A Phase II, Single Arm, Multicenter Open Label Trial to Determine the Efficacy and Safety of Tisagenlecleucel (CTL019) in Adult Patients With Refractory or Relapsed Follicular Lymphoma
Phase: PHASE2
Conditions: Follicular Lymphoma
Sponsor: Novartis Pharmaceuticals



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Oncology Protocol (Version No. 00)
Protocol No. CCTL019E2202
Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................15
Protocol summary:.............................................................................................................17
1
Background........................................................................................................................20
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............20
1.1.1
Historical experience with retroviral gene therapies.............................21
1.2
Introduction to investigational treatment(s) and other study treatment(s).............22
1.2.1
Overview of tisagenlecleucel................................................................22
1.2.2
Non-clinical experience ........................................................................23
1.2.3
Clinical experience................................................................................23
2
Rationale............................................................................................................................25
2.1
Study rationale and purpose...................................................................................25
2.2
Rationale for study design .....................................................................................26
2.3
Rationale for dose and regimen selection..............................................................26
2.4
Rationale for lymphodepletion ..............................................................................27
2.5
Rationale for choice of combination drugs............................................................28
2.6
Rationale for choice of comparators drugs............................................................28
2.7
Risks and benefits..................................................................................................28
2.7.1
Identified safety risks ............................................................................28
2.7.2
Potential safety risks .............................................................................33
2.7.3
Other risks .............................................................................................36
3
Objectives and endpoints...................................................................................................36
4
Study design ......................................................................................................................40
4.1
Description of study design ...................................................................................40
4.2
Timing of interim analyses and design adaptations...............................................41
4.3
Definition of end of study......................................................................................41
4.4
Early study termination..........................................................................................41
5
Population..........................................................................................................................42
5.1
Patient population..................................................................................................42
5.2
Inclusion criteria ....................................................................................................42
5.3
Exclusion criteria...................................................................................................43
6
Treatment...........................................................................................................................45

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6.1
Study treatment......................................................................................................45
6.1.1
Dosing regimen.....................................................................................45
6.1.2
Bridging therapy....................................................................................45
6.1.3
Lymphodepleting chemotherapy...........................................................46
6.1.4
Tisagenlecleucel infusion......................................................................47
6.1.5
Treatment duration................................................................................49
6.2
Dose escalation guidelines.....................................................................................49
6.2.1
Starting dose rationale...........................................................................49
6.2.2
Provisional dose levels..........................................................................49
6.2.3
Guidelines for dose escalation and determination of 
(MTD/RP2D/RDE) ...............................................................................49
6.2.4
Definitions of dose limiting toxicities (DLTs) in a phase II study .......49
6.2.5
Toxicity management, stopping rules and study termination ...............50
6.2.6
General toxicity management considerations .......................................50
6.2.7
Criteria for discontinuing a patient’s participation in the study ...........56
6.3
Dose modifications................................................................................................56
6.3.1
Dose modification and dose delay ........................................................56
6.3.2
Additional safety monitoring and follow-up for toxicities ...................56
6.4
Concomitant therapy..............................................................................................58
6.4.1
Prohibited concomitant therapy ............................................................59
6.5
Patient numbering, treatment assignment or randomization .................................60
6.5.1
Patient numbering .................................................................................60
6.5.2
Treatment assignment or randomization...............................................60
6.5.3
Treatment blinding................................................................................60
6.6
Tisagenlecleucel preparation and dispensation .....................................................60
6.6.1
Tisagenlecleucel packaging and labeling..............................................60
6.6.2
Tisagenlecleucel supply and storage.....................................................61
6.6.3
Tisagenlecleucel compliance and accountability..................................61
6.6.4
Tisagenlecleucel disposal and destruction ............................................61
6.6.5
Handling of other study treatment.........................................................61
7
Visit schedule and assessments .........................................................................................62
7.1
Study flow and visit schedule................................................................................62
7.1.1
Screening Phase ....................................................................................85
7.1.2
Pre-treatment phase...............................................................................87
7.1.3
Treatment and Follow-up Phase............................................................87
7.1.4
Survival follow-up ................................................................................89

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7.1.5
Discontinuation of study treatment .......................................................89
7.1.6
Discontinuation from study...................................................................89
7.1.7
Withdrawal of consent ..........................................................................90
7.1.8
Follow up for safety evaluations – Long-term follow-up study ...........90
7.1.9
Lost to follow-up...................................................................................91
7.2
Assessment types...................................................................................................91
7.2.1
Efficacy assessments.............................................................................91
7.2.2
Safety and tolerability assessments.......................................................96
7.2.3
Pharmacokinetics ..................................................................................99
106
110
7.2.6
Patient reported outcomes (PRO)........................................................110
8
Safety monitoring and reporting......................................................................................112
8.1
Adverse events.....................................................................................................112
8.1.1
Definitions and reporting ....................................................................112
8.1.2
Adverse Event of special reporting requirements ...............................114
8.1.3
Duration of adverse event reporting....................................................114
8.2
Serious adverse events.........................................................................................114
8.2.1
Definitions...........................................................................................114
8.2.2
SAE reporting......................................................................................115
8.3
Emergency unblinding of treatment assignment .................................................116
8.4
Pregnancies..........................................................................................................116
8.5
Warnings and precautions....................................................................................116
8.6
Reporting of study treatment errors including misuse/abuse ..............................116
8.7
Data Monitoring Committee................................................................................117
8.8
Steering Committee .............................................................................................117
9
Data collection and management.....................................................................................118
9.1
Site monitoring ....................................................................................................118
9.2
Data collection.....................................................................................................118
9.3
Database management and quality control..........................................................119
10 Statistical methods and data analysis ..............................................................................119
10.1
Analysis sets ........................................................................................................119
10.1.1
Screened Set........................................................................................119
10.1.2
Enrolled Set.........................................................................................119
10.1.3
Full Analysis Set .................................................................................120
10.1.4
Efficacy Analysis Set ..........................................................................120

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11.9
Audits and inspections.........................................................................................134
11.10 Financial disclosures............................................................................................134
12 Protocol adherence ..........................................................................................................134
12.1
Amendments to the protocol................................................................................135
13 References (available upon request)................................................................................136
14 Appendices ......................................................................................................................142
14.1
Appendix 1: Guidelines for efficacy evaluation in non-Hodgkin lymphoma 
studies ..................................................................................................................142
14.1.1
Introduction.........................................................................................144
14.1.2
Methodologies.....................................................................................144
14.1.3
Definitions...........................................................................................145
14.1.4
Efficacy assessments...........................................................................147
14.1.5
Data handling and programming conventions ....................................159
14.1.6
References...........................................................................................160
14.1.7
Appendices..........................................................................................160
14.2
Appendix 2: Eligibility based on serologic markers for hepatitis B and C .........161
14.3
Appendix 3: Tisagenlecleucel modified data reporting – Treatment and 
Follow-up Phase ..................................................................................................162
14.3.1
Adverse event (AE) and serious adverse event (SAE) reporting........163
14.3.2
Concomitant medication and laboratory reporting .............................164
14.4
Appendix 4: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................166
14.4.1
Liver Event and Laboratory Trigger Definitions ................................166
14.4.2
Follow Up Requirements for Liver Events and Laboratory Triggers.167
14.5
Appendix 5: Specific Renal Alert Criteria and Actions and Event Follow-up....170
14.5.1
Specific Renal Alert Criteria and Actions...........................................170

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Table 14-4
Censoring reasons ...............................................................................157
Table 14-5
Options for event dates used in PFS, EFS, TTP, DOR.......................157
Table 14-6
Follow-up of renal events....................................................................171

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List of abbreviations
ABC
Activated B-cell
ADCC
Antibody-dependent cell-mediated cytotoxicity 
AE
Adverse Event
AESI
Adverse events of special interest
Alb
Albumin
ALC
Absolute Lymphocyte Count 
ALL
Acute Lymphoblastic Leukemia
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT
ANC
Absolute Neutrophil Count
aPTT
Activated partial thromboplastin time 
ASH
American Society of Hematology
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT
ATC
Anatomical Therapeutic Chemical 
ATG
Anti-thymocyte Globulin
ATP
Adenosine 5'-triphosphate
AUC
Area Under the Curve 
AV
Atrioventricular
Bcl
Bcl-6
B-cell lymphoma 
B-cell lymphoma 6 protein
BCR
B cell receptor
BiPAP
Bilateral Positive Airway Pressure
bpm
beat per minute
BTK
Bruton’s Tyrosine kinase 
BUN
Blood Urea Nitrogen
CAR
Chimeric antigen receptor
CBC
Complete Blood Count
CCG
CD
CRF Completion Guidelines
Cluster of differentiation
CFR
Code of Federal Regulations
CGD
Chronic granulomatous disease
CI
Confidence Interval 
CIF
Cumulative incidence function
CKAS
Cellular Kinetic Analysis Set
CLL
Chronic Lymphocytic Leukemia
cm
Centimeter
Cmax
Maximum concentration 
CMV
Cytomegalovirus 
c-myc
c-mycproto-oncogene
CMR
Complete Metabolic Response
CNS
Central Nervous System 
CPAP
Continuous Positive Airway Pressure
CR
Complete Response 
CRi
Complete Response with incomplete bone marrow recovery
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization

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CRP
C-Reactive Protein 
CRR
Complete Response Rate
CRS
Cytokine Release Syndrome
CSF
Cerebral spinal fluid 
CSP
Clinical Study Protocol 
CSR
Clinical study report
CT
Computed tomography 
CTC
Common toxicity criteria 
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Cytotoxic T-lymphocyte 
CV
Coefficient of Variation
CYP
Cytochrome P
DLBCL
Diffuse large B-cell lymphoma 
DFS
Disease free survival 
DLT
Dose Limiting Toxicity
DMC
Data monitoring committee 
DMSO
Dimethylsulfoxide
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DS&E
Drug Safety and Epidemiology
EC
European Community
ECG
Electrocardiogram
ECHO
Echocardiogram 
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EFS
Event free survival
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
EOS
End Of Study
EQ-5D-3L
European Quality of Life-3 Dimensions
ESMO
European Society for Medical Oncology
EU
European Union
FACT-G
The Functional Assessment of Cancer Therapy – General 
FACT-Lym
The Functional Assessment of Cancer Therapy - Lymphoma
FAS
Full analysis set 
FDA
Food & Drug Administration
FDG
Fluorodeoxyglucose
FFP
Fresh frozen plasma 
FFPE
Formalin-fixed paraffin-embedded
FISH
Fluorescence in situ hybridization
FL
Follicular Lymphoma
FLIPI
Follicular Lymphoma International Prognostic Index
FNA
Fine Needle Aspirate
FPFV
First Patient First Visit 
g
gram

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GC
Germinal center-like
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
GELF
Groupe d’Etude des Lymphomes Folliculaires
GM-CSF
Granulocyte macrophage-colony stimulating factor
GVHD
Graft versus Host Disease 
HA
Health Authority
HBcAb
Hepatitis B core Antibody
HBsAg
Hepatitis B surface Antigen 
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus 
HIV
Human immunodeficiency virus
HR
Heart Rate
HSCT
Hematopoietic stem cell transplant
ICF
Informed consent form 
ICH
International Conference on Harmonization
ICU
Intensive Care Unit 
IEC
Independent Ethics Committee
Ig
Immunoglobulin 
IgH
Immunoglobulin heavy locus
IL
Interleukin
IL6R
Interleukin 6 receptor 
IN
Investigator Notification
INR
International Normalized Ratio 
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
IT
Intrathecal
ITP
Autoimmune thrombocytopenia/thrombocytopenic purpura
IUD
Intrauterine Device 
i.v.
Intravenous(ly) 
IWRS
Interactive Web Response System 
JCV
John Cunningham Virus 
Kg
Ki67
Kilogram
The murine cell proliferation antigen
KM
Kaplan Meier 
LDH
Lactate dehydrogenase
LFT
Liver function tests
LLOQ
Lower Limit of Quantification 
LOQ
Limit of Quantification 
LPLV
Last Patient Last Visit 
LSS
Lymphoma Specific Survival 
LTFU
Long Term Follow Up 
LTR
Long Terminal Repeat

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LVEF
Left Ventricular Ejection Fraction 
MAP
Master Analysis Plan
MAS
Macrophage Activation Syndrome
MedDRA
Medical Dictionary for Regulatory Authorities
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MCL
Mantle Cell Lymphoma
mRNA
messenger RNA
mg/m2
milligram per square meter
MHC
Major histocompatibility complex
min
minutes
mL
milliliter
MNC
Mononuclear cell
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging 
MTD
MTX
Maximum Tolerated Dose
methotrexate
MUGA
Multiple Uptake Gated Acquisition 
N/A
Not Applicable
NCCN
National Comprehensive Cancer Network
NE
Norepinephrine Equivalent
NE
Not Evaluable
NFkB
Nuclear Factor-kappa B
NHL
Non-Hodgkin’s Lymphoma
NK-cell
Natural Killer cell
NOS 
Not otherwise specified
NR
No Response
NYHA
New York Heart Association
O2
Oxygen 
ORR
Overall Response Rate 
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive disease
PD
PD-1
PD-L1
Pharmacodynamics
Programmed cell death protein-1
Programmed cell death ligand-1
PE
Physical Examination
PET
Positron emission tomography 
PFS
Progression Free Survival 
PGS-CRS
The Penn Grading Scale for Cytokine Release Syndrome 
PHI
Protected Health Information
PI
Principal Investigator
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetics
PMBCL
Primary mediastinal large cell lymphoma
PML
Progressive Multifocal Leukoencephalopathy
PMR
Partial Metabolic Response

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PPS
Per Protocol Set 
PR
Partial Response 
PRi
Partial Response with incomplete bone marrow recovery
PRO
Patient Reported Outcome
PT
Preferred Term
PT
Prothrombin time 
PTLD
Post-transplant lymphoproliferative disorders
q3M
Quarterly (every 3 months)
QA
Quality Assurance
QOL
Quality of Life 
qPCR
Quantitative Polymerase Chain Reaction
R/D
Relapsed Disease
r/r
Relapsed or refractory
R-CHOP
Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone
RCL
Replication competent lentivirus
RCR
Replication competent retrovirus
RDE
Recommended dose for expansion 
REB
Research Ethics Board
RNA
Ribonucleic acid
RP2D
Recommended phase two dose 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee 
scFv
Single chain variable fragment
SCID-X1
X-linked Severe Combined Immunodeficiency
SD
Stable Disease 
SD
Standard Deviation
SF-36
Short Form 36 health survey
SGOT
Serum glutamic-oxaluacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SMQ
Standard medical query
SOC
System Organ Class 
SPD
Sum of the product of the diameters 
SUSAR
Suspected unexpected serious adverse reactions
TBL
Total Bilirubin
TCR
T cell receptors
TKI
Tyrosine Kinase Inhibitor 
TLS
Tumor lysis syndrome 
Tmax
Time to peak concentration 
TNC
Total nucleated cells 
TNF
Tumor Necrosis Factor 
TTP
Time to progression
TTR
Time to Response 
UK
United Kingdom
ULN
Upper Limit of Normal 

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ULOQ
Upper Limit of Quantification 
UNK
Unknown 
UPENN
University of Pennsylvania 
US
United States
VASST
Vasopressin and Septic Shock Trial 
VH
Heavy Chain Variable Domain
VL
Light Chain Variable Domain
VSV-g
Vesicular Stomatitis Virus, Glycoprotein
WAS
Wiskott-Aldrich syndrome
WBC
White blood cells
WHO 
World Health Organization
yGT
Gamma glutamyl-transpeptidase

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject or study 
patient
Baseline Efficacy Assessment
If multiple assessments are performed prior to infusion then the one 
closest temporally prior to infusion will serve as baseline assessment.
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Final Enrollment
Point/time of patient entry into the study when the following have been 
confirmed: 
A. ICF signed
B. Local patient eligibility completed
C. Leukapheresis product received and accepted for manufacturing
HSCT
Hematopoietic stem cell transplantation (HSCT) refers to both 
allogeneic HSCT and autologous HSCT
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational treatment
Treatment whose properties are being tested in the study as well as 
their associated placebo and active treatment controls (when 
applicable). This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed combination. 
Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required 
or allowed by the protocol when used within approved 
indication/dosage
MAP
Master Analysis Plan documents project standards in the statistical 
methods which will be used within the individual clinical trial SAP 
documentation
Period
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, 
etc.
Personal Data
Patient (subject) information collected by the Investigator that is 
transferred to Novartis for the purpose of the clinical trial. This data 
includes subject identifier information, study information and biological 
samples.
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at 
this time all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed for 
progression and/or survival
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which
provides evidence of preplanned analyses
Stage related to study timeline
A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size 
of the tumor, whether lymph nodes contain cancer, and whether the 
cancer has spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later

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Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including lymphodepleting chemotherapy.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-
investigational treatments in combination.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason
Subject Number
A unique identifying number assigned to each patient (subject) who 
enrolls in the study
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, 
e.g. premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium.
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified time points
Withdrawal of consent
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, and does not want any further visits 
or assessments, and does not want any further collection of personal 
data

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Protocol summary:
Full title
A Phase II, single arm, multicenter open label trial to determine the efficacy and
safety of tisagenlecleucel (CTL019) in adult patients with refractory or relapsed 
follicular lymphoma
Brief title
Efficacy and safety of tisagenlecleucel in adult patients with refractory or 
relapsed follicular lymphoma
Sponsor and clinical 
phase
Novartis, Phase II
Investigation type
Biological
Study type
Interventional
Purpose and rationale
Despite recent progress, follicular lymphoma (FL) remains incurable. A recent 
analysis showed that FL patients who relapsed within 2 years of R-CHOP 
therapy (approximately 20% of all patients) had poor prognosis, with a 5-year 
OS of 50% versus 90% in those who relapsed later (Casulo et al 2015). These 
data challenge the indolent behavior of FL and emphasize the need for novel 
therapies. 
CD19 represents an attractive therapeutic target because it is widely expressed 
on malignant B-cells, including FL (Freedman 2014). Tisagenlecleucel consists 
of autologous T cells that are genetically modified ex vivo via lentiviral 
transduction to express a chimeric antigen receptor (CAR) consisting of a CD19 
antigen recognition domain attached to intracellular signaling domains that 
mediate T-cell activation.  Data from patients with B-cell acute lymphoblastic 
leukemia (ALL), chronic lymphocytic leukemia (CLL) and DLBCL show a potent 
anti-tumor activity of tisagenlecleucel. 
In Study A2101J, 14 patients with refractory FL were infused with
tisagenlecleucel. Ten (71%) patients achieved CR and maintained it after 28.6 
months of follow up (Schuster et al 2017). 
Primary objective
Evaluate the efficacy of tisagenlecleucel therapy as measured by complete 
response rate determined by Independent Review Committee in the full analysis 
set based on Lugano 2014 classification response criteria (Cheson et al 2014).
Secondary objectives

Evaluate the efficacy of tisagenlecleucel as measured by additional efficacy 
measures, including Overall Response Rate (ORR), Duration of Response
(DOR), Progression Free Survival (PFS) and Overall Survival (OS).

Evaluate safety of tisagenlecleucel

Characterize the in vivo cellular kinetics (levels, expansion, persistence) of  
tisagenlecleucel transduced cells into target tissues (blood, bone marrow,  
and other tissues if available) and CD3+  tisagenlecleucel cells in 
peripheral blood

Characterize the incidence and prevalence of tisagenlecleucel
immunogenicity (humoral and cellular)

Characterize the impact of pre-existing and treatment induced 
immunogenicity on cellular kinetics, efficacy and safety

Describe the effect of  tisagenlecleucel therapy on patient reported 
outcomes
Study design
Single arm, multi-center, phase II study to determine the efficacy and safety of 
tisagenlecleucel in adult patients with relapsed or refractory FL with the 
following sequential phases: Screening, Pre-treatment, Treatment and Follow-
up. Efficacy and safety will be evaluated for 2 years post-infusion. Afterwards, 
patients will continue to be followed until 15 years post-infusion as per health 
authority guidelines in a separate study protocol.
Population
Approximately 113 adult patients with relapsed or refractory FL will be enrolled 
to obtain 90 patients treated with tisagenlecleucel.
Key inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following 
criteria (for detailed criteria see Section 5.2):

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
Written informed consent prior to any screening procedures

≥18 years of age at the time of ICF signature

FL (Grade 1, 2, 3A) confirmed histologically by central pathology review 
before tisagenlecleucel infusion.

FL meeting one of the following criteria:
o
Refractory to a second line or later line of systemic therapy 
(including  anti-CD20 antibodies and alkylating agents) or 
relapsed within 6 months after completion of a second line or 
later line of systemic therapy
o
Relapsed during anti-CD20 antibody maintenance (following 
at least two lines of therapies as above) or within 6 months 
after maintenance completion
o
Relapsed after autologous HSCT 

Radiographically measurable disease at screening
Key Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:

Evidence of histologic transformation 

Follicular Lymphoma Grade 3B

Prior anti-CD19 therapy

Prior gene therapy

Prior adoptive T cell therapy

Prior allogeneic hematopoietic stem cell transplant

Active CNS involvement by malignancy
Study treatment
The recommended dose will consist of a single intravenous (i.v.) infusion of 0.6 
– 6.0 x 108 CAR-positive viable T cells. 
Efficacy assessments

Radiologic imaging by PET and CT (or MRI, if CT contraindicated)

Bone marrow biopsy or aspirate

Tumor biopsy or cytology
Key safety assessments

Vital signs

Adverse events

Laboratory tests
Pharmacodynamic 
assessments

B cell and T cell levels (peripheral blood), 
 
Pharmacokinetic 
assessments
Tisagenlecleucel cellular kinetics by q-PCR and flow cytometry
Other assessments

Leukocyte gene expression profiling

Flow cytometry of peripheral blood before leukapheresis

Flow cytometry of leukapheresis product

Patient reported outcomes (SF-36v2, FACT-Lym, and EQ-5D-3L)
Data analysis
The primary endpoint is the complete response rate as determined by 
independent review committee (IRC). The complete response rate is defined as 
the proportion of patients with a best overall response of CR recorded from 
tisagenlecleucel infusion until progressive disease or start of new anticancer 
therapy, whichever comes first.
One interim analysis for overwhelming efficacy is planned for the study when 
approximately 50 patients of the planned 90 (55.6%) have received infusion and 
have either completed 6 months from study day 1 infusion or discontinued 
earlier.
The primary analysis will be performed when 90 patients have received infusion 
and completed 6 months from study day 1 infusion or discontinued earlier. 

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The primary efficacy analysis will be performed by testing the null hypothesis of 
complete response rate being less than or equal to 15% at one-sided 
cumulative 2.5% level of significance. The complete response rate will be 
summarized along with the 2-sided 95% exact Clopper-Pearson confidence 
intervals. P-value from binominal exact test will be provided. 
Key words
Refractory/relapsed, follicular lymphoma, CTL019, tisagenlecleucel 

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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Non-Hodgkin lymphomas (NHLs) comprise a heterogeneous group of lymphoid malignancies, 
including immature lymphoid neoplasms, mature B-cell neoplasms, mature T-cell and NK-cell 
neoplasms, and post-transplant lymphoproliferative disorders (Swerdlow et al 2008). Mature 
B-cell lymphomas are further classified into indolent lymphomas, e.g. follicular lymphoma 
(FL), and aggressive lymphomas, e.g. diffuse large B-cell lymphoma (DLBCL).
FL is the second most common histologic NHL subtype in the Western hemisphere (Ghielmini 
et al 2013). The estimated number of new cases in the US was 13,960 in 2016 (Teras et al 2016). 
Most patients are diagnosed during the sixth decade of their life but approximately 25% of 
patients are 40 years of age or younger (Jaglowski et al 2009). The translocation 
t(14;18)(q32;q21) is the genetic hallmark of follicular lymphoma, which results in the 
constitutive overexpression of B-cell lymphoma 2 protein (Bcl-2). FL cells also express surface 
immunoglobulins, B-cell lymphoma 6 protein (Bcl-6), and B-cell associated antigens such as 
CD10, CD19, CD20, and CD22. FL is classified histologically into three grades based on the 
number of centroblasts (Swerdlow et al 2008). 
Most FL patients have widespread disease at diagnosis, including peripheral and central lymph 
nodes, spleen and bone marrow. Current therapeutic approaches include “watchful waiting”, 
radiotherapy, radioimmunotherapy, and anti-CD20 monoclonal antibodies with or without 
chemotherapy. Follicular lymphoma frequently relapses and therefore is considered incurable. 
Patients relapsing within 2 years of therapy with R-CHOP (rituximab, cyclophosphamide, 
doxorubicin, vincristine, prednisone), presenting approximately 20% of cases, have a poor 
prognosis with a median 5-year survival of only 50% (Casulo et al 2015). 
The management of relapsed or refractory FL (r/r FL) includes non-cross resistant agents, 
autologous/allogeneic 
hematopoietic 
stem 
cell 
transplantation 
(HSCT), 
and 
phosphatidylinositol 3-kinase (PI3K) inhibitors, such as idelalisib and copanlisib. PI3K plays a 
critical role in the B-cell receptor pathway and is overexpressed in B-cell malignancies. Both 
idelalisib and copanlisib are approved for the treatment of FL that relapsed after at least two 
prior systemic therapies based on single arm, open label, phase 2 studies. In idelalisib-treated 
FL patients, overall response rate (ORR) was 56%, including 14% with complete response (CR) 
and 42% with partial response (PR), while median progression free survival (PFS) was 11.0 
months (Salles et al 2017). In copanlisib-treated FL patients, ORR was 59% (CR 14%, PR 44%), 
and median PFS was 12.2 months (FDA 2017).
Autologous HSCT does not result in significant overall survival benefit in patients with relapsed 
FL when compared to those treated with salvage chemoimmunotherapy (Epperla et al 2017). 
Allogeneic HSCT, a potentially curative therapy, is eligible for a very small number of selected 
patients. Moreover, it leads to high transplant-related mortality of 8-17% at 1 year (Epperla et 
al 2017).
Tisagenlecleucel is an adoptive cellular immunotherapy that uses autologous peripheral blood 
T cells that have been genetically modified ex vivo to target CD19 on the surface of B cells. 

