardiogram (ECG), echocardiogram (ECHO), brain 
magnetic resonance image (MRI), a positron emission tomography–computed tomography (PET-
CT/CT), possible bone marrow aspirate/biopsy and leukapheresis.
Subjects will have lumbar punctures performed for the collection of CSF (see Section 11.9 and SOA) 
before and after axicabtagene ciloleucel infusion.
Routinely throughout the conduct of the study, subjects will be asked to report concomitant medications 
and adverse events and will have their disease assessed.
Methodology/Study Design: This is a Phase 2 single center, open-label study evaluating the safety and 
efficacy of anakinra when combined with axicabtagene ciloleucel in subjects with refractory 
aggressive NHL.  
Phase 2 Study
The Phase 2 study will enroll approximately 20 subjects with refractory aggressive NHL. 
Each subject will proceed through the following study periods:

Screening

Enrollment/Leukapheresis period

Bridging therapy (if applicable)

Lymphodepleting chemotherapy period

Investigational Product (IP) treatment period

Post treatment assessment period

Long term follow-up period
For study requirements assigned to each study period, refer to Section 7 for details.
Long-term Follow-up
All subjects who complete the study, and those who withdraw from the study after receiving CAR-19 
for reasons other than death, will be asked to participate in a long-term follow-up study for up to 15 
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NCI Protocol #: N/A
DF/HCC Protocol #: 19-348
Protocol Version Date: 26AUG2021
4
years after their last CAR-19 infusion, with a focus on long-term efficacy and safety. After Month 24 
patients will be followed via the CIBMTR immune effector cell therapy registry. 
Diagnosis and selection criteria: CD19+ NHL 
Inclusion Criteria 
1.
Relapsed or refractory large B-cell lymphoma after two or more lines of systemic 
therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise 
specified, primary mediastinal large B-cell lymphoma, high grade B-cell 
lymphoma, and DLBCL arising from follicular lymphoma.
2.
At least 1 measurable lesion according to the revised IWG Response Criteria for 
Malignant Lymphoma 1.  Lesions that have been previously irradiated will be 
considered measurable only if progression has been documented following 
completion of radiation therapy
3.
At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any 
prior systemic therapy at the time the subject is planned for leukapheresis, except for 
systemic inhibitory/stimulatory immune checkpoint therapy however steroids only 
require a 7-day washout. At least 3 half-lives must have elapsed from any prior 
systemic inhibitory/stimulatory immune checkpoint molecule therapy at the time the 
subject is planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, 
atezolizumab, OX40 agonists, 4-1BB agonists, etc). 
4.
Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for 
clinically non-significant toxicities such as alopecia)
5.
Age 18 or older
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7.
ANC ≥1000/uL
8.
Platelet count ≥75,000/uL
9.
Absolute lymphocyte count ≥100/uL
10.
Adequate renal, hepatic, pulmonary and cardiac function defined as:
o
Creatinine clearance (as estimated by Cockcroft Gault or CKD-EPI) ≥ 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 clinically significant pericardial effusion, and 
no clinically significant ECG findings
o
No clinically significant pleural effusion
o
Baseline oxygen saturation >92% on room air 
11.
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)
12.
Ability to understand and the willingness to sign a written informed consent 
document.
Exclusion Criteria
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1.
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ 
(e.g. cervix, bladder, breast) or follicular lymphoma unless disease free for at least 
3 years 
2.
History of Richter’s transformation of CLL
3.
Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel 
infusion
4.
History of allogeneic stem cell transplantation
5.
Prior CD19 targeted therapy with the exception of subjects who received 
axicabtagene ciloleucel in this study and are eligible for re-treatment
6.
Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
7.
History of severe, immediate hypersensitivity reaction attributed to 
aminoglycosides 
8.
Presence or suspicion of fungal, bacterial, viral, or other infection that is 
uncontrolled or requiring IV antimicrobials for management.  
9.
History of HIV infection or acute or chronic active hepatitis B or C infection.  
Subjects with history of hepatitis infection must have cleared their infection as 
determined by standard serological and genetic testing per current Infectious 
Diseases Society of America (IDSA) guidelines. 
10.
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 
11.
Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or 
with a history of CNS lymphoma or primary CNS lymphoma, cerebrospinal fluid 
malignant cells or brain metastases
12.
History or presence of CNS disorder such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease 
with CNS involvement 
13.
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
14.
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, 
or other clinically significant cardiac disease within 12 months of enrollment
15.
Expected or possible requirement for urgent therapy within 6 weeks due to 
ongoing or impending oncologic emergency (eg, tumor mass effect, tumor lysis 
syndrome)
16.
Primary immunodeficiency 
17.
History of symptomatic deep vein thrombosis or pulmonary embolism within 6 
months of enrollment
18.
Any medical condition likely to interfere with assessment of safety or efficacy of 
study treatment 
19.
History of severe immediate hypersensitivity reaction to any of the agents used in 
this study 
20.
Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen
21.
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. 
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Females who have undergone surgical sterilization or who have been 
postmenopausal for at least 2 years are not considered to be of childbearing 
potential
22.
Subjects of both genders who are not willing to practice birth control from the time 
of consent through 6 months after the completion of axicabtagene ciloleucel
23.
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
24.
History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic 
disease modifying agents within the last 2 years
1.1
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
DSMC & SRT
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this study. The committee is composed of medical oncologists, 
research nurses, pharmacists and biostatisticians with direct experience in cancer clinical 
research. Information that raises any questions about participant safety will be addressed with 
the Overall PI, study team and Kite/Gilead. The DSMC will review protocols up to, but not 
more than four times a year with the primary focus being accrual, protocol adherence, audit 
results and summary of all deaths while being treated and during active follow-up. Given the 
collaborative nature of this protocol, there will be an additional safety review team (SRT) 
comprised of the study sponsor/PI and Kite/Gilead meant to review all study safety data and 
be the primary driver of recommendations on further study conduct as described below.  .  
Refer to Section 13.2 and Section 8.4.4.
Statistical methods:
The primary objective of this study is to assess the impact of prophylactic regimens on the rate and 
severity of neurologic toxicities. With 20 patients the study will have 86% power to detect a decrease 
in the grade 2+ neurotoxicity rate from 45% to 15% via a two-sided exact binomial test with a 
significance level of 0.05. The secondary objectives of this study inclde analyses the rate and severity 
of CRS as well as efficacy endpoints (ORR, DOR, PFS, OS) and levels of anti-CD19 CAR T cells 
and cytokines in the blood. 
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Study Glossary
Abbreviation or Term
Definition/Explanation
AE
Adverse event
ALL
Acute lymphoblastic leukemia
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASCT
Autologous stem cell transplant
AST
Aspartate aminotransferase
CAR
Chimeric antigen receptor 
CAR
Chimeric antigen receptor positive
CBC
Complete blood count
CLL
Chronic lymphocytic leukemia
CMV
Cytomegalovirus
CNS
Central nervous system
CPF
Cell processing facility
CR
Complete response
CRF
Case report form
CRS
Cytokine release syndrome
CSF
Cerebrospinal fluid
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse large B cell lymphoma
DLT
Dose-limiting toxicity
DOR
Duration of response
DSMB
Data Safety Monitoring Board
DVT
Deep vein thrombosis
eACT™
Engineered autologous cell therapy 
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EEG
Electroencephalogram
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
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 
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Abbreviation or Term
Definition/Explanation
FAS
Full analysis set
FL
Follicular lymphoma 
Healthcare Facility
Clinical trial site
HGBCL
High grade B-cell lymphoma 
HLH
Hemophagocytic lymphohistiocytosis
IB
Investigator’s Brochure
ICF
Informed consent form
ICU
Intensive care unit
IP
Investigational product
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IRRC
Independent Radiological Review Committee
IWG
International Working Group 
KTE-C19/axicabtagene 
ciloleucel
Autologous T cells transduced with retroviral vector containing anti-CD19 
CD28/CD3 zeta chimeric antigen receptor
LTFU
Long-term follow-up
LVEF
Left ventricular ejection fraction
mITT
Modified intent-to-treat
MMSE
Mini-Mental Status Exam
MRI
Magnetic resonance imaging
MSGV1
Murine stem cell virus-based vector
NaCl
Sodium chloride
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
ORR
Objective response rate
OS
Overall survival
PET-CT
Positron emission tomography–computed tomography
PBMC
Peripheral blood mononuclear cell
PMBCL
Primary mediastinal B-cell lymphoma 
PD
Progressive disease
PR
Partial response
RCR 
Replication-competent retrovirus
SAE
Serious adverse event
scFv
Single chain variable fragment
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Protocol Version Date: 26AUG2021
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Abbreviation or Term
Definition/Explanation
SD
Stable disease
SMS
Safety management study
SOA
Schedule of assessment
SRT
Safety review team
SUSAR
Suspected unexpected serious adverse reaction
Study Day 0
Defined as the first day that axicabtagene ciloleucel is administered to the subject
TEAEs
Treatment-emergent adverse event
TFL
Transformed follicular lymphoma
ULN
Upper limit of normal
VAS
Visual analogue scale
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Page 10
SCHEMA
Figure 1.
Study Schema
Investigational Product (IP) Treatment 
Period 
(D0) of axicabtagene ciloleucel infusion
Subjects will receive sub-cutaneous 
anakinra prophylaxis starting on D0 pre-
infusion and continue daily through 
D+13. 
Screening
Lymphodepleting Chemotherapy 
Period
(Day -5 to day -3): 
Fludarabine, 
Cyclophosphamide 
Post Treatment Assessment Period 
Long Term Follow-up Period
Enrollment/ Leukapheresis
+/- Bridging Steroids
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Page 11
TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL SYNOPSIS ..........................................................................2
Inclusion Criteria .................................................................................................................4
Exclusion Criteria ................................................................................................................5
1.1
Inclusion of Women and Minorities ........................................................................6
SCHEMA.......................................................................................................................................10
2.
OBJECTIVES....................................................................................................................14
2.1
Study Design..........................................................................................................14
2.2
Protocol Objectives................................................................................................14
3.
BACKGROUND ...............................................................................................................15
3.1
Disease Background and Rationale .......................................................................15
3.2
T cell Therapy for Aggressive Refractory Lymphomas ........................................17
3.3
CRS, Neurotoxicity Management and IL-1...........................................................18
3.4
Correlative Studies Background ............................................................................20
4.
PARTICIPANT SELECTION...........................................................................................21
4.1
Inclusion Criteria ...................................................................................................21
4.2
Exclusion Criteria ..................................................................................................22
4.3
Inclusion of Women and Minorities ......................................................................23
5.
REGISTRATION PROCEDURES ...................................................................................23
5.1
General Guidelines for DF/HCC Institutions ........................................................24
5.2
Registration Process for DF/HCC Institutions.......................................................24
5.3
General Guidelines for Other Investigative Sites ..................................................24
5.4
Registration Process for Other Investigative Sites.................................................24
6.
TREATMENT PLAN........................................................................................................24
6.1
Study treatment......................................................................................................24
6.2
Treatment Regimen................................................................................................26
6.3
Rationale for Study Treatment Dosing ..................................................................27
6.4
T cell Therapy and Anakinra Administration........................................................28
6.5
General Concomitant Medication and Supportive Care Guidelines......................29
6.6
Excluded Medications............................................................................................30
6.7
Subsequent Therapy...............................................................................................30
6.8
Duration of Follow Up...........................................................................................30
6.9
Criteria for Taking a Participant Off Study ...........................................................31
7.
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................32
8.
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................32
8.1
Expected Toxicities................................................................................................32
8.2
Adverse Events ......................................................................................................33
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8.3
Adverse Event Characteristics...............................................................................34
8.4
Procedures for AE and SAE Collection and Reporting.........................................34
8.5
Reporting to the Food and Drug Administration (FDA) .......................................37
8.6
Reporting to the NIH Office of Biotechnology Activities (OBA).........................38
8.7
Reporting to the Institutional Biosafety Committee (IBC)....................................38
8.8
Reporting to Hospital Risk Management...............................................................38
8.9
Routine Adverse Event Reporting .........................................................................39
9.
PHARMACEUTICAL INFORMATION..........................................................................39
9.1
Axicabtagene ciloleucel .........................................................................................39
9.2
Anakinra.................................................................................................................42
10.
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................44
10.1
Biomarker Studies..................................................................................................44
10.2
Laboratory Correlative Studies..............................................................................44
11.
STUDY CALENDAR .......................................................................................................45
11.1
Informed Consent...................................................................................................45
11.2
Demographic Data .................................................................................................45
11.3
Medical and Treatment History .............................................................................45
11.4
Physical Exam, Vital Signs, Performance Status...................................................46
11.5
Neurological Assessment.......................................................................................46
11.6
Cardiac Function....................................................................................................46
11.7
Magnetic Resonance Imaging................................................................................46
11.8
Bone Marrow Biopsy.............................................................................................46
11.9
Lumbar Puncture....................................................................................................47
11.10 Laboratory..............................................................................................................47
11.11 Biomarkers and Correlative Analyses ...................................................................48
11.12 Description of Study Periods .................................................................................48
12.
MEASUREMENT OF EFFECT .......................................................................................61
12.1
Neurotox Response Assessment ............................................................................61
12.2
Disease Response Assessment...............................................................................61
13.
DATA REPORTING / REGULATORY REQUIREMENTS...........................................62
13.1
Data Reporting.......................................................................................................62
13.2
Data Safety Monitoring..........................................................................................62
14.
STATISTICAL CONSIDERATIONS...............................................................................62
14.1
Study Endpoints.....................................................................................................63
14.2
Sample Size, Accrual Rate and Study Duration ....................................................64
14.3
Interim Monitoring Plan ........................................................................................64
14.4
Analysis of Primary and Secondary Endpoints .....................................................65
14.5
Reporting and Exclusions ......................................................................................66
15.
Ethical and Regulatory requirements.................................................................................67
15.1
Independent Review Board/Independent Ethics Committee.................................67
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15.2
Subject Confidentiality ..........................................................................................67
15.3
Investigator Signatory Obligations ........................................................................67
15.4
Protocol Amendments and Termination................................................................68
15.5
Study Documentation and Archive........................................................................68
15.6
Study Monitoring and Data Collection..................................................................68
16.
PUBLICATION PLAN .....................................................................................................69
REFERENCES ..............................................................................................................................71
APPENDIX A................................................................................................................................75
APPENDIX B................................................................................................................................78
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NCI Protocol #: N/A
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2.
OBJECTIVES
The primary objective of this study is to assess the impact of anakinra as preventative management 
of neurotoxicity, as measured by the incidence and maximal grade, following axicabtagene 
ciloleucel in subjects with aggressive refractory NHL. 
The key secondary objectives include assessment of rate and severity of cytokine release 
syndrome and efficacy of axicabtagene ciloleucel in terms of DOR, ORR, PFS, and OS.
Exploratory objectives to include comparison of Zuma-1 CRS/NT grading criteria to new ASBMT 
criteria, levels of anti-CD19 CAR T cells in blood, levels of cytokines in serum and CSF, incidence 
of anti-axicabtagene ciloleucel antibodies and other investigation of potential biomarker 
development based on assessment of blood cells, tumor cells and the proposed actions of the 
investigational product.
2.1
Study Design
Study 19-348 is a Phase 2 single center, open-label study evaluating the safety and efficacy of 
anakinra when combined with axicabtagene ciloleucel in subjects with relapsed or refractory 
large B cell lymphoma.   
Approximately 20 subjects with aggressive refractory NHL, including DLBCL, PMBCL, high 
grade lymphoma or TFL will be enrolled to evaluate the safety of anakinra in combination with 
axicabtagene ciloleucel.  If the initial regimen is determined to be safe, the study may be expanded 
beyond the initial 20 patient cohort. A SRT comprised of the study sponsor and Kite/Gilead, will 
review the safety data and make recommendations on further study conduct
For study requirements assigned to each study period, please refer to the schedule of assessments 
(SOA) and Section 11 for details.
Each subject will proceed through the following study periods:

Screening

Enrollment/Leukapheresis period

Bridging therapy (if applicable)

Lymphodepleting chemotherapy period

Investigational Product (IP) treatment period

Post treatment assessment period

Long term follow-up period
A study schema is drawn out and described at the end of the protocol synopsis section.
2.2
Protocol Objectives
Primary Objective
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
To assess the impact of anakinra as preventative management of CAR-T related 
neurotoxicity. 
Secondary Objective:

To assess the efficacy of anakinra for prophylaxis of CRS when used in combination with 
axi-cel. 

