A Phase II, Single Arm, Multicenter Open Label Trial to Determine the Safety and Efficacy of Tisagenlecleucel in Pediatric Subjects With Relapsed or Refractory Mature B-cell Non-Hodgkin Lymphoma (NHL)
Phase: PHASE2
Conditions: Non-Hodgkin Lymphoma
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
CTL019, tisagenlecleucel, Kymriah™
CCTL019C22021&7
A Phase II, single arm, multicenter open label trial to 
determine the safety and efficacy of tisagenlecleucel in 
pediatric patients with relapsed or refractory mature B-cell 
non-Hodgkin lymphoma (NHL)(BIANCA)
Document type:
Oncology Clinical Trial Protocol
EUDRACT number:
2017-005019-15, EMEA-001654-PIP02-17
Version number:
01 (Amended Protocol) Clean
Development phase:
II
Document status:
Final
Release date:
14 Jan 2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 1.0 (01-Dec-2017)
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................14
Amendment 1 ....................................................................................................................16
Protocol Summary.............................................................................................................22
1
Introduction .......................................................................................................................27
1.1
Background............................................................................................................27
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment................................................................................................27
1.1.2
Overview of tisagenlecleucel................................................................31
1.1.3
Non-clinical experience ........................................................................32
1.1.4
Clinical experience................................................................................33
1.2
Purpose ..................................................................................................................35
2
Objectives and endpoints...................................................................................................36
3
Study design ......................................................................................................................37
4
Rationale............................................................................................................................40
4.1
Rationale for study design .....................................................................................40
4.1.1
Rationale for choice of bridging therapy ..............................................41
4.2
Rationale for dose/regimen and duration of treatment ..........................................41
4.3
Rationale for lymphodepletion ..............................................................................42
4.4
Purpose and timing of interim analyses.................................................................42
4.5
Risks and benefits..................................................................................................42
4.5.1
Identified safety risks ............................................................................43
4.5.2
Potential safety risks .............................................................................51
4.5.3
Other risks .............................................................................................54
5
Population..........................................................................................................................55
5.1
Inclusion criteria ....................................................................................................56
5.2
Exclusion criteria...................................................................................................57
6
Treatment...........................................................................................................................59
6.1
Study treatment......................................................................................................59
6.1.1
Investigational drugs.............................................................................59
6.1.2
Tisagenlecleucel dosing regimen ..........................................................60
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6.1.3
Pre-infusion evaluation .........................................................................60
6.1.4
Additional safety procedures prior to tisagenlecleucel infusion...........61
6.1.5
Additional treatments............................................................................62
6.1.6
Treatment duration................................................................................63
6.2
Other treatment(s)..................................................................................................63
6.2.1
Concomitant therapy.............................................................................63
6.2.2
Prohibited medications and non-drug therapies....................................64
6.3
Subject numbering, treatment assignment, randomization....................................65
6.3.1
Subject numbering ................................................................................65
6.4
Treatment Blinding................................................................................................66
6.5
Dose escalation and dose modification..................................................................66
6.5.1
Follow-up for toxicities.........................................................................66
6.6
Additional treatment guidance...............................................................................67
6.6.1
Treatment compliance...........................................................................67
6.6.2
Recommended treatment of adverse events..........................................68
6.7
Preparation and dispensation.................................................................................74
6.7.1
Handling of study treatment..................................................................74
6.7.2
Handling of additional treatment ..........................................................76
7
Informed consent procedures ............................................................................................76
8
Visit schedule and assessments .........................................................................................77
8.1
Screening ...............................................................................................................96
8.1.1
Subject demographics/other baseline characteristics............................97
8.1.2
Leukapheresis........................................................................................97
8.1.3
Re-screening..........................................................................................98
8.2
Enrollment .............................................................................................................98
8.3
Efficacy..................................................................................................................99
8.3.1
Efficacy assessments.............................................................................99
8.3.2
Other efficacy assessments .................................................................103
8.3.3
Appropriateness of efficacy assessments............................................103
8.4
Safety...................................................................................................................103
8.4.1
Tanner staging (only for subjects <18 years old)................................104
8.4.2
Performance status ..............................................................................105
8.4.3
Laboratory evaluations........................................................................106