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Recent studies indicate that tisagenlecleucel is highly effective in B cell malignancies, including 
r/r FL, where high CR rates and long duration of response are seen (Schuster et al 2017).
1.1.1
Historical experience with retroviral gene therapies
Retroviral vectors are useful gene delivery vehicles because they insert a deoxyribonucleic acid 
(DNA) copy of their genome into the host cell. However, insertion of vector sequences has the 
potential to up-regulate, dysregulate, or knockout local gene expression, which theoretically 
may lead to insertional oncogenesis. Malignant cell transformation after vector-mediated 
insertional mutagenesis has been observed in X-linked severe combined immunodeficiency 
(SCID-X1), chronic granulomatous disease (CGD), and Wiskott-Aldrich syndrome (WAS) 
where first-generation gamma-retroviral vectors harboring long terminal repeats (LTRs) with 
strong enhancer/promoter sequences were used (Hacein-Bey-Abina et al 2003, Howe et al 2008, 
Boztug et al 2010, Stein et al 2010, Persons and Baum 2011).  
Lentiviral vectors, a major subset of retroviral vectors, demonstrate distinct integration patterns 
compared to oncoretroviral vectors, which have been the predominant vector to date for gene 
transfer studies. The integration pattern of lentiviral vectors tends to be inside active 
transcription units as opposed to upstream in the locus control region where the insertion would 
have a greater chance of up-regulating gene expression. In addition, lentiviral vectors have no 
enhancer activity in their LTR regions and have lower levels of poly-A read-through, all factors 
which may improve gene transfer safety (Zaiss et al 2002). Thus, lentiviral vectors appear a 
safer alternative to oncoretroviral vectors, which is supported by animal models (Montini et al 
2006). Importantly, despite a very high transduction efficiency achieved using lentiviral vectors, 
molecular clonality studies have not indicated any reasons for concern, to date, in published 
clinical trials (Schambach et al 2013). 
With the exception of a single study in neonatal mice, lentiviral vectors have not been shown 
to be oncogenic in nature (Themis et al 2005).  A study in tumor prone mice demonstrated that 
lentiviral vector gene transfer into hematopoietic stem cells of up to an average of 6 copies per 
cell was not tumorigenic in contrast to retroviral vectors at an average copy number of 3 per 
cell (Montini et al 2006). It is notable that T cell leukemia is not a recognized side effect of 
human immunodeficiency virus (HIV) lentiviral infection.
A long-term retrospective study of >500 patient-years of collective patient samples tested for 
at least 11 years after infusion from three clinical trials using gamma-retroviral modified T cells 
did not show evidence of transgene silencing, atypical gamma-retroviral integration patterns, 
or clonal expansion (Scholler et al 2012). A favorable safety profile was also determined for a 
conditionally replicating HIV-derived lentivirus that delivered HIV envelope antisense to 
patient T cells. Moreover, no evidence for insertional mutagenesis or enrichment of vector 
copies near proto-oncogenes was observed after 21-36 months (Levine et al 2006) and 28-32 
weeks (Wang et al 2009). Another group reported no apparent risk of vector related adverse 
events (AEs) following 263 infusions of autologous, lentiviral transduced T cells with a long 
ribonucleic acid (RNA) antisense to HIV-1 envelope (McGarrity et al 2013). More recently ex 
vivo lentiviral transduced hematopoietic stem cells were used to correct an inherited storage 
disease in three children and in an inherited WAS in 3 children with follow up for up to 24 
months and 20-32 months, respectively. Lentiviral integration studies showed sustained gene 
marking with polyclonal engraftment of transduced cells with no evidence of aberrant clonal 

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expansion, no evidence of in vivo selection of clones carrying integrations near oncogenes and 
therefore no evidence of vector-induced genotoxicity (Biffi et al 2013, Aiuti et al 2013).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of tisagenlecleucel
Adoptive T cell therapy for cancer involves the infusion of native or genetically modified 
mature T cells that have the capacity to recognize and eliminate the patient’s malignant cells. 
In particular, chimeric antigen receptor-based approach involves engineering T cells with 
sequences that encode antibody-based antigen recognition moieties linked to signaling domains. 
Unlike T cell receptors (TCR), chimeric antigen receptors (CARs) allow the T cells to 
specifically target and destroy tumor cells in a Major Histocompatibility Complex (MHC) 
independent manner (Mellman et al 2011).
A promising target antigen for B cell malignancies is CD19, a cell-surface protein whose 
expression is restricted to B cells and their precursors (Sadelain et al 2003, Porter et al 2011), 
with no expression on hematopoietic stem cells or non-B cell tissues. It is a member of the 
immunoglobulin (Ig) superfamily and a component of a cell surface signal transduction 
complex that regulates signal transduction through the B cell receptor (Fearon et al 2000). Mice 
lacking CD19 have decreased number of B cells in peripheral lymphoid tissues, decreased B 
cell response to oral vaccines and mitogens, and decreased serum Ig levels (Fearon et al 2000).
First generation CARs contain the TCR activation signal domain consisting of TCRζ. Second 
generation CARs contain costimulatory signaling domains as well: either CD28 or 4-1BB. The 
3rd generation CARs contain further advancements such as double costimulatory modules 
comprised of CD28, 4-1BB plus TCRζ (June 2007, June et al 2009, Kohn et al 2011).
Tisagenlecleucel, a second generation CAR T cell therapy, is an adoptive cellular 
immunotherapy that uses the autologous peripheral blood T cells that have been genetically 
modified ex vivo to target CD19 on the surface of B cells. As shown in Figure 1-1, the CAR 
approach uses genetically programmed T cells transfected with chimeric receptor genes to 
combine the effector functions of T cells with the ability of antibodies to recognize predefined 
surface antigens with high specificity in a non-MHC restricted manner (Gross et al 1989, 
Pinthus et al 2003). These receptors have the ability to recognize intact membrane proteins 
independent of antigen processing. The tumor antigen binding function of CAR is usually 
accomplished by the inclusion of a single chain variable fragment (scFv) antibody, containing 
the heavy chain variable domain (VH) and light chain variable domain (VL) joined by a peptide 
linker of about 15 residues in length (Mullaney et al 2001).

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Figure 1-1
Tisagenlecleucel chimeric antigen receptor design
Recent clinical trials of tisagenlecleucel in r/r CLL, r/r ALL, and r/r B cell lymphomas 
(including FL) have shown promising and durable anti-tumor efficacy (Porter et al 2011, Grupp 
et al 2013, Maude et al 2014, Schuster et al. 2017). Consequently, tisagenlecleucel appears to 
be a therapeutic alternative for patients with B cell malignancies (including FL) refractory to 
the current therapies. For further information refer to the [Investigator’s Brochure].
1.2.2
Non-clinical experience
Extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent 
tumor models (Calogero et al 2000, Clay et al 2002, Hombach et al 2002, Pule et al 2003, 
Sadelain 2003). Others have used electroporation or retroviral vectors to create CAR T cells 
and have shown in vivo safety and efficacy of adoptively transferred T cells in immunodeficient 
mouse models (Willemsen et al 2000, Roessig et al 2002, Brentjens et al 2003, Cooper et al 
2003, Serrano et al 2006). The incorporation of costimulatory signaling modules such as CD28 
and 4-1BB in second generation CARs increases potency of the engineered T cells in pre-
clinical studies (Finney et al 1998, Krause et al 1998, Eshhar et al 2001, Maher et al 2002, 
Finney et al 2004, Friedmann-Morvinski et al 2005, Brentjens et al 2010). The pre-clinical data 
supporting CAR T cell persistence, expansion and anti-tumor efficacy have been published 
(Gross and Eshhar 1992, Milone et al 2009).
1.2.3
Clinical experience
There are currently 12 ongoing therapeutic studies of tisagenlecleucel therapy (Study B2101J, 
Study B2205J, Study B2202, Study B2208J, Study B2203J, Study A2201, Study A2101J, Study 
C2201, Study ZUS01T, Study UPCC-19416 and Study UPCC-39416), three ongoing long term 
follow up safety studies (Study A2207J, Study A2208J, and A2205B), and two single patient 
IND studies (Z2101I and B2002I). In addition, there is one completed study B2102J which had 
the last patient’s last visit on 06-Jul-2015. For more details on these studies please refer to the 
[Investigator’s Brochure].

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1.2.3.1
Clinical Cellular Kinetics
In adult r/r DLBCL patients from Study C2201, tisagenlecleucel typically exhibited an initial 
rapid expansion phase, achieving maximal expansion around Day 9 followed by a bi-
exponential decline. The persistence of tisagenlecleucel transgene in peripheral blood has been 
observed for up to 18 months. All responding patients demonstrated expansion of transgene 
levels. Neither patient characteristics nor prior therapy had any clinically relevant impact on 
expansion Cellular and humoral immunogenicity had no impact on the cellular kinetics or 
clinical outcome (Awasthi et al 2017).
1.2.3.2
Clinical efficacy
Tisagenlecleucel is approved by the FDA for the treatment of patients up to 25 years with B-
cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse
(Kymriah FDA 2017).
Tisagenlecleucel is being reviewed by the FDA and the EMA for the treatment of adult patients 
with refractory or relapsed DLBCL who are ineligible for autologous stem cell transplant, and 
by the EMA for the treatment of pediatric and young adult patients (age 3 to 25 years) with 
refractory or relapsed B-cell ALL.
Efficacy in r/r pediatric and young adult ALL
Out of the 63 tisagenlecleucel-infused patients, 52 (83%) achieved CR/CRi within 3 months 
after infusion, and all of them were MRD-negative. With a median follow-up of 4.8 months 
from response, the median duration of CR/CRi was not reached (range: 1.2 to 14.1+ months). 
Median time to onset of CR/CRi was 29 days (Kymriah FDA 2017).
Efficacy in adult r/r NHL
In Study C2201 (adult patients with r/r DLBCL), the overall response rate (ORR) was 53% (40% 
CR ad 14% PR), and 73.5% of the patients were relapse-free at 6 months of follow up. Most 
CR patients remained in CR at 3 months (Schuster et al 2017).
In Study A2101J, 14 patients with refractory FL were infused with tisagenlecleucel. Ten (71%) 
patients achieved CR and maintained it after 28.6 months of follow up (Schuster et al 2017).
1.2.3.3
Clinical Safety
Section 6.2.6 and Section 6.3.2 outline expected and potential toxicities related to 
tisagenlecleucel, most of which occur within 8 weeks of infusion.
Safety in r/r ALL
In patients with refractory or relapsed B cell precursor ALL, the most common adverse 
reactions were cytokine release syndrome (79%), hypogammaglobinemia (43%), infections-
pathogen unspecified (41%), pyrexia (40%), decreased appetite (37%), headache (37%), 
encephalopathy (34%), hypotension (31%), bleeding episodes (31%), tachycardia (26%), 
nausea (26%), diarrhea (26%), vomiting (26%), viral infectious disorders (26%), hypoxia (24%), 
fatigue (22%), acute kidney injury (22%), and delirium (21%). 

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Eleven deaths were reported for patients who received KYMRIAH, of which 2 deaths occurred 
within 30 days of infusion. Seven were disease-related, three were attributed to infections, and 
one to intracerebral hemorrhage (Kymriah FDA 2017).
Safety in adult r/r B-NHL
In study C2201, among the 99 patients assessed for safety, there were 58% with CRS (15% 
Grade 3, 8% Grade 4), 21% with neurological events (8% Grade 3, 4% Grade 4), 34% with 
infections (18% Grade 3, 2% grade 4), and 1% with tumor lysis syndrome (Grade 3 only). The 
median time to CRS onset was 3 days (range 1-51 days), median CRS duration was 7 days
(range 2-30 days); 15% of patients required tocilizumab and 11% of patients required 
corticosteroids. 
There were 16 patients who died after tisagenlecleucel infusion. Three patients died within 30 
days of tisagenlecleucel infusion due to DLBCL; 13 patients died more than 30 days (range 
from 41 to 236 days) after tisagenlecleucel infusion (12 due to DLBCL disease progression and 
1 due to chronic kidney disease not related to tisagenlecleucel). Overall, the safety events that 
occurred in study C2201 were manageable with close monitoring and established treatment 
algorithm; the safety profile has been well characterized (Schuster et al 2017).
In a recent published study conducted at the University of Pennsylvania (study A2101J), 36 
patients (20 DLBCL, 14 FL, 2 MCL) were treated with tisagenlecleucel. There was one death 
(possibly related to tisagenlecleucel) in a patient with FL who died 234 days after 
tisagenlecleucel infusion in pathological CR. For further information refer to the [Investigator’s
Brochure]. 
The recently approved CAR T cell therapy for adult r/r DLBCL caused CRS in 94% of patients 
(13% Grade ≥3) and neurologic toxicities in 87% of patients (31% Grade ≥3) (YESCARTA 
FDA 2017).
Vector-related Safety
To date, no vector-related AEs have been seen associated with higher tisagenlecleucel transgene 
levels of expression or persistence in three pediatric patients with r/r ALL and in 4 adult patients 
with r/r CLL.
Post-infusion monitoring for replication competent lentivirus (RCL) in trials with UPENN 
manufactured tisagenlecleucel therapy has shown no Vesicular Stomatitis Virus, Glycoprotein 
(VSV-G) by q-PCR detectable in any of the patient samples at time points up to 2 years
following infusion (7 patients from UPCC03712 trial; 16 patients form UPCC04409 trial, 11 
patients from CHP959 trial).
2
Rationale
2.1
Study rationale and purpose
Despite recent progress, FL remains incurable. A recent analysis showed that FL patients who 
relapsed within 2 years of R-CHOP therapy (approximately 20% of all patients) had poor 

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prognosis, with a 5-year OS of 50% versus 90% in those who relapsed later (Casulo et al 2015). 
These data challenge the indolent behavior of FL and emphasize the need for novel therapies. 
CD19 represents an attractive therapeutic target because it is widely expressed on malignant B-
cells but not on pluripotent stem cells or non-B cell tissues. CD19 is almost universally 
expressed in FL (Freedman 2014).  Tisagenlecleucel consists of autologous T cells that are 
genetically modified ex vivo via lentiviral transduction to express a chimeric antigen receptor 
(CAR) consisting of a CD19 antigen recognition domain attached to intracellular signaling 
domains that mediate T-cell activation.  Data from patients with B-cell acute lymphoblastic
leukemia (ALL), chronic lymphocytic leukemia (CLL) and DLBCL show a potent anti-tumor 
activity of tisagenlecleucel. 
In Study A2101J, 14 patients with refractory FL were infused with a single dose of CTL019 
cells (range 1×108 to 5×108 CTL019 cells). Ten (71%) patients achieved CR and maintained it 
after 28.6 months of follow up (Schuster et al 2017). 
The mechanism of action of tisagenlecleucel is independent of PI3K signaling. In addition, a 
cross-resistance with CD20-targeted therapies such as rituximab is not expected. Anti-CD19 
CAR T cells are also effective in CLL patients who progressed on ibrutinib (Turtle et al 2017).
2.2
Rationale for study design
This single arm, multi-center, phase II study will determine the efficacy and safety of 
tisagenlecleucel in adult patients with FL who failed at least 2 prior systemic therapies,
including an anti-CD20 antibody (e.g. rituximab) and an alkylating agent. Patients who were 
treated with other FL-targeting agents (including PI3K inhibitors) and patients who relapsed 
after autologous HSCT will also be included. 
The rarity of r/r FL patients, poor prognosis, no established standard of treatment, low response 
rates to currently available therapies (see section 1.1), and a high response rate to 
tisagenlecleucel reported recently in heavily pretreated FL patients (Schuster et al 2017) justify 
a single-arm study design.
2.3
Rationale for dose and regimen selection
The recommended dose in this trial is a single infusion of 0.6 – 6.0 x 108 CAR-positive viable
T cells, which is based on data from studies in CLL, ALL and NHL. The dose-response, dose-
safety, and dose-cellular kinetics analyses were performed using the data obtained from r/r 
DLBCL patients (data cut-off date: 8-March-2017) in Phase II study (Study C2201) to assess 
the impact of dose on exposure, response, and selected safety endpoints in order to select safe 
and efficacious doses for use in the prescribing setting (commercial) and Study E2202. 

Dose-response and dose-exposure: Across the dose range studied, dose and exposure 
were independent. Additionally, responses were observed across the full range of doses 
from 0.6 to 6.0×108 CAR-positive viable T cells.

Dose-safety: The probability of any grade neurologic events and time to resolution of 
cytopenia were not impacted by dose. There was an increase in probability of any grade 
and grade 3/4 CRS with increasing dose; however, the probability of grade 3/4 CRS was 
comparable across the dose range of 5.0 to 6.0×108 CAR-positive viable T cells. The 
model estimates from logistic regression analysis showed that the probability of grade 3/4 

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CRS for dose of 5.0×108 cells and 6.0×108 cells were comparable, i.e., 0.389 and 0.462, 
respectively. In addition, CRS is generally manageable in the study with the steps outlined 
in the CRS algorithm.
Based on the totality of the dose-safety, dose-efficacy, dose-exposure and exposure-response, 
and considering the positive benefit risk observed across the full range of doses, the following 
recommended dose will be utilized for Study E2202: 0.6 - 6.0×108 CAR-positive viable T cells. 
Clinically meaningful responses were seen across this range in patients with r/r DLBCL in 
Study C2201.
In a recently published study conducted the the University of Pennsylvania, 14 DLBCL and 14 
FL patients were infused with a median total tisagenlecleucel dose of 5.00 x 108 (range: 1.79 x 
108 – 5.00 x 108). The CAR T cell specific toxicities, such as CRS and neurotoxicity were less 
frequent and less severe than previously reported for tisagenlecleucel in ALL and CLL 
(Schuster et al 2017).   
For further information on tisagenlecleucel dosing in preclinical and clinical studies see 
[Investigator’s Brochure].
2.4
Rationale for lymphodepletion
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell 
proliferation (Dummer et al 2002), a finding that naive T cells begin to proliferate and 
differentiate into memory-like T cells when total numbers of naive T cells are reduced below a 
certain threshold (Goldrath 1999, Surh 2000). Host lymphodepletion may enhance the 
effectiveness of adoptively transferred T cells (Dummer et al 2002). Homeostatic T cell 
proliferation can lead to activation of certain immune cell subsets (King et al 2004), providing 
a clue to improved anti-tumor responses. T cells can undergo up to seven rounds of cell division 
after being deprived of contact with antigen presenting cells (Kaech 2001, van Stipdonk 2001). 
Lymphodepletion eliminates regulatory T cells and other competing elements of the immune 
system that act as “cytokine sinks”, enhancing the availability of cytokines such as IL-7 and IL-
15 (Klebanoff et al 2005). Data indicates that the increased antitumor efficacy of adoptive 
transfer following host conditioning is more than simply “making room” because the 
quantitative recovery of adoptively transferred T cells in mice reveals that in vivo proliferation 
following adoptive transfer is identical in mice with or without previous irradiation (Palmer et 
al 2004).
Fludarabine with cyclophosphamide has been the most commonly utilized lymphodepleting 
regimen with CD19 CAR-T cell therapies. It has been demonstrated that addition of fludarabine 
to cyclophosphamide  increases  CAR-T cell expansion and persistence and improves disease 
free survival rates in adult patients with r/r B-ALL (Turtle et al 2016).
In studies [B2202] and [B2205J] combined data (cut-off dates: 24-Apr-2017 for Study [B2202]; 
01-Feb-2016 for Study [B2205J]), 99 of 104 patients received lymphodepleting chemotherapy. 
Ninety-seven of these 99 patients received fludarabine and cyclophosphamide.
In study [C2201] 92 of 99 patients received lymphodepleting chemotherapy. Seventy-three
patients received fludarabine and cyclophosphamide, and 19 received Bendamustine.

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2.5
Rationale for choice of combination drugs 
Not applicable
2.6
Rationale for choice of comparators drugs 
Not applicable
2.7
Risks and benefits
Tisagenlecleucel administered to over 400 patients in clinical trials across the dose ranges tested 
has a well characterized safety profile in pediatric and adult patients with 14 patients with FL. 
Overall, it is anticipated that the benefits of tisagenlecleucel therapy, including complete and 
long-lasting remissions when compared to the current standards of care, will outweigh the risks
in this study.
Appropriate eligibility criteria are included in this protocol. Recommended guidelines for 
prophylactic or supportive management of study-drug induced AEs are provided in Section 
6.1.4 and Section 6.2.6.
The risk to patients in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, and adherence to the recommendations for the management of AEs known 
to be occur with tisagenlecleucel exposure, and guidance for the investigators in the
[Investigator’s Brochure].
Safety risks that have been identified with the use of tisagenlecleucel or are considered 
potentially associated with tisagenlecleucel are briefly outlined below.
2.7.1
Identified safety risks
2.7.1.1
Cytokine release syndrome (CRS) / macrophage activation syndrome 
(MAS)
Cytokine release syndrome (CRS) is an on-target toxicity that is associated with 
tisagenlecleucel cell expansion, activation and tumor cell killing. It is a result of systemic 
inflammatory response caused when cytokines are released by activated T cells, including IFNg, 
IL-6 and TNF.  Severe and life-threatening events have been observed in patients treated with
tisagenlecleucel. In r/r B-ALL, these appeared to be related to tumor burden, early CRS onset 
and early fever onset. In DLBCL, the probability of developing grade 3 and 4 CRS was 
increased with high tisagenlecleucel dose and exposure. In the majority of cases, CRS occurs 
within the first two weeks post-infusion and shows a wide range of clinical signs and symptoms 
(Table 2-1). Macrophage activation syndrome (MAS) is also associated with CRS as manifested 
by liver function test abnormalities, cytopenias, and coagulopathy. 
Life-threatening and fatal outcomes associated with CRS and severe concomitant infections 
have been observed in pediatric and adult patients treated with tisagenlecleucel.

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Table 2-1
Clinical signs and symptoms associated with CRS (Lee et al 2014)
Organ system
Symptoms
Constitutional
Fever ± rigors, malaise, fatigue, anorexia, myalgia, arthralgia, nausea, vomiting, headache
Skin
Rash
Gastrointestinal
Nausea, vomiting, diarrhea
Respiratory
Tachypnea, hypoxemia
Cardiovascular
Tachycardia, widened pulse pressure, hypotension, increased cardiac output (early), 
potentially diminished cardiac output (late)
Coagulation
Elevated D-dimer, hypofibrinogenemia ± bleeding
Renal
Azotemia
Hepatic
Transaminitis, hyperbilirubinemia
Neurologic
Headache, mental status changes, confusion, delirium, word finding difficulty or frank 
aphasia, hallucinations, tremor, dysmetria, altered gait, seizures
A therapeutic strategy for the management of CRS is provided in Section 6.2.6.1 that should be 
followed.
2.7.1.2
Neurological events
Neurological events have been observed in patients following various types of T cell directed 
therapy including tisagenlecleucel and other CAR-T cell therapies of other institutions. The 
pathophysiology for neurotoxicity is not fully understood but thought to be related to 
generalized T cell mediated inflammation rather than direct toxicity of CAR-T cells on the brain 
(Tey 2014). Some of the neurological events observed may be related to CRS, but whether this 
results from systemic cytokines crossing the blood brain barrier and engaging cytokine 
receptors in the brain or from direct cytokine production in the CNS is not clear (Maus et al 
2014). There are no clear predictors of neurologic toxicity. 
Manifestations of neurological events may include a multifarious set of symptoms and 
diagnoses including agitation, altered state of consciousness, aphasia, confusion, delirium, 
disorientation, encephalopathy, headache, mutism, seizures or tremor. Some of the events are 
severe and may have a life-threatening outcome. 
The majority of neurological events were observed within 8 weeks following tisagenlecleucel
infusion and were transient, however a delayed onset (i.e.> 8 weeks) may occur. 
Notably, the onset of neurological toxicity can be concurrent with CRS, following resolution of 
CRS or in the absence of CRS. Onset of neurological events may be concurrent with high fever 
during the development and at the time of maximal grade of CRS. The incidence appeared to 
be greater with higher CRS severity, prior history of CNS leukemia, and history of other prior 
CNS diseases, and did not appear to be prevented by tocilizumab. Encephalopathy typically 
occurred after peak CRS symptoms and tended to be self-limiting with some exceptions. A few 
have occurred after CRS and were not associated with high fevers. 
The causality assessment of neurological events in patients treated with tisagenlecleucel can be 
confounded as CNS toxicity may be associated with chemotherapy used for lymphodepletion 
and the presence of comorbid conditions such as CRS, fever and infections.
For the management of neurological events see Section 6.2.6.2.

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2.7.1.3
Hypersensitivity including acute infusion reactions
Since tisagenlecleucel is an autologous cellular product, hypersensitivity may occur due to the 
excipients (such as dimethyl sulfoxide (DMSO) or dextran 40) of the infused solution in which 
the cells are dispersed. In addition, host immune responses may result from presentation of 
CAR transgene expressed immunogenic epitopes including murine sequences in the scFv 
extracellular binding domain (derived from a murine monoclonal antibody) or novel epitopes 
arising at junctions between components of the CAR fusion polypeptide (Park et al 2007; 
Lamers et al 2006; Lamers et al 2007; Lamers et al 2011). 
Clinically, hypersensitivity reactions can be classified as 'immediate' or 'delayed' depending on 
their onset after drug administration (Corominas et al 2014; Limsuwan and Demoly 2010). In 
principle, immediate reactions including acute infusion reactions occur within less than 1 hour 
after drug administration and may present in a wide range of symptoms such as fever, chills, 
nausea, urticaria, angioedema, rhinitis, conjunctivitis, dyspnea, bronchospasm, tachycardia, 
hypotension, anaphylaxis or anaphylactic shock. Delayed hypersensitivity reactions appear 
after more than 1 hour and up to several days after drug exposure and could include variable 
cutaneous symptoms such as late-occurring urticaria, maculopapular eruptions, fixed drug 
eruptions, vasculitis, toxic epidermal necrolysis, Stevens- Johnson syndrome, or drug reaction 
with eosinophilia and systemic symptoms (DRESS) (Averbeck et all 2007; Descotes 2012; 
Corominas et al 2014; Vultaggio et al 2016). 
To date, the majority of events observed after tisagenlecleucel infusion were mild or moderate 
in severity, manageable and recovered. 
Patients will have typically received lymphodepleting chemotherapy that is completed several 
days prior to tisagenlecleucel infusion. Therefore it should be kept in mind that symptoms and 
findings at this time may also be the result of the onset of chemotherapy related toxicities.
A therapeutic strategy for the management of hypersensitivity including acute infusion 
reactions is provided in Section 6.2.6.3.
2.7.1.4
Tumor lysis syndrome (TLS)
Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic disorder that occurs 
when tumor cells undergo rapid decomposition spontaneously or in response to cytoreductive 
therapy. It tends to occur particularly with highly effective therapies and in patients with high 
tumor burden and cancers with a high potential for cell lysis include high-grade lymphomas, 
acute leukemias, and other rapidly proliferating tumors. 
Metabolic abnormalities characteristic of TLS include abnormally high serum uric acid levels 
(hyperuricemia) resulting from the breakdown of purine-containing nucleic acids and major 
electrolyte imbalances such as hyperkalemia, hyperphosphatemia, and hypocalcemia. Delayed 
recognition of the metabolic imbalances caused by the massive release of tumor cell contents 
may result in clinical complications such as acute kidney injury, seizures, and cardiac 
arrhythmias (Mughal et al 2010).
Tumor lysis syndrome was clinically observed in a timely relation to tisagenlecleucel T cell 
expansion. In the clinical experience with tisagenlecleucel thus far, most cases of TLS had a 

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grade 3 in CTCAE severity, however, the risk has been moderate to low with appropriate 
monitoring after lymphodepleting chemotherapy, prophylaxis and treatment as needed.
A therapeutic strategy for the management of TLS is provided in Section 6.2.6.4.
2.7.1.5
Infections
There is an increased risk and severity of infections in patients with longer and more intense 
immunosuppression. Patients treated with tisagenlecleucel are at risk of infection for several 
reasons: 

Lymphodepleting chemotherapy prior to treatment with tisagenlecleucel may cause severe 
neutropenia and B-cell depletion from tisagenlecleucel itself is known to be associated 
with infections.

B-cell depletion is known to be associated with hypogammaglobulinemia that also 
contributes to the risk.

Patient with prolonged and profound immunosuppression may be at enhanced risk for 
more frequent and severe opportunistic infections 

Underlying bone marrow disease or dysfunction further increases the risk of infections
Serious infections were observed in patients after tisagenlecleucel infusion, some of which were 
life-threatening or fatal.
Viral Reactivation
Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic 
failure and death, can occur in patients treated with drugs directed against B cells. Hepatitis 
cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive, and 
also in patients who are HBsAg-negative but hepatitis B core antibody (anti-HBc) positive. 
HBV reactivation has occurred in patients who appear to have resolved hepatitis B infection 
(i.e., HBsAg-negative, anti-HBc-positive and hepatitis B surface antibody [anti-HBs] positive).
HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid 
increase in serum HBV DNA level or detection of HBsAg in a person who was previously 
HBsAg-negative and anti-HBc-positive. Reactivation of HBV replication is often followed by 
hepatitis, as indicated by an increase in transaminase levels. In severe cases, increase in bilirubin 
levels, liver failure, and death can occur.
Patients with active or prior hepatitis B, hepatitis C or HIV confirmed by serology will not be 
enrolled in the study; for detailed exclusion criteria see Section 5.2, for serology assessment see 
Appendix 2.
A therapeutic strategy for the management of infections is provided in Section 6.2.6.5.
2.7.1.6
Febrile neutropenia
Febrile neutropenia observed with tisagenlecleucel can be caused due to multiple factors, 
including underlying bone marrow disease, prior chemotherapies, radiation treatments or 
lymphodepleting chemotherapy, reduced response to growth factors (either exogenous or 
endogenous) in addition to B-cell aplasia that may favor a production of auto-antibodies binding 

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to the neutrophil surface resulting in neutropenia and also disturb the balance between 
granulopoiesis and lymphopoiesis in the bone marrow (Tesfa and Palmblad 2011). 
Febrile neutropenia and associated events such as grade 3 or grade 4 decreased neutrophil 
counts with elevated temperature were reported in clinical studies with tisagenlecleucel. The 
use of chemotherapy is known to be associated with the risk of neutropenia and if severe, with 
febrile neutropenia. The risk of neutropenia depends on various factors such as type and dose 
of chemotherapy used, age, gender, performance status and baseline hematology lab data. As 
lymphodepleting therapy is used in all patients with a WBC count >1000 cells/μL, febrile 
neutropenia is seen in patients treated with tisagenlecleucel regimen. Also, as lymphodepleting 
therapy is given close to the infusion of tisagenlecleucel (within two weeks), therefore, 
overlapping toxicities can be expected.
A therapeutic strategy for the management of febrile neutropenia is provided in Section 6.2.6.6.
2.7.1.7
Prolonged depletion of normal B cells and agammaglobulinemia
B-cell aplasia is an expected on-target toxicity of a successful CD19-directed CAR T cell 
therapy and a useful surrogate reflecting the persistence of CAR T cells and effectiveness of 
treatment. B-cell aplasia is observed in all responding patients in B-ALL. The AEs observed 
after tisagenlecleucel infusion were managed well by treatment with immunoglobulins. 
Loss of B-cells can result in hypo- to agammaglobulinemia, potentially rendering the patients 
more susceptible to infections, especially with encapsulated organisms; and viral reactivation 
such as herpes viruses or rarely in progressive multifocal leukoencephalopathy (PML) (Section 
2.7.1.7.1). 
Given that a typical T-lymphocyte may have a lifespan of 40 years, tisagenlecleucel may 
potentially be detectable in a patient for a very prolonged period and prolonged depletion of B-
cells may occur, in particular in the subset of patients who continue to demonstrate a tumor 
response. Long term data are currently not available. 
2.7.1.7.1 Progressive multifocal leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous 
system (CNS) associated with reactivation of prior John Cunningham (JC) virus infection. 
Patients classically present with focal neurologic deficits (e.g., weakness, speech difficulties, 
unsteady gait and hemiparesis), ophthalmic symptoms (e.g., homonymous hemianopia 
progressing to cortical blindness), personality changes, and cognitive dysfunction. Imaging (CT 
or MRI) shows lesions in the white matter, most commonly of the occipitoparietal lobe and 
without mass effect.
A therapeutic strategy for the management of B cell depletion with resulting 
hypogammaglobulinemia is provided in Section 6.2.6.7.
2.7.1.8
Hematopoietic cytopenias lasting greater than or equal to 28 days
Haematopoietic cytopenias are an on-target effect after tisagenlecleucel infusion and activity of 
tisagenlecleucel on normal B-cells.