To evaluate the efficacy of axicabtagene ciloleucel in combination with preventative 
anakinra in terms of DOR, ORR, PFS, and OS.
Exploratory Objective:

To assess the function, expansion and phenotype of axicabtagene ciloleucel in patients 
receiving preventative anakinra. 

To assess mechanisms of tumor resistance and escape. 

To compare CRS/Neurotox grading used in Zuma-1 to new ASBMT guidelines
3. BACKGROUND
3.1
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 2.  Large 
B-cell lymphomas represent the most common sub-group of NHL 3.
3.1.1
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of large B-cell lymphoma, 
accounting for approximately 30% of NHL cases.  There are approximately 22,000 new diagnoses 
of DLBCL in the United States each year.  In the past two decades, progress has been made in 
understanding the biological heterogeneity of DLBCL and in improving survival with 
combinations of CHOP and immunotherapy.  The addition of rituximab into combination therapies 
for DLBCL have greatly improved patient outcomes.  However, patients with chemotherapy-
refractory DLBCL following treatment under the current standards of care still have a particularly 
dire prognosis, with no curative treatment options 4.
The population with the highest unmet need continues to consist of patients who do not respond 
to first line combination chemotherapy (typically R-CHOP) or who do not respond to their last 
course of combination chemotherapy, as the disease is mostly insensitive to subsequent 
combination chemotherapy (typically R-ICE, R-ESHAP) (Table 1).  In a review of 64 patients 
with DLBCL with disease progression during first line chemotherapy or only transient response 
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(≤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 5.  An analysis of outcome in 1126 patients with DLBCL after first line R-CHOP 
included 33 patients with primary refractory DLBCL who received second line therapy with 
curative intent.  Only 3 (9%) patients were able to receive autologous stem cell transplantation 
(ASCT), and only 1 (3%) patient achieved long term survival 6.  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 7.  Ardeshna et al followed 19 
patients with large B-cell lymphoma, and 9 patients with TFL who did not respond to second line 
chemotherapy.  Only 5 of the 28 total patients (18%) responded to third line chemotherapy 8. 
Table 1.
Historical Responses in Refractory NHL (SD or PD to Last Line of Therapy)
Setting
Outcome to Subsequent Therapy
Refractory to 1st line
     9 (n=28)
ORR 21%
     5 (n=64)
ORR 15%, median OS 6 mos
     8 (n=5)
ORR 0%
     6 (n=33)
Proceeded to ASCT 9%, 3% survived > 1 year
     10 (n = 111)
ORR 23%, median OS 10 mos
     11 (n=10)
ORR 10%
     
Refractory to 2nd line
     12 (n=55)
Median OS 5 mos
     8 (n=28)
ORR 18%, median OS (large B-cell lympohoma) <6 mos
     7 (n=73)
ORR 14%
Relapsed post ASCT
     13 (N=45)
Median OS 8 mos
These consistently discouraging results demonstrate that new treatment options are urgently 
needed for patients whose tumors have demonstrated a lack of response to chemotherapy.  
3.1.2
Primary Mediastinal B-cell Lymphoma and Transformed Follicular Lymphoma
Primary mediastinal B-cell lymphoma (PMBCL) has distinct clinical, pathological, and molecular 
characteristics compared to DLBCL.  PMBCL is thought to arise from thymic (medullary) B cells 
and represents approximately 3% of patients diagnosed with large B-cell lymphoma.  PMBCL is 
typically identified in the younger adult population in the fourth decade of life with a slight female 
predominance 14,15.  Gene expression profiling suggests deregulated pathways in PMBCL overlap 
with Hodgkin lymphoma.  Initial therapy of PMBCL generally includes anthracycline-containing 
regimens with rituximab with or without involved field radiotherapy.  A recent Phase 2, 
prospective study of infusional dose-adjusted etoposide, doxorubicin, and cyclophosphamide with 
vincristine, prednisone, and rituximab (DA-EPOCH-R) demonstrated radiotherapy may not be 
required 16.
Follicular lymphoma (FL), a B cell lymphoma, is the most common indolent (slow-growing) form 
of NHL, accounting for approximately 20% to 30% of all NHLs.  Some patients with FL will 
transform (TFL) histologically to DLBCL which is more aggressive and associated with a poor 
outcome.  Histological transformation to DLBCL occurs at an annual rate of approximately 3% 
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for 15 years with the risk of transformation continuing to drop in subsequent years.  The biologic 
mechanism of histologic transformation is unknown.  Initial treatment of TFL is influenced by 
prior therapies for follicular lymphoma but generally includes anthracycline-containing regimens 
with rituximab to eliminate the aggressive component of the disease 17.  
Treatment options for relapsed/refractory PMBCL and TFL are similar to those in DLBCL.  Given 
the low prevalence of these diseases, no large prospective randomized studies in these patient 
populations have been conducted.  Patients with chemotherapy refractory disease have a similar 
or worse prognosis 18 to those with refractory DLBCL.  
In addition, the international, multicohort retrospective non-Hodgkin lymphoma research 
(SCHOLAR-1) study retrospectively evaluated outcomes in patients with chemorefractory 
DLBCL, PMBCL, and TFL.  SCHOLAR-1 integrated data from two Phase 3 studies (LYSARC-
CORAL and Canadian Cancer Trials Group LY.12) and 2 observational cohorts (MD Anderson 
Cancer Center and Mayo Clinic/University of Iowa Specialized Program of Research Excellence).  
Among 861 patients, 635 were included based on chemorefractory search criteria.  Outcomes were 
consistently poor, regardless of refractory subgroup and across cohorts.  The results of SCHOLAR-
1 indicated that patients with chemorefractory, aggressive DLBCL represent a homogenous patient 
population with a response rate of 26% (complete response [CR] rate of 7%) and median overall 
survival of 6.3 months 19.
3.1.3
High Grade B-cell Lymphoma
In 2016, the World Health Organization introduced a new category of large B-cell lymphomas 
called high grade B-cell lymphoma (HGBCL) 20.  This designation includes large B-cell 
lymphomas with MYC and BCL2 and/or BCL6 rearrangements that are phenotypically 
intermediate to DLBCL or B-cell lymphoma, unclassifiable (this latter category has since been 
eliminated).  MYC rearrangements in large B-cell lymphomas are associated with a poor prognosis 
that is worsened in cases of concomitant BCL2 and/or BCL6 alterations, ie, double- or triple-hit 
lymphomas.  As such, patients with HGBCL are likely to face poor survival outcomes.
3.2
T cell Therapy for Aggressive Refractory Lymphomas
3.2.1
Axicabtagene Ciloleucel
Axicabtagene ciloleucel are anti-CD19 chimeric antigen receptor (CAR) 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 (Figure 2). 
An anti-CD19 CAR vector construct was previously designed, optimized and initially tested at the 
Surgery Branch of the National Cancer Institute (NCI, IND 13871) (Figure 2.) 21,22.  The scFv is 
derived from the variable region of the anti-CD19 monoclonal antibody FMC63 23.  A portion of 
the CD28 costimulatory molecule is added, as murine models suggest this is important for the anti-
tumor effect and persistence of anti-CD19 CAR T cells 24.  The signaling domain of the CD3-zeta 
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chain is essential for T cell activation.  These fragments were cloned into the murine stem cell 
virus-based (MSGV1) vector, utilized to genetically engineer the autologous T cells.  
Kite Pharma performed larger scale clinical development of autologous anti-CD19 CAR T cells, 
and named this therapeutic engineered cell product axicabtagene ciloleucel. Treatment with 
axicabtagene ciloleucel was FDA approved in 2017 based on data from the Zuma-1 study which 
demonstrated objective response rates upwards of 83%, with a median OS that has not been 
reached (Locke, Lancet Oncology 2018).  Real world data of axicabtagene has demonstrated 
similarly robust response rates and durability, but further emphasized the need for improved 
toxicity management. This real world experience demonstrated cytokine release syndrome (CRS) 
and neurotoxicty rates of 96% and 76% with grade ≥ 3 events seen in 17% and 38% respectively 
(Jacobson et al, ASH 2018).  
Figure 2.
Axicabtagene Ciloleucel 
3.3
CRS, Neurotoxicity Management and IL-1
The primary acute toxicities observed to date with CAR T cells have been CRS and neurotoxicity. 
CRS is defined as a constellation of symptoms which may include (but are not limited to) fever, 
chills, hypotension, hypoxia, and when extreme, macrophage activation syndrome. Manifestations 
of neurotoxicity vary and include confusion, obtundation, seizures, hallucinations, aphasia, ataxia, 
and more rarely, profound cerebral edema25. The future success and application of commercial 
product to a broader population of patients is limited by the frequency and severity of these 
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toxicities. CRS is managed in the inpatient setting with administration of the anti-IL6 receptor 
antibody tocilizumab, with or without steroids, only after the onset of CRS in the setting of clinical 
decline25. The CRS associated with CAR T cells shares many pathogenic features of macrophage 
activation syndrome26. CAR-T related neurotoxicity is thought to be cytokine mediated in the 
setting of macrophage and endothelial activation and is predominantly managed with steroids 
alone27, because tocilizumab has no therapeutic efficacy against CAR T cell-related neurotoxicity. 
Tocilizumab has been studied in the prophylactic setting as part of the third cohort of ZUMA-1; 
these data showed that despite 
improvement in the incidence of 
CRS, investigators found that 
there was an increase in the 
incidence 
of 
severe 
neurotoxicity. This was felt to be 
related 
to 
the 
poor 
CNS 
penetration 
of 
tocilizumab, 
which may have led to increased 
intracerebral levels of IL-6.28
Given these findings, other 
targets 
within 
the 
IL-6 
inflammatory 
pathway 
have 
been 
explored 
for 
the 
management of macrophage activation and cytokine release syndrome. Anakinra, a human 
interleukin 1 receptor antagonist, has demonstrated clinical efficacy in the treatment of rheumatoid 
arthritis and sepsis related macrophage activation syndrome, as well as in recent mouse models of 
CRS and neurotoxicity in which lethal CRS and neurotoxicity were abrogated with the use of 
anakinra (figure 3) 29-31. We also have anecdotal experience with the use of anakinra to treat 
tocilizumab-refractory cytokine release syndrome, and have noted improvements in neurologic 
function. These data suggest that IL-1 blockade may play a critical role in the pathophysiology of 
both CRS and neurotoxicity. Furthermore, it does not appear that IL-1 activity is required to 
maintain CAR-T cell efficacy.
3.3.1
Anakinra
Anakinra is a recombinant human IL-1 receptor antagonist (rhIL-1ra). Endogenous IL-1 is induced 
by inflammatory stimuli and mediates various immunological responses. Anakinra can be 
administered subcutaneously. Anakinra is currently FDA approved for cryopyrin-associated 
periodic syndromes and rheumatoid arthritis (RA). 
Sub-cutaneous and intravenous administration of anakinra have been studied in multiple contexts. 
Anakinra was administered intravenously to patients with sepsis in several randomized controlled 
trials (RCTs) conducted in the 1990s32-34. In these trials, rhIL-1ra was administered using different 
regimens; all included an intravenous (IV) loading dose of 100 mg administered over about 60 
seconds and followed by an IV infusion administered every 8 or 12 h by a volumetric infusion 
Figure 3. Anakinra, but not tocilizumab, abolishes neurotoxicity in 
a SGM3 mouse model of CRS and neurotoxicity.  (Norelli et al. 
2018)
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pump at a constant rate (17-133 mg/h, n=74, or 1- 2 mg/kg/h, n=941) for 72 h. The frequencies of 
(serious) adverse events were not significantly different between the treatment and placebo groups. 
No unique clinical or laboratory adverse events were significantly more frequent in the anakinra-
treated patients compared to the placebo group, and there was no evidence of delayed resolution 
of infection or increased frequency of secondary infections in the anakinra-treated group34. Before 
these trials of rhIL-1ra in sepsis, a phase I study of rhIL-1Ra administered intravenously at 
different doses had been conducted in 25 healthy individuals, generating safety and 
pharmacokinetic data35. In this study, the authors had found no clinically significant differences in 
clinical, hematological, biochemical, or endocrinological parameters between the groups receiving 
anakinra or saline. The only reaction occurred in one volunteer who developed a mild, transient 
case of hepatitis. 
Additional placebo controlled, randomized trials have occurred designed to assess the safety of 
patients receiving anakinra monotherapy and combinations with other immunosuppressive agents. 
One such study by Fleischmann et al. included 1414 patients receiving a variety of concurrent 
medications for RA including some disease modifying antirheumatic drugs (DMARDs), as well 
as patients who were DMARD-free. Concurrent DMARDs included MTX, sulfasalazine, 
hydroxychloroquine, gold, penicillamine, leflunomide, and azathioprine. Although Serious 
infectious episodes were observed more frequently in the anakinra group (2.1% versus 0.4% in the 
placebo group), this was ultimately felt to be secondary to combination with other 
immunosuppressive agents and therefore should be monitored36.
Several pharmacokinetic studies have been performed for subcutaneous treatment. In subjects with 
RA, maximum plasma concentrations of anakinra occurred 3 to 7 hours after subcutaneous 
administration of anakinra at clinically relevant doses (1 to 2 mg/kg; n = 18); the terminal half-life 
ranged from 4 to 6 hours. In RA patients, no unexpected accumulation of Kineret was observed 
after daily subcutaneous doses for up to 24 weeks. The mean plasma clearance of Kineret in 
subjects with mild (creatinine clearance 50-80 mL/min) and moderate (creatinine clearance 30-49 
mL/min) renal insufficiency was reduced by 16% and 50%, respectively and no significant dose 
reduction was recommended upon FDA approval. 
Refer to the most recent version of the package insert from the FDA label for additional details 
surrounding the anakinra.
3.4
Correlative Studies Background
Correlative studies will be performed on peripheral blood, bone marrow/tumor biopsies and, if 
available, CSF samples to evaluate PK/PD markers related to safety and/or efficacy. The 
effectiveness of axicabtagene ciloleucel T cells may depend on the expansion and persistence of 
CAR T cells in subjects. Therefore, the expansion and persistence will be monitored by flow 
cytometry and PCR analysis using peripheral blood samples as per standard SOPs. Samples will 
be collected per the protocol Schedule of Events (see 11.1 Schedule of Events). Periodic 
monitoring of anti-inflammatory cytokines secretion will be performed to determine correlation 
between axicabtagene ciloleucel efficacy and/or toxicity; in addition,  CD19 expression on tumor 
cells will be evaluated at the eligibility and in subjects failing to achieve a complete response.
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Additional testing may be done depending on the clinical condition; for instance, patients with 
symptoms suggestive of cytokine release syndrome or with skin rash or other findings that may 
concern the investigators may have more frequent monitoring to enhance the safety of this trial. 
If tumor tissues or bone marrow aspirates become available as part of routine clinical care, a 
sample will be collected for research analysis. Tissue samples will be analyzed for the presence of 
axicabtage ciloleucel T cells by PCR and/or flow cytometry. Additionally, different T cell subsets  
have demonstrated different effector function and persistence and, therefore, T cell 
immunophenotyping will be performed by flow cytometry. Peripheral blood samples will be 
analyzed for cytokine/chemokine levels by multiplex bead array technology. Tumor tissue will be 
analyzed for CD19 expression by immunohistochemistry and/or flow cytometry. Additional 
clinical samples testing may be performed based on the Exploratory Endpoints as listed in Section 
2.4.
All research samples will be delivered, processed, and frozen as per SOP to either Kite/Gilead (for 
VCN and cytokine analysis) or the Maus/Immune Monitoring Laboratory at the MGH Cancer 
Center for storage and bulk analyses (all other correlative studies). Documentation of sample 
receipt, processing, and storage and primary data from the research analyses will be collected and 
stored by the Immune Monitoring Lab personnel. All research analyses will be performed based 
on assay-specific SOP using qualified assays.
4. PARTICIPANT SELECTION
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 10 
for details.
Each subject who enters the screening period will receive a unique subject identification (ID)
number before any study specific procedures or activities are initiated.  This number will be used 
to identify the subject throughout the study and must be used on all study documentation related 
to the subject.  Furthermore, the subject identification number must remain constant throughout 
the entire clinical study, it must not be changed after enrollment or if the subject is rescreened or 
retreated.
4.1
Inclusion Criteria 
1.
Relapsed or refractory large B-cell lymphoma after two or more lines of systemic 
therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, 
primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL 
arising from follicular lymphoma.
2.
At least 1 measurable lesion according to the revised IWG Response Criteria for 
Malignant Lymphoma 1.  Lesions that have been previously irradiated will be 
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considered measurable only if progression has been documented following completion 
of radiation therapy
3.
At least 2 weeks or 5 half-lives, whichever is shorter, must have elapsed since any prior 
systemic therapy at the time the subject is planned for leukapheresis, except for systemic 
inhibitory/stimulatory immune checkpoint therapy however steroids only require a 7-day 
washout. At least 3 half-lives must have elapsed from any prior systemic 
inhibitory/stimulatory immune checkpoint molecule therapy at the time the subject is 
planned for leukapheresis (e.g. ipilimumab, nivolumab, pembrolizumab, atezolizumab, 
OX40 agonists, 4-1BB agonists, etc). 
4.
Toxicities due to prior therapy must be stable and recovered to ≤ Grade 1 (except for 
clinically non-significant toxicities such as alopecia)
5.
Age 18 or older
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7.
ANC ≥1000/uL
8.
Platelet count ≥75,000/uL
9.
Absolute lymphocyte count ≥100/uL
10.
Adequate renal, hepatic, pulmonary and cardiac function defined as:
o
Creatinine clearance (as estimated by Cockcroft Gault or CKD-EPI Equation)) ≥ 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 clinically significant pericardial effusion, and no 
clinically significant ECG findings
o
No clinically significant pleural effusion
o
Baseline oxygen saturation >92% on room air 
11.
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)
12.
Ability to understand and the willingness to sign a written informed consent document.
4.2
Exclusion Criteria
25.
History of malignancy other than nonmelanoma skin cancer or carcinoma in situ (e.g. 
cervix, bladder, breast) or follicular lymphoma unless disease free for at least 3 years 
26.
History of Richter’s transformation of CLL
27.
Autologous stem cell transplant within 6 weeks of planned axicabtagene ciloleucel
infusion
28.
History of allogeneic stem cell transplantation
29.
Prior CD19 targeted therapy with the exception of subjects who received axicabtagene 
ciloleucel in this study and are eligible for re-treatment
30.
Prior chimeric antigen receptor therapy or other genetically modified T cell therapy
31.
History of severe, immediate hypersensitivity reaction attributed to aminoglycosides 
32.
Presence or suspicion of fungal, bacterial, viral, or other infection that is uncontrolled 
or requiring IV antimicrobials for management.  
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33.
History of HIV infection or acute or chronic active hepatitis B or C infection.  Subjects 
with history of hepatitis infection must have cleared their infection as determined by 
standard serological and genetic testing per current Infectious Diseases Society of 
America (IDSA) guidelines. 
34.
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 
35.
Subjects with detectable cerebrospinal fluid malignant cells, or brain metastases, or 
with a history of CNS lymphoma or primary CNS lymphoma, cerebrospinal fluid 
malignant cells or brain metastases
36.
History or presence of CNS disorder such as seizure disorder, cerebrovascular 
ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with 
CNS involvement 
37.
Subjects with cardiac atrial or cardiac ventricular lymphoma involvement
38.
History of myocardial infarction, cardiac angioplasty or stenting, unstable angina, or 
other clinically significant cardiac disease within 12 months of enrollment
39.
Expected or possible requirement for urgent therapy within 6 weeks due to ongoing 
or impending oncologic emergency (eg, tumor mass effect, tumor lysis syndrome)
40.
Primary immunodeficiency 
41.
History of symptomatic deep vein thrombosis or pulmonary embolism within 6 
months of enrollment
42.
Any medical condition likely to interfere with assessment of safety or efficacy of study 
treatment 
43.
History of severe immediate hypersensitivity reaction to any of the agents used in this 
study 
44.
Live vaccine ≤ 6 weeks prior to planned start of conditioning regimen
45.
Women of child-bearing potential who are pregnant or breastfeeding because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus or infant. 
Females who have undergone surgical sterilization or who have been postmenopausal 
for at least 2 years are not considered to be of childbearing potential
46.
Subjects of both genders who are not willing to practice birth control from the time of 
consent through 6 months after the completion of axicabtagene ciloleucel
47.
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
48.
History of autoimmune disease (e.g. Crohn’s, rheumatoid arthritis, systemic lupus) 
resulting in end organ injury or requiring systemic immunosuppression/systemic 
disease modifying agents within the last 2 years
4.3
Inclusion of Women and Minorities
Both men and women of all races and ethnic groups are eligible for this trial.
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5. REGISTRATION PROCEDURES 
5.1
General Guidelines for DF/HCC Institutions
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. The registration 
process includes registration of the participant for study related, as well as initiation of treatment 
plan related activities. An investigator will confirm eligibility criteria and a member of the study 
team will complete the protocol-specific eligibility checklist. This does not include registration 
with Kite/Gilead for manufacturing of axicabtagene ciloleucel which will be performed separately 
by study staff via Kite IPM. 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the subject 
must be taken off-study in the CTMS (OnCore) with an appropriate date and reason entered.  
5.2
Registration Process for DF/HCC Institutions
Applicable DF/HCC policy (REGIST-101) must be followed.  
5.3
General Guidelines for Other Investigative Sites
N/A
5.4
Registration Process for Other Investigative Sites
N/A
6. TREATMENT PLAN
6.1
Study treatment 
6.1.1
Bridging Therapy 
Bridging refers to the time in between leukapheresis and initiation of lymphodepleting 
chemotherapy. Bridging therapy will be allowed at the discretion of the treating investigator.  
Chemotherapy given after leukapheresis as bridging therapy must be stopped ≥7 days prior to 
lymphodepleting chemotherapy. Corticosteroid therapy at a pharmacologic dose (≥ 5 mg/day of 
prednisone or equivalent doses of other corticosteroids) and other immunosuppressive drugs 
must be avoided for 7 days prior to leukapheresis, and 5 days prior to axicabtagene ciloleucel
administration. 
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6.1.2
Lymphodepleting Chemotherapy
Lymphodepleting chemotherapy will be supplied by the investigative site unless otherwise noted.  
Refer to the current product label for guidance on packaging, storage, preparation, administration 
and toxicity management associated with the administration of chemotherapy agents.
6.1.2.1
Fludarabine 
Fludarabine phosphate is a synthetic purine nucleoside that differs from physiologic nucleosides 
in that the sugar moiety is arabinose instead of ribose or deoxyribose.  Fludarabine is a purine 
antagonist antimetabolite.
Refer to the most recent version of the package insert for specific details surrounding the 
administration of fludarabine.
6.1.2.2
Cyclophosphamide
Cyclophosphamide is a nitrogen mustard-derivative alkylating agent.  Following conversion to 
active metabolites in the liver, cyclophosphamide functions as an alkylating agent; the drug also 
possesses potent immunosuppressive activity.  The serum half-life after IV administration ranges 
from 3-12 hours; the drug and/or its metabolites can be detected in the serum for up to 72 hours 
after administration.  
Refer to the most recent version of the package insert for specific details surrounding the 
administration of cyclophosphamide.
6.1.2.3
Mesna
Mesna is a detoxifying agent used to inhibit the hemorrhagic cystitis induced by chemotherapy.  
The active ingredient in mesna is a synthetic sulfhydryl compound designated as sodium-2-
mercaptoethane sulfonate with a molecular formula of C2H5NaO3S2. 
Mesna should be administered per institutional guidelines.  Refer to the most recent version of the 
package insert for specific details surrounding the administration of mesna.
6.1.3
Axicabtagene Ciloleucel 
Refer to the most current Investigator’s Brochure regarding axicabtagene ciloleucel and 
clinical experience.  
Axicabtagene ciloleucel is supplied cryopreserved in cryostorage bags.  The product in the bag is 
slightly cloudy, with cream to yellow color.  The cryostorage bags containing axicabtagene 
ciloleucel arrive frozen in a liquid nitrogen dry shipper.  The bags must be stored in vapor phase 
of liquid nitrogen and the product remains frozen until the subject is ready for treatment to assure 
viable live autologous cells are administered to the subject. Several inactive ingredients are added 
to the product to assure viability and stability of the live cells through the freezing, thawing, and 
infusion process.
Axicabtagene ciloleucel is a subject-specific product and the intended subject will be identified by 
a unique subject ID number.  Upon receipt, verification that the product and subject-specific labels 
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match the subject’s information (e.g., initials, subject ID number) is essential.  Do not infuse the 
product if the information on the subject-specific label does not match the intended subject.  The 
volume of axicabtagene ciloleucel infused, the thaw start/stop time, and axicabtagene ciloleucel 
administration start/stop time, will all be noted in the subject medical record.  The product must 
not be thawed until the subject is ready for the infusion.  Refer to Section 9 for details and 
instruction on storage, thawing, and administration of axicabtagene ciloleucel.  
6.1.4
Anakinra
Anakinra will be supplied by the investigative site unless otherwise noted. Anakinra is an 
antagonist of the interleukin-1 (IL-1) receptor. Endogenous IL-1 is induced by inflammatory 
stimuli and mediates various immunological responses. Anakinra will be administered 
subcutaneously via pre-filled syringes. The dose, schedule, and route of administration of anakinra 
on this protocol is described in section 6.4.3. Anakinra is currently approved for cryopyrin-
associated periodic syndromes and rheumatoid arthritis. Refer to the most recent version of the 
package insert from the FDA label for specific details surrounding the administration of anakinra.
6.2
Treatment Regimen
6.2.1
Chemotherapy General Instructions
Subjects will receive a non-myeloablative lymphodepleting 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 
lymphodepleting chemotherapy with cyclophosphamide and fludarabine beginning on Day -5 
through Day -3.  The 3-day lymphodepleting chemotherapy regimen may be administered in an 
outpatient setting.  
Subjects should be instructed to drink plenty of liquids during and for 24 hours following the 
chemotherapy.  In general, subjects should be kept well-hydrated but closely monitored to prevent 
fluid overload. 
6.2.2
Axicabtagene Ciloleucel General instructions
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility, followed by daily 
monitoring at a healthcare facility for at least 7 days to monitor for signs and symptoms of CRS 
and neurologic toxicities.  Subjects should be instructed to remain within proximity of the clinical 
study site for at least 4 weeks following axicabtagene ciloleucel infusion.  Subjects and their family 
members/caregivers should be educated on potential CRS and neurologic symptoms, such as fever, 
dyspnea, confusion, aphasia, dysphasia, somnolence, encephalopathy, ataxia, or tremor.  Subjects 
or their family members/caregivers should be instructed to immediately contact the treating 
investigator or seek immediate medical attention if any of these symptoms develop. 
Alternatively, subjects may be hospitalized to receive their axicabtagene ciloleucel infusion and 
be observed for CRS and neurologic toxicities in the hospital setting, if deemed appropriate by the 
investigator.  
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If subjects are hospitalized, subjects should not be discharged from the hospital until all 
axicabtagene ciloleucel-related non-hematological toxicities resolve to ≤ Grade 1 or return to 
baseline.  Subjects may be discharged with non-critical and clinically stable or improving toxicities 
(e.g., renal insufficiency) even if > Grade 1, if deemed appropriate by the investigator.  Subjects 
should remain in a hospital for ongoing axicabtagene ciloleucel-related fever, hypotension, 
hypoxia, or ongoing neurologic toxicities > Grade 1, or if deemed necessary by the investigator. 
All patients should be started on levetiracetam 750mg (PO or IV) twice daily starting day of 
infusion. 
The following medications should be administered approximately 1 hour prior to axicabtagene 
ciloleucel infusion.  Alternatives to the recommendations below should be discussed with the 
medical monitor.