8.4.4
Cardiac assessments............................................................................108
8.4.5
Pregnancy............................................................................................108
8.4.6
Other safety evaluations......................................................................110
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8.4.7
Appropriateness of safety measurements............................................110
8.5
Additional assessments........................................................................................110
8.5.1
Pharmacokinetics ................................................................................110
8.5.2
Biomarkers..........................................................................................117
8.5.3
Imaging ...............................................................................................120
8.5.4
Other Assessments ..............................................................................120
9
Study discontinuation and completion ............................................................................120
9.1
Discontinuation....................................................................................................120
9.1.1
Discontinuation of study, prior to tisagenlecleucel infusion...............120
9.1.2
Discontinuation from study, post-tisagenlecleucel infusion...............121
9.1.3
Withdrawal of informed consent.........................................................121
9.1.4
Lost to Follow-up................................................................................122
9.1.5
Early study termination by the sponsor...............................................122
9.2
End of study and long term Follow-up................................................................123
10 Safety monitoring and reporting......................................................................................124
10.1
Definition of adverse events and reporting requirements....................................124
10.1.1
Adverse events ....................................................................................124
10.1.2
Serious adverse events ........................................................................126
10.1.3
SAE reporting......................................................................................127
10.1.4
Adverse events of special reporting requirements ..............................127
10.1.5
Duration of adverse event reporting....................................................127
10.1.6
Pregnancy reporting ............................................................................127
10.1.7
Reporting of study treatment errors including misuse........................128
10.2
Additional Safety Monitoring..............................................................................128
10.2.1
Liver safety monitoring.......................................................................128
10.2.2
Renal safety monitoring......................................................................129
10.2.3
Follow-up of secondary malignancy...................................................129
10.2.4
Data Monitoring Committee ...............................................................130
10.2.5
Steering Committee.............................................................................130
11 Data Collection and Database management....................................................................130
11.1
Data collection.....................................................................................................130
11.2
Database management and quality control..........................................................131
11.3
Site monitoring ....................................................................................................131
12 Data analysis and statistical methods ..............................................................................132
12.1
Analysis sets ........................................................................................................132
12.1.1
Screened Set........................................................................................132
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12.1.2
Enrolled Set.........................................................................................132
12.1.3
Full Analysis Set .................................................................................132
12.1.4
Efficacy Analysis Set ..........................................................................133
12.1.5
Safety Set ............................................................................................133
12.1.6
Cellular kinetic analysis set.................................................................133
133
12.1.8
Other analysis sets...............................................................................133
12.2
Subject demographics and other baseline characteristics....................................133
12.3
Treatments ...........................................................................................................133
12.4
Analysis of the primary endpoint(s) ....................................................................134
12.4.1
Definition of primary endpoint(s).......................................................134
12.4.2
Statistical model, hypothesis, and method of analysis........................135
12.4.3
Handling of missing values/censoring/discontinuations.....................135
12.4.4
Sensitivity and supportive analyses ....................................................135
12.5
Analysis of secondary endpoints .........................................................................135
12.5.1
Efficacy and/or pharmacodynamic endpoint(s) ..................................135
12.5.2
Safety endpoints..................................................................................138
12.5.3
Pharmacokinetics ................................................................................140
141
141
143
143
12.7
Interim analyses...................................................................................................144
12.8
Sample size calculation........................................................................................144
12.8.1
Primary endpoint(s).............................................................................144
13 Ethical considerations and administrative procedures ....................................................144
13.1
Regulatory and ethical compliance......................................................................144
13.2
Responsibilities of the investigator and IRB/IEC................................................144
13.3
Publication of study protocol and results.............................................................145
13.4
Quality Control and Quality Assurance...............................................................145
14 Protocol adherence ..........................................................................................................145
14.1
Protocol Amendments .........................................................................................146
15 References .......................................................................................................................147
16 Appendices ......................................................................................................................157
16.1
Appendix 1: Guidelines for efficacy evaluation in pediatric non-Hodgkin 
lymphoma studies ................................................................................................157
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16.1.1
Introduction.........................................................................................157