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Patients may exhibit haematopoietic cytopenias for several weeks as a result of exposure to 
tisagenlecleucel, bridging and lymphodepleting chemotherapies. Prolonged neutropenia has 
been associated with increased risk of infection. Myeloid growth factors, particularly GM-CSF, 
are not recommended during the first 3 weeks after tisagenlecleucel infusion or until CRS has 
resolved.
A therapeutic strategy for the management of hematopoietic cytopenias is provided in Section 
6.2.6.8.
2.7.2
Potential safety risks
Thus far, an association with the potential safety risks briefly described below and 
tisagenlecleucel have not been confirmed. However, these topics are being closely monitored 
due to their clinical relevance.
2.7.2.1
Cerebral edema
Fatal cases of cerebral edema, soon after infusion with rapid evolution, have been reported with 
CAR-T cell therapies other than tisagenlecleucel; in five patients in the Rocket study evaluating 
JCAR015 for the treatment of ALL and in one patient in the Zuma-1 study evaluating KTE-19 
for the treatment of CLL. The patient in the Zuma-1 study is described as becoming febrile on 
Day 1 and progressing from grade 3 to grade 4 CRS, refractory to tocilizumab and 
dexamethasone, by Day 4. Cerebral edema developed on Day 9, was refractory to siltuximab 
and mannitol, and led to death on Day 11 (Turtle et al 2017).
To date there have been no such cases reported for tisagenlecleucel. 
2.7.2.2
Replication competent lentivirus (RCL) production
Replication-competent lentivirus (RCL) may be generated during tisagenlecleucel
manufacturing using a lentiviral vector to encode anti-CD19 CAR or subsequently after 
introduction of vector transduced viable T cells into the patient. 
However, an RCL resulting from manufacturing is highly unlikely since elements are 
incorporated in the design of the vector system that minimize vector recombination and 
generation of RCL. Furthermore, the vector used to transduce the product undergoes sensitive 
assays for detection of RCL Thus patients will only receive cell products that meet RCL release 
criteria considered sufficient to confirm the absence of RCL in tisagenlecleucel and the 
negligible probability of de novo generation of any RCL.
No AEs related to generation of RCL were noted post-infusion in the tisagenlecleucel
development program. However, generation of an RCL following tisagenlecleucel infusion 
remains a theoretical possibility. The development of RCL could pose a risk to both the patients 
and their close contact(s), and therefore, monitoring for RCL will be conducted during the 
course of the trial (see [Investigational Product Handling Manual] for a description of the 
assays). Since the probability and characteristics of an RCL are unknown, no regulatory 
guideline for the management of RLC positive patients exist to date.

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As per guidance for gene therapy medicinal products, patients exposed to tisagenlecleucel will 
be monitored for 15 years following last treatment for vectors persistence and RCL within the 
long-term follow-up study.
The Management of this potential risk is addressed in Section 6.2.6.9.
2.7.2.3
New or secondary malignancies (including vector insertion site 
oligo/monoclonality)
Insertion of lentiviral vector sequences throughout the genome has the potential to dysregulate 
local host cell gene expression with a theoretical risk of insertional oncogenesis resulting from 
disruption of normal function of genes that control cell growth and potential risk of development 
of secondary malignancies.
Vector-mediated insertional mutagenesis  and subsequent malignant cell transformation after 
gene correction based on autologous HSC gene therapy has been observed in X-linked severe 
combined immunodeficiency (SCID-X1), chronic granulomatous disease (CGD), and Wiskott-
Aldrich syndrome (WAS), where first-generation gamma-retroviral vectors harboring long 
terminal repeats (LTRs) with strong enhancer/promoter sequences were used (Hacein-Bey-
Abina et al 2003, Howe et al 2008, Botzug et al 2010, Stein et al 2010, Persons and Baum 2011).
In contrast, tisagenlecleucel uses third generation self-inactivating lentiviral vector. Insertional 
mutagenesis was addressed in two lentivirus insertion site analysis (LISA) studies where 12 
batches of manufactured patient product ready for infusion and two batches of product 
manufactured from healthy donor cells were analyzed. The results indicate that there was no 
preferential integration near genes of concern, no preferential sites of integration (hot spots), 
and no preferential outgrowth of cells harboring integration sites of concern.
Tisagenlecleucel is based on autologous, fully differentiated T cells and therefore the 
carcinogenicity risk is considered to be low in comparison to genetic modification or repair 
such as HSC. In a recent review of CAR-T cell therapies, Bonifant et al (2016) as well as 
Mohanlal et al (2016) discussed that to date no cases of malignant transformation have been 
reported for genetic modification of T cells and that there currently is no evidence for vector-
induced immortalization, clonal expansion, or enrichment for integration sites near genes 
implicated in growth control or transformation. This is supported by the results of the lentivirus 
insertion site analysis (LISA) studies performed during the development of tisagenlecleucel.
Theoretically, CAR-positive viable T cells could proliferate without control of normal 
homeostatic mechanisms. In pre-clinical studies (Milone et al 2009) and clinical experience to 
date (Porter et al 2011, Grupp et al 2013, Maude et al 2014), CAR-positive viable T cells have 
only proliferated in response to physiologic signals or upon exposure to CD19 antigen. In the 
context of tisagenlecleucel therapy, it is expected that the T cells will proliferate in response to 
signals from the CD19 expressing malignant tumor and normal B cells. This could be either 
harmful depending on the extent of proliferation or beneficial, since clonal dominance of 
adoptively transferred T cells has been associated with tumor reduction in adoptive transfer 
trials (Dudley 2002, Dudley 2005).
The management of this potential risk is addressed in Section 6.2.6.10.

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2.7.2.4
Exacerbation of an existing or new incidence of autoimmune disease
The risk of autoimmune reaction with tisagenlecleucel is low since CD19 is not present on most 
normal tissue other than normal B-cells. New incidence or exacerbation of an autoimmune 
disorder has not been observed with tisagenlecleucel thus far. However, instances of new or 
exacerbation of autoimmune disorder were reported in the literature, both for diseases without 
an obvious underlying autoimmune cause such as stroke (Kamel and Iadecola 2012) and for 
ones with a clear autoimmune basis such as multiple sclerosis and optic neuritis (Feldman et al 
2015). Both cellular and cytokine driven exacerbations have been observed in patients receiving 
chemotherapy; CNS autoimmune disorders (such as optic neuritis) have been reported to be 
exacerbated by both mechanisms (Skaper et al 2014, Cramer et al 2015). In addition, the use of 
tocilizumab, a monoclonal antibody against the IL-6 receptor, can exacerbate demyelinating 
disease, and therefore it is to be used with precaution in cases of demyelinating disease 
(Actemra® USPI). Prior chemotherapy and radiation also contribute to the risk.
No AEs associated with this potential were observed in tisagenlecleucel clinical trials.
2.7.2.5
New incidence of a hematologic disorder
There is potential risk of a hematologic disorder such as myelodysplastic syndrome, aplastic 
anemia or bone marrow failure, given that tisagenlecleucel is a genetically modified cell product 
that may have the potential to affect hematopoietic cell function, as could prior chemotherapy 
and radiation given for the underlying malignancy.
2.7.2.6
New incidence or exacerbation of an existing neurological event
Neurological events is an identified risk for tisagenlecleucel (see Section 2.7.1.2). Underlying 
neurological disorders may become exacerbated by chemotherapy, lymphodepletion or 
subsequent immunosuppression of tisagenlecleucel treatment. There is currently no evidence 
that tisagenlecleucel is associated with exacerbation of an existing neurological event. 
2.7.2.7
Graft versus host disease (GVHD)
The chance of graft versus host disease (GVHD) occurring in patients is low, but it is a potential 
risk with tisagenlecleucel therapy in patients with mixed chimerism of host and donor 
hematopoietic cells due to prior allogeneic HSCT. A study of activated donor lymphocyte 
infusions (ex vivo activated cells collected from the donor and grown in the same fashion as 
tisagenlecleucel but without the CAR introduction) did not show high rates of GVHD (2/18 
patients with grade 3 GVHD and none with grade 4) (Porter et al 2006). Of 18 ALL patients 
treated with autologous tisagenlecleucel therapy who had relapsed after prior allogeneic HSCT 
with residual mixed chimerism, none have developed GVHD after autologous tisagenlecleucel 
infusion (Maude et al 2014). Long term data are currently limited.
For the management of GVHD see Section 6.2.6.11.

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2.7.3
Other risks
2.7.3.1
Pregnancy, lactation, and effects on fertility
No preclinical reproductive studies have been conducted with tisagenlecleucel to assess whether 
it can cause fetal harm when administered to a pregnant woman. There is a potential risk that 
immunologically active maternal tisagenlecleucel positive T cells may cross the placenta. The 
survival of normal maternal cells in the fetus is usually limited owing to effective rejection by 
an immunocompetent target. However maternal cells can persist in immunocompetent offspring 
into adult life (maternal microchimerism (MMc)). MMc has been observed in healthy fetus and 
adults, and was observed in up to 42% of cord blood samples from healthy newborns (Muller 
et al 2001). The persistence of maternal cells in offspring’s tissues and circulation has been 
associated with autoimmune disorders. The histocompatibility antigens (HLA) disparity 
between mother and fetus has been hypothesized as responsible for the pathogenesis of some 
auto-immune diseases. 
Maternal CD19 CAR T cells may be expected to cross the placental barrier and potentially 
exhibit MMc similar to that of normal T cells. The impact on the offspring’s B cells is unknown. 
The testicular environment is usually immunosuppressive to T cells, leading to control and low 
numbers of T lymphocytes including CD19 CART cells (Hedger and Meinhardt 2000). If 
transferred to female reproductive tract along with sperm, T cells are likely to be recognized as 
non-self by the female immune system and therefore be destroyed. A fundamental risk may 
arise from the presence of RCL the female organism may be exposed to after sexual intercourse. 
However, the principal design of the vector and the analytic measures taken during 
manufacturing of tisagenlecleucel will exclude the presence of RCL with highest probability, 
and the female risk for exposure to tisagenlecleucel and/or RCL is considered extremely low.
As it is also not known whether tisagenlecleucel can cause fetal harm when administered to a 
pregnant woman or can affect reproduction capacity, tisagenlecleucel should not be 
administered to pregnant women and care should be taken to avoid conceptions. 
Therefore, women of child bearing potential (WOCBP), defined as all women physiologically
capable of becoming pregnant, and sexually active males are excluded from clinical trials with 
tisagenlecleucel unless they use adequate contraception. No data are currently available to 
determine the duration of contraception after receiving tisagenlecleucel. Women of child 
bearing potential and sexually active males must be informed that taking the study treatment 
may involve unknown risks to the fetus if pregnancy were to occur during the study, and agree 
that in order to participate in the study they must adhere to the contraception requirements 
outlined in the exclusion criteria. If there is any question that the patient will not reliably comply, 
they should not be entered or continue in the study.
There is no information regarding the presence of tisagenlecleucel in human milk, the effect on 
the breast-fed child or the effects of tisagenlecleucel on milk production. Nursing women are 
excluded from participation in this study.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.

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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to 
Section 10.4
Evaluate the efficacy of tisagenlecleucel 
therapy as measured by CRR determined 
by IRC
Complete response rate (CRR) determined by an Independent Review Committee (IRC) in the efficacy 
analysis set (EAS) based on Lugano 2014 classification response criteria (Cheson et al 2014). 
Key secondary
Refer to 
Section 10.5.1
Not applicable
Not applicable
Other Secondary 
Refer to 
Section 10.5.2
Evaluate the efficacy of tisagenlecleucel as 
measured by additional efficacy measures, 
including ORR, DOR, PFS and OS
ORR, including complete response (CR) and partial response (PR) determined by IRC in the FAS 
based on Lugano 2014 classification. 
DOR, defined as time from achievement of CR or PR to relapse or death due to FL, based on IRC
DOR for CR only, defined as time from achievement of CR to relapse or death due to FL, based on IRC
PFS, defined as time from tisagenlecleucel infusion to first documented disease progression or death 
due to any cause, based on IRC
OS, defined as time from tisagenlecleucel infusion to death due to any cause
Evaluate safety of tisagenlecleucel
Type, frequency and severity of adverse events and laboratory abnormalities
Characterize the in vivo cellular kinetics 
(levels, expansion, persistence) of 
tisagenlecleucel transduced cells into 
target tissues (blood, bone marrow,  and 
other tissues if available) and CD3+ 
tisagenlecleucel cells in peripheral blood, 
summarized by clinical response
Summary of qPCR detected tisagenlecleucel transgene concentrations in peripheral blood, bone 
marrow and other tissues by time point and clinical response status
Summary of cellular kinetic parameters: Cmax, Tmax, AUC0-28 and AUC0-84d, T1/2, and/or other 
relevant parameters in peripheral blood; bone marrow  and other tissues by clinical response as 
appropriate 
Summary of exposure and cellular kinetic parameters of CD3+ tisagenlecleucel cells in peripheral blood 
detected by flow cytometry
Characterize the incidence and prevalence 
of tisagenlecleucel immunogenicity
(humoral and cellular) 
Summary of pre-existing and treatment induced immunogenicity (cellular and humoral)  of 
tisagenlecleucel
Characterize the impact of pre-existing and 
treatment induced immunogenicity (cellular 
Levels of pre-existing and treatment induced immunogenicity
Cellular kinetic parameters (Cmax, AUCs, Tlast), concentration-time profile tisagenlecleucel by 
immunogenicity category (positive/negative)

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Objective
Endpoint
Analysis
and humoral) on cellular kinetics, efficacy
and safety
Efficacy (ORR, DOR, PFS)
Safety (B-cell levels, CRS grades, neurologic events)
Describe the effect of tisagenlecleucel
therapy on Patient reported outcomes 
(PRO)
Summary scores of PRO measured by SF-36 version 2, EQ-5D-3L and FACT-Lym quality of life 
questionnaires

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Objective
Endpoint
Analysis

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4.2
Timing of interim analyses and design adaptations
One interim analysis is planned for the study when approximately 50 patients have received 
tisagenlecleucel infusion and all of them have completed 6 months from infusion or
discontinued earlier. The study will not be stopped for outstanding efficacy at the interim 
analysis regardless of the analysis results.
Please refer to Section 10.7.
4.3
Definition of end of study
The end of study is when all patients have completed Month 24 evaluation or discontinued
prematurely. Patients who have completed their Month 24 visit before the end of the study will 
be followed for assessments at onsite visits every 6 months (Q6M) until the end of the study.
The primary analysis will be performed when 90 patients have received tisagenlecleucel
infusion and completed 6 months from study Day 1 infusion or discontinued earlier.
In addition, semiannual and annual evaluations will be performed for up to 15 years from the 
date of infusion on all patients under a separate long term follow-up (LTFU) protocol as 
recommended by Health Authority guidance for patients treated with gene therapies. All 
patients who either complete or prematurely discontinue from the study will be enrolled in this 
destination protocol at the time of study completion/discontinuation (a separate informed 
consent form will be provided for this protocol; Section 7.1.8).
Patients may continue to be followed under the current protocol for survival, which can be 
conducted via a form or telephone contact until the end of the study as defined above and then 
under the LTFU protocol [CCTL019A2205B].
4.4
Early study termination 
The study can be terminated at any time for any reason by Novartis. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the patient welfare and safety. Should this be necessary, the 
patient must be seen as soon as possible and the same assessments should be performed as 
described in Section 7.1.6 for a withdrawn patient. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the patient’s interests. For patients who have received tisagenlecleucel infusion, 
a long term post-study follow-up for delayed AEs including monitoring for lentiviral safety will 
still continue under a separate destination protocol (CCTL019A2205B) for 15 years post 
infusion per health authority guidelines. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial.

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5
Population
5.1
Patient population
Approximately 113 adult patients with r/r FL will be enrolled (for r/r/ FL definition see 
Inclusion Criterion 4) to obtain 90 patients treated with tisagenlecleucel. Patients enrolled in 
this study are not permitted to participate in additional investigational drug or device studies
simultaneously. The investigator or designee must ensure that only patients who meet all the 
following inclusion and none of the exclusion criteria are offered treatment in the study.
It is anticipated that the life expectancy of enrolled patients is 12 weeks or more.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent prior to any screening procedures
2. ≥18 years of age at the time of ICF signature 
3. FL (Grade 1, 2, 3A) confirmed histologically by central pathology review before 
tisagenlecleucel infusion.
Sufficient formalin-fixed paraffin-embedded (FFPE) tumor samples obtained for this study 
with a corresponding pathology report must be submitted. If not clinically feasible, an 
archival tumor biopsy from the most recent relapse may be submitted. However, in case of 
clinical symptoms, abnormal laboratory tests, and radiological images suggesting histologic 
transformation, a fresh biopsy will be required. Excisional biopsies should be submitted; if
not possible, a core needle biopsy is allowed. Fine needle aspiration (FNA) is not allowed. 
4. FL meeting one of the following criteria:

Refractory to a second line or later line of systemic therapy (including an anti-CD20 
antibody and an alkylating agent) or relapsed within 6 months after completion of a 
second line or later line of systemic therapy 

Relapsed during anti-CD20 antibody maintenance (following at least two lines of 
therapies as above) or within 6 months after maintenance completion

Relapsed after autologous HSCT 
NOTE: Previous treatment with other FL-targeting medications (e.g. PI3K inhibitors) is 
allowed provided that patients recovered from all treatment-related adverse events.
5. Radiographically measurable disease at screening defined as:

At least one nodal lesion greater than 20 mm in the long axis, regardless of the length 
of the short axis AND/OR

Extranodal lesions (outside lymph node or nodal mass, including liver and spleen) 
greater than 10 mm in long AND short axis
For detailed information please refer to Appendix 1 Guidelines for efficacy evaluation in 
lymphoma studies
6. ECOG performance status that is either 0 or 1 at screening
7. Patients must meet the following laboratory values without transfusion at screening:

Absolute neutrophil count (ANC) ≥ 1,000/mm3 (≥ 1×109/L)

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
Absolute lymphocyte count (ALC) > 300/mm3 (> 0.3×109/L) 

Absolute number of CD3+ T cells > 150/mm3 (> 0.15×109/L)

Platelets ≥ 50 000/mm3 (≥ 50×109/L)

Hemoglobin ≥8.0 g/dl (≥4.9 mmol/L)

A serum creatinine of ≤1.5 times ULN or eGFR ≥ 60 mL/min/1.73 m2

ALT/AST ≤ 5 times the ULN

Total bilirubin ≤ 1.5 times ULN (with the exception of patients with Gilbert’s 
syndrome. Patients with Gilbert’s syndrome may be included if their total bilirubin is 
≤ 3.0 times ULN and direct bilirubin ≤ 1.5 times ULN
8. Adequate pulmonary function defined as:

No or mild dyspnea (≤ Grade 1)

Oxygen saturation measured by pulse oximetry > 90% on room air 
9. Must have a leukapheresis product of non-mobilized cells accepted for manufacturing 
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Evidence of histologic transformation
2. Follicular Lymphoma Grade 3B
3. Prior anti-CD19 therapy
4. Prior gene therapy
5. Prior adoptive T cell therapy 
6. Prior allogeneic hematopoietic stem cell transplant
7. Active CNS involvement by malignancy 
8. Active neurological autoimmune or inflammatory disorders (e.g. Guillain-Barre 
syndrome, Amyotrophic Lateral Sclerosis)
9. Investigational medicinal product within the last 30 days or five half-lives (whichever is 
longer) prior to screening 
NOTE: Investigational therapies must not be used at any time while on study until the first 
progression following tisagenlecleucel infusion
10. Presence of active or prior hepatitis B or C as indicated by serology (for detailed criteria 
see Appendix 2) Serology must be repeated, if the interval between testing prior to 
lymphodepletion and tisagenlecleucel infusion exceeds 8 weeks
11. Presence of HIV antibody. Serology must be repeated, if the interval between testing 
prior to lymphodepletion and tisagenlecleucel infusion exceeds 8 weeks
12. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture 
positive ≤ 72 hours prior to tisagenlecleucel infusion)
13. Cardiac or cardiac repolarization abnormality, including any of the following:

History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft 
(CABG) within 6 months prior to starting study treatment

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
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II 
and third degree AV block)

LVEF <45% as determined by ECHO or MRA or MUGA

NYHA functional class III or IV (Chavey et al 2001)
14. Previous or concurrent malignancy with the following exceptions:
a. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is 
required prior to enrollment)
b. In situ carcinoma of the cervix or breast, treated curatively and without evidence of 
recurrence for at least 3 years prior to enrollment
c. A primary malignancy which has been completely resected and in complete remission 
for ≥ 3 years at the time of enrollment
15. Pregnant or nursing (lactating) women
NOTE: female study participants of reproductive potential must have a negative serum 
or urine pregnancy test performed within 24 hours before leukapheresis, 
lymphodepletion and prior to tisagenlecleucel infusion.
16. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while
taking study treatment and for at least 12 months after the tisagenlecleucel infusion and 
until CAR T-cells are no longer present by qPCR on two consecutive tests. Highly 
effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. In case of use of oral contraception women should have been stable on 
the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. 
age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not 
of child bearing potential.

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NOTE: If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
17. Sexually active males must use a condom during intercourse while taking study treatment 
and for at least12 months after the tisagenlecleucel infusion and until CAR T-cells are no 
longer present by qPCR on two consecutive tests. A condom is required for all sexually 
active male participants to prevent them from fathering a child AND to prevent delivery of 
study treatment via seminal fluid to their partner. In addition, male participants must not 
donate sperm for the time period specified above. 
18. Intolerance to the excipients of the tisagenlecleucel cell product.
6
Treatment
6.1
Study treatment
Tisagenlecleucel is an autologous cellular immunotherapy product that is comprised of CD3+ 
T cells that have undergone ex vivo T cell activation, gene modification, expansion and 
formulation in infusible cryomedia. The transgene to be expressed via lentiviral vector 
transduction is a CAR targeted against the CD19 antigen. The CAR contains a murine scFv that 
targets CD19 linked to a transmembrane region derived from the CD8 receptor, which is linked 
to an intracellular bipartite signaling chain of TCR-ζ (or CD3-ζ) and 4-1BB intracellular 
signaling domains. The extracellular scFv with specificity for CD19 is derived from a mouse 
monoclonal antibody. T cells which are enriched from a patient leukapheresis unit are expanded 
ex vivo using commercially available magnetic beads that are coated with anti-CD3 and anti-
CD28 monoclonal antibodies. The cells are transduced with the CD19 CAR lentiviral vector 
which ensures that only peripheral white blood cells enriched for lymphocytes are exposed to 
the vector. The residual non-integrated vector is washed away during the process. 
Tisagenlecleucel cells will be expanded ex vivo for up to 10 days. At the end of the culture, the 
tisagenlecleucel cells are depleted of magnetic beads, washed, concentrated, and cryopreserved. 
Results from a release testing procedure are required prior to release of the product for infusion.
6.1.1
Dosing regimen
The recommended dose will consist of a single intravenous (i.v.) infusion of 0.6 – 6.0 x 108
CAR-positive viable T cells. 
6.1.2
Bridging therapy
As it is not expected that the patients will progress rapidly during the screening and pre—
treatment period, the patients are unlikely to need bridging therapy. If, however, a bridging 
therapy is administered, the investigator should follow the recommendations described in 
Section 6.4.1 Prohibited concomitant therapy.
PET-CT should be performed after bridging and prior to tisagenlecleucel infusion unless the 
bridging therapy consists of steroids only. Patients with no measurable disease at baseline after 
bridging therapy will still receive tisagenlecleucel infusion.   