Acetaminophen 650 mg PO

Diphenhydramine (12.5 to 25 mg IV or 25 mg PO)
Central venous access, such as a port or a peripherally inserted central catheter, is required for the 
administration of axicabtagene ciloleucel.  Catheter care, per institutional guidelines, should be 
followed.  Materials and instructions for the thawing, timing, and administering of axicabtagene 
ciloleucel are outlined Section 9.  
Research sites should follow institutional guidelines for the infusion of cell products.
6.2.3
Anakinra General Instructions: 
All subjects will receive anakinra subcutaneous injections at a healthcare facility as in section 
6.4.3.  In brief, patients will receive their first dose 4 hours (+/- 30 min) prior to CAR-T cell 
infusion on day 0 and daily thereafter through D+13. Specific dosing strategy is detailed in section 
6.4.3. 
6.3
Rationale for Study Treatment Dosing 
6.3.1
Rationale for Lymphodepleting Chemotherapy 
Increasing levels of lymphodepleting chemotherapy correlates with clinical responses to adoptive 
cell therapy 38.  Specifically, there appears to be a link between adequate lymphodepletion and 
adoptively transferred T cell expansion and function in pre-clinical models.  The depth and 
duration of the lymphodepletion in preclinical models correlate with anti-tumor activity of the 
adoptively transferred tumor-specific CD8+ T cells 39.  Lymphodepletion may function by 
eradicating cytokine sinks for the transferred cells, eliminating T regulatory cells, or enhancing 
antigen presenting cell activation 40.  Cyclophosphamide and fludarabine is a potent 
lymphodepleting regimen.  Optimizing the doses of cyclophosphamide and fludarabine to improve 
the depth and duration of lymphodepletion may enhance the activity of axicabtagene ciloleucel.  
As per the FDA approved label for axicabtagene ciloleucel, the lymphodepleting chemotherapy 
dose in will be cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) both given for 
3 concurrent days with the target dose of 2 x 106 anti-CD19 CAR T cells/kg.  Cyclophosphamide 
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(500 mg/m2) and fludarabine (30 mg/m2) both given for 3 concurrent days has been studied and 
tolerated in subjects with B cell malignancies 41.  
6.3.2
Rationale for Patient Population to be Included in Phase 2 Study
The proposed patient population mirrors that of Zuma-1, a multicenter phase 2 study of 
axicabtagene ciloleucel in relapsed/refractory large cell lymphoma that led to FDA approval. 
Additionally, based on real-world experience, less stringent eligibility criteria have demonstrated 
comparable outcomes when compared to Zuma-1.
6.3.3
Rationale for using Anakinra
Cytokine release syndrome is driven by a multitude of inflammatory cytokines culminating in 
varying degrees of macrophage activation syndrome and clinical CRS. Currently, IL-6R targeting 
therapy is the standard of care for the management of CRS42. Pre-clinical data suggest that while 
IL-6 is a primary mediator of CRS and possibly neurotoxicity, IL-6R targeting is insufficient to 
prevent these toxicities29,43. CRS and neurotoxicity prophylaxis has been attempted with 
tocilizumab and although lower rates of CRS were observed, high, if not higher rates of Grade 4+ 
neurotoxicity were seen (Locke ASH 2017). IL-1 is a pro-inflammatory cytokine that has been 
targeted in various inflammatory states including rheumatoid arthritis and refractory macrophage 
activation syndromes30,44.  Recent animal data has demonstrated that IL-1 plays a key role in CRS 
and neurotoxicity and may even prime the myeloid compartment for subsequent IL-6 signaling 
and activation. Anakinra dosed subcutaneously can achieve 95% bioavailability with a time to 
peak of 3 to 7 hours, making it ideal for daily prophylactic dosing. Weight based dosing of anakinra 
at 100 mg (if <50kg) vs 200 mg (if ≥50kg) was selected based on currently approved dosing as 
well as substantial clinical data demonstrating safety at doses beyond 200mg45. Daily dosing was 
selected given the short half-life of Anakinra and ongoing cytokine production during CAR-T 
expansion, as seen in pre-clinical animal models and prior clinical trial experience29. 
6.4
T cell Therapy and Anakinra Administration
6.4.1
Lymphodepleting Chemotherapy
Subjects will receive the 3-day lymphodepleting chemotherapy regimen followed by 2-day rest 
period (48 hrs):

IV hydration with 1L of 0.9% NaCl (or isotonic [crystalloid] fluid) given prior to 
cyclophosphamide on the day of infusion followed by:

Cyclophosphamide 500 mg/m2 IV over 60 minutes on Day -5, Day -4, and Day -3 followed 
by:

Fludarabine 30 mg/m2 IV over 30 minutes on Day -5, Day -4, and Day -3 followed by:

An additional 1L of 0.9% NaCl (or isotonic [crystalloid] fluid) at the completion of the 
fludarabine infusion 

Add mesna (sodium 2-mercaptoethanesulfonate) per institutional guidelines 
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6.4.2
Axicabtagene ciloleucel Administration
Axicabtagene ciloleucel will be administered at a target dose of 2 x 106 anti-CD19 CAR T 
cells/kg.  Subjects who receive doses between 1-2 x 106 anti-CD19 CAR T cells/kg will be 
included in the mITT analysis set.  For subjects weighing greater than 100 kg, a maximum flat 
dose of 2 x 108 anti-CD19 CAR T cells will be administered.
As part of the FDA REMS requirement, an appropriate REMS specific medication guide and 
patient identification card will be supplied to the patient prior to axicabtagene infusion.  
6.4.3
Anakinra administration
Anakinra will be administered on days 0 through D+13 as detailed below. 
Anakinra dosing strategy: 

Patients will be given their first dose of Anakinra 4 hours (+/- 30 min) prior to CAR-T 
infusion on day 0.  

Patients will start with subcutaneous Anakinra as a weight based dose.
o
100 mg SQ for subjects <50kg
o
200 mg SQ for subjects ≥50 kg 
Example of 80kg patient 
Day 0 (4 hrs 
prior to CAR-
T infusion)
Day+1
Day+2
Day+3
Day+4
Day+5
Day +6
Anakinra SQ@
200mg
200mg
200mg
200mg
200mg
200mg
200mg
Day+7
Day+8
Day+9
Day+10
Day+11
Day+12
Day +13
Anakinra SQ@
200mg
200mg
200mg
200mg
200mg
200mg
200mg
@ Anakinra will be administered sub-cutaneously per weight based dosing (100mg SQ for subjects <50kg and 200mg 
SQ for subjects ≥50 kg.). Dosing allowed +/- 30 min of 4 hour window. 
Additional doses of anakinra following D+13 will not be provided unless discussed with the 
principal investigator. It is acceptable to give tocilizumab, steroids or 3rd line agents for the 
management of CRS in combination with anakinra per institutional guidelines. 
6.5
General Concomitant Medication and Supportive Care Guidelines
During the course of the study, investigators may prescribe any concomitant medications or 
treatment deemed necessary to provide adequate supportive care except those medications listed 
in Section 6.6. This includes following institutional guidelines for standard management of CRS 
and neurotoxicity, including use of tocilizumab and/or high dose steroids as per appendix A.  
All concurrent therapies, including medications, intubation, dialysis, oxygen, and blood products, 
will be recorded from the date of the informed consent through 1 month after completing treatment 
with axicabtagene ciloleucel.  After 1 month of follow-up, only targeted concomitant medication 
will be collected for 24 months after axicabtagene ciloleucel infusion or disease progression, 
whichever occurs first.  Targeted concomitant medications include gammaglobulin, 
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immunosuppressive drugs, anti-infective drugs, and vaccinations.  
For subjects who are enrolled but not dosed with axicabtagene ciloleucel, concurrent therapies will 
only be recorded from the date of the informed consent through 30 days after the last study specific 
procedure (e.g., leukapheresis, lymphodepleting chemotherapy).  For subjects who are not enrolled 
(e.g., screen failure or not leukapheresed), only concurrent therapies related to any serious adverse 
event(s) will be recorded.
Specific concomitant medication collection requirements and instructions are included in the case 
report form (CRF) completion guidelines.
6.6
Excluded Medications
Corticosteroid therapy at a pharmacologic dose (≥ 5 mg/day of prednisone or equivalent doses of 
other corticosteroids) and other immunosuppressive drugs must be avoided for 7 days prior to 
leukapheresis, and 5 days prior to axicabtagene ciloleucel administration. 
Corticosteroids and other immunosuppressive drugs should also be avoided for 3 months after 
axicabtagene ciloleucel administration, unless used to manage axicabtagene ciloleucel related 
toxicities. Other medications that might interfere with the evaluation of the axicabtagene ciloleucel 
in combination with the investigational product, such as non-steroidal anti-inflammatory agents 
should also be avoided for the same time period unless medically necessary.  
Treatment for lymphoma such as chemotherapy, immunotherapy, targeted agents, radiation, and 
high dose corticosteroid, other than defined/allowed in this protocol, and other investigational 
agents are prohibited, except as needed for treatment of disease progression after the axicabtagene 
ciloleucel infusion.
6.7
Subsequent Therapy 
Subsequent therapy administered after the axicabtagene ciloleucel infusion for a subject’s disease, 
such as non-study specified chemotherapy, immunotherapy, targeted agents, as well as stem cell 
transplant and radiation therapy, will be recorded until the subject completes the long-term follow-
up period, is considered lost to follow-up, withdraws consent, or dies.  
6.8
Duration of Follow Up
Long-term Follow-up Period
All enrolled subjects will be followed in the long-term follow-up period for survival and disease 
status, if applicable.  Subjects will begin the long-term follow-up period after they have completed 
the Month 3 visit of the post treatment assessment period (whether they have responded to 
treatment or went straight to the Month 3 visit due to disease progression) 

Every 3 months (± 2 weeks) through Month 18

Every 6 months (± 1 month) between Month 24 
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All subjects will be consented to the CIBMTR immune effector cell therapy registry at the same 
time as consent for this protocol and data will be reported on standard schedules immediately 
following infusion as required by FDA. Following Month 24 patients, protocol long-term followup 
will continue through the  CIBMTR immune effector cell therapy registry as part of the FDA 
mandated 15-year follow-up period. 
6.9
Criteria for Taking a Participant Off Study
6.9.1
Subject Withdrawal
Subjects have the right to withdraw from the study at any time and for any reason without prejudice 
to their future medical care by the physician or at the institution.
Subjects can decline to continue to receive study required treatment and/or other protocol required 
procedures at any time during the study but continue to participate in the study.  This is referred to 
as partial withdrawal of consent.
If partial withdrawal of consent occurs, the investigator must discuss with the subject the 
appropriate process for discontinuation from investigational product, study treatment or other 
protocol required therapies and must discuss options for continued participation, completion of 
procedures and the associated data collection as outlined in the SOA. The level of follow-up and 
method of communication should also be discussed between the research staff and the subject and 
documented in the source documents.
Withdrawal of full consent from a study means that the subject does not wish to receive further 
protocol required therapy or undergo procedures and the subject does not wish to continue further 
study follow-up.  Subject data collected up to withdrawal of consent will be retained and included 
in the analysis of the study, and where permitted by local regulations, publicly available data (death 
records) can be included after withdrawal of consent.  The investigator is to discuss with the subject 
appropriate procedures for withdrawal from the study. 
As part of the study sites may be asked to conduct searches of public records, such as those 
establishing survival status, if available, to obtain survival data for any subject for whom the 
survival status is not known. Sites may be also asked to also retrieve autopsy reports to confirm 
status of disease at the time of death. 
The investigator and/or sponsor can also decide to withdraw a subject from the investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a whole or 
at any time prior to study completion.
6.9.2
Reasons for Removal from Treatment
Reasons for removal from protocol required investigational products or procedures include any of 
the following:

Adverse Event

Subject request

Product not available
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
Lost to Follow-up

Death

Decision by sponsor
6.9.3
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
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101.
7. DOSING DELAYS/DOSE MODIFICATIONS
In the case of medical or natural emergencies (i.e. holidays, snowstorms, acute infection) occurring 
after initiation of chemotherapy, the infusion of axicabtagene ciloleucel may be delayed up to one 
week at the investigator’s discretion. Subjects who do not initiate chemotherapy within 4 weeks 
of enrollment will be withdrawn; however, their CAR T cell product will be stored for up to 1 year 
if they re-enroll at a later date. No modifications to the doses will be made at the physician level. 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications. A 
copy of the CTCAE version 4.03 can be downloaded from the CTEP website
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. CTCAE 4.03 was 
chosen given its utilization during the Zuma-1 study which will act as a historical control. 
8. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
8.1
Expected Toxicities
To date, the following important risks have been identified with axicabtagene ciloleucel:  CRS, 
neurologic toxicities, infections, and cytopenias.  
Anakinra has been associated with an increased incidence of serious infections (2%) vs. Placebo 
(< 1%) in clinical trials in RA. Treatment with anakinra should not be initiated in patients with 
active infections. Hypersensitivity reactions, including anaphylactic reactions and angioedema, 
have been reported with anakinra. If a severe hypersensitivity reaction occurs, administration of 
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anakinra should be discontinued and appropriate therapy initiated. Patients receiving anakinra may 
experience a decrease in neutrophil counts. Neutrophil counts should therefore be assessed prior 
to initiating anakinra treatment. 
8.2
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. AE reporting will not begin until day 0 of the cellular 
therapy infusion, unless felt to be directly related to a study related procedure during the 
leukapheresis and/or lymphodepletion period. 
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition has increased in severity, frequency, 
and/or duration or has an association with a worse outcome.  A pre-existing condition that has not 
worsened during the study or involves an intervention such as elective cosmetic surgery or a 
medical procedure while on study, is not considered an adverse event.
Interventions for pretreatment conditions (such as elective cosmetic surgery) or medical 
procedures that were planned before study participation are not considered adverse events.  
Hospitalization for study treatment infusions or precautionary measures per institutional policy are 
not considered adverse events.
The term “disease progression” as assessed by measurement of malignant lesions on radiographs 
or other methods should not be reported as adverse events.  Death due to disease progression in 
the absence of signs and symptoms should be reported as the primary tumor type (e.g., B-Cell 
Lymphoma). 
For situations when an adverse event or serious adverse event is due to the disease under 
investigation report the signs and symptoms.  Worsening of signs and symptoms of the malignancy 
under study should also be reported as adverse events in the appropriate section of the CRF. 
The investigators clinical judgment is used to determine whether a subject is to be removed from 
treatment due to an adverse event.  In the event a subject request to withdraw from protocol 
required therapies or the study due to an adverse event, the subject should undergo the procedures 
outlined in the Month 3 visit of the SOA. 
8.2.1
Definition of Serious Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the following serious 
criteria:

Fatal

Life threatening (places the subject at immediate risk of death)

Requires in patient hospitalization or prolongation of existing hospitalization
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
Results in persistent or significant disability/incapacity

Congenital anomaly/birth defect

Other medically important serious event
An adverse event would meet the criterion of “requires hospitalization” if the event necessitated 
an admission to a healthcare facility (eg, overnight stay). 
Events that require an escalation of care when the subject is already hospitalized should be 
recorded as a serious adverse event. Examples of such events include movement from routine care 
in the hospital to the 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.” 
8.3
Adverse Event Characteristics
Adverse Event Assessment
For all AEs, the Investigator must determine both the severity of the AE and the relationship of 
the AE to CAR T cells treatment.

CTCAE term (AE description) and grade:  The descriptions and grading scales found in 
the revise NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 
will be utilized for AE reporting of all toxicities (including neurotoxicity) EXCEPT for 
cytokine release syndrome (CRS), which will use Lee 2014 48 criteria.  All appropriate 
treatment areas should have access to a copy of the CTCAE version 4.03.  A copy of the 
CTCAE version 4.03 can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm

For expedited reporting purposes only: 
o
 AEs for agents utilized in this study should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information 
which is provided. 
o
Other AEs for the protocol that do not require reporting are outlined in the next 
section (Expedited Adverse Event Reporting) and under the sub-heading of 
Protocol-Specific Expedited Adverse Event Exclusions.

Attribution of the AE: 
o
Definite – The AE is clearly related to the study treatment.
o
Probable – The AE is likely related to the study treatment.
o
Possible – The AE may be related to the study treatment.
o
Unlikely – The AE is doubtfully related to the study treatment.
o
Unrelated – The AE is clearly NOT related to the study treatment.
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8.4
Procedures for AE and SAE Collection and Reporting  
8.4.1
Reporting of Adverse Events
The investigator is responsible for reporting adverse events directly related to study related 
procedures following study registration (leukapheresis) which includes mandated biopsies, lumbar 
punctures and/or lab draws. Following enrollment (cellular therapy infusion and initiation of 
anakinra), the investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur from through 3 months after treatment with 
axicabtagene ciloleucel infusion, and investigational product use, are monitored and reported.  
After 3 months, targeted adverse events including (eg, neurological, hematological, infections, 
autoimmune disorders, and secondary malignancies) will be monitored and reported for 24 months 
after treatment with axicabtagene ciloleucel, and investigational product use, or until disease 
progression, whichever occurs first.
For subjects who are enrolled, but do not receive axicabtagene ciloleucel, and/or the investigational 
product, the adverse event reporting period ends 30 days after the last study-specific procedure 
(eg, leukapheresis, lymphodepleting chemotherapy). 
The investigator must address the below for adverse events: 

Adverse event diagnosis or syndrome (if not known, signs or symptoms)

Dates of onset and resolution

Severity

Assessment of relatedness to investigational product, lymphodepleting chemotherapy, 
axicabtagene ciloleucel or study procedures

Action taken
In reviewing adverse events, investigators must assess whether the adverse event is possibly 
related to 1) the investigational product (anakinra), 2) lymphodepleting chemotherapy, 3) 
axicabtagene ciloleucel or 4) 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. In general, abnormal laboratory findings without clinical significance 
(based on the Investigator's judgment) are not to be recorded as adverse events.  However, 
abnormal laboratory findings that result in new or worsening clinical sequelae, require therapy or 
adjustment in current therapy are considered 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.  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.
8.4.2
Reporting of Serious Adverse Events and Non-serious CRS events Grade ≥ 3
The investigator is responsible for reporting all serious adverse events observed by the investigator 
or reported by the subject that occur after signing of the consent through 3 months after the 
axicabtagene ciloleucel infusion.  After 3 months, only serious targeted adverse events (e.g., 
neurological, hematological, infections, autoimmune disorders, and secondary malignancies) 
observed by the investigator or reported by the subject will be reported for 24 months after
axicabtagene ciloleucel infusion or until disease progression, whichever occurs first.   For subjects 
who screen fail or are enrolled but do not receive axicabtagene ciloleucel, and/or anakinra, the 
reporting period for serious adverse events ends 30 days after the last procedure (e.g., screen 
procedure, leukapheresis, lymphodepleting chemotherapy).  
Serious events that the investigator assesses as related to axicabtagene ciloleucel and/or 
anakinra should be reported regardless of the study period.
All serious adverse events and non-serious CRS events ≥ Grade 3 48 must be submitted within 24 
hours following the investigators knowledge of the event using a Medwatch Report Form. For 
all SAE’s, submit Medwatch Report forms to the IND  Sponsor, health authorities per local 
reporting guidelines, and Kite/Gilead (Safety_FC@gilead.com). 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 lymphodepleting therapy, axicabtagene ciloleucel, 
or investigational product then the event leading to death must be recorded as a serious adverse 
event with CTCAE Grade 5.
Death must be reported if it occurs during the serious adverse event reporting period, irrespective 
of any intervening treatment.
Any death occurring after the first dose of chemotherapy, for the purpose of pre-lymphodepletion, 
and within 3 months of the axicabtagene ciloleucel infusion, regardless of attribution to treatment, 
requires expedited reporting within 24 hours.  Any death occurring greater than 3 months after the 
axicabtagene ciloleucel infusion requires expedited reporting within 24 hours only if it is 
considered related to treatment.
8.4.3
Pregnancy and Lactation
There is no relevant clinical experience with axicabtagene ciloleucel and anakinra in pregnant or 
lactating women, and animal reproductive studies have not been performed.  Women of 
childbearing potential must have a negative pregnancy test prior to enrollment because of the 
potentially dangerous effects of the preparative chemotherapy on the fetus.  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 and anakinra administration, 
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the pregnancy must be reported to Safety_FC@gilead.com within 24 hours of awareness.  
Information regarding the pregnancy and/or the outcome may be requested by the key sponsor. 
In addition to reporting any pregnancies occurring during the study, investigators should monitor 
for pregnancies that occur after the last dose of axicabtagene ciloleucel and anakinra through the 
duration of study follow up.
The pregnancy should be reported to the key sponsor contact 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 Safety_FC@gilead.com.
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.
8.4.4
Criteria to Pause Enrollment
As part of its oversight of the study, the SRT also will assess criteria to pause enrollment after 8 
subjects have been treated with axicabtagene ciloleucel and anakinra and have had the opportunity 
to be followed for 30 days.  Enrollment will be paused if any of the following criteria are met 
during the duration of the protocol until the SRT is able to review:
1) Any fatality within the 30 day FDA risk mitigation period (REMS). 
or
2) Subject incidence of the following Grade 4+ axicabtagene ciloleucel-related adverse events 
lasting more than 7 days is > 33%:

Neurologic toxicities per CTCAE version 4.03

CRS (per Lee 2014 criteria) 