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6.1.3
Lymphodepleting chemotherapy
It is anticipated that many patients will have been receiving chemotherapy for relapsed or 
resistant disease. Prior to tisagenlecleucel
infusion, each patient should receive 
lymphodepleting chemotherapy. This may be omitted in case of significant cytopenia (e.g. 
WBC <1,000 cells/µL, absolute lymphocyte count <200/µL) or any condition that, in the 
investigator’s opinion, precludes lymphodepleting chemotherapy.
When given, lymphodepleting chemotherapy should be started 1 week before tisagenlecleucel
infusion so that the tisagenlecleucel cells will be given 2 to 6 days after completion of the
lymphodepleting chemotherapy. The chemotherapy start date will vary based on the selected 
chemotherapy. The purpose of this chemotherapy is to induce lymphopenia in order to facilitate 
engraftment and homeostatic expansion of tisagenlecleucel cells. For lymphodepleting 
chemotherapy, cyclophosphamide-based regimens are preferred agents as there is the most 
experience with the use of these agents in facilitating adoptive immunotherapy. The first option 
as lymphodepleting regimen is:

Fludarabine (25 mg/m2 intravenously [i.v.] daily for 3 doses) and cyclophosphamide (250 
mg/m2 i.v. daily for 3 doses starting with the first dose of fludarabine)
Note: Side effects of fludarabine can include severe nervous system events of seizure, agitation, 
blindness, coma and death. Instances of life-threatening and sometimes fatal autoimmune 
phenomena such as hemolytic anemia, autoimmune thrombocytopenia/thrombocytopenic 
purpura (ITP), Evans syndrome, and acquired hemophilia have been reported to occur after one 
or more cycles of treatment with fludarabine phosphate injection. It may also severely decrease 
bone marrow function (Fludarabine full prescribing information).  Cyclophosphamide toxicities 
include cardiac dysfunction.  Acute cardiac toxicity has been reported with doses as low as 2.4 
g/m2 to as high as 26 g/m2, usually as a portion of an intensive antineoplastic multi-drug regimen 
or in conjunction with transplantation procedures. In a few instances with high doses of 
Cyclophosphamide, severe, and sometimes fatal, congestive heart failure has occurred after the 
first Cyclophosphamide dose. Severe marrow suppression is seen and occasional anaphylactic 
reactions have been reported. Hemorrhagic cystitis, pulmonary toxicity (pneumonitis, 
pulmonary fibrosis and pulmonary veno-occlusive disease leading to respiratory failure) and 
veno-occlusive liver disease may occur (Cyclophosphamide full prescribing information). 
If there was previous grade IV hemorrhagic cystitis with cyclophosphamide, or the patient 
demonstrated resistance to a previous cyclophosphamide-containing regimen, then the 
following regimen should be used:

Bendamustine 90 mg/m2 i.v. daily for 2 days
Note: Side effects of bendamustine include severely decreased bone marrow function, nausea, 
vomiting and diarrhea; jaundice may occur, including without other signs of hepatic dysfunction. 
Fatal and serious cases of liver injury have been reported (Bendamustine full prescribing 
information). 
No other regimen is allowed for lymphodepletion.
Female patients of childbearing potential must have a negative serum pregnancy test within 24 
hours prior to the start of lymphodepleting therapy.  If the patient does not require 

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lymphodepleting therapy, she should still have a negative pregnancy test at the required visit 
that takes place within 24 hours prior to tisagenlecleucel infusion.
6.1.4
Tisagenlecleucel infusion
Manufacturing of the tisagenlecleucel cell product will start once a leukapheresis product has 
been accepted by the Novartis designated manufacturing facility and the patient has been 
enrolled.  The tisagenlecleucel cell product will be prepared and released by the manufacturing 
facility to the study site approximately 4-6 weeks after manufacturing has commenced, 
provided all required safety and quality release criteria have been met. For details on the 
cryopreserved components, and the specific storage and handling requirements of the 
tisagenlecleucel cell product, see the [Investigational Product Handling Manual].
6.1.4.1
Pre-Infusion Evaluation
If any of the following criteria is met tisagenlecleucel infusion must be delayed until resolution
to grade 1. If the period of delay is more than 4 weeks from completing lymphodepletion and 
there is no significant cytopenia (see Section 6.1.3) lymphodepletion should be repeated, and 
these criteria will need to be re-checked prior to tisagenlecleucel infusion.
1. Rapidly progressing primary disease 
2. Clinical evidence of CNS involvement by primary disease
3. Laboratory abnormalities that, in the opinion of the investigator, may impact patient safety 
or the patient’s ability to receive tisagenlecleucel.
4. Following clinical abnormalities:

Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 
90% or presence of progressive radiographic abnormalities on chest x-ray

Cardiac arrhythmia not controlled with medical management

Hypotension requiring vasopressor support

Active infection, as evidenced by positive blood cultures for bacteria, fungi, or PCR 
positivity for viral DNA in blood within 72 hours of tisagenlecleucel cell infusion, or 
clinical or radiographic evidence
5. A significant change in clinical status that would, in the opinion of the investigator, 
increase the risk of adverse events associated with tisagenlecleucel
6. Concomitant medications as described in Section 6.4.1
7. Positive influenza test within 10 days prior to tisagenlecleucel infusion (please refer to Table 
7-1). If the patient is positive for influenza, oseltamivir phosphate or zanamivir should 
administered for 10 days as preventative treatment (see Tamiflu® or Relenza® package 
insert for dosing). The patient must complete their 10 day preventative treatment course 
prior to receiving tisagenlecleucel. The test does not need to be repeated prior to 
tisagenlecleucel infusion however if flu-like or respiratory signs and symptoms are present, 
tisagenlecleucel infusion should be delayed until the patient is asymptomatic. For patients
residing in the United States, Canada, Europe and Japan, influenza testing is required during 
the months of October through May (inclusive). For patients residing in the southern 
hemisphere such as Australia, influenza testing is required during the months of April 

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through November (inclusive). For patients with significant international travel, both 
calendar intervals above may need to be considered.
8. Live vaccines must not be used in tisagenlecleucel recipients for at least 2 weeks prior to 
the start of lymphodepleting chemotherapy, during tisagenlecleucel treatment, and until 
immune recovery following treatment with tisagenlecleucel.
6.1.4.2
Additional safety procedures prior to administration
Tumor Lysis Syndrome
The risk of tumor lysis syndrome (TLS) is dependent on disease burden. Patients will be closely 
monitored both before and after lymphodepleting chemotherapy and tisagenlecleucel infusion 
including blood tests for potassium and uric acid. Patients with elevated uric acid or high tumor 
burden will receive prophylactic allopurinol, or a non-allopurinol alternative (e.g. febuxostat). 
Infection prophylaxis should follow local guidelines dictated only by the preceding 
lymphodepleting chemotherapy. Infection prophylaxis per se for tisagenlecleucel is not 
recommended.
Infections
Infection prophylaxis with regard to lymphodepletion and other additional treatments should 
follow local guideline. Infection prophylaxis is not recommended in the setting of
tisagenlecleucel infusion.
Cytokine Release Syndrome
Prior to tisagenlecleucel infusion two doses of tocilizumab per patient (for the first 3 weeks 
after tisagenlecleucel infusion) must be confirmed as available and must be available for 
infusion within 2 hours for the management of CRS related adverse events (see Section 6.2.6.1
for details).
Premedication 
Side effects from T cell infusion can include fever, chills and/or nausea. All patients should be 
pre-medicated with acetaminophen (paracetamol) and diphenhydramine or another H1 
antihistamine. These medications can be repeated every 6 hours as needed. Non-steroidal anti-
inflammatory medication may be prescribed if the patient continues to have fever not relieved 
with acetaminophen (paracetamol). Steroids should NOT be used for premedication. It is 
recommended that patients NOT receive systemic corticosteroids other than physiologic 
replacement, except for serious emergency, since this may have an adverse effect on 
tisagenlecleucel cell expansion and function.
Supportive care
Local guidelines will be followed for the supportive care of immunosuppressed and 
chemotherapy treated patients. All blood products administered should be irradiated. For details 
about prohibited concomitant medications and non-drug therapies please refer to Section 6.4.1.

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6.1.4.3
Cell thawing and infusion of tisagenlecleucel product
Coordination of the timing of thaw of tisagenlecleucel product and infusion will be done. For 
detailed instructions on the storage, handling, preparation and administration of the 
tisagenlecleucel cell product, refer to the [Investigational Product Handling Manual]. 
Vital signs (temperature, respiration rate, pulse, pulse oximetry, and blood pressure) will be
taken prior to, during and immediately after the infusion and then approximately every 15 
minutes for one hour and then every hour for the next two hours, or until these signs are 
satisfactory and stable.
A study investigator MUST evaluate the patient just prior to infusion to ensure the patients 
meets tisagenlecleucel infusion criteria. Trained study staff will administer the tisagenlecleucel
infusion using precautions for immunosuppressed patients. Protective isolation should follow 
institutional standards and policies. Emergency medical equipment should be available during 
the infusion in case the patient has a significant reaction to the infusion such as anaphylaxis or 
severe hypotension. After cell thawing, tisagenlecleucel cell product should NOT be washed 
prior to infusion, and all contents will be infused. A single dose of 0.6 to 6 x 108 CAR-positive 
viable T cells will be administered via intravenous infusion, preferably through a central line. 
Following tisagenlecleucel infusion, should emergency treatment be required in the event of 
life-threatening hypersensitivity or other acute infusion-related reaction, supportive therapy 
such as oxygen, bronchodilators, epinephrine, antihistamines, and corticosteroids should be 
given according to local institutional guidelines. Patients should be evaluated and carefully 
monitored until complete resolution of signs and symptoms.
6.1.5
Treatment duration
A single dose of tisagenlecleucel will be administered.
6.2
Dose escalation guidelines
Not applicable
6.2.1
Starting dose rationale
Not applicable
6.2.2
Provisional dose levels
Not applicable
6.2.3
Guidelines for dose escalation and determination of (MTD/RP2D/RDE)
Not applicable
6.2.4
Definitions of dose limiting toxicities (DLTs) in a phase II study
Not Applicable

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6.2.5
Toxicity management, stopping rules and study termination
It is expected that AEs will occur frequently in this population based on the underlying 
advanced malignancy and that these can be SAEs. Therefore, there is no specific occurrence of 
SAEs that define a stopping rule, but the review of SAEs will form the basis for potential early 
stopping of the study. The review of these adverse events, and any decision to prematurely stop 
patient enrollment, will be determined by the Steering Committee (SC) and reviewed by the 
IRB.
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
change in opinion of the IRB, the SC, or determination that there are problems in the cell product 
generation or safety at the discretion of the study investigators. Additionally, recruitment may 
be stopped at the sponsor’s discretion and may include reasons such as low recruitment, 
protocol violations, or inadequate data recording.
6.2.6
General toxicity management considerations
Patients infused with tisagenlecleucel are at risk of developing a number of AE that are related 
either to tisagenlecleucel itself, other therapies (e.g. immunochemotherapy) and conditions 
concurrent with the patient’s primary disease. Following tisagenlecleucel infusion, patients can 
be discharged from the treating site only if, in the investigator’s opinion, they do not 
demonstrate any adverse events or worsening of underlying diseases. This chapter describes the 
management of such AEs. 
Drug and non-drug therapies used to treat AEs must be recorded on appropriate CRFs.
6.2.6.1
Cytokine Release Syndrome (CRS)  
Ensure that tocilizumab is available on site prior to infusion of tisagenlecleucel. Supportive care, 
tocilizumab, and corticosteroids have been used for effective management of CRS. Prompt 
responses to tocilizumab have been seen in most patients. 
Identify cytokine release syndrome (CRS) based on clinical presentation (see Section 2.7.1.1). 
Evaluate for and treat other causes of fever, hypoxia, and hypotension. Although signs and 
symptoms of CRS occur in most cases within 1-14 days after tisagenlecleucel infusion, monitor 
patients for signs or symptoms of CRS for at least 4 weeks after treatment with tisagenlecleucel. 
Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur 
at any time.
At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment 
with supportive care, tocilizumab and/or corticosteroids as indicated.
A detailed treatment algorithm for the management of CRS (Lee at al 2014) is presented below 
in Table 6-1 and Table 6-2. Patients will be required to remain proximal to the treating site for 
the first 4 weeks.

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Table 6-1
CRS management 
CRS severity 
Symptomatic 
treatment
Tocilizumab 
Corticosteroids
Grade 1 
Mild general symptoms 
requiring symptomatic treatment 
only e.g. fever, nausea, fatigue, 
headache, myalgia, etc.
After excluding other 
causes (e.g. infection), 
treat specific symptoms 
with e.g. antipyretics, 
anti-emetics, anti-
analgesics, etc.
Not applicable
Not applicable
Grade 2 
Symptoms requiring moderate 
intervention:
Hypoxia requiring low-flow 
oxygen supplementation (<40%) 
or
Hypotension requiring 
intravenous fluids and low dose 
of one vasopressor or
Grade 2 organ toxicities
Oxygen 
supplementation
Start intravenous fluids 
and, if no improvement, 
follow with a low-dose 
vasopressor
Treat organ toxicities as 
per local guidelines
8 mg/kg intravenously 
(maximum 800 mg) over 
1 hour. 
Repeat every 8 hours, if 
not responsive to 
intravenous fluids and 
increasing oxygen 
supplementation. 
Limit to 3 doses within 24 
hours: maximum total of 
4 doses.
If no improvement after 
24 hours of treatment 
with tocilizumab, 
administer 1 mg/kg 
methylprednisolone 
intravenously twice 
daily (2 mg/kg as initial 
bolus can be given) or 
equivalent steroid 
dose. 
Continue until Grade 1 
or less, then taper over 
3 days.
Grade 3 
Symptoms requiring aggressive 
intervention: 
Hypoxia requiring high-flow 
oxygen supplementation (≥40%) 
or
Hypotension requiring high-
dose* or multiple vasopressors 
or
Grade 3 organ toxicities or 
Grade 4 transaminitis
Oxygen 
supplementation
Intravenous fluids and 
high-dose*
vasopressor/s
Treat organ toxicities as 
per local guidelines
See Grade 2
See Grade 2
Grade 4 
Life-threatening symptoms 
requiring ventilator support, etc. 
or
Grade 4 organ toxicity 
(excluding transaminitis)
Oxygen 
supplementation incl. 
ventilator support
Intravenous fluids and 
high-dose* 
vasopressor/s
Treat organ toxicities as 
per local guidelines
See Grade 2
Administer 
methylprednisolone 
1000 mg intravenously 
daily (or equivalent 
steroid dose) for 3 
days. If improves, then 
manage as per Grade 
2.
*See Table 6-2

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Table 6-2
High-dose vasopressors
Vasopressor
Dose to be given for ≥ 3 hours
Norepinephrine monotherapy
≥ 20 mcg/min
Dopamine monotherapy
≥ 10 mcg/kg/min
Phenylephrine monotherapy
≥ 200 mcg/min
Epinephrine monotherapy
≥ 10 mcg/min
If on vasopressin
Vasopressin + norepinephrine equivalent (NE)  of ≥ 10 mcg/min*
If on combination vasopressors (not 
vasopressin)
NE of ≥ 20 mcg/min*
*Vasopressin and Septic Shock Trial (VASST) Norepinephrine Equivalent Equation:
NE dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + [epinephrine (mcg/min)] + [phenylephrine 
(mcg/min) ÷10] (Russell et al 2008)
Other anti-cytokine therapies may also be considered upon their availability, if the patient does 
not respond to tocilizumab. If the patient experiences ongoing CRS despite administration of 
anti-cytokine directed therapies, anti-T cell therapies such as cyclophosphamide, anti-
thymocyte globulin (ATG) or alemtuzumab may be considered. These therapies need to be 
captured in appropriate CRFs.
The management of CRS is based solely upon clinical parameters as described in Section 
2.7.1.1. Ferritin, CRP and serum cytokine levels should NOT be used for clinical management 
decisions. Cases of transient left ventricular dysfunction, as assessed by ECHO, have  been  
reported  in  some  patients  with  severe  (Grade  4)  CRS.  Therefore consideration should be 
given to monitoring cardiac function by ECHO during severe CRS, especially in cases with 
prolonged severe hemodynamic instability, delayed response to high dose vasopressors, and/or 
severe fluid overload.
6.2.6.2
Neurological adverse events during CRS
Patients should be monitored for neurological events following tisagenlecleucel infusion, in 
particular during and after resolution of CRS. Prompt and effective management of CRS may 
prevent some neurological complications associated with tisagenlecleucel therapy. Supportive 
treatment should be given for tisagenlecleucel associated neurological events as per standard of 
care and diagnostic work-up considered to exclude other causes for these symptoms. 
6.2.6.3
Hypersensitivity including acute infusion reactions
Patients should be monitored for signs and symptoms of hypersensitivity following initiation of 
tisagenlecleucel infusion and treated appropriately. Tisagenlecleucel is contraindicated in 
patients with known hypersensitivity to tisagenlecleucel or to any component of the product 
formulation.
As appropriate, prophylactic medications should be administered to minimize the risk of 
immediate hypersensitivity including acute infusion reactions. It is recommended to pre-
medicate all patients with acetaminophen (paracetamol) and diphenhydramine or another H1 
antihistamine within approximately 30-60 minutes prior to tisagenlecleucel infusion. These 
medications can be repeated every 6 hours as needed. Non-steroidal anti-inflammatory 
medication may be prescribed for fever not responding to acetaminophen. Steroids should not 
be used for premedication. Systemic corticosteroids should only be used for severe conditions. 

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Should emergency treatment be required in the event of life-threatening hypersensitivity or 
other infusion-related reaction, supportive therapy such as oxygen and drug treatment should
be given according to local institutional guidelines. Patients should be evaluated and carefully 
monitored until complete resolution of signs and symptoms.
6.2.6.4
Tumor Lysis Syndrome (TLS)
Patients should be closely monitored for signs and symptoms of TLS both before and after 
lymphodepleting chemotherapy and tisagenlecleucel infusion including relevant laboratory 
tests.  To minimize risk of TLS, patients with elevated uric acid or high tumor burden should 
receive allopurinol, or an alternative prophylaxis, prior to tisagenlecleucel infusion. Events 
should be managed according to local guidelines.
Depending on the study phase, the following measures should be followed:

Screening phase:

Prophylactic allopurinol, or a non-allopurinol alternative (e.g. febuxostat), and 
increased oral/ i.v. hydration prior to lymphodepleting chemotherapy and 
tisagenlecleucel infusion should be given in patients with elevated uric acid or high 
tumor burden

Prompt supportive care in case of acute TLS (i.v. fluids and rasburicase as clinically 
indicated, when uric acid continues to rise despite allopurinol/febuxostat and fluids) 

Post-infusion monitoring phase:

Frequent monitoring of the following laboratory tests (2 to 3 times/week for 3 weeks 
from start of lymphodepleting chemotherapy, then weekly): potassium, phosphorus, 
calcium, creatinine, and uric acid 

Encourage oral hydration
Based on laboratory and clinical TLS criteria (modified from Cairo and Bishop (2004)), the 
following measures for TLS should be also followed:
Laboratory TLS
Laboratory TLS is defined as two or more of the following values within three days before or 
in the days following tisagenlecleucel infusion:

Uric acid ≥ 8 mg/dL or 25% increase from baseline

Potassium ≥ 6 mEq/L or 25% increase from baseline

Phosphorus ≥ 6.5 mg/dL (children) or ≥ 4.5 mg/dL (adults) or 25% increase from baseline

Calcium ≤ 7 mg/dL or 25% decrease from baseline
Regimen:
If none or one of the laboratory values above is abnormal, continue to manage with allopurinol 
or a non-allopurinol alternative (e.g. febuxostat) and oral fluids. If uric acid remains elevated, 
consider i.v. fluids, rasburicase, and hospital monitoring. 
Laboratory TLS should be managed with i.v. fluids, laboratory blood tests every 6 to 8 hours 
and inpatient care. Cardiac monitoring and rasburicase should be considered if uric acid remain 
elevated

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Clinical TLS

Defined as the presence of laboratory TLS and ≥ 1 of the following criteria that cannot be 
explained by other causes:

Serum creatinine ≥ 1.5 times the upper limit of the age-adjusted normal range

Symptomatic hypocalcemia

Cardiac arrhythmia
Clinical TLS should be managed with i.v. fluids, laboratory blood tests every 6 to 8 hours, 
cardiac monitoring, rasburicase/allopurinol/febuxostat and inpatient care (consider ICU).
6.2.6.5
Infections
Patients with active, uncontrolled infection should not start tisagenlecleucel treatment until the 
infection is resolved. 
Patients should be monitored for signs and symptoms of infection and treated appropriately. As 
appropriate, prophylactic antibiotics should be administered and surveillance testing prior to 
and during treatment with tisagenlecleucel should be employed.
Institutional guidelines for vaccination (e.g. pneumococcus) should be followed before starting 
tisagenlecleucel therapy. As the lack of effective B cells after infusion makes the likelihood of 
a systemic infection considerable, vaccination with live virus vaccines should not be given for 
at least 2 weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel and 
until immune recovery following treatment with tisagenlecleucel.
Any suspected cases of viral hepatitis or HIV should be referred to a specialist.
In patients with low immunoglobulin levels preventive measures such as immunoglobulin 
replacement and rapid attention to signs and symptoms of infection should be implemented as 
per age and local specific guidelines. 
6.2.6.6
Febrile neutropenia
Febrile neutropenia (significantly decreased neutrophil count with fever) may develop in the 
course of chemotherapy (including lymphodepletion) and may be concurrent with CRS. A 
febrile patient should be evaluated for infection (Section 2.7.1.5) and CRS (Section 2.7.1.1) and 
managed appropriately with fluids, antibiotics, and supportive care, if applicable.
In the event that the patient develops sepsis or systemic bacteremia following tisagenlecleucel
cell infusion, appropriate cultures and medical management should be initiated. If a 
contaminated tisagenlecleucel cell product is suspected, the product can be retested for sterility 
using archived samples that are stored at the manufacturing site. 
6.2.6.7
B cell depletion and/ or hypogammaglobulinemia
Monitor immunoglobulin levels after treatment with tisagenlecleucel, use infection precautions 
including antibiotic prophylaxis and immunoglobulin replacement as appropriate and per local 
standard of care.
In case of new or worsening symptoms suggestive of PML, consultation with a neurologist 
should be considered

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6.2.7
Criteria for discontinuing a patient’s participation in the study
If a patient develops a condition that precludes tisagenlecleucel infusion after enrollment but 
before infusion, the patient will be prematurely discontinued. This will be done at the judgment 
of the PI, and could include for example, the occurrence of an intercurrent illness requiring the 
institution of systemic immunosuppression.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
Not applicable
6.3.2
Additional safety monitoring and follow-up for toxicities
6.3.2.1
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of 
tisagenlecleucel, a standardized process for identification, monitoring and evaluation of liver 
events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as non-serious AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 14.4.1 in Appendix 4 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 14.4.1 should be followed up by the investigator or 
designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Table 14.4.1. Repeat liver chemistry tests (ALT, 
AST, TBL, PT/INR, ALP and G-GT) to confirm elevation.
These liver chemistry repeats should be performed using the local laboratory used by the site. 
Repeated laboratory test results must be reported as appropriate. If the initial elevation is 
confirmed, close observation of the patient will be initiated, including consideration of 
treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to Section 7.1.5), if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event, which can include based on investigator’s 
discretion: 

Serology tests, imaging (e.g., such as abdominal US, CT or MRI, as appropriate) and 
pathology assessments, gastroenterologist’s or hepatologist’s consultancy; obtaining 
more detailed history of symptoms and prior or concurrent diseases, history of 

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concomitant drug use, exclusion of underlying liver disease, obtaining a history of 
exposure to environmental chemical agents.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
6.3.2.2
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:
For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x ULN 
combined with TBIL > 2.0 x ULN
For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x baseline 
AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x baseline AND 
> 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
4. Obtain PK sample, as close as possible to last dose of, if PK analysis is performed in the 
study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 

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significant”, thus, met the definition of SAE and reported as SAE using the term “potential 
drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.3.2.3
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR new onset dipstick 
proteinuria ≥ 3+ OR new onset dipstick hematuria ≥ 3+ (after excluding menstruation, 
UTI, extreme exercise, or trauma)
Renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first assessment.
Every renal laboratory trigger or renal event as defined in Appendix 5, Section 14.5 should be 
followed up by the investigator or designated personnel at the trial site as summarized in 
Appendix 5.
6.4
Concomitant therapy
Clinically significant prescription and nonprescription medication, excluding vitamins, and 
herbal and nutritional supplements, and procedure-related (inpatient or outpatient) medications 
taken by the patient during the 30 days prior to screening will be recorded. At every visit 
following the screening visit up to the end of the study, concomitant medications will be 
recorded in the medical record and on the appropriate CRF. During selected trial phases, 
concomitant medication collection will be modified as outlined in Appendix 3: Tisagenlecleucel
Modified Data Reporting- Treatment and Follow-Up Phase, CRF Completion Guidelines 
(CCGs). Modified collection of concomitant medication information during these periods is 
designed 
to 
capture 
tisagenlecleucel-related 
toxicity, 
severity, 
interventions 
and 
response/resolution following intervention. Any additions, deletions, or changes of these 
medications will be documented. 
The following guidelines must be adhered to during the study:

Granulocyte macrophage-colony stimulating factor (GM-CSF) should be avoided due to 
the potential to worsen CRS symptoms. Short acting granulocyte colony stimulating factor 
(G-CSF) should not be given within 72 hours of tisagenlecleucel infusion and long acting 
G-CSF should not be given within 10 days of tisagenlecleucel infusion. The effects of 
granulocyte colony stimulating factor (G-CSF) on the other hand, are unknown.

Steroids or other immunosuppressant drugs should NOT be used as pre-medication for 
tisagenlecleucel therapy (refer to Section 6.1.4.1) or following tisagenlecleucel infusion, 
except as required for physiological glucocorticoid replacement therapy, or under life 
threatening circumstances. Use of steroids with blood product administration should be 
eliminated just prior to and following tisagenlecleucel if possible or at least minimized.

Patients with moderate to severe signs and symptoms attributable to CRS should be 
managed with supportive care and administration of tocilizumab as defined in Table 6-2
and Section 6.2.6.1.

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
The patient must be told to notify the investigational site about any new medications 
he/she takes after the start of the study.
6.4.1
Prohibited concomitant therapy
The patient must be told to notify the investigational site about any medications he/she takes. 
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered during the study must 
be listed on the appropriate CRFs.
Medication restrictions prior to leukapheresis
For medication restrictions before leukapheresis, please refer to the recent [Investigational 
Leukapheresis, Cryopreservation and Scheduling Manual].
Medication restrictions prior to tisagenlecleucel infusion
1. Steroids: Therapeutic doses of steroids must be stopped > 72 hours or 5 half-lives, 
whichever is greater, prior to tisagenlecleucel infusion. However, the following 
physiological replacement doses of steroids are allowed: ≤40 mg/day hydrocortisone or 
equivalent
2. Steroids or other immunosuppressant drugs should NOT be used as pre-medication for 
tisagenlecleucel therapy (refer to Section 6.1.4.1/ Pre-Infusion Evaluation) or following 
tisagenlecleucel infusion, except as required for physiological glucocorticoid replacement 
therapy, or under life threatening circumstances. Use of steroids with blood product 
administration should be avoided just prior to and following tisagenlecleucel if possible or 
at least minimized.
3. Antibody use including anti-CD20 therapy (e.g., rituximab) should not be used within 4 
weeks prior to tisagenlecleucel infusion 
4. CNS disease prophylaxis or intrathecal therapy must be stopped > 1 week prior to 
tisagenlecleucel infusion (e.g. intrathecal methotrexate) 
5. Radiation therapy must be stopped >2 weeks prior to tisagenlecleucel infusion 
6. Investigational therapies must not be used at any time while on study until the first 
progression following tisagenlecleucel infusion 
7. Live vaccines must not be used in tisagenlecleucel recipients for at least 2 weeks prior to 
lymphodepletion and during tisagenlecleucel treatment until immune recovery 
8. Granulocyte macrophage-colony stimulating factor (GM-CSF) should be avoided due 
to its potential to worsen CRS symptoms. Short acting granulocyte colony stimulating 
factor (G-CSF) should not be given within 72 hours of tisagenlecleucel infusion and long 
acting G-CSF should not be given within 10 days of tisagenlecleucel infusion.
9. Antiproliferative therapies, other than lymphodepletion including low dose daily or 
weekly maintenance chemotherapy) should not be used within 2 weeks of leukapheresis 
and 2 weeks prior to infusion.
10. Short acting drugs used to treat primary disease (e.g. hydroxyurea, tyrosine kinase 
inhibitors) must be stopped > 72 hour prior to leukapheresis and > 72 hours prior to 
tisagenlecleucel

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6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the informed consent form, the patient is assigned to the next sequential Subject No. 
available to the investigator through the Clinical Data Management System interface.
The investigator or designated staff will contact the IRT system and provide the requested 
identifying information for the patient to register them into the IRT system. Once assigned, the 
Subject No. must not be reused for any other subject. If the patient fails to be enrolled or to start 
treatment for any reason, the reason will be entered into the appropriate CRF page. The IRT
system must be notified within 2 days that the patient was not treated.
6.5.2
Treatment assignment or randomization
This is a single-arm open-label study. Patients will be enrolled and assigned to treatment upon 
confirmation of all clinical eligibility criteria by the investigator, and acceptance of the 
leukapheresis product for manufacturing.
6.5.3
Treatment blinding
This is a single-arm open-label study.
6.6
Tisagenlecleucel preparation and dispensation
For details on the cryopreserved components, and the specific storage and handling 
requirements of the tisagenlecleucel product, see the [Investigational Leukapheresis, 
Cryopreservation & Scheduling Manual and Investigational Product Handling Manual].
6.6.1
Tisagenlecleucel packaging and labeling
The tisagenlecleucel product will be shipped from Novartis in a dry vapor shipper where 
temperature is maintained and continuously monitored. Confirmation of temperature excursions 
during transport and unloading of the tisagenlecleucel product and accompanying 
documentation will be done. The tisagenlecleucel product will be carefully examined to ensure 
that it is intact and free from damage. The tisagenlecleucel product will be transferred to on-
site storage. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number.
Each infusion bag will typically contain 10 mL-50 mL of cells. Higher volumes may 
occasionally be necessary depending on transduction efficiency to formulate the recommended 
dose of 6 x 108 viable transduced T cells.

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Each infusion bag will have affixed to it a label containing the following: A product identifier, 
the proper name of the product, and appropriate product modifiers. The study number and the 
wording, “FOR AUTOLOGOUS USE ONLY” will be included in the label. In addition the 
label will have at least two unique identifiers such as the patient’s alphanumeric identifier and 
birth date according to applicable regulations. Additional label elements required by local 
regulatory guidelines will also be included. Prior to the infusion, two individuals will verify all 
of this information, to ensure that the information is correctly matched to the patient, and that 
the patient receives only their autologous product.
6.6.2
Tisagenlecleucel supply and storage
Tisagenlecleucel cell product must be received by designated personnel at the study site, 
handled and stored safely and properly, and kept in a secured location to which only the 
investigator and designated site personnel have access. Upon receipt, the tisagenlecleucel cell 
product should be stored according to the instructions specified on the product labels and in the 
[Investigator’s Brochure] as well as the [Investigational Product Handling Manual].
6.6.3
Tisagenlecleucel compliance and accountability
Novartis has established methods to ensure full traceability between the patient’s autologous 
leukapheresis and the tisagenlecleucel product in line with the requirements outlined in 
Regulation (EC) 1394/2007, the Directive 2004/23/EC as well as the rules and principles of the 
EU “Detailed guidelines on good clinical practice specific to advanced therapy medicinal 
Products” and 21 CFR1271.250 and 21CFR1271.290. The data contributing to the full 
traceability of the cells are stored for a minimum of 30 years. Any product quality complaints 
are documented by the clinical site and reported to the Novartis Clinical Supplies Quality 
Assurance (QA) Department. A unique patient identifier will be used in order to maintain the 
chain of identity between the autologous leukapheresis product and the tisagenlecleucel batch 
and the link between patient identity and unique patient identifier will be confirmed prior to 
infusion. The [Investigational Product Handling Manual] provides an overview of how the 
company ensures that the cells which are procured, processed, stored, and distributed by or on 
behalf of the Novartis can be traced from leukapheresis to infusion.
6.6.3.1
Tisagenlecleucel compliance
As a single administration study, compliance will be assessed by the investigator and/or study 
personnel and captured in the Drug Accountability Form.
6.6.4
Tisagenlecleucel disposal and destruction
For details on disposal and destruction of any unused tisagenlecleucel product or infusion 
supplies, please refer to the specific guidance provided in the [Investigational Product Handling 
Manual].
6.6.5
Handling of other study treatment
Not applicable.

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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments through the end of the Treatment and Follow-up Phase 
(Section 7.1.1, Section 7.1.2, Section 7.1.3, and Section 7.1.4). 
In the table, required assessments are indicated with an “X” at the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source
documentation. The tables indicate which assessments produce data to be entered into the 
clinical database (D) or remain in source documents only (S) (“Category” column).
No CRF will be used as a source document.

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Table 7-1
Visit evaluation schedule
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Obtain 
Informed 
Consent
D
7.1.1
X
IWRS/IRT 
Registration
S
6.5
X
X
X
X
Demography
D
7.1.1
X
Inclusion/excl
usion criteria
D
5.2
5.3
X
Medical 
history
D
7.1.1
X

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Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Prior 
antineoplastic 
therapy
D
7.1.1
X
Prior/concomi
tant 
medications 
and non-drug 
therapies
D
6.4
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
antineoplastic 
therapies
D
6.4
X
X
X
X
X
X

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Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Antineoplastic 
therapies 
after 
tisagenlecleuc
el  infusion
D
7.1.6
X X
X
X
X
X
X
X
X
X
X
X
X
X
Central 
confirmation 
of diagnosis 
D
7.2.1
X
Diagnosis and 
extent of 
cancer and 
prognostic 
factors
D
7.1.1
X

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Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Physical 
examination
S
7.2.2.
1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance 
status
D
7.2.2.
4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.
3
X
Weight
D
7.2.2.
3
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.
2
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Pulse 
oximetry
D
7.2.2.
2
X
X
X X
X
X
X

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Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Cardiac 
imaging
D
7.2.2.
6.2
X
Local 
Electrocardio
gram (ECG)
D
7.2.2.
6.1
X
X
Leukapheresi
s
D
7.1.1
X
Lymphodeplet
ing 
chemotherapy
D
7.1.2.
1
X
Tisagenlecleu
cel infusion 
prerequisite 
assessment
S
7.1.2.
3
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Tisagenlecleu
cel infusion
D
7.1.3.
1
X
B-symptoms
D
7.2.1
X
X 
  
X
X
X
X
X
PET-CT with 
contrast-
enhanced 
diagnostic 
(Dx) CT –
Neck, Chest, 
Abdomen, 
Pelvis 
D
7.2.1
X
X if 
applic
able
X, M3 
and M 
6 only 

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
CT/MRI –
Neck, Chest, 
Abdomen, 
Pelvis
D
7.2.1
X if 
no 
Dx 
PET-
CT
X     if 
no Dx 
PET-
CT 
and if   
applic
able
X if 
no Dx 
PET-
CT
X 
X 
X 
X 
Dedicated 
PET
D
7.2.1
X if 
no 
PET
CT
X if no 
PET-
CT 
and if  
applic
able
X if 
no 
PET-
CT, 
only 
M3 
and 
M6

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Response 
(CR) 
confirmation 
by PET-CT or 
PET
D
7.2.1
Only for new CR and not previously documented, +/- 14 days from the CT image
CT/MRI brain 
D
7.2.1
As clinically indicated
Response 
evaluation per 
Lugano 
classification 
2014
D
7.2.1
X
X if 
applic
able
X
X
X
X
X
Bone marrow 
biopsy or 
aspirate 
D
7.2.1
X
only if new CR with a prior bone marrow involvement 

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
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Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
CSF cytology 
by lumbar 
puncture
D
7.2.1
As clinically indicated
Adverse 
events
D
8.1
8.2
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
D
7.2.2.
5
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.
5
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Flow 
cytometry 
before 
leukapheresis 
(peripheral 
blood)
D
7.1.1
X
Flow 
cytometry 
(leukapheresi
s product) 
D
7.1.1
X
Pregnancy 
test - serum
S
7.2.2
X
X
X
X
Pregnancy 
test - urine
S
7.2.2
X
X
X
X
X
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Pregnancies
S
8.4
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Viral serology 
D
7.2.2.
5
X
If > 8 weeks from 
screening
Coagulation 
D
7.2.2.
5
X
X
X
X
X
Serum 
immunoglobul
in levels 
D
7.2.2.
5
X
X
X
X
Urinalysis
D
7.2.2.
5
X
X
X
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
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Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Rapid 
Influenza
Testing
D
6.1.4.
1
7.1.3
7.2.2.
5
Within 10 days 
prior to infusion
Immunogenici
ty (humoral) –
serum
D
7.2.3
X
X
X
X M3, 
M6, 
M12 
only
X
X
X
Immunogenici
ty (cellular) –
peripheral 
blood
D
7.2.3
X
X
X
X M3, 
M6, 
M12 
only
X
X
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
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Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Serum  
cytokines 
(peripheral 
blood)
D
7.2.3
7.2.4
X
X
X X
X
X
X
X
X
X
X M3 
M6 
M12 
only

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
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Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
CRS 
assessments 
in peripheral 
blood (serum 
cytokines, 
inflammatory 
markers  
tisagenlecleuc
el PK)
D
7.2.3
7.2.4
As clinically indicated dependent upon the presence and 
time-course of CRS and administration of anti-cytokine 
therapies – refer to Table 7-7, Table 7-8, Table 7-13

Novartis
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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Tisagenlecleu
cel  cellular 
kinetics by 
qPCR 
(peripheral 
blood)
D
7.2.3
X
X
X X
X
X
X
X
X
X
X    M2 
only
X
X
X
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
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Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Tisagenlecleu
cel cellular 
kinetics by 
flow 
cytometry 
(peripheral 
blood)
D
7.2.3
X
X
X X
X
X
X
X
X
X
X
M2 only
X
X
X
Tumor biopsy 
(CD19 
expression, 
PD1, PDL1, 
Ki67)
D
7.2.3
X
as clinically indicated

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Tisagenlecleu
cel cellular 
kinetics -
bone marrow 
(qPCR)
D
7.2.3
X
M3 and as clinically indicated
Tisagenlecleu
cel  cellular 
kinetics -
bone marrow 
(flow 
cytometry)
D
7.2.3
X
M3 and as clinically indicated

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Peripheral 
blood
(B cell and T 
cell levels–
central 
assessment)
D
7.2.4
X
X
X
X
X
X
   
X  M3 
M6 
M12 
only
X
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Peripheral 
blood 
leukocyte 
transcriptional 
profiling
D
7.2.4
X
X
X
X
X
RCL by VSV-
g q-PCR 
(aliquots from 
tisagenlecleuc
el PK by 
qPCR)
D
7.2.2.
5
X
X  
X 
X
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Leukapheresi
s sample for 
correlative 
studies
D
7.1.1.
1
X
Tisagenlecleu
cel cell 
product 
sample for 
correlative 
studies 
(manufacturin
g site)
D
7.1.1.
1
X

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Electronic 
patient 
reported 
outcomes 
(SF-36, 
version 2; 
EQ-5D-3L; 
FACT-Lym)
D
7.2.6
X
X  
X
X
X
Disposition
D
7.1
X
(X)
X

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Page 84
Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
Phase
Screening
Pre-Treatment
Treatment and Follow-up
Visit
Category
Protocol Section
Screening
Leukapheresis
Enrollment
Pre-lymphodepletion 
evaluation
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Study
Visit Number
1
2
3
110
120
1
3
0
21
0
2
2
0
23
0
24
0
25
0
26
0
27
0
28
0
29
0
300,320,
330
310, 
340,3
50, 
360
37
0
38
0
390..
19
99
Study day
W -
10 
to  
W     
-6
W
-
1
0 
to 
W
-8
W 
-6 
to 
W 
-4
W
-4
to
D
-8
D
-6 
to
D
-2
D
-
1
D
1
D
2
D
4
±1
d
D
7  
±1
d
D 
11  
±1
d
D 
14  
±1
d
D 
17  
±1
d
D
21  
±3
d
D 
28  
±7
d
M
2,
4,
5,
±14d
M
3,
6,
9,
12 
±14d
M
18 
±1
4d
M 
24 
±1
4d
Q6M 
... 
(M30 
...) 
±14d
EO
S  
+1
4d
Subject 
Status
D
n/a
X
X
X
X
X
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Survival 
follow-up
D
7.1.4
Every 3 months until end of the study. Refer to Protocol section 7.1.4

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Oncology Clinical Trial Protocol v00
Protocol No. CCTL019E2202
7.1.1
Screening Phase
Patients must sign the IRB/EC approved ICF before any study specific screening procedures. 
Screening assessments to determine eligibility should be performed as per the visit evaluation 
schedule detailed in Table 7-1.
Patients who have signed an informed consent will be registered in the IRT system and undergo 
a routine lymphoma staging workup including all screening assessment outlined in Table 7-1.
For detailed screening procedures, related to the use of Interactive Response Technology (IRT), 
please refer to the [IRT User Manual].
The assessments below do not need to be repeated if performed as part of clinical routine within
the periods defined below:

Serum immunoglobulin levels as per Table 7-5 within 6 weeks of the ICF signature 

Viral serology as per Table 7-5 within 6 weeks of the ICF signature

Bone marrow biopsy within 6 months of the ICF signature provided that there are no 
symptoms or laboratory abnormalities suggesting bone marrow involvement by lymphoma 

LVEF assessment by ECHO/MRI or MUGA within 6 months of the ICF signature
provided that there are no clinical symptoms of impaired cardiac function
7.1.1.1
Leukapheresis
Leukapheresis will be scheduled for cell procurement prior to final enrollment. It is strongly 
recommended to schedule leukapheresis prior to any planned chemotherapy or non-physiologic 
dose of steroids as an absolute T-cell count (absolute lymphocyte count multiplied by the 
percentage of CD3 positive lymphocytes) ≤ 300/mm3 may result in a poor T-cell collection and 
manufacturing failure. 
Cryopreserved non mobilized leukapheresis products collected prior to study entry (historical) 
may be usable for manufacturing if collected at a certified leukapheresis center and if the 
product is accepted for manufacturing.
Please refer to the Leukapheresis Key Requirements within the most recent [Leukapheresis, 
Cryopreservation & Scheduling Manual] for more detailed instructions on optimal timing of 
leukapheresis collection and the recommended procurement, handling and shipment procedures 
of the leukapheresis samples to the designated manufacturing facility
Flow cytometry should be performed before leukapheresis in peripheral blood and post 
leukapheresis on leukapheresis product (i.e. ALC, absolute CD45+/CD3+, CD45+/CD3+/CD28-
/CD27-, CD4+/CD25+, CD45+/CD14+).
Viably frozen samples from the leukapheresis material as well as the tisagenlecleucel product 
will be collected at the manufacturing site for correlative studies.
The date of Leukapheresis will be registered in the IRT system. 
For patients who undergo leukapheresis collection on study after signing ICF, the following 
criteria must be met prior to leukapheresis collection:

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Protocol No. CCTL019E2202
Peripheral blood absolute lymphocyte count (ALC) ≥ 500/µL (0.5x109/L), or if ALC < 500/µL 
(<0.5x109/L), then the absolute CD3 lymphocyte count must be ≥ 150/µL 
Please also refer to the [Leukapheresis, Cryopreservation & Scheduling Manual] for further 
details on the requirements prior to leukapheresis collection. 
7.1.1.2
Re-screening
A patient who has a laboratory test result(s) that does not satisfy the entrance criteria may have 
the test(s) repeated. These test(s) may be repeated as soon as the investigator believes the re-
test result(s) is/are likely to be within the acceptable range to satisfy the entrance criteria, but 
should be completed within approximately 3 weeks of the original screening visit date. In this 
case, the patient will not be required to sign another ICF, and the original patient ID number 
assigned by the investigator will be used. In the event that the laboratory test(s) cannot be 
performed within 3 weeks of the original screening visit, or the re-test(s) do not meet the 
entrance criteria, or other eligibility criteria have changed and are not met anymore, the patient 
is considered a screen failure, and must be discontinued from the study.
A new ICF will need to be signed if the investigator chooses to re-screen the patient after a 
patient has screen failed, and the patient will be assigned a new patient ID. All required 
screening activities must be performed when the patient is re-screened for participation in the 
study. An individual patient may only be re-screened once for the study. Once the number of 
patients screened and enrolled is likely to ensure target enrollment, the Sponsor may close the 
study to further screening. In this case, the patients who screen failed will not be permitted to 
re-screen.
7.1.1.3
Enrollment 
Following informed consent, information on the patient’s leukapheresis product including 
sample sentinel vials collected from leukapheresis (when available) will be sent to Novartis 
manufacturing separately or together with leukapheresis product. Final enrollment is defined as 
the point at which a patient meets all clinical inclusion/exclusion criteria and the patient’s 
leukapheresis product is received and accepted for manufacturing. The patient is then enrolled 
using the same Subject Number assigned at screening by the site investigator or designated staff. 
Once assigned, the Subject Number must not be reused for any other patient and the Subject 
Number for that individual must not be changed. If a screened patient is not enrolled for any 
reason, the specific reason will be entered into the clinical database.
Enrollment will be entered in the IRT system. For detailed enrollment procedures, related to the 
use of Interactive Response Technology (IRT), please refer to the [IRT User Manual]. A 
Disposition CRF should be completed indicating the date of enrollment and the specific reason 
if a patient is not enrolled as applicable. 
7.1.1.4
Information to be collected on patients not enrolled (screen failure)
The reason for not being enrolled will be entered in the clinical database. The demographic 
information, informed consent, Inclusion/Exclusion pages, Leukapheresis information and any 
adverse events leading to patient discontinuation and death information (if applicable) must also 

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minutes for one hour and then every hour for the next two hours, or until these signs are 
satisfactory and stable. 
An additional blood sample will be collected post-infusion for tisagenlecleucel cellular kinetics 
assessment as per Table 7-1.
Details on the administration of the tisagenlecleucel infusion are found in Section 6.1.4.3.
The tisagenlecleucel infusion visit must be registered in the IRT system.
7.1.3.2
Post-tisagenlecleucel infusion visits: D2 to M2±14d
Following CT019 infusion, patients will undergo assessments as per Table 7-1.
Weekly (or more frequent, see Table 7-1) sample collections for serum cytokines, 
tisagenlecleucel cellular kinetics, and inflammatory markers (e.g. ferritin and CRP) are 
mandated during the first 28 days following tisagenlecleucel infusion. However, as the time-
course and rapidity of CRS development varies among patients, additional unscheduled samples 
for these markers may also be collected as needed, if it is clinically feasible. Frequent 
monitoring of serum CRP, ferritin and cytokines should be considered during the clinical course 
of CRS of any severity (e.g. every day to several days) especially around the following clinical 
events: initial persistence of fevers, hemodynamic instability, initial and worsening of 
respiratory distress, rapid clinical deterioration, just prior to and daily for 2 days following 
tocilizumab administration, around other clinically significant events and upon the clinical 
resolution of CRS.
Please note that results of cytokine analyses are NOT to be used for clinical management 
decisions of CRS. A detailed treatment algorithm has been established with clear criteria for 
CRS management (see Table 6-1 and Table 6-2).
7.1.3.3
Post-tisagenlecleucel infusion visits: M3±14d to M24±14d, Q6M... ±14d
At the intervals listed in the Table 7-1, patients will undergo assessments including disease 
response evaluation with efficacy assessment sent to IRC for review.  
If at any of these visits the patient has a radiological CR based upon imaging assessments, a 
bone marrow biopsy or aspirate needs to be performed in patients that had prior bone marrow 
involvement to confirm the CR.
If at any of these visits the patient is confirmed to have relapse or disease progression, no further 
imaging assessments 
(see 
Section 7.2.1 and Section 7.2.4). Patients will continue to be followed for safety according to 
the assessments described in Table 7-1. Cellular kinetic sampling will only continue to assess 
B- and T-cell levels, transgene persistence, and immunogenicity. For details please refer to 
Section 7.2.3. Assessments of patient-reported outcomes (SF-36 version 2; EQ-5D-3L; FACT-
Lym) will be continued for the next two visits as per Table 7-1 (see Section 7.2.6).
Note: For patients with tisagenlecleucel transgene levels equal to or greater than 1% of WBC:
If ≥ 1% of the WBC in peripheral blood are positive for CD19 CAR vector sequences by qPCR 
at > 12 months from tisagenlecleucel infusion, then the patient will be asked to return for a 
confirmatory blood test prior to the next 6 month visit. If ≥1% of the WBC is positive upon the 

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receipt of the confirmatory qPCR result, then the genomic vector integration sites will be 
determined. Identified vector integration sites will be evaluated using bioinformatic approaches 
to determine the frequency of integration events in regions with known relationships to human 
cancers (i.e. near oncogenes). If integration site analysis reveals mono- or oligo-clonality 
pattern and/or integration at or near an oncogenic locus, a monitoring plan, including follow-
up molecular analyses, will be developed in collaboration between the Investigator, Sponsor 
and Health Authorities that is specific for the health care risks that are anticipated given the 
nature of the integration site and vector target cell type.
7.1.3.4
End of study visit
The End of Study (EOS) visit for each patient will be at the time when all patients have 
completed their Month 24 evaluation or discontinued prematurely. Patients who have 
completed their Month 24 visit before the end of the study will be followed for assessments at 
onsite visits every 6 months (Q6M) until the end of the study. See Section 4.3 for more 
information. During the EOS visit patients will undergo the assessments specified in Table 7-1, 
and a Disposition CRF should be completed. Following the EOS visit, patients will be enrolled 
in the LTFU study [CCTL019A2205B].
7.1.4
Survival follow-up 
For all patients who receive a tisagenlecleucel infusion, follow-up for survival every 3 months 
until end of study is required. If a patient misses a quarterly scheduled visit where survival 
status is required, or if the quarterly time-point where survival status is required does not align 
with a scheduled visit, survival status can be obtained via phone contact. After the end of this 
study, patients will continue to be followed for survival under the LTFU protocol 
[CCTL019A2205B].
7.1.5
Discontinuation of study treatment
Tisagenlecleucel infusion may be discontinued if, in the investigator’s opinion, its continuation 
would be detrimental to the patient's safety. Patients who discontinue from tisagenlecleucel 
treatment should NOT be considered withdrawn from the study and should continue to be 
followed as per assessment schedule provided in Table 7-1. A Disposition CRF should be 
completed.
If for any reason a patient is discontinued from study treatment while or after receiving 
lymphodepleting chemotherapy and before the scheduled infusion of tisagenlecleucel, a visit 
should be scheduled as soon as possible, at which time all of the assessments listed for the End 
of Study visit will be performed. A Disposition CRF should be completed, giving the date and 
reason for stopping the Study.
7.1.6
Discontinuation from study
Patients may voluntarily withdraw from the study or be withdrawn from the study at the 
discretion of the investigator at any time. 

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If a patient discontinues early from the study, a visit should be scheduled as soon as possible, 
at which time all of the assessments listed for the End of Study visit will be performed. A 
Disposition CRF should be completed, giving the date and reason for stopping the Study.
Patients may be withdrawn from the study if any of the following occur:

The patient is lost to follow-up

Patient noncompliance with study therapy and/or clinic appointments

Voluntary withdrawal; a patient may remove himself/herself from the study at any time 
without prejudice.

Termination of the study by the sponsor or the health authorities
7.1.7
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.1.8
Follow up for safety evaluations – Long-term follow-up study
As a single administration study, patients are followed on study for at least 2 years post-infusion 
for safety and efficacy evaluations. A long term post-study follow-up for lentiviral vector safety 
will continue under a separate destination protocol [CCTL019A2205B]. Patients will continue 
to be followed until 15 years post-tisagenlecleucel infusion as per health authority guidelines.

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Under the long term follow-up protocol, semiannual and annual evaluations will be performed 
on all patients who have received a tisagenlecleucel cell product infusion as recommended by 
the FDA and EMA in accordance with the relevant guidelines. All patients who either complete 
or prematurely discontinue from the study will be enrolled in this destination protocol at the 
time of study completion/discontinuation. A separate informed consent/assent forms will be 
provided for this protocol. One to two times a year patients will visit the clinical site for a 
physical exam and medical history (including concomitant medications and adverse events) 
with careful attention to features possibly related to lentiviral associated events such as new 
malignancies, new incidence or exacerbation of a pre-existing neurologic disorder, new 
incidence or exacerbation of a prior rheumatologic or other autoimmune disorder, or new 
incidence of other hematologic disorders. In addition, labs will be drawn to evaluate routine 
safety endpoints, tisagenlecleucel vector persistence and RCL.
7.1.9
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the Study 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Efficacy assessments will be performed as indicated in Table 7-2 until disease progression or 
relapse, start of another anticancer therapy, death, lost to follow-up or withdrawal of consent. 
Efficacy will be evaluated by an Independent Review Committee (IRC) using the Lugano 
classification 2014 (Cheson et al 2014; Barrington et al 2014) as detailed in Appendix 14.1. The 
latest efficacy assessments after bridging therapy and prior to infusion will be used as baseline.
Radiological imaging will be transmitted by the sites to the imaging Contract Research 
Organization (CRO) designated by Novartis to undergo quality checks and central review by 
the IRC. Clinical data such as, physical exam, bone marrow results, pathology/histology and 
cytology results; as well as, information regarding prior interventions, pre-existing radiographic 
findings that may mimic lymphoma at screening/Pre-lymphodepletion evaluation (pre-infusion) 
and on-study interventions will be transmitted to the imaging CRO for review by a medical 
oncologist/hematologist.  At IRC, during the overall review the available clinical data will be 
integrated with the pathological and radiological response data to provide the overall disease 
response:
The presence of one (1) or more stable, but persistent clinical lesions will downgrade a 
radiology CR to an overall PR.
The presence of one (1) or more new or worsening clinical lesions will result in Overall PD.

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If bone marrow biopsy is not negative, a radiographic TPR of CR at that time point would be 
downgraded to an overall PR.
A new lesion biopsy result indicating a malignancy would result in overall PD, if not already 
assessed as PD during the radiology review.
For any given time point, any clinical listings that are within a +14 day window (+28 day 
window for bone marrow data) of the radiographic time point date can be used for the 
corresponding oncology time point assessments.  Clinical listings that are +15 days after a 
radiographic time point will be grouped with the next radiographic time point. For example, if 
the radiographic time point date is 01Mar, and the non-bone marrow clinical evaluations on the 
listings occur on 10Mar and 16Mar, the listings from 10Mar will be associated with the 
radiographic time point date of 01Mar.  The listings from 16Mar will not be associated with the 
01Mar radiographic time point and will be grouped with the next radiographic time point. Any 
clinical listings that fall outside the allowable window will be evaluated with the next 
radiographic time point. A definition of assessment date is provided in Appendix 1, Section 
14.1.4.5.3.
For bone marrow data, the assessment window will be extended to +42 days if there are no 
subsequent radiographic time points.  This +42 day window will only apply to overall 
assessments associated with the patients’s last radiographic time point.
Further details regarding the IRC will be provided in the IRC charter. The decision regarding 
patient management will remain with the local investigator. Eligibility will be determined by 
local assessment of the required images obtained during screening. Imaging studies used to 
determine eligibility must be submitted to the IRC.
Disease status at baseline and efficacy during the study will be evaluated using the following:

Lesions from physical exam findings

Pathology assessment

Imaging

Bone marrow biopsy or aspirate

CSF cytology

Procedures (e.g surgeries) performed on study 
The results of the IRC assessment will be used for primary and secondary analysis purposes. 
Any imaging assessments already completed during the regular work-up of the patient within 8
weeks prior to start of infusion, including before signing the main study ICF, may be considered 
as the pre-infusion images for this study. Any imaging assessments obtained after infusion 
cannot be considered pre-infusion images.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable (non-index) lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.  