Other non-hematological serious adverse event

Infection (treatment-related)
Additional stopping criteria for futility are outlined in section 14.3. 
DF/HCC Adverse Event Reporting Guidelines
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for Human 
Research Studies (OHRS) per the DFCI IRB reporting policy. 
8.5
Reporting to the Food and Drug Administration (FDA)
The Sponsor of this study will be responsible for all communications with the FDA. The Sponsor 
will report to the FDA, any serious adverse event that meets the FDA’s criteria for expedited 
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reporting following the reporting requirements and timelines set by the FDA.
8.6
Reporting to the NIH Office of Biotechnology Activities (OBA)
The Study sponsor will be responsible for all communications with the OBA. The Sponsor will 
report to the OBA, any serious adverse event that meets the OBA’s criteria for expedited reporting 
following the reporting requirements and timelines set by the OBA.
If the dosing site is a recipient of funding from the National Institutes of Health (NIH) for 
recombinant research, the dosing site will ensure that an Institutional Biosafety Committee (IBC) 
is in place that is composed of at least 5 appropriately-qualified members. The IBC will ensure 
that the site conforms to the requirements set forth in the Section IV-B-2 of the NIH Guidelines 
for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, promulgated by the 
NIH/Office of Biotechnology Activities (NIH/OBA). The Investigator will be responsible for 
petitioning the IBC and obtaining approval prior to enrolling any subject in the study. The 
Investigator will also be required to obtain and follow all biohazard safety guidelines promulgated 
by the IBC, and to report all findings as required to the IBC and to NIH/OBA.
This protocol and any accompanying material provided to the subject (such as subject information 
sheets, Informed Consent Form, or descriptions of the study used to obtain informed consent) will 
be submitted by the Sponsor and/or the site to the legally constituted and chartered Institutional 
Biosafety Committee (IBC). The clinical site will be approved by the IBC in accordance with local 
procedures and country specific regulatory requirements. Documentation of IBC approval must be 
in place prior to product shipment to the site. At the discretion of the specific IBC and within 
federal requirements, IBC oversight of individual sites is suggested to be terminated provided (1) 
all subjects at that site have completed dosing by at least 90 days, and (2) all investigational 
materials have been fully accounted for and either returned to the Sponsor, destroyed on site, or 
shipped to a duly licensed destruction facility.
8.7
Reporting to the Institutional Biosafety Committee (IBC)
Participating investigators will register and report on research protocols involving biohazards (i.e., 
recombinant DNA or infectious agents) according to the reporting requirements set by their 
respective IBC. 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC and other appropriate institutional regulatory bodies will review all 
appropriate study documentation in order to safeguard the rights, safety, and well-being of the 
subjects. The study will only be conducted at sites where IRB/IEC and other appropriate 
institutional regulatory body approvals have been obtained. The protocols, informed consents, 
written information given to the subjects, safety updates, annual progress reports, and any revisions 
to these documents will be provided to the IRB/IEC and other appropriate institutional regulatory 
bodies by the Investigator.
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8.8
Reporting to Hospital Risk Management
Participating investigators will report to their local Risk Management office any participant safety 
reports, sentinel events or unanticipated problems that require reporting per institutional policy. 
8.9
Routine Adverse Event Reporting
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions.
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 8.1) and the characteristics of an 
observed AE (Section 8.2) will determine whether the event requires expedited reporting in 
addition to routine reporting.
9. PHARMACEUTICAL INFORMATION
9.1
Axicabtagene ciloleucel
9.1.1
Description
Axicabtagene ciloleucel is an autologous treatment in which the subject’s own T cells, 
obtained by leukapheresis, are genetically engineered ex vivo, by retroviral transduction of 
a construct encoding an anti-C19 chimeric antigen receptor (CAR), to target CD19 
expression on B-cell malignancies. The active ingredients are anti-CD19 CAR T cells. 
Please refer to the most recent FDA product label for additional information.
9.1.2
Storage & Stability
Each axicabtagene ciloleucel infusion bag is individually packed in a metal cassette. 
Axicabtagene ciloleucel is stored in the vapor phase of liquid nitrogen and supplied in a 
liquid nitrogen dry shipper. Axicabtagene ciloleucel must be stored at ≤ 150°C immediately 
after axicabtagene ciloleucel receipt and inspection until the time of thawing and infusion. 
The site will follow standard operating procedures and/or guidelines for logging or other 
documentation practices required for inventory and/or storage of cell therapy products. 

For storage in the vapor phase freezer:
o
Ensure the cassette is stored in a designated location within the chosen vapor 
phase freezer to prevent potential mix-up with other products. 
o
Per institutional SOPs and/or guidelines, log the temperature of the vapor 
phase freezer at the time the axicabtagene ciloleucel is placed in the vapor 
phase freezer. 
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o
Temperature should be monitored by continuous reading of the vapor phase 
freezer temperature. 
o
Temperature monitoring/recording should follow institutional SOPs. 

In the event that the axicabtagene ciloleucel must be temporarily stored in the LN2 
dewar (eg, for transport or for immediate infusion): 
o
Carefully place the cassette back into the rack after axicabtagene ciloleucel 
inspection.
o
Re-insert the rack containing the cassette into the LN2 dewar. 
o
Close the lid over LN2 dewar ensuring that the thermocouple remains intact. 
o
Check the temperature monitor per institutional procedures. 
The axicabtagene ciloleucel must remain stored in the vapor phase freezer, or within the 
LN2 dewar if infusing immediately, until the time of thawing and infusion. 
Axicabtagene ciloleucel is stable at room temperature for up to 3 hours after thaw. 
Please refer to the most recent FDA product label for additional information.
9.1.3
Compatibility
The bag of axicabtagene ciloleucel T cells is compatible for infusion with normal saline. 
No other medications should be administered in the same tubing through the same 
intravenous access line during axicabtagene ciloleucel T cell infusion. Please refer to the 
most recent FDA product label for additional information.
9.1.4
Handling
Axicabtagene ciloleucel must be maintained at ≤ –150°C until ready to thaw. The 
axicabtagene ciloleucel must be thawed prior to infusion. Thawing will be done in 
accordance to SOPs and/or other institutional guidelines but must be done at the location 
specified on the Chain of Custody Site Questionnaire. 
Thawing of axicabtagene ciloleucel should not start until the subject and site staff are 
prepared for infusion. Frozen cells will be thawed at the bedside using a water bath 
maintained at 36°C to 38°C or dry warming device. The bag will be gently massaged until 
the cells have just thawed. There should be no frozen clumps left in the container. If the 
axicabtagene ciloleucel cell product appears to have a damaged or leaking bag, or 
otherwise appears to be compromised, it should not be infused, and should be returned to 
the GMP Facility as specified below. 
Thawed axicabtagene ciloleucel CAR T cells should be administered to the subject at the 
bedside within 60 min of thaw following GCP specific procedures.
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Qualified personnel, familiar with procedures that minimize undue exposure to themselves 
and the environment, should undertake the preparation, handling, and safe disposal of the 
biotherapeutic agent in a self-contained and protective environment. 
Please refer to the most recent FDA product label for additional information.
9.1.5
Availability
The product is commercially available and will be provided by Kite/Gilead. 
9.1.6
Preparation
Axicabtagene ciloleucel is supplied in an infusion bag containing approximately 68 mL of 
frozen suspension of genetically modified autologous T cells in 5% DMSO and 2.5% 
albumin (human). Axicabtagene ciloleucel comprises a suspension of 2 × 106 CAR-
positive viable T cells per kg of body weight, with a maximum of 2 × 108 CAR-positive 
viable T cells in approximately 68 mL. Please refer to the most recent FDA product label 
for additional information.
9.1.7
Administration
Axicabtagene is for autologous use only. Infusions should be performed per institutional 
guidelines and SOPs for the infusion of IEC products, of note:

Do NOT use a leukodepleting filter. 

Central venous access is recommended for the infusion of axicabtagene ciloleucel. 

Confirm the patient’s identity matches the patient identifiers on the axicabtagene 
ciloleucel product bag. 

Prime the tubing with normal saline prior to infusion. 

Infuse the entire contents of the axicabtagene ciloleucel bag within 30 minutes by 
either gravity or a peristaltic pump.

Gently agitate the product bag during axicabtagene ciloleucel infusion to prevent 
cell clumping. 

After the entire content of the product bag is infused, rinse the tubing with normal 
saline at the same infusion rate to ensure all product is delivered. 

Prior in infusion, confirm that two doses of tocilizumab are available for the patient 
during the recovery period. 
Axicabtagene ciloleucel contains human blood cells that are genetically modified with 
replication incompetent retroviral vector. Follow universal precautions and local biosafety 
guidelines for handling and disposal to avoid potential transmission of infectious diseases. 
Please refer to axicabtagene ciloleucel IB label and institutional protocols for additional 
information.  
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9.1.8
Ordering
Ordering refers to the physician order for initiation of lymphodepleting chemotherapy and 
infusion of manufactured cellular therapy product. The physician investigator will provide 
such order through their protocol specific order set in their standard electronic ordering 
system. Drug ordering for manufacturing is initiating through the use of the Kite 
Clinical system during the enrollment (screening) portion of the study. This will provide 
the subject ID, registration (triggering the drug order) and oversight and management of 
the study from a cell journey perspective.
9.1.9
Accountability
Axicabtagene ciloleucel accountability and traceability is ultimately the responsibility of 
the Investigator and Sponsor. However, this responsibility may be delegated to suitably 
qualified personnel listed on Food and Drug Administration (FDA) Form 1572 who has 
had appropriate study-specific training and whose name has been appropriately listed on 
the Delegation of Responsibility Log for this task. 
Detailed records will be maintained to allow for accurate accountability of the axicabtagene 
ciloleucel as per applicable sponsor and clinical site procedures. These records will include 
details of storage of axicabtagene ciloleucel; transfer axicabtagene ciloleucel from the 
transduction facility, administration to subjects, and disposal of remaining materials. 
For any remaining drug product after infusion or drug product that cannot be administered 
due to triggering of stopping rules or other reasons, drug product will be kept cryopreserved 
in the vapor phase of liquid nitrogen until further instruction by the sponsor. 
9.1.10 Destruction and Return
All material containing axicabtagene ciloleucel will be treated and disposed of as 
hazardous waste in accordance with governing regulations and clinical site procedures.
9.2
Anakinra
9.2.1
Description
Anakinra is a recombinant, nonglycosylated form of the human interleukin-1 receptor 
antagonist (IL-1Ra). Anakinra differs from native human IL-1Ra in that it has the addition 
of a single methionine residue at its amino terminus. Anakinra consists of 153 amino acids 
and has a molecular weight of 17.3 kilodaltons. It is produced by recombinant DNA 
technology using an E coli bacterial expression system. Please refer to the most recent FDA 
product label for additional information.
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9.2.2
Storage, Stability & Handling
Anakinra should be stored in the refrigerator at 2° to 8°C (36° to 46°F). DO NOT 
FREEZE OR SHAKE. Protect from light. Please refer to the most recent FDA product 
label for additional information. 
9.2.3
Preparation
Anakinra is supplied in single-use preservative free, prefilled glass syringes with 27 gauge 
needles. Each prefilled glass syringe contains 100 mg of anakinra per 0.67 mL. The full 
syringe contains 100 mg anakinra. Please refer to the most recent FDA product label for 
additional information.
9.2.4
Administration
Anakinra should be injected subcutaneously 4 hours (+/- 30 mins) prior to T cell infusion. 
The prescribed dose of Anakinra should be administered according to the instructions for 
use and any unused portions discarded. After administration of Anakinra it is essential to 
follow the proper procedure for disposal of syringes and any residual drug. See the 
“Information for Patients” insert for detailed instructions on the handling and injection of 
Anakinra. 
Do not use Anakinra beyond the expiration date shown on the carton. Visually inspect the 
solution for particulate matter and discoloration before administration. There may be trace 
amounts of small, translucent-to-white amorphous particles of protein in the solution. The 
prefilled syringe should not be used if the solution is discolored or cloudy, or if foreign 
particulate matter is present. If the number of translucent-to-white amorphous particles in 
a given syringe appears excessive, do not use this syringe. Please refer to the most recent 
FDA product label for additional information.
9.2.5
Ordering
Anakinra will be provided free of charge to patients. Pharmacy should place the order 
using the MGH -supplied cost center number. 
9.2.6
Accountability
Anakinra accountability and traceability is ultimately the responsibility of the Investigator 
and Sponsor. However, this responsibility may be delegated to suitably qualified personnel 
listed on Food and Drug Administration (FDA) Form 1572 who has had appropriate 
study-specific training and whose name has been appropriately listed on the Delegation of 
Responsibility Log for this task. 
Detailed records will be maintained to allow for accurate accountability of the anakinra as 
per applicable sponsor and clinical site procedures. These records will include details of 
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storage of anakinra; transfer anakinra from the transduction facility, administration to 
subjects, and disposal of remaining materials. 
For any remaining drug product after infusion or drug product that cannot be administered 
due to triggering of stopping rules or other reasons, drug product will be kept cryopreserved 
in the vapor phase of liquid nitrogen until further instruction by the sponsor. 
9.2.7
Destruction and Return
Unused/expired doses of anakinra will be destroyed per pharmacy institutional standards. 
Please refer to the most recent FDA product label for additional information.
10. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES
10.1
Biomarker Studies
N/A, no biomarker studies.
10.2
Laboratory Correlative Studies
Biomarker analysis will be performed on blood and tumor samples to evaluate predictive and 
pharmacodynamic markers for axicabtagene ciloleucel.  Prognostic markers specific for large B-
cell lymphoma and related to the tumor immune environment may also be evaluated in archived 
and fresh tumor biopsies. 
The presence, expansion, persistence, and immunophenotype of transduced anti-CD19 CAR T 
cells will be monitored in the blood primarily by PCR analysis, complemented by flow 
cytometry.  Expansion and persistence in peripheral blood will also be monitored by a CD19 CAR 
specific quantitative polymerase chain reaction assay (qPCR).  
Levels of serum cytokines will be evaluated in serum to characterize the pharmacodynamic and 
safety profile of axicabtagene ciloleucel in combination with anakinra.  The following pro-
inflammatory, homeostatic and immune modulating cytokines may be included in the panel:  IL-
6, IL-15, IL-17a, TNF-, GM-CSF, IFN-, IL-12p40/p70 and IL-13; immune effector molecules: 
Granzyme A, B and Perforin; correlates of acute phase response: CRP and SAA; Chemokines 
MIP-1, MIP-1β, MCP-1, IP-10, and IL-8.  In addition, IL1Ra, IL2Rα and ferritin, will also be 
measured.   
Lumbar punctures for collection of CSF samples will be performed at the following time points:  
after eligibility is confirmed and prior to start of lymphodepleting chemotherapy, after 
axicabtagene ciloleucel infusion on Day 5 (± 3 days), and at the Week 4 visit (± 3 days).  Collection 
of CSF samples will enable measurement of baseline cytokine levels prior to axicabtagene 
ciloleucel infusion.  Changes in levels of cytokines after axicabtagene ciloleucel infusion will be 
measured at the time of peak CAR T-cell expansion (Day 5) and at Week 4 when it is anticipated 
that cytokine levels would return to baseline levels.  Infiltration of CAR T cells will also be 
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assessed by flow cytometry in post-axicabtagene ciloleucel infusion CSF samples.  Exploratory 
analysis of cells, analytes, or immune cell markers within the CSF will be analyzed in conjunction 
with the clinical data to better understand the pathogenesis of neurologic toxicities.
Additional translational samples of PBMC, serum cytokines, tissue, bone marrow, and CSF may 
be taken for additional genomics sequencing, RNA expression profiling, cytokine/biomarker 
analysis and flow cytometry, and tumor profiling. This may also include tumor samples for 
genomic, transcriptional and protein expression analysis. Samples will be analyzed at the MGH 
Immuno Monitoring Laboratory. 
11. STUDY CALENDAR
Assessments must be performed prior to administration of any study agent. Study assessments and 
agents should be administered within + 3 days of the protocol-specified date, unless otherwise 
noted.
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.  
11.1
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.
11.2
Demographic Data
Demographic data will be collected to include sex, age, race, ethnicity, and country of enrollment 
to study their possible association with subject safety and treatment effectiveness.
11.3
Medical and Treatment History
Relevant medical history prior to the start of adverse event reporting will be collected.  Relevant 
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medical history is defined as data on the subject’s concurrent medical condition that would be 
typically shared in a referral letter.  All findings will be recorded in the CRFs.
In addition to the medical history, all history related to the subject’s disease, treatment and 
response to treatment will be collected and must date back to the original diagnosis.
For subjects who are being referred from another clinic or institution to the participating research 
center, copies from the subjects chart should be obtained.
11.4
Physical Exam, Vital Signs, Performance Status
Physical and neurological 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. 
Vital signs including blood pressure, heart rate, oxygen saturation, and temperature will be 
monitored before and after the axicabtagene ciloleucel infusion and then routinely per 
institutional guidelines.  If the subject has a fever (temperature 38.0oC or greater), vital signs will 
be monitored more frequently as clinically indicated.
Performance status as measured by the ECOG scale will be performed to quantify the subject’s 
general well-being and ability to perform activities of daily life.
11.5
Neurological Assessment 
Neurological assessments will include ICE scores as per the schedule of assessments. In addition, 
standardized assessments using IPCG guidelines will be used in collaboration with neuro-
oncology. A full neurological assessment will be completed during screening to establish a 
baseline.  Subsequent assessments will be performed before axicabtagene ciloleucel administration 
at screening, Month 1 and Month 3 visits. 
11.6
Cardiac Function 
Each subject’s cardiac function, as measured by ECHO will be assessed during the screening 
period to confirm study eligibility.  Both LVEF and pericardial effusion will be assessed prior to 
study entrance by ECHO.  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. To establish a baseline, an ECG will also be performed during the screening period. 
11.7
Magnetic Resonance Imaging
Each subject will undergo a screening brain MRI to rule out CNS metastasis during the screening 
period of the study.  Evaluation of any new onset of ≥ Grade 2 neurologic toxicities should include 
a brain MRI as described in Section 6.4. 
11.8
Bone Marrow Biopsy
Bone marrow aspirate/biopsy may be performed at screening if not previously performed to assess 
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bone marrow involvement.  For subjects with a potential complete response to axicabtagene 
ciloleucel, a follow-up bone marrow aspirate/biopsy will be performed in subjects presenting with 
bone marrow involvement prior to therapy or if new abnormalities in the peripheral blood counts 
or blood smear cause clinical suspicion of bone marrow involvement with lymphoma after 
treatment.  To confirm a complete response, the bone marrow aspirate and biopsy must show no 
evidence of disease by morphology or if indeterminate by morphology it must be negative by 
immunohistochemistry.  Refer to Section 12 and Appendix B for treatment response assessment 
requirements per the revised IWG Response Criteria for Malignant Lymphoma 1.  Bone marrow 
aspirate/biopsy should also be considered to evaluate HLH.  A portion of the bone marrow sample 
collected to evaluate HLH or other toxicities should be submitted to the central laboratory as 
outlined in the central laboratory manual. 
11.9
Lumbar Puncture
Subjects with symptoms of central nervous system malignancy such as new onset severe 
headaches, neck stiffness, or any focal neurologic findings on physical exam will have lumbar 
puncture performed at the screening visit for examination of cerebral spinal fluid.  In addition, 
lumbar puncture may be performed as applicable for subjects with new onset of ≥ Grade 2 
neurologic toxicities after axicabtagene ciloleucel infusion (see Section 8).
Lumbar punctures for the collection of CSF samples will be performed pre- and post-axicabtagene 
ciloleucel infusion at times outlined in the SOA.  Samples will be submitted to the central 
laboratory as outlined in the central laboratory manual.  Adequate platelet support should be 
provided prior to performing a lumbar puncture (e.g. platelet >50,000/mm3). Lumbar punctures 
will only be performed when felt to be clinically safe by investigator. 
11.10 Laboratory
The below samples will be collected at the time points indicated in the SOA.  Additional samples 
(eg, blood, urine, CSF, tissue, etc) may be collected as needed for further safety testing.
Local lab analysis:  