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Imaging Assessments
Imaging assessments will be performed at screening and within 8 weeks from screening 
imaging to infusion or if bridging chemotherapy was given.  Baseline/Pre-infusion imaging 
assessment should be done as close to infusion as possible. In the event more than one imaging 
assessment is performed after ICF and prior to infusion then the assessment dated closest to 
infusion will be used as baseline/pre-infusion.   
Any imaging assessments already completed during the regular work-up of the patient within 8 
weeks prior to infusion, including before signing the main study ICF, can be considered as the 
baseline images for this study. Any imaging assessments obtained after infusion cannot be 
considered baseline images.  The patient should not receive any anticancer therapy between the 
screening images and infusion. One of the following assessments are required at screening
and/or baseline, month 3 and Month 6 and at other timepoints only for new CR on CT scan not 
previously documented to confirm response:
PET-CT with diagnostic CT (or PET-CT without diagnostic CT + dedicated diagnostic CT/MRI 
or dedicated CT/MRI of diagnostic quality + dedicated PET when PET-CT with diagnostic
contrast-enhanced CT is not available) must be performed at screening, Months 3, 6 and prior 
to or after Months 3/6 only for new CR not previously documented to confirm response.  The 
CT component of the PET-CT may be used in lieu of a standalone CT/MRI, only if the CT 
component is of similar diagnostic quality as a contrast enhanced CT performed without PET.
If a contrast enhanced PET-CT with diagnostic CT is not available, a PET (using a PET-CT 
without diagnostic CT or a dedicated PET scanner) must be performed and a dedicated contrast-
enhanced diagnostic CT/MRI should be performed in addition to the FDG-PET scan. If 
independent CT and PET scanners are used, and both scans are to be done on the same day, the 
PET must be performed prior to the contrast-enhanced CT as to not compromise PET results. 
The PET-CT acquisition methodology (e.g., administration of intravenous contrast) should 
remain consistent between baseline, Months 3, 6, 9, 12, 18, 24, Q6M (if applicable), and EOS
for any given patient.
PET imaging is always required in order to confirm the first documented complete response 
(CR).  If the first documented radiological CR is seen on CT scan only, a confirmatory PET 
scan (either FDG PET or PET-CT) should be obtained within 14 days in order to confirm that 
timepoint’s response of CR.  If the PET scan is not obtained within 14 days, the timepoint must 
be assessed as a PR, and the next scan should be done by one of the 3 methods above as soon 
as possible to confirm the CR. Once CR has been established by PET imaging, subsequent CR 
and/or PD may be followed by CT imaging only. 
The possible scanning scenarios that are to occur are:
1. PET-CT with diagnostic CT
2. PET-CT with non-diagnostic CT + dedicated diagnostic CT/MRI
3. Dedicated diagnostic CT/MRI + dedicated FDG PET
It is preferred to obtain a PET-CT with diagnostic CT at all protocol required imaging visits 
when possible.
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial  a non-contrast CT of the neck and chest (MRI is 

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not recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed.
Brain MRI or CT should be completed if clinically indicated at screening and post infusion. 
Contrast enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then 
MRI without contrast or CT with/without contrast is acceptable.
If skin lesions are present as a result of a physical exam, these are to be documented via the 
Lugano classification 2014 assessment as a physical exam, skin lesion. 
If EOS is performed outside of the scheduled study visits, efficacy assessments only have to be 
performed if the last assessment was done >30 days before this visit.  
Additional imaging assessments for suspicion of PD or to support efficacy evaluation may be 
performed at any time during the study at the investigator’s discretion.  If imaging is done for 
safety reasons only there should be no efficacy assessment and/or submission to the imaging 
CRO.  (All imaging submitted to the imaging CRO are expected to have a corresponding local 
efficacy assessment).
Any on protocol scheduled and/or unscheduled imaging assessments done within +/- 14 day 
window are to be assessment under a single evaluation.    
Clinical suspicion of disease progression at any time requires prompt physical examination and 
imaging without waiting for the next scheduled imaging assessment. It is recommended to 
verify disease progression by CT and tumor biopsy, if applicable (see Table 7-2).
Once disease progression has been confirmed, no further efficacy assessments will have to be 
performed.
Table 7-2
Imaging or Disease Assessment Collection Plan
Procedure
Screening
Pre-infusion 
Post-infusion Assessment
PET-CT with 
diagnostic (Dx)  
contrast 
enhanced CT 
(Neck, Chest, 
Abdomen, Pelvis)
Mandated
Mandated if >8 weeks from 
screening imaging to infusion 
or if bridging chemotherapy” 
was given
Mandated at Months 3, 6 and 
at any visit a new CR by CT 
needs to be confirmed, not 
seen previously
Once CR is confirmed with 
PET, additional PET imaging is 
not required (CT only)
CT/MRI (Neck, 
Chest, Abdomen, 
Pelvis)
Mandated if PET-CT 
with diagnostic CT  is 
not available
Mandated if >8 weeks from 
screening imaging to infusion 
or if  bridging chemotherapy” 
was given and  if PET-CT 
with diagnostic CT  is not 
available
Mandated at Months 9, 12, 18, 
24,  Q6M (if applicable), EOS 
and any time to confirm PD or  
relapse  
Mandated at Month 3, 6 and at 
any visit a new CR by CT 
needs to be confirmed, not 
seen previously, if PET-CT 
with diagnostic CT is not 
available 
PET-CT with diagnostic CT is 
preferred at all imaging visits 
when possible

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**Bridging therapy consisting of steroids only does not require additional imaging before infusion
7.2.1.1
PET Imaging-Five Point Scale
To standardize PET interpretation, a simple reproducible scoring method called the five point 
scale (5PS) or the Deauville criteria has been implemented for initial staging and assessment of 
interim and end of treatment responses. The 5PS assesses the most intense uptake in a site of 
disease. 
Table 7-3
Five Point Scale (5PS) 
Score
Findings
Score 1
No uptake above background
Score 2
Uptake ≤mediastinum
Score 3*
Uptake > mediastinum, but ≤ liver
Score 4**
Uptake moderately > liver
Score 5**
Uptake markedly higher than liver and/or new lesions
*  Score 3 will be considered PET negative for this study 
**Score 4 should be applied to uptake greater than the maximum standard uptake value (SUV) in a large region 
\ of normal liver and score 5 to uptake 2 times greater than the maximum SUV in the liver. PET images should 
be converted to SUV maps to support comparison across time points and to standardize viewing conditions. 
Dedicated PET
Mandated if  PET-CT is 
not available
Mandated if >8 weeks from 
screening imaging to infusion 
or if  bridging chemotherapy” 
was given and  if PET-CT  is 
not available
Mandated at Months 3 and 6 if 
PET-CT is not available
Any new visit a new CR by 
CT needs to be confirmed, not 
seen previously
Once CR is confirmed with 
PET, additional PET imaging is 
not required (CT only)
Response (CR) 
confirmation by 
PET-CT or PET  
NA
NA
PET imaging is required +/- 14 
days within the same CT 
timepoint window when CR is 
seen by CT, only for new CR
and not previously 
documented.  Once CR has 
been confirmed PET imaging 
is no longer needed however 
remains the preferred method 
when possible.
CT/MRI Brain 
As clinically indicated
As clinically indicated
As clinically indicated
Bone marrow 
biopsy or 
aspirate FL cells
Mandated
NA
Mandated at time of Complete 
Response if BM was involved  
prior to treatment and as 
clinically indicated
CSF Cytology
As clinically indicated
As clinically indicated
As clinically indicated
Tumor biopsy 
(FFPE) for 
pathology and 
molecular 
assessment 
Mandated 
NA
NA

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Score
Findings
  (New) areas of uptake unlikely to be related to lymphoma will be marked as “X” (Barrington et al. 2014).
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing various parameters including physical examination, ECG, 
and vital signs, immunogenicity against tisagenlecleucel, lab abnormalities and collecting AEs 
through Month 12. After Month 12 only selected AEs will be collected. For complete details 
on AE collection, reporting and adverse events of special interest, refer to Section 8.
For all patients, any pregnancies will need to be reported and followed up.
7.2.2.1
Physical examination
A complete evaluation will generally include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities and vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History CRF page. Any lesions, detected during a physical exam at any time-
point that are not detectable by imaging should be recorded on the Tumor Evaluation CRF page 
as a non-targeted lesion and does not need to be recorded on the Adverse Event CRF page. 
Significant new findings, other than new lesions, that begins or worsens after informed consent 
must be recorded on the Adverse Event CRF page.
7.2.2.2
Vital signs
Vital signs include temperature, blood pressure, pulse rate, respiratory rate, and pulse oximetry. 
They should be assessed according to Table 7-1 and Section 6.1.4.3.
7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1.
7.2.2.4
Performance status
At visits according to Table 7-1, the ECOG performance scale index will be used to evaluate 
the performance status of the patients.
Table 7-4
ECOG Performance status grade
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; up and about 
more than 50% of waking hours 
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking hours

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lymphodepletion and prior to tisagenlecleucel infusion. Following tisagenlecleucel infusion, 
monthly urine pregnancy tests will then be required to be performed until Month 12 and until 
CAR T-cells are no longer present by qPCR on two consecutive tests (as per Table 7-1). At this 
time, a serum pregnancy test should be performed. A serum pregnancy test will also be required 
at the End of Study visit. Women of child-bearing potential will be tested for pregnancy monthly 
via a urine test either at their scheduled Visit or they perform at-home urine pregnancy testing 
monthly using kits provided.
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study should they have a positive pregnancy test. In case of positive urine pregnancy 
testing, - additional testing must be performed to confirm pregnancy and if confirmed follow 
reporting requirements as described in Section 8.4. 
For more information about the effects of tisagenlecleucel on reproduction please refer to the 
recent [Investigator’s Brochure].
7.2.3
Pharmacokinetics
Blood and bone marrow samples will be collected from all patients for the assessment of 
tisagenlecleucel transgene levels by qPCR and the tisagenlecleucel transduced cells by flow 
cytometry of CD3-positive cells. Blood samples will be collected at the time points indicated 
in Table 7-7 and Table 7-8 while bone marrow aspirates will be collected as indicated in Table 
7-9 and 7-10. Sampling times are relative to date and time of tisagenlecleucel infusion unless 
otherwise specified. The exact date and actual time of blood sampling must be recorded on the 
appropriate CRF pages. All samples will be used for PK evaluations and estimation of cellular 
kinetic parameters as detailed in Section 10.5.4. Levels of tisagenlecleucel transgene and 
tisagenlecleucel transduced cells will be summarized as detailed in Section 10.5.4.
7.2.3.1
Pharmacokinetic blood collection and handling
Refer to the [Laboratory Manual] for detailed instructions for the collection, handling, and 
shipment of PK and cellular kinetics samples.
Table 7-7
Tisagenlecleucel cellular kinetics by q-PCR in peripheral blood 
collection log
Day*
Scheduled time point 
relative to dosing
DRID 
(tisagenlecleucel)
PK1 Sample No. 
(tisagenlecleucel)
Blood 
Volume 
(mL)
W-4 to D-8 Pre-
Lymphodepletion 
evaluation
D-8 (0h Pre-dose)a
111
201
4
D1 (10 minutes ± 
5 minutes post-
infusion)
D1 (10 min post-dose ±5 
min)
111
202
4
D2
D2 (24h post- dose +/-6h)
111
203
4
D4±1d
D4
111
204
4
D7±1d
D7
111
205
4
D11±1d
D11
111
206
4
D14±1d
D14
111
207
4
D17±1d
D17
111
208
4

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Day*
Scheduled time point 
relative to dosing
DRID 
(tisagenlecleucel)
PK1 Sample No. 
(tisagenlecleucel)
Blood 
Volume 
(mL)
D21±3d
D21
111
209
4
D28±7d
D28
111
210
4
M2±14d
D60
111
211
4
M3±14d
D90
111
212
4
M6±14d
D180
111
213
4
M9±14d
D270
111
214
4
M12±14d 
D360
111
215
4
M18±14d
D540
111
216
4
M24±14d 
D720
111
217
4
Q6Ma
111
1001
4
Unscheduled PK 
samples related 
to CRSb
111
2001
4
Unscheduled (PK 
samples related 
to safety events, 
relapse) c,d
111
3001
4
*All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
** Additional unscheduled samples may be collected as needed dependent upon individual patient differences 
in the clinical time-course of CRS, if clinically feasible. See Section 7.1.3
aPK samples from all patients in follow-up Q6M visits beyond M24 till EOS are uniquely, sequentially numbered 
1001, 1002, etc.
bUnscheduled PK samples related to a CRS events whereby Tocilizumab is not administered are uniquely, 
sequentially numbered 2001, 2002, etc
cUnscheduled PK samples related to other non-CRS safety events are uniquely, sequentially numbered 3001, 
3002, etc.
dIn the event patient relapses or starts a new treatment, an unscheduled PK sample should be collected along 
with corresponding immunogenicity sample (refer to Table 7-11 and Table 7-12)
Table 7-8
Tisagenlecleucel cellular kinetics by flow cytometry in peripheral 
blood collection log
Day*
Scheduled 
time point 
relative to 
dosing
DRID (tisagenlecleucel)
PK2 Sample No. 
(tisagenlecleucel)
Blood Volume 
(mL)
W-4 to D-8 Pre-
Lymphodepletion
evaluation
D-8
111
301
2
D1 10 minutes ± 
5 minutes post-
infusion
D1 (10 min 
post-dose 
±5 min)
111
302
2
D4±1d
D4 
111
303
2
D7±1d
D7
111
304
2
D11±1d
D11
111
305
2
D14±3d
D14
111
306
2
D17±1d
D17
111
307
2
D21±3d
D21
111
308
2
D28±7d
D28
111
309
2

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Day*
Scheduled 
time point 
relative to 
dosing
DRID (tisagenlecleucel)
PK2 Sample No. 
(tisagenlecleucel)
Blood Volume 
(mL)
M2±14d
D60
111
310
2
M3±14d
D90
111
311
2
M6±14d
D180
111
312
2
M9±14d
D270
111
313
2
M12±14d (EOS) 
D360
111
314
2
M18±14d
D540
111
315
2
M24±14d
D720
111
316
2
Unscheduled PK 
samples related 
to CRSa
111
4001
2
Unscheduled (PK 
samples related 
to safety events, 
relapse) b,c
111
5001
2
*All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
** Additional unscheduled samples may be collected as needed dependent upon individual patient differences 
in the clinical time-course of CRS, if clinically feasible. See Section 7.1.3
aUnscheduled PK samples related to a CRS events whereby tocilizumab is not administered are uniquely, 
sequentially numbered 4001, 4002, etc
bUnscheduled anytime PK samples related to other non-CRS safety events will be uniquely, sequentially 
numbered 5001, 5002, etc.
cIn the event patient relapses or starts a new treatment, an unscheduled PK sample should be collected along 
with corresponding immunogenicity sample (refer to Table 7-11 and Table 7-12)
Table 7-9
Tisagenlecleucel cellular kinetics by q-PCR in bone marrow aspirate 
collection log
To be completed only if bone marrow examined
Day*
Scheduled 
time point 
relative to 
dosing
DRID (tisagenlecleucel)
PK3 Sample No. 
(tisagenlecleucel)
Sample Volume 
(mL)
W-10 to W-6 
Screening
Pre-dose
111
401
2
M3±14d
M3
111
402
2
Unscheduled 
(e.g. at time 
of 
radiological 
CR, related 
to relapse) a
111
6001
2
*All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
a. Unscheduled time points begin with 6001, 6002, 6003 series
Table 7-10
Tisagenlecleucel pharmacokinetics by flow cytometry in bone marrow 
aspirate collection log
To be completed only if bone marrow examined

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Day*
Scheduled 
time point 
relative to 
dosing
DRID (tisagenlecleucel)
PK4 Sample No. 
(tisagenlecleucel)
Sample 
Volume 
(mL)
W-10 to W-6 
Screening
Pre-dose
111
501
2
M3±14d
M3
111
502
2
Unscheduled 
(e.g. at time 
of radiological 
CR, related to 
relapse) a
111
7001
2
*All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
a. Unscheduled time points begin with 7001, 7002, 7003 series..." 
Table 7-11
Immunogenicity (humoral) serum sample collection log
Day*
Scheduled 
time point 
relative to 
dosing
DRID (tisagenlecleucel)
IG1 Sample No. 
(tisagenlecleucel)
Sample 
Volume 
(mL)
W-4 to D-8 Pre-
Lymphodepletion 
evaluation
Pre-dose
111
601
3
D14±1d
D14
111
602
3
D28±7d
D28
111
603
3
M3±14d
D90
111
604
3
M6±14d
D180
111
605
3
M12±14d 
D360
111
606
3
M18±14d
D540
111
607
3
M24±14d 
D720
111
608
3
Q6Ma
111
6601
3
Unscheduled (e.g. 
related to 
relapse)b,c
111
8001
3
*All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
aIG1 samples from all patients in follow-up Q6M visits beyond M24 till EOS are uniquely, sequentially 
numbered 6601, 6602, etc.
bUnscheduled anytime PK samples related to other non-CRS safety events will be uniquely, sequentially 
numbered 8001, 8002, etc.
cIn the event patient relapses or starts a new treatment, an unscheduled immunogenicity sample should be 
collected along with corresponding PK sample (refer to Table 7-7, Table 7-8)
Table 7-12
Immunogenicity (cellular) whole blood sample collection log
Day*
Scheduled 
time point 
relative to 
dosing
DRID (tisagenlecleucel)
IG2 Sample No. 
(tisagenlecleucel)
Sample 
Volume 
(mL)
W-4 to D-8 Pre-
Lymphodepletion 
evaluation
Pre-dose
111
701
10
D14±1d
D14
111
702
10
D28±7d
D28
111
703
10

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Day*
Scheduled 
time point 
relative to 
dosing
DRID (tisagenlecleucel)
IG2 Sample No. 
(tisagenlecleucel)
Sample 
Volume 
(mL)
M3±14d
D90
111
704
10
M6±14d
D180
111
705
10
M12±14d 
D360
111
706
10
M18±14d
D540
111
707
3
M24±14d 
D720
111
708
3
Q6Ma
111
7701
3
Unscheduled (e.g. 
related to 
relapse)b,c
111
9001
10
*All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
aIG2 samples from all patients in follow-up Q6M visits beyond M24 till EOS are uniquely, sequentially 
numbered 7701, 7702, etc.
bUnscheduled anytime PK samples related to other non-CRS safety events will be uniquely, sequentially 
numbered 9001, 9002, etc.
cIn the event patient relapses or starts a new treatment, an unscheduled immunogenicity sample should be 
collected along with corresponding PK sample (refer to Table 7-7, Table 7-8)

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7.2.3.2
Analytical method
The quantitative polymerase chain reaction (qPCR) or flow cytometry methods will be used for 
estimation of cellular kinetics of tisagenlecleucel [SBP pALL-Section 1.6].
The entities measured are summarized below:

CAR19 transgene levels as generated by q-PCR

CAR-positive viable T cells measured by flow cytometry of CD3+

CAR-positive viable T cells measured by flow cytometry of CD3+/CD8+ cells
Additional details are provided in the bioanalytical data report [GDX-RPT-1292] [GDX-RPT-
1243] [CTL019C2201-flow cytometry bioanalytical data report].

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7.2.6
Patient reported outcomes (PRO)
Three questionnaires will be used in this study to capture patient reported outcomes (PROs) at 
the visits specified in Table 7-1: SF-36v2 (Acute Form), FACT-Lym and EQ-5D-3L. Brief 
description of each questionnaire is given in the sections below. For patients who relapse or 
progress, assessments of patient-reported outcomes (SF-36 version 2; EQ-5D-3L; FACT-Lym) 
will be continued for the next two visits as per Table 7-1.

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PRO data will be collected by electronic devices (i.e. tablet). Each of the questionnaires 
described below is designed for patient self-administration. The method of activating and 
operating the data capture device is provided in a separate user guide.
The patient should be given the electronic device to complete the questionnaire(s) at the 
scheduled visit before other clinical assessments are conducted. The questions should be 
completed in the language the respondent is most familiar with, at the scheduled visit before 
the patient sees the investigator for clinical assessments. The patient should be given sufficient 
space and time to complete the questions.
The study coordinator should check the patients’ responses for completeness and encourage the 
patient to complete any missing responses. Detailed instructions relating to the administrative 
procedures of the questionnaires will be provided to the sites. Patient’s refusal to complete all 
or any part of a questionnaire should be documented in the study data capture system.
The completed ePRO data and any unsolicited comments made by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs, 
including SAEs, before any clinical study examinations. This assessment should be documented 
in study source records. If AEs or SAEs are confirmed, study investigators should not encourage 
the patient to change responses reported in the completed ePRO data. Study investigators must 
follow reporting instructions outlined in Section 8.1.2.
7.2.6.1
FACT-Lym
The Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) is a questionnaire to 
assess the quality of life in patients with Lymphoma. It consists of a general quality of life 
instrument (FACT-G) and a condition specific module Lym. The FACT-Lym is a fully 
validated QOL questionnaire applicable for patients with lymphoma and includes a module 
which assesses specific concerns of patients with lymphoma. The FACT-G has 27 statements 
that patients will need to endorse on a five-point scale (not at all, a little, somewhat, quite a bit, 
very much). The statements cover five subscales (Physical Well-Being, Social/Family Well-
Being, Emotional Well-Being, Functional Well-Being and Additional Concerns). The Lym 
module consists of 15 statements patients need to endorse on an identical five-point scale. This 
scale is designed for patient self-administration. Patients should be instructed to read the brief. 
After the patient's correct understanding has been confirmed they should be encouraged to 
complete every item in order without skipping any. Some patients may feel that a given question 
is not applicable to them and therefore will skip the item altogether. Patients should be 
encouraged to check the response most applicable.
7.2.6.2
SF-36 v2 (Acute form)
The Short Form Health Survey (SF-36) is a widely used and extensively studied instrument to 
measure health-related quality of life among healthy patients and patients with acute and 
chronic conditions. It consists of eight subscales that can be scored individually: Physical 
Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-
Emotional, and Mental Health. Two overall summary scores, the Physical Component 
Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-
36 has proven useful in monitoring general and specific populations, comparing the relative 

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burden of different disease, differentiating the health benefits produced by different treatments, 
and in screening individual patients.
7.2.6.3
EQ-5D-3L
The EQ-5D-3L is a widely used, self-administered questionnaire designed to assess health 
status in adults. 
The measure is divided into two distinct sections. The first section includes one item addressing 
each of five dimensions (mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression).
Patients rate each of these items from “no problem,” “some problem,” or “extreme problem.” 
A composite health index is then defined by combining the levels for each dimension. The 
second section of the questionnaire measures self-rated (global) health status utilizing a 
vertically oriented visual analogue scale where 100 represents the “best possible health state” 
and 0 represents the “worst possible health state.” Respondents are asked to rate their current 
health by placing a mark along this continuum. The recall period is “today,” and the 
questionnaire requires approximately 5 to 10 minutes to complete.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a patient or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the infusion 
of tisagenlecleucel. 
The investigator has the responsibility for managing the safety of individual patient and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
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Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 8.2):
1. Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03, with the exception of CRS, which will 
follow Table 6-1. If CTCAE grading does not exist for an AE, the severity of mild, 
moderate, severe, life-threatening and fatal, corresponding to Grades 1 - 5, will be used
2. its relationship to the study treatment and other investigational treatment If the event is 
due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected’. The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single patient
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a serious adverse events (SAE) (see Section 8.2 for definition of 
SAE) and which seriousness criteria have been met
5. action taken regarding with study treatment.
6. All adverse events must be treated appropriately. Treatment may include treatment 
interruption or withdrawal.
7. its outcome, i.e., its recovery status or whether it was fatal
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history CRF.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for the duration as specified in Appendix 3
Section 14.3.1.
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment should be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
study treatment, the interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented as per Lugano guideline, 
should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 

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be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the treatment.
Information about adverse drug reactions for the investigational drug can be found in the 
[Investigator’s Brochure].
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease.
Detailed AE reporting requirements during the periods of screening, pre-treatment and
treatment and follow-up are outlined in Appendix 3 Section 14.3.1.
8.1.2
Adverse Event of special reporting requirements
If specifically requested by a local Health Authority, expedited reporting of pre-specified AEs 
will occur.
8.1.3
Duration of adverse event reporting 
Detailed guidance to determine whether or not a non-serious AE, an SAE, concomitant 
medication, or laboratory result has to be recorded in the eCRF during the relevant study period 
is provided in Appendix 3 (Section 14.3).
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as any adverse event [appearance of (or worsening of 
any pre-existing)] undesirable sign(s), symptom(s) or medical conditions(s)) which meets any 
one of the following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the patient was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically
might have caused death if it were more severe (please refer to the ICH-E2D Guidelines).

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Requires inpatient hospitalization or prolongation of existing hospitalization,
Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

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
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
8.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has
provided informed consent must be reported to Novartis safety within 24 hours of learning of 
its occurrence for the duration as specified in Appendix 3 (Section 14.3.1). Additional SAE 
reporting requirements, including those for the periods of screening, pre-treatment, treatment 
and follow-up, are also outlined in Appendix 3 (Section 14.3.1). Detailed instructions regarding 
the submission process and requirements are to be found in the investigator folder provided to 
each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 

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investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with [EU Guidance 
2011/C 172/01] or as per national regulatory requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy follow up in this study will end after birth or after any adverse pregnancy outcome 
associated with the end of the pregnancy. In case of live birth the newborn will be followed up 
until 12 months of age to detect any developmental issue or abnormality that would not be seen 
at birth. Pregnancy outcomes must also be collected for the female partners of any males who 
received tisagenlecleucel in this study. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to tisagenlecleucel infusion 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
For more information about the effects of tisagenlecleucel on reproduction please refer to the 
recent [Investigator’s Brochure].
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator’s
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 8-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing CRF 
(Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
8.7
Data Monitoring Committee 
Not applicable
8.8
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, and Novartis representatives from the Clinical Trial team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will perform 
review of safety data during their regular meetings. This review will include deaths, SAEs, 
AESI or any new safety signals observed in the study. The SC will review protocol amendments 
as appropriate. Together with the clinical trial team, the SC will also develop recommendations 
for publications of study results including authorship rules. The details of the role of the Steering 
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9
Data collection and management
9.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
CRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient’s file. The investigator must also keep the original informed consent form signed by the 
patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
9.2
Data collection
The designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs and, allow modification or verification of the entered 
data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. The Investigator must 
certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site.

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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
9.3
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis.
10
Statistical methods and data analysis
Data from all participating centers will be combined.
The primary analysis will be performed when 90 patients have received tisagenlecleucel
infusion and completed 6 months from study day 1 infusion or discontinued earlier. A final 
Clinical Study Report (CSR) will be produced once all patients complete the study.
10.1
Analysis sets
The analysis sets to be used are defined as below. The Efficacy Analysis Set (EAS) will be used 
as the primary efficacy analysis set. The Safety Set will be used for all the safety analysis. The 
Cellular Kinetic Analysis Set (CKAS) will be used for the cellular kinetic analysis.
All tables and listings will be presented by one treatment arm of tisagenlecleucel.
10.1.1
Screened Set
The Screened Set comprises all patients who have signed informed consent and screened in the 
study.
10.1.2
Enrolled Set
The enrolled set comprises all patients who are enrolled in this study. Enrollment is defined as 
the point at which the patient meets all inclusion/exclusion criteria, and the patients’ 
leukapheresis product is received and accepted by the manufacturing facility.

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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The total cells infused (cells) and total tisagenlecleucel transduced viable T cells infused (cells) 
will be listed and summarized using descriptive statistics. Patients will be categorized as below, 
within or above the prescribed dose range.
Prior and concomitant medications and significant non-drug therapies prior to and after the start 
of infusion will be listed by patient and summarized by the Anatomical Therapeutic Chemical
(ATC) term. Transfusion during the study will be listed. In addition, whether patients have 
received anti-cytokine medications for the management of CRS will be summarized.
10.4
Primary objective
The primary objective is to evaluate the efficacy of tisagenlecleucel reflected by the complete 
response rate (CRR) determined by an independent review committee (IRC). 
10.4.1
Variable
The primary endpoint is the CRR as determined by IRC. The CRR is defined as the proportion 
of patients with a best overall response of CR recorded from tisagenlecleucel infusion until 
progressive disease or start of new anticancer therapy, whichever comes first. 
10.4.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be performed by testing the null hypothesis of CRR being 
less than or equal to 15% at one-sided cumulative 2.5% level of significance, i.e. 
H0: p ≤ 0. 15 vs. Ha: p > 0.15
The CRR will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence 
intervals. P-value from binominal exact test will be provided. 
The primary efficacy endpoint, CRR will be analyzed based on the data observed in the EAS.
In addition, sensitivity analysis will be performed using the local investigator response 
assessments instead of the IRC assessment.
10.4.3
Handling of missing values/censoring/discontinuations
Patients in this study who are of unknown clinical response will be treated as non-responders. 
See also the Novartis guideline for efficacy evaluation in lymphoma studies (based on Lugano 
2014 response criteria) (Section 14.1) for more details.
Other missing data are simply noted as missing on appropriate tables/listings.
10.4.4
Supportive and Sensitivity analyses
The primary analysis will also be performed on the Enrolled Set and PPS using the same 
methodology. In addition, analysis will also be performed using all patients who satisfy all 
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10.4.4.1 Subgroup analysis
Subgroup analyses will be performed on the following based on the patient’s baseline status: 

Age: <65 years, ≥ 65 years

Gender: Male, Female

Race: Asian, Black, Caucasian, Native American, Other, Pacific Islander, Unknown

Ethnicity: Hispanic or Latino, Chinese, Indian, Japanese, Mixed ethnicity, Other

FLIPI at enrollment: low/intermediate, high

FL grade: 1, 2, 3

Number of prior lines of anti-neoplastic therapy: ≤2 lines, 3 to 4 lines, >4 lines

PI3K inhibitor use: naïve, pretreated
Subgroup analyses will only be performed if at least 5 patients are present in each subgroup. 
Grouping of classes will be considered if there are too few patients in some subgroups.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
Not applicable because no formal hypothesis testing is planned other than for the primary 
objective.
10.5.2
Other secondary efficacy objectives
IRC assessment will be used in the main analysis of secondary endpoints that involve disease
response.
10.5.2.1 Overall response rate (ORR)
Overall response rate is defined as the proportion of patients with a best overall disease response 
of CR or PR. 
The ORR will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence 
intervals
10.5.2.2 Duration of response (DOR)
Duration of response (DOR) applies only to patients whose best overall disease response was 
CR or PR. It is defined as the time from the date of first documented disease response (CR or 
PR) to the date of first documented progression or death due to FL. If a patient has not had an 
event, duration of overall response is censored at the date of the last adequate assessment.
In case a patient does not have progression or death due to FL prior to data cutoff, DOR will be 
censored at the date of the last adequate assessment on or prior to the earliest censoring event. 
The censoring reason could be:

Ongoing without event

Lost to follow-up

Withdrew consent

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
New anticancer therapy (also see below for handling HSCT)

Event documented after at least two missing tumor assessments

Adequate assessments no longer available
In the main analysis of DOR, death due to reason other than FL will be considered as a 
competing risk event to other events of interest (progression or death due to FL). In this analysis, 
the median response duration as well as proportion of patients without events following 
response (progression or death due to FL) at 3, 6, 9, 12 months, etc. will be presented with 95% 
confidence intervals using the cumulative incidence function (CIF). Distribution of DOR will 
also be estimated using the Kaplan-Meier method in which death due to reason other than FL 
will be censored.
As HSCT is an important treatment option in responding patients, it is appropriate to consider 
the date of HSCT as censoring date, instead of censoring at the last tumor assessment date. If a 
patient received HSCT after a CR or PR, relapse or survival status after HSCT will be recorded 
on the corresponding follow-up CRFs, although data on individual disease response 
components (e.g. CT scan) will not be collected. In such cases, the date of relapse or death (if 
due to FL) after HSCT will be used for calculation of DOR as a sensitivity analysis.
Distribution of DOR will be estimated using the Kaplan-Meier method and the median response 
duration as well as proportion of patients without event at 3, 6, 9, and 12 months will be 
presented along with 95% confidence interval.
Duration of response will be summarized for patients with CR only as well as with CR or PR.
10.5.2.3 Progression free survival (PFS)
Progression-free survival (PFS) is defined as the time from the date of first tisagenlecleucel
infusion to the date of event defined as the first documented progression or death due to any
cause. If a patient has not had an event, progression-free survival is censored at the date of the 
last adequate assessment.
In case a patient does not have progression or death prior to data cutoff, PFS will be censored at
the date of the last adequate assessment on or prior to the earliest censoring event. The 
censoring reason could be:

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (see below for handling of HSCT)

Event documented after at least two missing tumor assessments

Adequate assessments no longer available
In the main analysis of PFS, patients who proceed to HSCT after tisagenlecleucel infusion will be 
censored at the time of HSCT. In addition, a sensitivity analysis of PFS will be performed without 
censoring for HSCT.