Sodium (Na), potassium (K), chloride (Cl), total CO2 (bicarbonate), creatinine, glucose, 
blood urea nitrogen (BUN) or urea (if BUN test cannot be analyzed by the local lab), 
albumin, calcium total, magnesium total (Mg), inorganic phosphorus, alkaline 
phosphatase, ALT/GPT, AST/GOT, total bilirubin, direct bilirubin, LDH, uric acid

C-reactive protein (CRP) 

Complete Blood Count (CBC) with Differential 

A urine or serum sample will be collected and assessed locally for females of childbearing 
potential.  If the screening pregnancy test is positive, the subjects should not be enrolled.  
If a standard of care pregnancy test is collected during the course of the study, and the 
result is positive, the investigator should contact the Kite Pharma medical monitor for 
instructions.  If a female partner of a male subject becomes pregnant during the conduct of 
the study, it must be reported by contacting Kite Pharma Medical Monitor for instructions. 
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
Additional blood draws for PBMC and serum, as well as CSF, bodily fluids and tissue 
may be collected and stored locally for subsequent translational research studies to 
include, but not limited to, cytokine analysis, FLOW and expression phenotyping, 
DNA/RNA sequencing, IHC/RNA ISH, and/or correlative studies. 
Central lab analysis:

Blood draws for PBMC (lymphocyte subsets, RCR, and axicabtagene ciloleucel levels) 
and cytokine analysis will be performed at intervals outlined in the SOA.  

Serum samples may also be evaluated centrally for anti-axicabtagene ciloleucel antibodies.
o
Anti-axi-cel antibodies will be examined at baseline, days 7-14, 28, 60, and 90 after the 
first administration of the drug and 4 weeks post study. If any anti-drug antibodies are 
detected in patients, monitoring should continue until patient antibody levels return to the 
baseline. 

Archived tumor tissue
o
If possible, fresh tumor samples will be collected for central pathology review and 
evaluation of prognostic markers specific for large B-cell lymphoma and pertaining to the 
tumor immune environment.  Additional analysis may include CD19 expression, gene 
expression profiling, and analysis of tumor-specific DNA alterations.  Remaining 
tumor samples may be stored for future exploratory analysis of DNA (somatic 
mutations), RNA, or protein markers. In the event that a fresh biopsy is not possible, 
or would significantly delay treatment, archival tissue is acceptable. If no archival 
tissue is available and it is not clinically safe to get a fresh biopsy, biopsy will be 
deferred. 

CSF and possibly bone marrow samples will also be collected and analyzed at the central 
laboratory as outlined in the schedule of assessments and per Section 10.

See central laboratory manual for details on sample collection, processing, and shipping 
instructions. 
11.11 Biomarkers and Correlative Analyses
Laboratory Correlative analysis will be performed on blood and tumor samples to evaluate 
predictive and pharmacodynamic markers for axicabtagene ciloleucel and described in Section 
10.2 
11.12 Description of Study Periods
11.12.1
 Screening
The screening period begins on the date the subject signs the IRB/IEC approved ICF and continues 
through confirmation of enrollment.  Informed consent must be obtained before completion of any 
non-standard of care study specific procedures.  Procedures that are part of standard of care are 
not considered study specific procedures and may be performed prior to obtaining consent and 
used to confirm eligibility.  Confirmation of this data must occur within the time allowance as 
outlined below and in the SOA.
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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 3 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, or any focal neurologic findings on physical exam 
will have lumbar puncture for examination of cerebral spinal fluid.

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

ECOG performance status 

Neurocognitive function post infusion per standard IPCG guidelines.

ECG

ECHO/MUGA for LVEF and pericardial effusion assessment
o
An ECHO/MUGA 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. 

 If PET CT is performed > 28 days prior to the initiation of lymphodepleting 
chemotherapy or if subject receives any anti-cancer therapy between 
screening and lymphodepleting chemotherapy, the scans must be repeated 
to establish a new baseline.  PET CT should be performed as close to 
enrollment as possible. 

Bone marrow aspirate/biopsy as needed (if not done at initial diagnosis or between 
diagnosis and screening)

Labs 
o
Chemistry panel
o
CBC with differential
o
β-HCG pregnancy test (serum or urine) on all women of child-bearing potential

Serious Adverse Event reporting (refer to Section 8 for safety reporting guidelines)

Concomitant medications documentation and previous cancer treatment history

Once eligibility confirmed, collection of archived or fresh tumor sample, as well as CSF 
samples. 

Lumbar puncture for collection of CSF samples to be performed after eligibility confirmed 
and prior to start of lymphodepleting chemotherapy
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11.12.2
 Rescreening
Subjects who are unable to complete or meet the eligibility criteria during the 28-day screening 
period will be permitted to rescreen one time.  Subjects will retain the same subject 
identification number assigned at the original screening.  If rescreening occurs within 28 
days of the signing of the original informed consent, only the procedure(s)/assessment(s) that 
did not originally meet the eligibility criteria needs to be repeated; all other initial screening 
procedures/assessments do not need to be repeated.  If rescreening occurs, or leukapheresis 
is delayed, more than 28 days from the signing of the original informed consent, subjects 
must be reconsented and repeat all screening procedures/assessments.
11.12.3
 Enrollment/Leukapheresis
Before leukapheresis commences, the following criteria must be met.  If criteria are not met, 
leukapheresis must be delayed until the event resolves.   

No evidence or suspicion of an infection

Corticosteroid therapy at a pharmacologic dose (≥5 mg/day of prednisone or equivalent 
doses of other corticosteroids) and other immunosuppressive drugs must be avoided for 7 
days prior to leukapheresis. 
Once a subject commences leukapheresis, the subject will be considered enrolled into the study.  
The following procedures/requirements will occur within 24hrs of leukapheresis collection day 
and as outlined in the SOA:

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

Weight 

Labs (to be drawn prior to leukapheresis, on the day of or day before leukapheresis)
o
Chemistry panel
o
CBC with differential
o
C-reactive protein (CRP)
o
Anti-CD19 CAR T cells
o
Lymphocyte subsets 
o
Cytokine levels
o
Translational lab collection

Leukapheresis

Adverse/Serious Adverse Event reporting 

Concomitant medications documentation 
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11.12.4
 Bridging Therapy 
If prescribed, bridging therapy must be administered after enrollment and completed prior to 
initiating lymphodepleting chemotherapy per the specifications outlined in Section 6 for bridging 
therapy.
11.12.5
 Lymphodepleting  Chemotherapy Period 
If PET-CT will be older than 28 days at the initiation of lymphodepleting chemotherapy or if the 
subject receives any anti-cancer therapy with therapeutic intent (eg, radiation, supraphysiologic 
doses of steroids, chemotherapy) between the last PET-CT and initiation of lymphodepleting  
chemotherapy, the PET-CT must be repeated to establish a new baseline.
Before lymphodepleting chemotherapy commences, the following criteria must be met.  If these 
criteria are not met, then lymphodepleting chemotherapy must be delayed until these events 
resolve.
No evidence or suspicion of infection 
No clinically evident changes in bone marrow, renal, hepatic, pulmonary, or cardiac 
function since date of informed consent
No acute neurologic toxicity > Grade 1 (with the exception of peripheral neuropathy)
In addition, if any of the following are known to occur, a delay in lymphodepleting chemotherapy 
may be required.  Contact the Kite Pharma medical monitor before lymphodepleting chemotherapy 
commences for guidance.
Temperature is ≥ 38.0ºC within 48 hours prior to lymphodepleting chemotherapy.  
Unexplained fever requires pan-culture, respiratory viral panel, chest computed 
tomography (CT), and any additional symptom-directed workup to rule out occult infection. 
The following procedures will be completed during Day –5 to Day –3 at the time points outlined 
in the SOA:

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

Labs (to be drawn prior to chemotherapy)
o
Chemistry Panel 
o
CBC with differential
o
Translational lab collection

Fludarabine and cyclophosphamide administration

Adverse/Serious Adverse Event reporting 

Concomitant medications documentation 
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11.12.6
 Treatment Period
Corticosteroid therapy at a pharmacologic dose (≥ 5 mg/day of prednisone or equivalent doses of 
other corticosteroids) and other immunosuppressive drugs must be avoided for 5 days prior to 
axicabtagene ciloleucel administration. 
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).
•
No clinically evident changes in bone marrow, renal, hepatic, pulmonary, or cardiac 
function since screening
•
Serum creatinine < 2 x ULN
•
No acute neurologic toxicity > Grade 1 (with the exception of peripheral neuropathy)
In addition, if any of the following are known to occur, a delay in axicabtagene ciloleucel infusion 
may be required.  Contact the Kite medical monitor before axicabtagene ciloleucel infusion 
commences for guidance.

Temperature is ≥ 38.0ºC within 48 hours prior to axicabtagene ciloleucel infusion.  
Unexplained fever requires pan-culture, respiratory panel, chest X-ray, and any additional 
symptom-directed workup to rule out occult infection.

If any screening assessments or procedures are repeated between leukapheresis and the 
axicabtagene ciloleucel infusion and results are outside the eligibility criteria (Section 3; 
with the exception of lymphodepleting chemotherapy-induced cytopenias)
Should an event not meet these criteria immediately prior to receiving axicabtagene ciloleucel, the 
axicabtagene ciloleucel infusion must be delayed until the event resolves.  If the axicabtagene 
ciloleucel infusion is delayed > 2 weeks, lymphodepleting chemotherapy must be repeated.  
All subjects will receive axicabtagene ciloleucel infusion at a healthcare facility followed by daily 
monitoring at a healthcare facility for at least 7 days to monitor for signs and symptoms of CRS 
and neurologic toxicities.  Alternatively, subjects may be hospitalized to receive their axicabtagene 
ciloleucel infusion and be observed for CRS and neurologic toxicities in the hospital setting, if 
deemed appropriate by the investigator. 
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If subjects are hospitalized, subjects should not be discharged from the hospital until all 
axicabtagene ciloleucel related non-hematological toxicities return to ≤ Grade 1 or return to 
baseline.  Subjects may be discharged with non-critical and clinically stable or improving toxicities 
(eg, renal insufficiency) even if > Grade 1, if deemed appropriate by the investigator.  Subjects 
should remain in a hospital for ongoing axicabtagene ciloleucel-related fever, hypotension, 
hypoxia, or ongoing central neurologic toxicities > Grade 1, or if deemed necessary by the 
investigator.
Subjects should be instructed to remain within proximity of the clinical study site for at least 
4 weeks following axicabtagene ciloleucel infusion.  Subjects and their family members/caregivers 
should be educated on potential CRS and neurologic symptoms, such as fever, dyspnea, confusion, 
aphasia, dysphagia, somnolence, encephalopathy, ataxia, or tremor.  Subjects or their family 
members/caregivers should be instructed to immediately contact the treating investigator or seek 
immediate medical attention if any of these symptoms develop.
During this period, the following procedures will be completed at the time points outlined in the 
SOA:

Neurological assessment for subjects to include ICANS consensus criteria (ICE 
scores). 

Vital signs including blood pressure, heart rate, oxygen saturation, and temperature, daily 
at a health care facility for at least 7 days 

Labs (before axicabtagene ciloleucel infusion, as described in the SOA)
o
Chemistry Panel 
o
CBC with differential
o
Lymphocyte subsets 
o
Cytokine levels 
o
Anti-CD19 CAR T cells
o
RCR analysis

Infusion of axicabtagene ciloleucel

Administration of weight based anakinra (<50kg = 100mg, ≥50kg =200mg) as detailed in 
section 6.4.3. 

Lumbar puncture as described in the SOA when clinically appropriate.  

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 regard to CRS/neurologic toxicities.  It is, therefore, 
recommended that CRP, ferritin, and LDH (if elevated at baseline) be monitored daily starting at 
Day 0 and for at least 7 days at a healthcare facility. In addition, lactate should be monitored as 
clinically indicated.   
11.12.7
Post-treatment Assessment Period
After completing axicabtagene ciloleucel infusion and completing the minimum 7-day 
observation period, all subjects will be followed in the post-treatment assessment period.  
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Counting from Day 0 (axicabtagene ciloleucel infusion), subjects will return to the clinic at the 
following intervals.

Week 2 (± 2 days)

Week 3 (± 2 days) 

Week 4 (± 3 days)

Month 2 (± 1 week)

Month 3 (± 1 week)
Subject will allow key sponsor contacts to continue to access medical records so that information 
related to subjects health condition and initial treatment response may be obtained.  The following 
procedures will be completed for subjects as outlined in the SOA:

Neurological assessment for subjects to include ICANS consensus criteria (ICE 
scoring). 

PET-CT for disease assessment:  If the PET-CT is not of high enough resolution, the scan 
must be repeated.  Refer to the imaging charter for detailed instructions.

As applicable, bone marrow aspirate/biopsy to confirm response (i.e., for subjects 
presenting with bone marrow involvement prior to therapy or if new abnormalities in the 
peripheral blood counts or blood smear cause clinical suspicion of bone marrow 
involvement with lymphoma after treatment)

Physical exam 

Vital signs, including blood pressure, heart rate, oxygen saturation, and temperature

Labs
o
Chemistry Panel 
o
CBC with differential
o
β-HCG pregnancy test (serum or urine) on all women of child-bearing potential
o
Cytokine levels
o
Lymphocyte subsets 
o
Anti-CD19 CAR T cells
o
RCR analysis 
o
Translational lab collection

Discontinue levetiracetam as clinically indicated.  

Lumbar puncture for collection of CSF samples at Week 4 (± 3 days)

Adverse/Serious Adverse Event reporting (refer to Section 8 for safety reporting 
guidelines)

Concomitant medications documentation 
If a subject is admitted to the hospital during the 7-day observation period, discharged, and is 
subsequently re-admitted to the hospital with any axicabtagene ciloleucel related adverse 
event(s), the following labs will be collected on the day of hospital re-admission and then 
weekly through and including on the day of discharge:

PBMCs (anti-CD19 CAR T cells)
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
Cytokines 
At any time during the post treatment assessment period, if a subject progresses and is either not 
eligible for re-treatment or chooses not to pursue re-treatment, the subject will proceed directly to 
the Month 3 visit and be followed for survival, subsequent therapy and disease outcomes in the 
long term follow-up period.  A PMBC (for anti-CD19 CAR T cells) and serum sample (for 
cytokine evaluation) should be collected at the time of progression, prior to starting any 
subsequent anti-cancer therapy.
11.12.8
Long-term Follow-up Period
All enrolled subjects will be followed in the long-term follow-up period for survival and disease 
status, if applicable.  Subjects will begin the long-term follow-up period after they have completed 
the Month 3 visit of the post treatment assessment period (whether they have responded to 
treatment or went straight to the Month 3 visit due to disease progression) 

Every 3 months (± 2 weeks) through Month 18

Every 6 months (± 1 month) between Month 24 
The following procedures will be completed for subjects who are enrolled and receive 
axicabtagene ciloleucel at the time points outlined in the SOA:

Physical exam

PET-CT/ Disease assessment through 24 months or until disease progression, whichever 
occurs first. If subject’s disease has not progressed by Month 24, disease assessments will 
continue to be performed per institutional standard of care. 

Survival status

Labs 
o
CBC with differential 
o
Anti-axicabtagene ciloleucel antibodies (refer to Section 10.10)
o
Lymphocyte subsets 
o
Anti-CD19 CART-cell levels
o
Replication-competent retrovirus (RCR) analysis 
o
Immune Monitoring Laboraotory collections

Subsequent therapy for the treatment of NHL 

Refer to Sections 8.4 for targeted adverse/serious adverse event reporting
o
Including neurological, hematological, infections, autoimmune disorders, and 
secondary malignancies 

Targeted concomitant medication documentation (for 24 months or until disease 
progression, whichever occurs first)
o
Including 
gammaglobulins, 
immunosuppressive 
drugs, 
anti-infectives, 
and 
vaccinations
Subjects may be contacted by telephone to confirm survival status and report targeted concomitant 
medication use.
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If a subject progress in the LTFU phase, the subject will continue to be followed for survival status 
and subsequent therapy for the treatment of NHL.  A PMBC sample (for anti-CD19 CAR T cells) 
and serum (for cytokine evaluation) should be collected at the time of progression, prior to starting 
any subsequent anti-cancer therapy.
The following procedures/assessments will be completed for subjects who are enrolled, but do not 
receive axicabtagene ciloleucel or anakinra, 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 and concomitant medication documentation 
until 30 days after last procedure (e.g., leukapheresis, lymphodepleting  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. 
All subjects will be consented to the CIBMTR immune effector cell therapy registry at the same 
time as consent for this protocol and data will be reported on standard schedules immediately 
following infusion as required by FDA. Following Month 24 patients, protocol long-term followup 
will continue through the  CIBMTR immune effector cell therapy registry as part of the FDA 
mandated 15-year follow-up period.
11.12.9
Retreatment 
Subjects may have an option to receive a second course of lymphodepleting chemotherapy and 
axicabtagene ciloleucel without administration of anakinra prophylaxis under the following 
conditions:

Subject had no better than a PR 

Subjects disease subsequently progresses

CD19 tumor expression confirmed locally by biopsy after disease progression and prior to re-
treatment.  A portion of the biopsy should be sent to the central laboratory. 

Subject continues to meet the original study eligibility criteria with exception of prior
axicabtagene ciloleucel use in this study.  Screening assessments should be repeated if 
clinically indicated, as determined by the investigator, to confirm eligibility.

Subject has not received subsequent therapy for the treatment of lymphoma

Toxicities related to lymphodepleting chemotherapy (fludarabine and cyclophosphamide), 
with the exception of alopecia, have resolved to ≤ Grade 1 or returned to baseline prior to re-
treatment

There is a second infusion available from the patient’s original manufacturing. 
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The decision to administer re-treatment should be made in consultation with the Sponsor.  In 
addition, a discussion regarding benefits and risks of retreatment and including the potential need 
to undergo leukapheresis a second time for the manufacturing of axicabtagene ciloleucel should 
occur with the subject prior to performing any study related procedures or treatment.  This 
conversation should also be recorded in the subject’s source document.  
A maximum of 1 retreatment course may occur per subject.  Subjects who are retreated will follow 
the same treatment schedule and procedural requirements per the initial treatment. 
Allowance for retreatment is based on clinical experience reported in the 2 studies conducted at 
the pediatric 49 and Surgery Branch 50 of the NCI where 6 subjects in total have been re-treated 
upon progression.  Three of the re-treated subjects (indolent lymphoma/leukemia) experienced 
durable responses to retreatment after an initial response and disease progression. Given limited 
experience with re-treatment, re-infusions will be censored from the primary end-point and 
efficacy outcomes will be analyzed separately.
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Table 2.
Schedule of Assessments
Procedures
Screening
Enrollment/
Leukapheresis
Lymphodepleting 
Chemotherapy
Period
IP 
Administration 
Period
Post Treatment Follow-up
(each visit calculated from Day 0)
Day
Within 28 days 
of enrollment
Within approx. 
5 days of 
eligibility 
confirmation
-5
-4
-3
-
2
-1
0
+1 -+13
Week 2
(± 2 days)
Week 
3
(± 2 
days)
Week 
4
(± 3 
days)
Month 2
(± 1 
week)
Month 
3
(± 1 
week)
Medical history 
X
ECOG Performance Status
X
X
X
Neurological assessment per standard 
IPCG guidelines
X
X
X
X
Neurotoxicity assessment per CTCAE v4.03 
11,12
X
X
X
X
X
X
X
ICANS Consensuses grading of neurotox 
(ICE score required)11
X
X
X
X
X
X
X
ECG
X
ECHO
X
Archival/Fresh tumor1
X
Brain MRI
X
PET-CT/ disease assessment 2, 14
X
X
X
Physical exam
X
X
X
X
X
Vital signs (BP, HR, O2 sat, temp)
X
X
X
X
X
X
X
X
X
X
X
Weight (plus Height at screening)
X
X
Pregnancy test (serum or urine)
X
X
Lumbar Puncture6
X
X
X
Blood draw for Chemistry panel
X
X
X
X
X
X
X
X
X
X
X
Blood draw for CBC w/differential
X
X
X
X
X
X
X
X
X
X
X
Blood draw for C-reactive protein (CRP)
X
Blood draw for Anti-axicabtagene ciloleucel
antibodies 3
X
X
X
Blood draw for Lymphocyte subsets
X
X
X
X
Blood draw for Cytokines 7, 10, 13
X
X
QOD 10
X
X
Blood draw for Anti-CD19 CAR T cells7, 13
X
X
Day +3, +7
X
X
X
X
Blood draw for RCR analysis 4 
X
X
Blood draw for translational lab collection13
X
X
QOD
X
X
X
X
X
Blood draw for minimial residual disease 
testing 
X
X
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Procedures
Screening
Enrollment/
Leukapheresis
Lymphodepleting 
Chemotherapy
Period
IP 
Administration 
Period
Post Treatment Follow-up
(each visit calculated from Day 0)
Day
Within 28 days 
of enrollment
Within approx. 
5 days of 
eligibility 
confirmation
-5
-4
-3
-
2
-1
0
+1 -+13
Week 2
(± 2 days)
Week 
3
(± 2 
days)
Week 
4
(± 3 
days)
Month 2
(± 1 
week)
Month 
3
(± 1 
week)
Leukapheresis 
X
Fludarabine/Cyclophosphamide
X
X
X
Axicabtagene ciloleucel infusion IV
X
Anakinra8
Day 0 through day +13 .
Levetiracetam9
Starting on Day 0
Adverse events/ Concomitant medication
X
X
1  Archival/Fresh tumor sample: Either FFPE tumor block or up to 20 unstained slides. Either archived or  a fresh tumor samples (either will suffice) will be submitted to central laboratory after eligibility 
has been confirmed and prior to start of lymphodepleting chemotherapy. See central laboratory manual for details
2 PET-CT (Neck-Chest-Abdomen-Pelvis)/disease assessment: If PET-CT performed > 28 days prior to the initiation of lymphodepleting chemotherapy or if subject receives any anti-cancer therapy 
between screening and lymphodepleting  chemotherapy, baseline scans must be repeated. Screening PET-CT should be completed as close to enrollment as possible.  As applicable, bone marrow 
aspirate/biopsy will be performed to confirm response (i.e., for subjects presenting with bone marrow involvement prior to therapy or if new abnormalities in the peripheral blood counts or 
blood smear cause clinical suspicion of bone marrow involvement with lymphoma after treatment).  Bone marrow samples may also be collected and analyzed centrally for subjects who 
develop toxicities post axicabtagene ciloleucel.  
3 Blood draw for Anti-axicabtagene ciloleucel antibodies:  Baseline antibody sample to be collected prior to start of leukapheresis. Anti-axi-cel antibodies will be examined at baseline, days 28 and 90 
after the first administration of the drug and 4 weeks post study. If any anti-drug antibodies are detected in patients, monitoring should continue until patient antibody levels return to the baseline. 
4  Blood draw for RCR:  on Day 0 prior to administration of axicabtagene ciloleucel and at Month 3, 6 and 12; then collect yearly for up to 15 years. Yearly samples will only be analyzed if positive at 
Month 3, 6, or 12.
5  Cytokines: prior to axicabtagene ciloleucel infusion on Day 0, then on Day 1 and then every other day during the 7 day post infusion monitoring period.
6  Lumbar Puncture:  subjects with symptoms of CNS malignancy (e.g., new onset severe headaches, neck stiffness, or focal neurological findings) will have lumbar puncture performed at screening to 
assess cerebral spinal fluid for possible CNS involvement.  Subjects will have lumbar puncture for the collection of CSF performed at baseline prior to axicabtagene ciloleucel infusion (if not already 
performed as part of screening and within 28 days of axicabtagene infusion), post axicabtagene ciloleucel infusion (Day 5 ± 3 days) and at week 4 visit (±3 days).  
7 If a subject is admitted to the hospital within the 7-day observation period is discharged and then subsequently re-admitted to the hospital with any axicabtagene ciloleucel related adverse events, 
blood samples for anti-CD19 CAR T cells and cytokines will be collected on day of hospital re-admission and then weekly through and including the day of discharge. Blood samples for anti-CD19 
CAR T cells and cytokines should also be collected at the time of disease progression prior to starting any subsequent anticancer therapy.
8 Anakinra, weight-based dosing (100mg for subjects <50kg, 200mg for subjects ≥ 50kg). Anakinra will be given subQ for prophylactic dosing on days 0 through day +13 per section 6.4.3. The first dose 
of anakinra should be given 4 hours (+/- 30 min) prior to planned axicabtagene ciloleucel infusion. 
9  Levetiracetam at a dose of 750mg (PO or IV) twice daily starting day of infusion (Day 0) See Sections 5.1 and 7 for further details.
10 Cytokines: prior to axicabtagene ciloleucel infusion on Day 0, then on Day 1, and then every other day during the 7 day post infusion monitoring period.
11 In the event of hospitalization, ICANS neurotoxicity assessments (including ICE scores) will be obtained daily until discharge. 
12 Specific grading based on CTCAE 4.03 can be found in appendix A “Grading and Management of Neurologic Toxicities” for grading of nervous system disorders involving somnolence, confusion, 
memory impairment,  encephalopathy, dysphagia, seizures, and cerebral edema.
13For weekend/holiday sample collections following axicabtagene infusion, allow for +/- 24hr window.
14 While PET-CT is preferred, CT assessment may be used in place of PET-CT in the event of failure to obtain insurance coverage. Baseline, month 1, 6 and 12 should be assessed via PET/CT.  
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Table 3.
Schedule of Assessments (Long-term Follow-up Period)
Procedure
Long Term Follow-up Period 
(Each visit calculated from Day 0)
Visit Frequency
Month 6
Month 9
Month 12
Month 15
Month 18
Month 24
Physical exam1
X
X
X
X
X
X
PET-CT/disease assessment2,9
X
X
X
X
X
Survival Status
X
X
X
X
X
X
Blood draw for CBC w/differential 3
X
X
X
X
X
X
Blood draw for Anti-axicabtagene
ciloleucel antibodies 4
X
X
X
Blood draw for Lymphocyte subsets 3
X
X
X
X
X
X
Blood draw for anti-CD19 CAR T 
cells3 
X
X
X
Blood draw for RCR analysis 5
X
X
X
Targeted AE/SAEs 6
X
X
X
X
X
X
Targeted concomitant medication 7
X
X
X
X
X
X
Subsequent therapy for NHL8
X
X
X
X
X
X
Blood draw for minimial residual 
disease testing
X
1 Physical exams will continue through Month 24
2 PET-CTs/disease assessments will continue through Month 24 or until disease progression, whichever comes first.  If subject’s disease has not progressed by Month 24, disease assessments will 
continue to be performed per standard of care.
3 Subjects will continue to provide samples for CBC w/diffs, lymphocyte subsets and anti-CD19 CAR T cells through Month 24
4  Anti-axicabtagene ciloleucel antibody samples.
5  RCR samples:  collect  and measured at Month 3, 6 and 12, then collect yearly for up to 15 years. Yearly samples will only be analyzed if positive at Month 3, 6, or 12.
6 Targeted AEs/SAEs will be collected for 24 months or until disease progression (whichever occurs first)
7  Targeted concomitant medications will be collected for 24 months or until disease progression (whichever occurs first)
8 Subsequent therapy administered after axicabtagene ciloleucel infusion for a subjects’ disease such as non-study specified chemotherapy, immunotherapy, targeted agents, as well as stem cell 
transplant and radiation therapy must be collected until subject completes the long term follow up period, is considered lost to follow up, withdraws consent, or dies.  Subjects may be contacted by
telephone to collect information about subsequent therapy for NHL and to assess survival status.
9 While PET-CT is preferred, CT assessment may be used in place of PET-CT in the event of failure to obtain insurance coverage. Month 1, 6 and 12 should be assessed via PET/CT.  
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12. MEASUREMENT OF EFFECT
12.1
Neurotox Response Assessment
Neurotox will be graded using CTCAE 4.03 as was done for Zuma-1 which will act as a historical 
control. Specific grading based on CTCAE 4.03 can be found in appendix A “Grading and 
Management of Neurologic Toxicities” for grading of nervous system disorders involving 
somnolence, confusion, memory impairment,  encephalopathy, dysphagia, seizures, and cerebral 
edema. Additionally, information required for Neurotox grading per ASTCT consensus criteria 
will also be collected as an exploratory endpoint. Specific ICANS related ASTCT grading 
requirements, including ICE scores, can be found in appendix A “ASBMT Grading of ICANS.”
12.2
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 1.  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 undergo additional PET-CT or CT tumor 
assessments after their axicabtagene ciloleucel infusion.  While PET-CT is preferred, CT 
assessment may be used in place of PET-CT in the event of failure to obtain insurance 
coverage. Baseline, month 1, 6 and 12 should be assessed via PET/CT. The first of these post-
treatment PET-CT tumor assessments will occur 4 weeks after infusion; subsequent 
assessments will occur at regular intervals throughout the post-treatment and long-term 
follow-up portions of the study, as highlighted in the SOA.
After axicabtagene ciloleucel and anakinra 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 1, 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.  
For subjects who discontinue the study due to an assessment of progressive disease which was not 
subsequently confirmed by a central radiology reviewer, any additional imaging data, subsequent 
to the image in question will be submitted to the central reviewer to confirm disease response. 
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13. DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements).
13.1
Data Reporting
13.1.1 Method
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the 
data for this study.
13.1.2 Responsibility for Data Submission
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies.
13.2
Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists and biostatisticians with direct experience in cancer clinical research.  
Information that raises any questions about participant safety will be addressed with the Overall 
PI, study team and Kite/Gilead. The DSMC will review protocols up to, but not more than four 
times a year with the primary focus being accrual, protocol adherence, audit results and summary 
of all deaths while being treated and during active follow-up. Given the collaborative nature of 
this protocol, there will be an an additional safety review team (SRT) comprised of the study 
sponsor/PI and Kite/Gilead meant to review all study safety data and make recommendations on 
further study conduct as described below.  As both axicabtagene ciloleucel and anakinra are FDA 
approved therapies with known toxicity profiles, the goal of the SRT will be to observe for 
unforeseen toxicities not previously observed in the initial phase I/II studies that led to FDA 
approval of both agents. Specific guidance as outlined in section 8.4.4. 
The DSMC will review each protocol up to four times a year with the frequency determined by 
the outcome of previous reviews. Information to be provided to the committee may include: up-
to-date participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring within 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
14. STATISTICAL CONSIDERATIONS
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The primary objective of the study is to assess the impact of anakinra as preventative management 
of neurotoxicity.  Secondary objectives will include evaluate the impact of anakinra  as 
preventative management of CAR-T related CRS, to evaluate the efficacy of axicabtagene 
ciloleucel in combination with preventative anakinra in terms of DOR, ORR, PFS, and OS in 
comparison to the pivotal Zuma-1 study.
14.1
Study Endpoints
Primary Endpoint:

Rate and severity of neurotoxicity as per CTCAE v4.03 criteria within the first 30 days of 
infusion. 
Secondary Endpoints:

Rate and severity of CRS as per Lee 2014 criteria within the first 30 days of infusion in 
comparison to the pivotal Zuma-1 study. 