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PFS will be estimated using the Kaplan-Meier method and the median PFS as well as proportion 
of patients without event at 3, 6, 9, and 12 months will be presented along with 95% confidence 
interval.
10.5.2.4 Overall survival (OS)
Overall survival (OS) is the time from date of first tisagenlecleucel infusion to date of death due 
to any reason. If a death has not been observed by the date of analysis cutoff, OS will be 
censored at the date of last contact.
OS will be assessed in all patients (FAS). The distribution function of OS will be estimated 
using the Kaplan Meier (KM) method. The median OS and the proportion of patients alive at 3, 
6, 12, 18, and 24 months with 95% confidence intervals will be presented.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used, unless otherwise specified. All listings and 
tables will be presented by one treatment arm of tisagenlecleucel.
The overall observation period will be divided into three mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first 
lymphodepleting chemotherapy dose or the pre-infusion visit if the lymphodepleting 
chemotherapy is not given.

Lymphodepleting period (note: this period only applies to patients who received 
lymphodepleting chemotherapy): from the first day of lymphodepleting chemotherapy

to the day before infusion of tisagenlecleucel, for patients who received infusion, or

to the earlier of date of discontinuation and 30 days after last dose of lymphodepleting 
chemotherapy for patients who didn’t receive infusion of tisagenlecleucel

Post-infusion period: starting at day of tisagenlecleucel infusion
10.5.3.2 Adverse events (AEs)
Reporting of adverse events will be based on MedDRA and CTCAE version 4.03.
Adverse events that start or worsen after informed consent should be recorded in the patient’s 
source documents. New or worsening adverse events prior to starting study treatment (i.e.
lymphodepleting chemotherapy or the pre-infusion visit if the lymphodepleting chemotherapy 
is not given per Section 6.1.3) are not required to be recorded in the CRF unless it is an AE 
meeting criteria outlined in Section 8.1 or SAE meeting criteria outlined in Section 8.2.2. Once 
the patients begin lymphodepleting chemotherapy or the pre-infusion visit, all new or worsening 
adverse events will be recorded in the Adverse Event CRF. Summary tables for adverse events 
will be provided for AEs that start or worsen during the post-infusion period, i.e. the 
tisagenlecleucel-treatment-emergent AEs. In addition, AEs that start or worsen during the 
lymphodepleting period will be summarized for all patients who received lymphodepleting 
chemotherapy. All safety data (including those from the pre-treatment period) will be listed 
along with the period (as defined in Section 10.5.3.1) of the starting date of AE.

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assessment will be provided based on all available data at the time of final analysis. FAS will 
be used for all analyses.

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10.7
Interim analysis
One interim analysis for overwhelming efficacy is planned for the study when approximately 
50 patients of the planned 90 (55.6%) have received tisagenlecleucel infusion and have either 
completed 6 months from study day 1 infusion or discontinued earlier. An α-spending function 
according to Lan-DeMets (O’Brien-Fleming), as implemented in EAST 6.3, will be used to 
construct the efficacy stopping boundary (Lan and DeMets 1983). Based on this choice of α-
spending function, if the interim analysis is performed with 50 patients, the lower bound of the 
2-sided 99.48% exact confidence interval for CRR will need to be greater than 15% to declare 
statistical significance. As a result, a CRR of 16/50=32% will be needed to claim success at 
interim analysis. At the final analysis when 90 patients are treated and followed for at least 6 

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months, 2-sided 95.16% exact CI will be used correspondingly, requiring an CRR of 
21/90=23.3% to claim success.
In case the actual number of patients included in the interim analysis cut-off date is not exactly 
equal to the planned 50 patients, the efficacy boundaries will be re-calculated based on the 
actual number of patients using the pre-specified α-spending.
By the time of the interim analysis, all patients are expected to have been treated. Therefore, 
the study will not be stopped for outstanding efficacy regardless of the interim analysis results.
The operating characteristics of certain scenarios are summarized in Table 10-2 below.
Table 10-2
Scenarios for interim and final analysis 
Scenario
Probability (%) to claim 
success at interim analysis
Probability (%) to claim success 
at interim or final analysis
p=0.15 (H0)
0.19
2.35
p=0.20
3.08
24.45
p=0.25 
16.31
67.06
p=0.30(Ha)
43.08
92.94
p=0.35
71.99
99.23
10.8
Sample size calculation
The observed CRR was 14% in a recent study of idelalisib-treated patients with relapsed or 
refractory follicular lymphoma (Salles et al 2017). 
Based on the null hypothesis of CRR ≤ 15% and assuming the underlying CRR of 30% for 
tisagenlecleucel, 90 patients in the primary analysis will provide at least 90% cumulative power 
to demonstrate statistical significance, using a 2-look Lan-DeMets group sequential design with 
O’Brien-Fleming type boundary and an exact confidence interval at one-sided cumulative 0.025 
level of significance, if the underlying CRR is 30%. In this setting, a CRR of 21/90=23.3% will 
be needed to claim success.
Assuming 20% enrolled patients will not be infused due to reasons such as manufactory failure, 
worsening of patient’s condition, etc., at least 113 patients need to be enrolled to ensure 90 
patients are treated and hence will be used for the primary analysis. 
10.9
Power for analysis of key secondary variables
Not applicable because no formal hypothesis testing is planned other than for the primary 
objective.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.

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11.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, patient recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
regulatory authority, the investigator must inform Novartis immediately that this request has 
been made.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC -approved informed consent
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that complies with the ICH GCP guideline and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the informed 
consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the patient.
Women of child bearing potential must be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirements.
Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.

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11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
11.6
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
11.7
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.

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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.8
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.9
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.10
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.

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12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.

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14
Appendices
14.1
Appendix 1: Guidelines for efficacy evaluation in non-Hodgkin 
lymphoma studies
Author(s):
Document type:
TA Specific Guideline
Development phase
Final Version 03: 22-Feb-2018
Release date:
22-Feb-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis

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List of Abbreviations
BOR
Best overall response
CMR
Complete metabolic response
CR
Complete response
CT
Computed tomography
DFS
Disease-free survival
DLBCL
Diffuse large B cell lymphoma
EFS
Event-free survival
FDG
Fluorodeoxyglucose
FL
Follicular lymphoma
HSCT
Hematopoietic stem cell transplantation
LDi
Longest diameter
LSS
Lymphoma-specific survival
MRI
Magnetic resonance imaging
NHL
Non-Hodgkin lymphoma
NMR
No metabolic response
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression free survival
PMD
Progressive metabolic disease
PMR
Partial metabolic response
PR
Partial response
PPD
Product of the perpendicular diameters
RD
Relapsed disease
SCT
Stem cell transplantation
SD
Stable disease
SDi
Shortest diameter
SPD
Sum of the product of the perpendicular diameters for multiple lesions
SUV
Standard uptake value
TTCR
Time to complete response
TTP
Time to progression
TTR
Time to response
UNK
Unknown
5PS
PET five point scale

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14.1.1
Introduction
The purpose of this document is to provide working definitions and rules to evaluate efficacy 
in non-Hodgkin lymphoma (NHL) studies conducted by Novartis. This document is based on 
the International Working Group response criteria (Cheson et al 1999), the International 
Harmonization Project revised response criteria (Cheson et al 2007), and the revised Consensus 
of the International Conference on Malignant Imaging Working Group and the Lugano 
Classification (Barrington et al 2014; Cheson et al 2014), and it is intended for studies of 
radiographically measurable disease. For studies without measurable disease, e.g., studies of 
consolidation of complete response, maintenance treatment, or autologous stem cell 
transplantation, see [Appendix A].
14.1.2
Methodologies
14.1.2.1 Computed tomography (CT)
The same method of assessment and technique should be used to characterize each identified 
and reported lesion throughout the study. Contrast-enhanced CT of neck, chest, abdomen and 
pelvis, from skull base through lesser trochanters ensuring complete coverage of the pelvis and 
inguinal areas, should be performed using a ≤ 5 mm slice thickness with a contiguous 
reconstruction algorithm. If a patient has a CT contrast allergy or develops it during the trial, 
non-contrast CT of the chest plus contrast-enhanced MRI of abdomen and pelvis are acceptable 
for a follow up. Chest MRI is not recommended due to respiratory artifacts.
14.1.2.2 Positron emission tomography (PET)
Studies of FDG-avid histologies require PET using the radiotracer 18F-fluorodeoxyglucose 
(FDG) to confirm any new CR determined by CT. PET will not be required to confirm 
progression or relapse.
PET scans should cover the whole body from base of skull to mid-thigh. Examinations should 
be consistent across all time points including amount of tracer, location of injection, arm 
location, and scan delay. Information of height, weight, gender, administered dose, time 
between dose administration and imaging, and glucose level are required for each time point. 
PET images should be converted to SUV maps to support comparison across time points and to 
standardize viewing conditions.
14.1.2.3 PET-CT
Hybrid PET-CT may be used to acquire PET and CT images if CT images produced by the 
scanner are of diagnostic quality and include intravenous contrast. Non-diagnostic CT images 
acquired for attenuation purposes during PET-CT are NOT acceptable as the only images for 
the time point.
If diagnostic CT and PET are to be acquired on the same day, PET must be performed prior to 
CT with IV contrast to avoid compromising PET results.
Thus, any of the three following imagining methodologies are possible in a lymphoma study:

PET-CT with diagnostic

PET-CT with non-diagnostic CT and dedicated diagnostic CT

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
Dedicated diagnostic CT and dedicated FDG PET
14.1.2.4 Magnetic resonance imaging (MRI) and PET-MRI
MRI or PET-MRI is an acceptable method of imaging if CT is contraindicated e.g., due to CT 
contrast allergy. If at baseline a patient is known to be allergic to CT contrast or develops allergy 
during the trial, the following change in imaging modality will be accepted for follow up: a 
non-contrast CT of the chest plus contrast-enhanced MRI of abdomen and pelvis (MRI of the 
chest is not recommended due to respiratory artifacts).
14.1.2.5 Five point scale (5PS)
To standardize PET interpretation, a simple reproducible scoring method called the five point 
scale (5PS) or the Deauville criteria has been implemented for initial staging and assessment of 
interim and end of treatment responses (Barrington et al 2014). The 5PS assesses the most 
intense uptake in a site of disease (Table 14-1).
Table 14-1
Five Point Scale (5PS)
Score
Findings
Score 1
No uptake above background
Score 2
Uptake ≤mediastinum
Score 3*
Uptake > mediastinum, but ≤ liver
Score 4**
Uptake moderately > liver
Score 5**
Uptake markedly higher than liver and/or new lesions
*  The protocol will need to define the significance of a score 3, depending on the studied disease, patient 
characteristics and goal of therapy
●
Score 3 may be considered PET negative in low risk disease (e.g. follicular lymphoma) and where no 
further treatment is necessary
●
Score 3 may be considered PET positive in high risk disease that is curable and aggressive (e.g. Hodgkin 
lymphoma, diffuse large B cell lymphoma) and in de-escalation studies
** Score 4 should be applied to uptake greater than the maximum standard uptake value (SUV) in a large 
region \ of normal liver and score 5 to uptake 2 times greater than the maximum SUV in the liver. PET images 
should be converted to SUV maps to support comparison across time points and to standardize viewing
conditions. 
(New) areas of uptake unlikely to be related to lymphoma will be marked as “X” (Barrington et al. 2014).
14.1.3
Definitions
14.1.3.1 Disease stage
Extent and involvement by lymphoma is described by the disease stage and is an important 
prognostic factor. Stage can also influence treatment decisions.
14.1.3.2 Baseline
Baseline examination should be as close as possible to the randomization/start of treatment (e.g., 
within 4 weeks prior to randomization/start of treatment). Longer periods may be allowed 
depending on the disease studied and the study design.

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14.1.3.3 Nodal vs. extranodal lesion
A lesion can be categorized as:

Nodal lesion (a lymph node or a nodal mass)

Extranodal lesion (a lesion located in other organs, including spleen and liver)
14.1.3.4 Measurable disease
All anatomic measurements should be taken in two perpendicular dimensions and recorded in 
metric notation, using a ruler or calipers.
Throughout this document, a lesion will be called measurable if:

It can be measured accurately in two perpendicular dimensions: longest diameter (LDi) 
(also known as transverse diameter), and shortest diameter (SDi), which is the longest 
diameter perpendicular to LDi (also known as perpendicular diameter). The LDi and SDi 
must be measured on the same slice.

For a nodal lesion, LDi is greater than 15 mm, regardless of SDi

For an extranodal lesion, if both LDi and SDi are greater than 10 mm
A lymph node not meeting the measurability criteria but with LDi greater than 15 mm (e.g. SDi 
cannot be measured accurately) will constitute a non-measurable nodal lesion if FDG-avid (for 
FDG-avid histologies).
A lymph node not meeting the measurability criteria but with LDi ranging from 11 mm to 15 
mm and with SDi greater than 10 mm will be checked for relationship to disease as follows:

If it is related to lymphoma, it will constitute a non-measurable nodal lesion (referred to as 
“involved node” in Cheson et al 2007)

If not related to lymphoma and not FDG-avid, it will constitute an abnormal lymph node 
but not a nodal lesion for FDG-avid histologies
All lesions visible on PET but not on CT/MRI will be treated as non-measurable.
Bulky disease
Bulky disease is captured by means of the longest measurement by CT scan. The definition of 
bulky disease (a minimum size) should be included in the study protocol.
14.1.3.5 Assessable disease
Assessable disease refers to disease presentations that are consistent with lymphoma but are not 
suitable for measurement, e.g., pleural effusion, ascites, etc. Assessable disease will be followed 
qualitatively.
14.1.3.6 Index lesion

Up to 6 of the largest nodes, nodal masses or other lymphomatous lesions, including 
extranodal lesions, measurable in two diameters (LDi and SDi)

Should represent overall disease burden and include mediastinal and retroperitoneal 
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14.1.3.7 Non-index lesion

All other lesions which are not selected as index lesions but are consistent with lymphoma

Abnormal nodes and extranodal lesions, both measurable and non-measurable, such as 
cutaneous, gastrointestinal, and bone lesions, pleural or pericardial effusions, and ascites
14.1.3.8 New lesions

Regrowth of previously resolved lesions

A new nodal lesion > 15 mm in any axis

A new extranodal lesion > 10 mm in any axis

A new extranodal lesion ≤ 10 mm in any axis that is unequivocal and attributable to 
lymphoma

A new assessable lesion attributable to lymphoma (e.g., ascites, pleural effusion)
14.1.4
Efficacy assessments
14.1.4.1 Eligibility
In general, patients should have at least one measurable nodal lesion (greater than 15 mm in the 
long axis) or at least one measurable extranodal lesion (with both LDi and SDi greater than 10 
mm).
14.1.4.2 Methods of disease assessment
14.1.4.2.1
PET combined with diagnostic CT
The integration of PET into more frequently acquired CT evaluation does present a challenge 
to the way response is assessed in a clinical trial. The study protocol must clearly define the 
imaging intervals and imaging methods to be used at each imaging visit. PET scans should be 
performed at pre-specified times for example at randomization before treatment and at clearly 
defined times during and/or after the end of treatment. PET may also be acquired to confirm 
CT results.
The same CT imaging modality should be used at baseline and all post-baseline assessments in 
order to reduce the risk of false responses or progressions based on measurement error. A 
change in modality can be either a change in contrast use (i.e., with contrast versus without 
contrast) or a change in technique (e.g. from CT to MRI). Response assessments made after a 
change in imaging modality should be queried, and if the investigator or blinded central 
reviewer can provide sufficient justification, then the response can be accepted.
In order to calculate the sum of the product of the perpendicular diameters (PPD) of all index 
lesions, their size must be recorded throughout the study. Actual lesion measurements should 
be entered on the corresponding CRFs. If, during the course of the study, either of the 
perpendicular diameters of a lesion cannot be reliably measured because of its small size, it is 
recommended to enter the minimum limit of detection as the diameter size (e.g., 5 mm for spiral 
CT). In other cases when, during the course of the study, the diameter cannot be reliably 
measured for reasons other than its size (i.e., borders of the lesion are confounded by 

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neighboring anatomical structures), no measurement should be entered and the lesion cannot be 
evaluated.
If lesions become confluent over time, it is recommended to measure them as one lesion, report 
the overall diameters to one of the lesions and assign 0 mm × 0 mm to each of the other 
previously measured lesions. The PPD of the current confluent mass should be used to measure 
response, with more than 50% increase in the PPD of the confluent mass compared with nadir 
of the sum of individual nodes necessary to indicate progressive disease.
If a lesion splits into several discrete lesions, the individual product of the perpendicular 
diameters (PPDs) of each lesion should be summed together to represent the PPD of the split 
lesion; this PPD is added to the sum of the PPDs of the remaining lesions to measure response. 
If subsequent growth of any or all of these discrete nodes occurs, the nadir of each individual 
node is used to determine progression (as if each individual node was selected as an index lesion 
at baseline).
14.1.4.2.2
Bone marrow assessment
Bone marrow should be evaluated by biopsy or aspirate in all patients at baseline. If lymphoma 
involvement in bone marrow is observed at baseline, then biopsy or aspirate should be 
performed post-baseline to confirm radiological CR. Any deviation from this approach should 
be justified in the study protocol.
14.1.4.2.3
Physical examination
Skin lesions must be histologically confirmed for lymphoma involvement (the investigational 
site must document the histological confirmation (yes or no) on the corresponding CRF) and 
photographed including a ruler (color photography using digital camera). Response assessment 
of skin lesions will be performed and results will be recorded on the corresponding CRF at 
baseline and at the time of each radiological assessment.
14.1.4.3 Documentation of disease
For the evaluation of disease at baseline and throughout the study, the following will be 
recorded.
14.1.4.3.1
FDG uptake
FDG uptake in a nodal or extranodal site that is suggestive of lymphoma will be assessed using 
5PS.
14.1.4.3.2
Index lesions
A minimum of one measurable index lesion and a maximum of six of the largest dominant 
nodal and extranodal lesions must be documented at baseline and assessed throughout the study 
in two dimensions. The lesions should come from different body regions representative of the 
patient’s overall disease burden and should include mediastinal and retroperitoneal disease, if 
involved. Two perpendicular dimensions (LDi, SDi) must be recorded on the corresponding 
CRF at each assessment of a measurable lesion selected to be an index lesion.
Index nodal lesions

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Index nodal lesions are selected from the measurable nodal lesions and should be documented 
at baseline and assessed throughout the study. Index nodal lesions should be from disparate 
regions of the body including mediastinal and retroperitoneal areas of disease whenever these 
sites are involved.
Index extranodal lesions
Other organs such as breast and lung can be occasionally involved by lymphoma. Such 
extranodal lesions (e.g. hepatic nodules) may be included (if measurable) in the six index lesions 
to be assessed throughout the study. In some cases histological examination may be necessary 
to confirm that these lesions represent lymphoma involvement (e.g. skin lesions).
14.1.4.3.3
Non-index lesions
Non-index nodal lesions
Nodal lesions not selected as index lesions (both measurable and non-measurable) are 
considered as non-index lesions. Non-index lesions should be documented at baseline and 
assessed throughout the study. Measurements of these lesions are not required to be documented 
on the CRF.
Non-index extranodal lesions
Measurable extranodal lesions not selected as index lesions and all non-measurable extranodal 
lesions (including non-measurable but assessable disease e.g. pleural effusion) will be 
documented at baseline and assessed throughout the study as non-index lesions. Measurements 
of these lesions are not required to be documented on the CRF.
14.1.4.3.4
Spleen involvement
Splenic involvement is determined by imaging: vertical (cranial to caudal) length > 13 cm is 
considered as involved, and spleen length must be assessed at each imaging time point. 
Intrasplenic lesions should be followed as index, non-index and new extranodal lesions.
14.1.4.3.5
Liver involvement
Given variability in physical habitus and the impact of numerous medical conditions, 
assessment of liver size is not considered a reliable measure of hepatic involvement and 
therefore liver assessment is not included in the Lugano 2014 classification. Intrahepatic lesions 
should be followed as index, non-index and new extranodal lesions.
14.1.4.3.6
Bone marrow involvement
Lymphoma involvement in bone marrow should be documented in the CRF as “Yes” or “No” 
at each bone marrow biopsy and/or aspiration.
14.1.4.4 Response evaluation
The efficacy variables in the statistical analysis are based on overall disease response, which 
is a combined evaluation of response based on both radiological and clinical findings, and is 
determined at each post-baseline assessment. The radiological response is first obtained from 
CT and PET studies according to the Lugano criteria (Table 14-2) and overall disease response 

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is then determined by taking into account results of bone marrow biopsies and other clinical 
information (Table 14-3).
14.1.4.4.1
Radiological response
There are three separate components to radiological response, all of which should be collected 
on the CRF at each post-baseline assessment:
1. CT response based on anatomical measurements of index/non-index/new lesions and 
spleen length. The possible response outcomes are complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD) as defined in Table 14-2.
2. PET response based on 5PS, changes in intensity or extent of standard uptake values 
(SUVs) and bone marrow assessments directly from the PET scan. The possible outcomes 
for PET response are complete metabolic response (CMR), partial metabolic response 
(PMR), no metabolic response (NMR), or progressive metabolic disease (PMD) as defined 
in Table 14-2.
3. Overall radiological response combines CT response with PET response. The outcomes 
include CR, PR, SD, and PD. For time points when both CT and PET are available, PET 
response overrules CT response. Overall radiological response at a time point with CT 
only may also be affected by PET response obtained at a different time point.
1. Example 
2. A CT response of PR at the same assessment as a PET response of CMR will constitute 
an overall radiological response of CR, and (i) a subsequent time point with CT only and 
CT response of PR will still constitute an overall radiological response of CR, (ii) a 
previous time point with CT only and CT response of PR may be upgraded to CR at the 
discretion of the investigator or blinded central reviewer.
Table 14-2
Radiological response assessment
PET-based response
CT-based response
Complete Metabolic Response 
(CMR)
(All of the following)
Complete Response (CR)
(All of the following)
Complete 
Response
Index 
5PS† of 1, 2, or 3* with or without 
residual mass on 5PS
Nodal lesion: ≤ 15 mm in Ldi
Extranodal lesion: Absent (0 mm x 
0 mm)
Non-index
Absent
Spleen
Return to normal (≤ 13 cm)
New lesions
None
None
Bone 
marrow
No FDG-avid disease
Not applicable
Partial Metabolic Response (PMR)
(all of the following)
Partial Response (PR)
(all of the following)
Partial 
Response
Index 
5PS of 3*, 4 or 5 with reduced uptake 
compared to baseline with respect to 
SUV intensity or extent. This may apply 
to the specific hot spot and/ or overall 
the subject. It is expected that there will 
be residual mass(es) present.
≥ 50% decrease from baseline in 
SPD across all index lesions
Non-index
No increase
Spleen
≥ 50% decrease from baseline in 
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PET-based response
CT-based response
Complete Metabolic Response 
(CMR)
(All of the following)
Complete Response (CR)
(All of the following)
Example: If 16 cm, then enlarged 
portion is 3 cm. A decrease by 2 cm 
gives a 66.6% decrease
New lesions
None
None
Bone 
marrow
●
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline
●
Persistent focal changes in the 
marrow with nodal response
Not applicable
No Metabolic Response (NMR)
(all of the following)
Stable Disease (SD)
(all of the following)
Stable 
Disease
Index 
5PS of 3*, 4 or 5 with no significant 
change in FDG uptake from baseline
●
<50% decrease from baseline in 
SPD across all index lesions
●
No criteria for PD are met
Non-index
No progression
Spleen
No progression
New lesions
None
None
Bone 
marrow
No change in FDG uptake from 
baseline
Not applicable
Progressive Metabolic Disease (PMD
(At least one of the following)
Progressive Disease (PD)
(At least one of the following)
Progressive 
Disease
Index 
5PS of 3*, 4 or 5 with increased uptake 
compared to the visually determined 
nadir with respect to SUV intensity or 
extent. This may apply to the specific 
hot spot and/ or overall the subject.
and/or
●
New FDG-avid foci consistent with 
lymphoma
●
Consider biopsy or interval scan if 
etiology of new lesions uncertain
PPD Progression#:
An individual node/lesion must be 
abnormal with:
●
LDi > 15 mm AND
●
Increase by >= 50% from PPD  
      nadir AND
●
An increase in LDi or SDi from  
      nadir:
●
≥ 5 mm for lesions with LDi ≤ 20 
mm at current assessment
●
≥ 10 mm for lesions with LDi > 
20 mm at current assessment
Non-index
Unequivocal Progression
Spleen
●  Progression (increase from 
baseline by >50% in enlarged 
portion). Example: If 15 cm at 
baseline then enlarged portion is
     
2 cm and an increase by >1 cm 
would be progression
●  New splenomegaly (> 13 cm and 
increase by > 2 cm from normal  at 
baseline)
●  Recurrent splenomegaly 
(normalization followed by  increase
by > 2 cm from nadir reaching > 13 
cm)
New lesions
●  Regrowth of previously resolved     
lesions

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PET-based response
CT-based response
Complete Metabolic Response 
(CMR)
(All of the following)
Complete Response (CR)
(All of the following)
●
New node > 15 mm in any axis
●
New extranodal site > 10 mm in    
      any axis
●
New extranodal site ≤ 10 mm in 
      LDi, unequivocal and 
      attributable to lymphoma
●
Assessable disease of any size 
      Unequivocally attributable to 
      Lymphoma
Bone 
marrow
New/recurrent FDG-avid foci
Not applicable
Abbreviations: LDi Longest diameter; SDi Shortest diameter; PPD Product of perpendicular diameters; SPD 
Sum of the product of the perpendicular diameters.
* The protocol will need to define the significance of a score 3, depending on the disease under study 
   (risk: benefit analysis), patient characteristics and goal of therapy
   - Score 3: PET negative - Low risk disease and no further treatment necessary (e.g. follicular
      lymphoma)
   - Score 3: PET positive - High risk disease that is curable and aggressive (e.g. DLBCL)
# In the context of an agent associated with a flare reaction, caution must be exercised not to confuse 
   the possible tumor flare with progressive disease. It is recommended that either a biopsy be  
   performed or the lesion be reassessed in at least 2 weeks, and if there is continued evidence of 
   tumor progression, the date of progressive disease is the previous evaluation.
† PET 5PS 1: no uptake > background; 2: uptake ≤ mediastinum; 3: uptake > mediastinum but ≤ liver; 
   4: uptake moderately > liver; 5: uptake markedly > liver and/or new lesions; X: new areas of uptake 
    unlikely to be related to lymphoma.
14.1.4.4.2
Overall disease response
Overall disease response is determined by assessing whether the combined radiological 
responses at each time point are appropriate, based on bone marrow biopsies and other clinical 
findings that may be available, such as cytology results, physical examination results of 
palpable lesions or skin lesions, and biopsies of lymph nodes or extra-nodal lesions (Table 14-
3). The possible outcomes for overall disease response are CR, PR, SD, and PD.
For example, suppose there was lymphoma involvement in the baseline bone marrow biopsy, 
and the month 3 combined radiological response was CR (implying that PET-based bone 
marrow involvement at month 3 was negative). In that case, overall disease response could only 
be CR if there was a negative bone marrow biopsy otherwise overall disease response would be 
downgraded to PR. This is a case where the bone marrow biopsy results overrule the bone 
marrow findings on PET. Another example is when the combined radiological response is SD, 
but cytology results of a pleural effusion show lymphoma involvement: this could lead to an 
overall disease response of PD.
Overall disease response at each post-baseline assessment should be captured on the CRF, along 
with the date of response. In addition, the source of any clinical data that affected the overall 
disease response should be documented.