Duration of response (DOR): Among subjects who experience an objective response, 
DOR is defined as the date of their first objective response to disease progression per the 
revised IWG Response Criteria for Malignant Lymphoma 1 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.

Objective response rate (ORR): ORR is defined as the incidence of either a complete 
response or a partial response by the revised IWG Response Criteria for Malignant 
Lymphoma 1.  All subjects that do not meet the criteria for an objective response by the 
analysis data cutoff date will be considered non-responders.  

Progression-free Survival (PFS): PFS is defined as the time from the axicabtagene 
ciloleucel infusion date to the date of disease progression per the revised IWG Response 
Criteria for Malignant Lymphoma 1 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):  OS is defined as the time from axicabtagene ciloleucel infusion 
to the date of death.  Subjects who have not died by the analysis data cutoff date will be 
censored at their last contact date.
Exploratory Endpoints:

Levels of anti-CD19 CAR T cells in blood

Levels of cytokines in serum and CSF

Incidence of anti-axicabtagene ciloleucel antibodies

Investigation of potential biomarker development based on assessment of blood cells, 
tumor cells and the proposed actions of the investigational product.
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
Rates of CRS/NT based on grading used in Zuma-1 (i.e. Lee 2014 for CRS, and CTCAE 
version 4.03 for neurotoxicity) vs ASTCT consensus guidelines 
The primary objective of this study is to assess the impact of prophylactic regimens or earlier 
interventions on the rate and severity of CRS and neurologic toxicities.  The assessment of ORR 
is a secondary objective, and the analysis will be descriptive. 
14.2
Sample Size, Accrual Rate and Study Duration
The anticipated enrollment in this study is approximately 20 patients over a 2-year period. The 
goal is to accrue one patient/month to the study protocol over this period. 
With 20 patients the study will have 86% power to detect a decrease in the neurotoxicity rate from 
45% to 15% via a two-sided exact binomial test with a significance level of 0.05.  The secondary 
objectives of this study include analyses the rate and severity of CRS as well as efficacy endpoints 
(ORR, DOR, PFS, OS) and levels of anti-CD19 CAR T cells and cytokines in the blood.
All subjects will be followed for survival for up to approximately 15 years after the last subject 
receives axicabtagene ciloleucel per FDA requirements and data will be collected through the 
CIBMTR data registry starting at Month 24. 
14.3
Interim Monitoring Plan
Interim Analysis and Early Stopping Rules
The SRT will review safety data when 8 subjects treated have had the opportunity to be followed 
for 30 days, respectively.  
The rate of grade 2+ neurotoxicity will be evaluated using a Simon’s two-stage design. Initially, 8 
patients will be enrolled. If 3 or more of the initial 8 patients experience grade 2+ neurotoxicity, 
enrollment will be terminated early or dosing modification discussed. The probability of early 
termination is 0.78 if the true rate of grade 2+ neurotoxicity is 45% or higher. Otherwise, 
enrollment will continue to a total of 20 patients. The treatment will be considered promising if 5 
or fewer of 20 patients experience grade 2+ neurotoxicity. The two-stage design provides 86% 
power to demonstrate that the treatment is associated with a favorable neurotoxicity rate if the true 
rate is 15%. In contrast, there is a 4% (alpha) probability of concluding that the treatment has a 
favorable neurotoxicity rate if the true rate is 45% or higher.
Safety Interim Analysis
The SRT will review AE and SAE information on a regular basis throughout subject treatment in 
Phase 2 of the study.  AE and SAE information will be collected to assure no unforeseen toxicities 
are noted with this combination. The SRT may request additional safety data or modify the study 
conduct.  The sponsor may request additional reviews by the SRT if safety concerns are identified. 
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Data submitted to the SRT may be monitored or unmonitored to facilitate timely review. 
Additional stopping rules per section 8.4.4.   
Efficacy Interim Analysis
There is no planned efficacy interim analysis for this portion of the study. 
14.4
Analysis of Primary and Secondary Endpoints
Planned Method of Analysis
The primary analysis of all treated subjects have had the opportunity to be followed for 8 weeks 
and 6 months for primary and secondary endpoints respectively.  No central radiologic review of 
disease assessment will be performed for these cohorts.
Descriptive analyses may occur at any time.
Neurotoxicity Rate
The incidence of grade 2+ neurotoxicity will be assessed in comparison to a historical rate of 45% 
via a two-sided exact binomial test with significant level of 0.05. Exact 2-sided 95% confidence 
intervals for the neurotoxicity rate will be generated.
Objective Response Rate
The incidence of objective response and exact 2-sided 95% confidence intervals will be generated.  
Duration of Response
The Kaplan-Meier survival method will be used to estimate the cumulative incidence of relapse.  
The cumulative incidence of relapse in the presence of non-disease related mortality (Kaplan-
Meier method) will be estimated along with 2-sided 95% confidence intervals at 3-month 
intervals.  
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.
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.
Safety
Subject incidence rates of adverse events including all, serious, fatal, CTCAE version 4.03 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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In the event of changes in the safety management using steroids, sensitivity analyses will explore 
the effect of these changes on outcomes via stratification and/or adjustment for use of steroids in 
multivariable models.
14.5
Reporting and Exclusions
The statistical reporting of the safety and efficacy endpoints will be compared to historical controls 
from the Zuma-1 study. Subject incidence rates of treatment-emergent CRS, neurologic toxicities, 
axicabtagene ciloleucel-related adverse events, and ORRs will be summarized. DOR, PFS, and 
OS will also be summarized. 
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, 2 x 106 CAR T cells/kg (range 
1 x 106 to 2.4 x 106 CAR T cells/kg) and at least one dose of anakinra. This analysis set will be 
used for all efficacy analyses.
Safety Analysis Subset: The safety analysis subset is defined as all subjects treated with any dose 
of axicabtagene ciloleucel and at least one dose of anakinra. For retreated subjects, only the initial 
treatment will contribute to the safety analyses while events following retreatment will not be 
included in the safety analysis. 
Retreatment Subset: Separate safety and efficacy analyses will be conducted in subjects who are 
retreated. These analyses will include data from non-initial treatments and follow the inclusion 
criteria specified above for safety and efficacy analysis.  
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 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.
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15. ETHICAL AND REGULATORY REQUIREMENTS
15.1
Independent Review Board/Independent Ethics Committee
A copy of the protocol, ICF and any additional subject or trial information such as subject 
recruitment materials must be submitted to each sites respective IRB/IEC for approval. Once 
approval is obtained from the IRB/IEC, all documents must be provided to the key sponsor contact 
before subject recruitment can begin.
The investigator must also receive IRB/IEC approval for all protocol and ICF changes or 
amendments. Investigators must ensure that ongoing/continuous IRB/IEC approval (ie, annual 
approval) is provided throughout the conduct of the study.  Copies of IRB/IEC approval are to be 
forwarded to the key sponsor contact for archiving.
During the course of the study, investigators are to submit site specific and study serious adverse 
events (provided to the site by the key sponsor contact) along with any protocol deviations to their 
IRB/IEC in accordance with their respective IRB/IEC policies. 
15.2
Subject Confidentiality
Subject confidentiality must be contained at all material submitted to the key sponsor contact. The 
following rules are to be applied.

Subjects will be identified by a unique identification number

Date of birth or year of birth/age at time of enrollment will be reported according with local 
laws and regulations
For reporting of serious adverse events, subjects will be identified by their respective subject 
identification number, initials and data of birth or year of birth (as per their local reporting 
requirements for both initials and date of birth)
Per federal regulations and 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.
15.3
Investigator Signatory Obligations
Each clinical study report will be signed by the coordinating investigator.  The coordinating 
investigator will be identified by the Sponsor under the following criteria:

A recognized expert in the disease setting

Provided significant contributions to the design or analysis of study data

Participate in the study and enrolled a high number of eligible subjects
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15.4
 Protocol Amendments and Termination
If the protocol is amended, the investigators agreement with the amendment and the IRB/IEC 
approval of the amendment must be obtained.  Documentation acknowledging approval from both 
parties are to be submitted to the key sponsor contact.
Both Sponsor 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.
15.5
Study Documentation and Archive
The investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated.  These individuals authorized to fulfil these responsibilities should be outlined and 
included in the Delegation of Authority Form.
Source documents are original documents, data and records for which the study data are collected 
and verified.  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 Sponsor 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.
15.6
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 
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respect to local regulations will be confirmed. Monitors will have access to subject records as 
identified in Section 14.5.
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 com
16. PUBLICATION PLAN
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome data 
are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and 
Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial 
release may be an abstract that meets the requirements of the International Committee of Medical 
Journal Editors. A full report of the outcomes should be made public no later than three (3) years 
after the end of the study. 
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.
Authorship of publications from data generated in the 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) 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
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 the Sponsor for 
review and approval. The study contract between the institution, principal investigation and 
Sponsor or its delegate will outline the requirements for publication review in collaboration with 
Kite/Gilead.
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real-life clinical practice: a nationwide multicenter retrospective observational study. Clin 
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APPENDIX A
Grading and Management of CRS – Lee 2014
CRS Grade
Supportive Care
Tocilizumab
Steroids
Follow up
Grade 1: 
Symptoms are not 
life threatening and 
require symptomatic 
treatment only (eg, 
fever, nausea, 
fatigue, headache, 
myalgia, malaise)
Supportive care 
per institutional 
standard of care
N/A
N/A
N/A, no toci/steroids for 
patients with prolonged 
grade 1 CRS 
Grade 2: 
Symptoms require 
and respond to 
moderate 
intervention 
Oxygen requirement 
<40% FiO2 or 
hypotension 
responsive to fluids 
or low dose of one 
vasopressora or 
Grade 2 organ 
toxicityb
Continuous 
cardiac telemetry 
and pulse 
oximetry as 
indicated
IV fluids bolus for 
hypotension with 
0.5 to 1.0 L 
isotonic fluids
Vasopressor 
support for 
hypotension not 
responsive to IV 
fluids
Supplemental 
oxygen as 
indicated
Tocilizumab: 
8mg/kg over 1 
hour (not to 
exceed 800 mg)
Repeat 
tocilizumab every 
8 hours as needed 
if not response to 
IV fluids or 
increasing 
supplemental 
oxygen; 
maximum of 3 
doses in a 24-hour 
period; maximum 
total of 4 doses. 
N/A 
Improving: 
Discontinue tocilizumab
Not Improving:
Manage as Grade 3 
(below)
Grade 3: 
Symptoms require 
and respond to 
aggressive 
intervention
Oxygen requirement 
≥ 40% FiO2 or 
hypotension 
requiring high-dose 
or multiple 
vasopressorsa or 
Grade 3 organ 
toxicity or Grade 4 
transaminitisb
Management in 
monitored care or 
intensive care unit
Per Grade 2 
Methylprednisolon
e 1 mg/kg IV BIDc
Improving: 
Discontinue tocilizumab
Taper corticosteroids
Not Improving:
Manage as Grade 4 
(below)
Grade 4: 
Life-threatening 
symptoms
Requirements for 
ventilator support or 
continuous veno-
venous hemodialysis 
(CVVHD)
Grade 4 organ 
toxicity (excluding 
transaminitis)b
Per Grade 3
Mechanical 
ventilation and/or 
renal replacement 
therapy may be 
required
Per Grade 2 
High-dose 
corticosteroids: 
Methylprednisolon
e 
1000 mg/day IV x 
3 days
Improving:
Discontinue tocilizumab
Taper corticosteroids
Not improving:
1 gram BID to TID of 
methylprednisolone and 
other immunosuppressive 
(e.g. siltuximab) and anti-
thymocyte globulin (ATG 
2mg/kg x 1 and reassess)
aHigh-dose vasopressor doses
bSeverity based on CTCAE
c or equivalent dexamethasone
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Grading and Management of Neurologic Toxicities 
Neurologic Toxicities
Supportive Care
Tocilizumab
Corticosteroids
Follow up
Grade 1 examples include:
Somnolence-mild 
drowsiness or sleepiness
Confusion-mild 
disorientation
Encephalopathy-mild 
limiting of ADLs
Dysphagia-not impairing 
ability to communicate
Supportive care 
per institutional 
standard of care
Closely monitor 
neurologic status
Consider 
prophylactic 
levetiracetam 
N/A
N/A
Continue supportive 
care
Grade 2 examples include:
Somnolence-moderate, 
limiting instrumental 
ADLs
Confusion-moderate 
disorientation
Encephalopathy-limiting 
instrumental ADLs 
Dysphagia-moderate 
impairing ability to 
communicate 
spontaneously
Seizure(s)
Continuous 
cardiac telemetry 
and pulse 
oximetry as 
indicated
Closely monitor 
neurologic status 
with serial neuro 
exams to include 
fundoscopy and 
Glasgow Coma 
Score. Consider 
neurology consult
Perform brain 
imaging (eg, 
MRI), EEG, and 
lumbar puncture 
(with opening 
pressure) if no 
contraindications
Levetiracetam/ 
antiepileptics if 
subject has 
seizures
N/A
Dexamethasone 
10mg 
intravenously 
every 6 hours
Improving:
Taper corticosteroids
Not improving:
Manage as Grade 3 
(below)
Grade 3 examples include:
Somnolence-obtundation 
or stupor
Confusion-severe 
disorientation
Encephalopathy-limiting 
self-care ADLs
Dysphagia-severe 
receptive or expressive 
characteristics, impairing 
ability to read, write, or 
communicate intelligibly
Management in 
monitored care of 
intensive care unit
N/A 
Dexamethasone 
10mg 
intravenously 
every 6 hours
Improving:
Taper corticosteroids
Not improving:
Manage as Grade 4 
(below)
Grade 4 examples include:
Life-threatening 
consequences
Urgent intervention 
indicated
Requirement for 
mechanical ventilation
Consider cerebral edema 
Per Grade 3
Mechanical 
ventilation, may 
be required
N/A 
Methylpredniso
lone 1 gram 
daily for 3 days 
Improving:
Taper corticosteroids
Not improving:
Consider 1 gram of 
methylprednisolone 
TID,  alternative 
immunsuppressive 
(e.g. siltuximab) and 
anti-thymocyte 
globulin  (ATG 
2mg/kg x 1 and 
reassess)
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ASBMT Grading of ICANS
ICE Score
Scoring: 10, no impairment;
7-9, grade 1 ICANS; 
3-6, grade 2 ICANS;
0-2, grade 3 ICANS;
0 due to patient unarousable and unable to perform ICE assessment, grade 4 ICANS. 
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APPENDIX B
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 PET scan is only indicated in subjects with one or at most 
two residual masses that have regressed by 50% on CT scan.
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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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