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Table 14-3
Overall disease response
Overall radiological 
response
Bone marrow 
biopsy/aspirate
Clinical findings
Overall disease 
response
CR/PR/SD
Negative at baseline or 
negative ± 28 days from 
assessment
Any except new or 
recurrent lymphoma 
involvement
CR/PR/SD
CR
Positive at baseline and 
either positive (without 
new or recurrent 
involvement) or not done 
± 28 days from 
assessment
Any except new or 
recurrent lymphoma 
involvement
PR
PR/SD
Positive at baseline and 
either positive (without 
new or recurrent 
involvement) or not done 
± 28 days from 
assessment
Any except new or 
recurrent lymphoma 
involvement
PR/SD
PD
Any
Any
PD
Any
New or recurrent 
involvement
Any
PD
Any
Any
New or recurrent 
lymphoma involvement
PD
14.1.4.5 Efficacy analysis definitions
14.1.4.5.1
Best overall response
The best overall response (BOR) is the best overall disease response recorded from 
randomization/start of treatment until progressive disease or start of new anticancer therapy, 
whichever comes first. The definition of new anticancer therapy may need to be defined in the 
study protocol (e.g., high-dose chemotherapy with autologous stem cell transplantation).
A patient will have a best overall response of CR if they have CR as overall disease response 
for at least one of the assessments.
A patient will have a best overall response of PR if at least one overall disease response of PR 
is available (and the patient does not qualify for CR).
A best overall response of SD will be declared when at least one overall disease response of SD 
is available at least 6 weeks after randomization/start of treatment (and the patient does not 
qualify for CR or PR). If SD is observed before this minimum follow-up period, and the patient 
does not qualify for CR, PR or PD, then the best overall response would be unknown (UNK). 
If a different minimum follow-up period for SD is more appropriate (e.g., if first post-baseline 
visit is at 28 days) then this must be specified in the Study Protocol.
A patient will have a best overall response of PD if overall disease response is PD between 
randomization/start of treatment and the second scheduled post-baseline assessment (and the 
patient does not qualify for CR, PR or SD).
For example, assuming 12 weeks between assessments and a permitted variation in visit timing 
of ± 1 week, this would mean during the first 25 weeks after randomization/start of treatment. 
If PD is observed after this maximum follow-up period, and the patient does not qualify for CR, 

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PR or SD, then the best overall response would be UNK. If a different maximum follow-up 
period for PD is more appropriate then this must be specified in the Study Protocol.
A patient will have a best overall response of UNK if the patient does not qualify for CR, PR, 
SD or PD.
Overall disease response at a given assessment may be provided from different sources:

Per Investigator: overall disease response based on local radiological assessments, using 
investigator choice of index lesions, measurements and assessments of lesion status and 
5PS along with clinical findings

Per Central Blinded Review, with or without blinded adjudication: based on central review 
of local radiological assessments, using central reviewer choice of index lesions, 
measurements and assessments of lesion status and 5PS, along with clinical findings
In studies that include a central blinded review, the Study Protocol should state which source 
will be used for the primary analysis.
Best overall response is summarized by calculating the overall response rate (ORR), which is 
defined as the proportion of patients with a best overall response of CR or PR.
Similarly, the complete response rate is the proportion of patients with a best overall response 
of CR.
14.1.4.5.2
Time to event variables
Most of the time to event variables are defined in this section according to the revised 
International Working Group response criteria (Cheson et al 2007). Further details on dates and 
censoring rules are provided respectively in Section 14.1.4.5.3 and Section 14.1.4.5.4.
Overall survival
Overall survival (OS) is defined as the time from the date of randomization/start of treatment 
to the date of death due to any cause. If a patient is not known to have died, OS will be censored 
at the date of last contact.
Progression-free survival
Progression-free survival (PFS) is defined as the time from the date of randomization/start of 
treatment to the date of event defined as the first documented progression (overall disease 
response = PD) or death due to any cause. If a patient has not had an event, PFS is censored at 
the date of the last adequate assessment as defined in Section 14.1.4.5.3.
Time to progression
Time to progression (TTP) is defined as the time from the date of randomization/start of 
treatment to the date of first documented progression (overall disease response = PD) or death 
due to lymphoma. If a patient has not had an event, TTP is censored at the date of the last 
adequate assessment.
Duration of response
Duration of response (DOR) applies only to patients with best overall disease response of CR 
or PR. It is defined as the time from the date of the first documented overall disease response 

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of CR or PR to the date of first documented progression or death due to lymphoma. If a patient 
has not had an event, DOR is censored at the date of the last adequate assessment. It should be 
stated that this analysis might introduce a bias as it includes only responders.
Duration of complete response applies only to patients with best overall disease response of CR. 
It is defined as the time from the date of the first documented overall disease response of CR to 
the date of first documented progression or death due to lymphoma. If a patient has not had an 
event, duration of CR is censored at the date of the last adequate assessment. Duration of CR 
might be calculated in addition for studies in which a reasonable number of complete responders 
are seen.
The analysis of DOR should only be used as a descriptive analysis. If used as an inferential 
comparison between treatments, clear justification must be given in the study protocol.
Time to response
Time to response (TTR) is defined as the time from the date of randomization/start of treatment 
to the date of first documented overall disease response of PR or CR. Depending on the study 
design, this analysis could be based on all patients only, or on responders only, or both of these 
analysis populations may be used. The choice of analysis population for TTR should be stated 
in the study protocol.
For analysis using all patients, TTR will be censored for patients who did not achieve a PR or 
CR:

At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. either progressed or died due to any cause)

At the date of the last adequate assessment otherwise
Time to complete response (TTCR) is defined similarly to TTR except using CR only instead 
of either PR or CR, and with this difference, the above rules and definitions for TTR also apply 
to TTCR.
Lymphoma specific survival
Lymphoma specific survival (LSS) is defined as the time from the date of randomization/start 
of treatment to the date of death documented as a result of lymphoma. If a patient has not had 
an event, LSS will be censored:

at the date of last contact if the patient is not known to have died

at the date of death if the patient died for reason other than lymphoma
Event-free survival
Event-free survival (EFS) may be appropriate in studies of advanced disease where early 
discontinuation is typically related to intolerance of the study drug. In some protocols, EFS may 
be considered as a sensitivity analysis for TTP. If a patient has not had an event, EFS is censored 
at the date of the last adequate assessment as defined in Section 14.1.4.5.3. The definition of 
event needs to be defined in the Study Protocol according to study design.

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14.1.4.5.3
Definition of start and end dates for time to event variables
Assessment date
For each assessment, the assessment date is calculated as:

the latest date of all radiological measurements (e.g. PET-CT, CT, or MRI), excluding 
bone marrow biopsy, if overall disease response at that assessment is CR/PR/SD/UNK

the earliest date of all measurements (e.g. PET-CT, CT, or MRI), including bone marrow 
biopsy if overall disease response at that assessment is PD
Start date
For all “time to event” variables other than the duration of response variables, the date of 
randomization/start of treatment will be used as the start date.
For the calculation of duration of response variables the following start date should be used:

Date of first documented response is the assessment date of the first overall disease 
response of CR for duration of complete response or CR/PR for duration of response
End date
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death as reported on the disposition CRF

Date of last contact is defined as the last date the patient was known to be alive as derived 
from different CRF pages (see details in Section 14.1.4.5.2)

Date of progression is the first assessment date at which the overall disease response was 
recorded as PD

Date of last adequate assessment is the date of the last assessment with overall disease 
response of CR, PR or SD which was made before an event or a censoring reason 
occurred. If no post-baseline assessments are available (before an event or a censoring 
reason occurred) the date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate assessment plus the 
protocol specified time interval between assessments. This date may be used if back-
dating is considered when the event occurred beyond the acceptable time window for the 
next radiological assessment as per protocol.
Example (if protocol defined schedule of assessments is 3 months): response assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of treatment discontinuation is the last known date subject took study drug (to be 
used, if applicable)

Date of new anti-cancer therapy is defined as the start date of first new antineoplastic 
therapy (including medication, radiotherapy, surgery or HSCT)
14.1.4.5.4
Censoring and sensitivity analyses
Censoring reasons

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This section outlines the possible censoring reasons for each time to event variables. In order 
to summarize the various reasons for censoring, the following categories (Table 14-4) will be 
calculated for each time to event variable based on the information reported.
Table 14-4
Censoring reasons
Time to event variables
Possible censoring reasons
OS
●
Alive
●
Lost to follow-up
PFS, EFS, TTP and DOR
●
Ongoing without event
●
Lost to follow-up
●
Withdrew consent
●
Death due to reason other than lymphoma (only used for TTP and DOR)
●
New anti-cancer therapy added (except for EFS optional, see Table 14-5)
●
Event documented after two or more missing response assessments 
(optional, 
see Table 14-5)
●
Adequate assessment no longer available1
LSS
●
Alive
●
Lost to follow-up
●
Death due to reason other than lymphoma
1Adequate assessment is defined in Section 14.14.4.5.3. This reason corresponds to any censoring reasons 
after two or more missing response assessments. This reason will also be used for censor in case of no 
baseline assessment
Event date, censoring date and sensitivity analyses
This section outlines the possible event and censoring dates for progression (Table 14-5), as 
well as addressing the issues of missing response assessments during the study. It is important 
that the protocol and analysis plan specify the primary analysis in detail with respect to the 
definition of event and censoring dates and also include a description of one or more sensitivity 
analyses to be performed.
Based on definitions outlined in Section 14.1.4.5.2, and using the draft FDA guideline on 
endpoints (FDA 2007) as a reference, the following analyses can be considered:
Table 14-5
Options for event dates used in PFS, EFS, TTP, DOR
Situation
Options for end-date (progression)1
(1) = default unless specified differently in 
the protocol or analysis plan
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment2
Censor
B
Progression at or before next 
scheduled assessment
(1) Date of progression
(2) Date of next scheduled assessment1
Event
Event
C1
Progression or death due to any 
reason after exactly one missing 
assessments
(1) Date of progression (or death)
(2) Date of next scheduled assessment1
Event
Event
C2
Progression or death due to any 
reason after two or more missing 
assessments
(1) Date of last adequate assessment1
(2) Date of next scheduled assessment1
(3) Date of progression (or death)
Censor
Event
Event
D
No progression
(1) Date of last adequate assessment
Censor

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Situation
Options for end-date (progression)1
(1) = default unless specified differently in 
the protocol or analysis plan
Outcome
E
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Event
F
New anticancer therapy given 
(except for EFS, in which this is 
always an event)
(1) Date of last adequate assessment
(2) Date of new anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censor
Censor
Event
Ignored
G
Death due to reason other than 
lymphoma
(1) Date of last adequate assessment
Censor
(only TTP and 
DOR)
1 = Definitions can be found in Section 14.1.4.5.3
2 = The rare exception to this is if the patient dies no later than the time of the second scheduled assessment 
as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the Study Protocol. 
Clearly define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments:
The primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of response assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the response due to clinical deterioration.
Situation F: New cancer therapy given (except for EFS): the handling of this situation must 
be specified in detail in the protocol. However, option (1), i.e. censoring at last adequate 
assessment may be used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for response assessments, e.g.:

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
By assigning the dates for censoring and events only at scheduled visit dates. The latter 
could be handled by replacing in Table 14-5 the “Date of last adequate assessment” by the 
“Date of previous scheduled assessment (from baseline)”, with the following definition:
Date of previous scheduled assessment (from baseline) is the date when a response assessment 
would have taken place, if the protocol assessment scheme was strictly followed from baseline, 
immediately before or on the date of the last adequate assessment.
The need for these types of sensitivity analyses will depend on the requirements for a specific 
study and disease area and have to be specified in the Study Protocol or SAP documentation.
14.1.5
Data handling and programming conventions
The following rules should be used and specified in the SAP documentation:
14.1.5.1 Calculation of ‘time to event’ variables
Time to event = enddate - startdate + 1 (in days)
When no post-baseline assessments are available, the date of randomization/start of treatment 
will be used as enddate (duration = 1 day) when time is to be censored at last assessment, i.e. 
time to event variables can never be negative.
14.1.5.2 Date of last contact
The date of last contact will be derived for patients alive using the latest complete date among 
the following:

Assessment dates (e.g., vital signs assessment, performance status assessment, efficacy 
assessment, laboratory, pharmacokinetics assessment)

Medication dates including study medication and antineoplastic therapies administered 
after study treatment discontinuation

Adverse events dates

Last known date subject alive collected on the ‘Survival information’ eCRF

Randomization date
14.1.5.3 Date of new anti-cancer therapy
The date of new anti-cancer therapy is the date of the first antineoplastic therapy (including 
medicine, radiotherapy and surgery) reported on the post-treatment antineoplastic therapy CRF 
or from other sources (e.g., HSCT CRF).
14.1.5.4 Incomplete assessment dates
All investigation dates (e.g., PET-CT scan) must be completed with day, month and year. If one 
or more investigation dates are incomplete but other investigation dates are available, this/these 
incomplete date(s) are not considered for calculation of the assessment date (and assessment 
date is calculated as outlined in Section 14.1.4.5.3). If all measurement dates have no day 
recorded, the 1st of the month is used.

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If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.5.5 Incomplete dates for last contact or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.1.6
References
Barrington SF, Mikhaeel NG, Kostakoglu L, et al (2014) Role of imaging in the staging and 
response assessment of lymphoma: Consensus of the International Conference on Malignant 
Lymphomas Imaging Working Group. J Clin Oncol 32 :3048-3058.
Cheson BD, Horning SJ, Coiffier B, et al (1999) Report of an international workshop to 
standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17:1244-1253.
Cheson BD, Pfistner B, Juweid ME, et al (2007) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586.
Cheson BD, Fisher RI, Barrington SF, et al (2014) Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma: The Lugano 
Classification. J Clin Oncol 32:3059-3067.
FDA Guideline (2007) Clinical trial endpoints for the approval of cancer drugs and biologics, 
May 2007.
14.1.7
Appendices
Appendix A: Adaptation for use in maintenance/adjuvant settings
For study populations without measurable disease at baseline (e.g., maintenance), the event of 
interest is no longer progression but relapse, and the main endpoint is no longer progression-
free survival but disease-free survival (see below).
Relapsed disease
Any of the following meets the definition of relapsed disease (RD):

Any new nodal lesion > 15 mm in any axis (i.e. previously normal lymph node 
becoming >1.5 cm in any axis) on CT (or MRI) after baseline

Any discrete extranodal lesion (including liver or spleen) reliably appearing on CT (or 
MRI) after baseline

≥ 50% increase in long axis from baseline of any residual lymph node or mass. A residual 
lymph node or mass is defined as a previously lymphoma-involved lymph node or mass 
(>10 mm in short axis (without any upper limit)) that was PET negative at baseline and 
only reliably detected by baseline CT (or MRI). Note: If a residual lymph node or mass at 
baseline decreases in size during treatment and becomes normal (i.e. complete 
disappearance of extranodal mass or ≤ 10 mm in short axis and ≤ 15 mm long axis for 
nodal mass), then reappearance of an extranodal lesion at the same site or increase of the 

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same nodal mass to > 15 mm in the long axis, will be considered RD and will be recorded 
as a new lesion.

Any new bone marrow involvement

Any new malignant effusion
Disease-free survival
Disease-free survival (DFS) is the time from date of randomization / start of treatment to the 
date of event defined as the first documented relapse of the disease or death due to any cause. 
If a patient has not had an event, DFS is censored at the date of the last adequate assessment. 
Similar censoring rules and reasons as the ones used for PFS can be applied.
14.2
Appendix 2: Eligibility based on serologic markers for hepatitis B 
and C
Test
Result
HBsAg
+
-
-
-
-
HBcAb
Any
+
-
+
-
HBsAb
Any
-
+
+
-
HCV Ab
Any
Any
-
-
-
Eligibility
Not Eligible
Not Eligible
Eligible
Eligible
Eligible
If indeterminate results are obtained, viral DNA (hepatitis B) or RNA (hepatitis C) should 
be measured to confirm negative viral status.
HBsAg positive: Indicates active infection and risk for reactivation with fulminant hepatitis. 
These patients are not eligible for this trial.
HBcAb positive: As a standalone marker, it indicates active infection and risk for reactivation.   
These patients are not eligible for this trial.
HBsAb positive: As a standalone marker, it indicates successful vaccination or previous 
infection that has been successfully resolved if the only positive finding. These patients are 
eligible for this trial.
HBsAg negative, HBcAb positive, HBsAb positive: Resolved or latent infection. These 
patients are eligible for this trial, however, they are at risk for viral reactivation (see Kymriah 
label, Warnings and Precautions).
HCV Ab positive: Indicates active infection and risk for reactivation. These patients are not 
eligible for this trial.
All markers negative: No prior exposure or vaccination to hepatitis B and no prior exposure 
to Hepatitis C. Patients are eligible for this trial.

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14.3
Appendix 3: Tisagenlecleucel modified data reporting –
Treatment and Follow-up Phase
This guidance is used to determine whether or not an AE, SAE, concomitant medication, or 
laboratory result has to be recorded in the CRF during the relevant study period. Before using 
this guidance, the investigator should determine whether or not an adverse event is serious using 
the criteria found in the protocol section 8, and then use the applicable row of this guidance to 
determine whether or not that event is to be recorded in the CRF.

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14.3.1
Adverse event (AE) and serious adverse event (SAE) reporting
Screening and Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment and Follow-up 
Period
(Starting from LD chemo/pre-
infusion visit)
Post-treatment Period (After Month 12, through End of 
Study and under LTFU protocol CTL019A2205B for 15 
years post-infusion)
Through Month 12 Visit
After Month 12 Visit
Non-serious Adverse 
Events (AE)
Modified:
All infections
All laboratory abnormalities deemed clinically 
significant by the investigator
All clinical AEs grade ≥ 3
All AEs related to a study procedure
All AEs leading to study discontinuation
All, including all laboratory 
abnormalities deemed clinically 
significant by the investigator
Modified –Whether serious or non-serious, report 
following:
Events leading to death
Related to a study procedure
Serious or opportunistic infections. Defined as bacterial, 
viral, fungal or parasitic infections that fulfill one of the 
following criteria: Lead to significant disability or 
hospitalization OR Need surgical or other intervention
New incidence or exacerbation of a pre-existing 
neurologic disorder (tisagenlecleucel patients only)
New incidence or exacerbation of a prior rheumatologic 
or other autoimmune disorder
New incidence of other hematologic disorder
Any severe adverse event or condition the investigator 
believes may have a reasonable relationship to CD19 
CART therapy
Positive RCL test result (tisagenlecleucel patients only)
Vector insertion site sequencing result with a mono-or 
oligoclonality pattern or in a location near a known 
human oncogene (tisagenlecleucel patients only)
New malignancy (T-cell & non T-cell), other than the 
primary malignancy
Progressive multifocal leucoencephalopathy (PML)
Hepatitis B reactivation
Serious Adverse 
Events (SAE)
Modified:
All events leading to death
All events related to a study procedure
Any AE reportable for this study period that also 
meets criteria for serious
All pulmonary or cardiac abnormalities
All infections
Any substantial change in the status of the 
patient that precludes the patient from 
proceeding to study treatment (e.g. GVHD, rapid 
progression of malignancy, marked decline in 
performance status)
Any other substantial change in the status of the 
patient that the investigator deems may have a 
potential impact on the patients during 
lymphodepletion and tisagenlecleucel treatment
All

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14.3.2
Concomitant medication and laboratory reporting
Screening and Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment and Follow-up Period
(Starting from LD chemo/pre-infusion visit, 
through Month 12 )
Post-treatment Period
(After Month 12)
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient
Concomitant 
medications
Modified:
Drugs:
Record all of the following medications:
Anticytokine therapies (e.g. tocilizumab, or other)
Corticosteroids (including prophylactically for blood product 
administrations, physiologic replacement doses, high or stress 
doses, etc.)
Anti-seizure medications
Allopurinol, or non-allopurinol alternatives
Rasburicase
Immunoglobulin therapy
Any medication given therapeutically for an SAE
Vasopressors and cardiac inotropic agents (see below)
Narcotics and sedatives (see below)
Antineoplastic therapies (e.g. lymphodepleting chemotherapy)
Related to an AE or SAE defined as reportable for this period
Vasopressors and cardiac inotropic agents:
For dose, record only maximum daily rate (e.g. µg/kg/hr, mg/hr, 
etc.)
Narcotics and sedatives:
For dose, record only total daily dose
Blood products (e.g. red cells, platelets, FFP, cryoprecipitate):
Record all blood products, including prophylaxis
Electrolyte & vitamin replacement:
Record all electrolyte replacement if given for a clinically significant 
electrolyte disturbance and list these as an adverse event (AE).
Do not record  prophylactic use of electrolyte or vitamin 
replacements
Do not record total parenteral nutrition (TPN) on concomitant 
medication CRF
Fluids:
Do not record fluid boluses and maintenance fluids
Antibiotics:
All
Modified:
Related to an AE or SAE defined as reportable for this 
period
Mutagenic agents (including cytotoxic drugs)
Radiation & antineoplastic therapy (including SCT)
Immunoglobulin therapy
Immunosuppressive agents (including dose of steroids 
higher than physiologic replacement therapy doses of 
steroids (< 12 mg/m2/day hydrocortisone or equivalent)
Investigational therapy

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Screening and Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment and Follow-up Period
(Starting from LD chemo/pre-infusion visit, 
through Month 12 )
Post-treatment Period
(After Month 12)
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient
Record all antibiotics starting from day of infusion, even if given 
prophylactically
Laboratory 
data
Modified:
Record all scheduled labs (per Visit Evaluation Schedule)
Record all results (scheduled or unscheduled) for: LDH, Uric acid, 
CRP, Ferritin, and fibrinogen (related to CRS/TLS/MAS)
Record all other laboratory values if they are ≥ Grade 3
For laboratory abnormalities reportable as AE/SAE, record 
laboratory results that support the event (scheduled or 
unscheduled)
For any AE/SAE that may be caused by a laboratory abnormality, 
the laboratory value(s) (any grade) must also be recorded (e.g. 
“muscle cramps” potentially caused by hypokalemia)
Laboratory abnormalities that are not clinically significant and 
treated prophylactically are NOT to be recorded (e.g. maintenance 
electrolyte replacement, platelets given without clinical bleeding)
All
Modified:
Record all scheduled labs (per Visit Evaluation 
Schedule)
Record all results (scheduled or unscheduled) for: LDH, 
Uric acid, CRP, Ferritin, and fibrinogen (related to 
CRS/TLS/MAS)
Record all other laboratory values if they are ≥ Grade 3
For laboratory abnormalities reportable as AE/SAE, 
record laboratory results that support the event 
(scheduled or unscheduled)
For any AE/SAE that may be caused by a laboratory 
abnormality, the laboratory value(s) (any grade) must 
also be recorded (e.g. “muscle cramps” potentially 
caused by hypokalemia)
Laboratory abnormalities that are treated 
prophylactically are NOT to be recorded (e.g. 
maintenance electrolyte replacement, platelets given 
without clinical bleeding)

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14.4
Appendix 4: Liver event and Laboratory trigger Definitions and Follow-up Requirements
14.4.1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS
3 x ULN  ALT / AST ≤ 5 x ULN
1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related conditions; the non-infectious hepatitis; the benign, malignant 
and unspecified liver neoplasms TBL: total bilirubin; ULN: upper limit of normal

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14.4.2
Follow Up Requirements for Liver Events and Laboratory Triggers 
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea
Discontinue the study treatment immediately (if applicable)
Hospitalize, if clinically appropriate
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
ALT, AST, TBL, indirect and direct bilirubin, albumin, Alb, PT/INR,  
ALP and GGT, until resolution (frequency at investigator discretion)
ALT or AST
> 8 × ULN
Discontinue the study treatment immediately (if applicable)
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
ALT, AST, TBL, indirect and direct bilirubin, albumin, Alb, PT/INR,  
ALP and GGT until resolutionc (frequency at investigator discretion)
> 3 × ULN and INR > 1.5
Discontinue the study treatment immediately (if applicable)
Hospitalize, if clinically appropriate
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
ALT, AST, TBL, indirect and direct bilirubin, albumin, Alb, PT/INR,  
ALP and GGT until resolutionc (frequency at investigator discretion)
> 5 to ≤ 8 × ULN
Repeat LFT within 48 hours
If elevation persists, continue follow-up monitoring
If elevation persists for more than 2 weeks, discontinue the 
study treatment (if applicable)
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
ALT, AST, TBL, indirect and direct bilirubin, albumin, Alb, PT/INR,  
ALP and GGT until resolutionc (frequency at investigator discretion)
> 3 × ULN accompanied by 
symptomsb
Discontinue the study treatment immediately (if applicable)
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
ALT, AST, TBL, indirect and direct bilirubin, albumin, Alb, PT/INR,  
ALP and GGT until resolutionc (frequency at investigator discretion)
> 3 to ≤ 5 × ULN (patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate close observation of the 
patient
Investigator discretion
Monitor LFT within 1 to 4 weeks

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Criteria
Actions required
Follow-up monitoring
ALP (isolated)
> 2 × ULN (in the absence of 
known bone pathology)
Repeat LFT within 48 hours
If elevation persists, establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)
Repeat LFT within 48 hours
If elevation persists, discontinue the study drug immediately 
(if applicable)
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
ALT, AST, TBL, indirect and direct bilirubin, albumin, Alb, PT/INR,  
ALP and GGT until resolutionc (frequency at investigator discretion)
Test for hemolysis (e.g., reticulocytes, haptoglobin, unconjugated 
[indirect] bilirubin)
> 1.5 to ≤ 2 × ULN (patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate close observation of the 
patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or at next visit
Jaundice
Discontinue the study treatment immediately (if applicable)
Hospitalize the patient
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
ALT, AST, TBL, indirect and direct bilirubin, albumin, Alb, PT/INR,  
ALP and GGT until resolutionc (frequency at investigator discretion)
Any AE potentially indicative of a 
liver toxicity*
Consider study treatment interruption or discontinuation  (if 
applicable)
Hospitalization if clinically appropriate
Establish causality
Record the AE and contributing factors (e.g., concomitant 
medication, medical history, lab) in the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, 
or rash with eosinophilia cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at three subsequent monitoring 
visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, (4) liver transplantation, and (5) death.

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Based on investigator’s discretion investigation(s) for contributing factors for the liver event can include: serology tests, imaging and pathology 
assessments, hepatologist’s consultancy; obtaining more detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease.

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14.5
Appendix 5: Specific Renal Alert Criteria and Actions and Event Follow-up
14.5.1
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%
Consider causes and possible interventions
Follow up within 2-5 days
Serum creatinine increase ≥50 % +
OR if <18 years old, eGFR ≤35 mL/min/1.73 m2
Consider causes and possible interventions 
Repeat assessment within 24-48 hours if possible 
Consider drug interruption or discontinuation unless other causes are diagnosed and corrected
Consider patient hospitalization and specialized treatment
New onset dipstick proteinuria ≥ 3+ OR
(Spot) urinary protein-creatinine ratio (PCR) ≥ 1g/g 
(or mg/ mmoL equivalent as converted by the 
measuring laboratory)
Consider causes and possible interventions 
Assess serum albumin & serum total protein
Repeat assessment to confirm 
Consider drug interruption or discontinuation unless other causes are diagnosed and corrected
New onset hematuria ≥3+ on urine dipstick
Assess & document 
Repeat assessment to confirm 
Distinguish hemoglobinuria from hematuria 
Urine sediment microscopy 
Assess serum creatinine
Exclude infection, trauma, bleeding from the distal urinary tract/bladder, menstruation 
Consider bleeding disorder
+Corresponds to KDIGO criteria for Acute Kidney Injury

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Table 14-6
Follow-up of renal events
Assess, document and record in the appropriate CRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells (dysmorphic/glomerular 
vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF. 
Monitor patient regularly (frequency at investigator’s discretion) until: 

Event resolution: serum creatinine within 10% of baseline or PCR <1 g/g or albumin-creatinine ratio <300 
mg/g)
or

Event stabilization: serum creatinine  level with ± 10% variability over last 6 months or PCR stabilization at a 
new level with ± 50% variability over last 6 months
Analysis of urine markers in samples collected over the course of the renal event