16.1.2
Methodology and Definitions .............................................................157
16.1.3
Definitions...........................................................................................158
16.1.4
Efficacy assessments...........................................................................160
16.1.5
Data handling and programming conventions ....................................178
16.1.6
References (available upon request) ...................................................179
16.1.7
Additional Information........................................................................179
16.2
Appendix 2: Eligibility based on serologic markers for hepatitis B and C .........181
16.3
Appendix 3: Tisagenlecleucel modified data reporting.......................................182
16.4
Appendix 4: Liver event and laboratory trigger definitions and Follow-up 
requirements ........................................................................................................187
16.5
Appendix 5: Specific renal alert criteria and actions and event Follow-up.........190
16.6
Appendix 6: Graft versus host disease (GVHD) .................................................192
List of tables
Table 2-1
Objectives and related endpoints ..........................................................36
Table 4-1
Clinical signs and symptoms associated with CRS (modified from 
Lee et al 2014).......................................................................................44
Table 4-2
Cytokine Release Syndrome Grading (Lee et al 2014).........................44
Table 4-3
Immune effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) Grading (Lee et al, 2019).......................................................46
Table 4-4
Encephalopathy Assessment for Children Age ≤12 Years Using the 
Cornell Assessment of Pediatric Delirium (CAPD) (Lee et al, 
2019) .....................................................................................................47
Table 4-5
Immune effector Cell-associated Encephalopathy (ICE) score for 
Subjects Age >12 years (Lee et al, 2019) .............................................47
Table 6-1
CRS management..................................................................................68
Table 6-2
Definition of high dose vasopressors ....................................................69
Table 8-1
Assessment Schedule ............................................................................78
Table 8-2
Efficacy Assessment Collection Plan..................................................100
Table 8-3
Physical Assessments..........................................................................104
Table 8-4
Karnofsky/Lansky Performance Scales ..............................................106
Table 8-5
Laboratory Assessments (local) ..........................................................107
Table 8-6
Laboratory Assessments (central).......................................................108
Table 8-7
Tisagenlecleucel pharmacokinetics by qPCR in peripheral blood 
collection log.......................................................................................111
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Table 8-8
Tisagenlecleucel pharmacokinetics by flow cytometry in peripheral 
blood collection...................................................................................112
Table 8-9
Tisagenlecleucel pharmacokinetics by qPCR in bone marrow 
aspirate collection log .........................................................................113
Table 8-10
Tisagenlecleucel pharmacokinetics by flow cytometry in bone 
marrow aspirate collection log............................................................113
Table 8-11
Tisagenlecleucel pharmacokinetics by qPCR in CSF collection log..113
Table 8-12
Immunogenicity (humoral) serum sample collection log ...................114
Table 8-13
Immunogenicity (cellular) peripheral blood sample collection log....115
 
 
115
Table 8-15
Rituximab PK......................................................................................116
.118
Table 10-1
Guidance for capturing the study treatment errors..............................128
Table 12-1
Non-compartmental pharmacokinetic parameters ..............................141
Table 12-2
95% exact confidence interval assuming various observed response 
rates .....................................................................................................144
Table 16-1
Possible imaging methodologies in lymphoma study.........................158
Table 16-2
Five Point Scale (5PS) to determine FDG uptake...............................164
Table 16-3
Definitions of response criteria...........................................................166
Table 16-4
Overall Disease Response...................................................................169
Table 16-5
Censoring reasons ...............................................................................176
Table 16-6
Options for event dates used in PFS, EFS, TTP, DOR, RFS..............177
Table 16-7
Adverse event reporting......................................................................183
Table 16-8 
Concomitant medication and laboratory reporting .............................184
Table 16-9
Liver Event and Laboratory Trigger Definitions ................................187
Table 16-10
Follow-Up Requirements for Liver Events and Laboratory Triggers.187
Table 16-11
Specific Renal Alert Criteria and Actions...........................................190
Table 16-12
Follow-up renal events........................................................................191
Table 16-13
Staging and grading of acute Graft-Versus-Host Disease (adapted 
from Harris et al, 2016).......................................................................192
Table 16-14
Definition of chronic Graft-Versus-Host-Disease ..............................193
List of figures
Figure 1-1
Tisagenlecleucel chimeric antigen receptor design...............................32
Figure 3-1
Study Design .........................................................................................39
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List of abbreviations
5PS
PET five point scale
ABC
activated B-cell
AE
adverse event
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASCT
autologous stem cell transplant
AST
aspartate aminotransferase
ASTCT
American Society for Transplantation and Cellular Therapy
ATC
anatomical therapeutic chemical
ATG
anti-thymocyte globulin
AV
atrioventricular
B-AL
B-cell leukemia
BCLU
B-cell lymphoma, unclassifiable
b.i.d.
bis in die/twice a day
BL
Burkitt lymphoma
BM
bone marrow
BMI
body mass index
BOR
best overall response
BSA
bovine serum albumin
BUN
blood urea nitrogen
CABG
coronary artery bypass graft
CAPD
Cornell Assessment of Pediatric Delirium
CAR
chimeric antigen receptor
CCG
CRF completion guidelines
CFR
code of federal regulations
CGD
chronic granulomatous disease
CI
confidence interval
CKAS
cellular kinetic analysis set
CLL
chronic lymphoblastic leukemia
CMO
contract manufacturing organizations
CMO&PS
chief medical office and patient safety
CMR
complete metabolic response
CMV
cytomegalovirus
CNS
central nervous system
COA
clinical outcome assessment
COG
children’s oncology group
CR
complete remission
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CRA
CRES
clinical resource associate
CAR-T cell related encephalopathy syndrome
CRi
complete remission with incomplete blood count
CRF
case report/record form (paper or electronic)
CRO
contract research organization
CRS
cytokine release syndrome
CSF
cerebral spinal fluid
CSR
clinical study report
CT
computerized tomography
CTC
common terminology criteria
CTCAE
common terminology criteria for adverse events
ctDNA
circulating tumor DNA
CV
coefficient of variation
CYVE
high-dose cytarabine and etoposide
DFS
disease-free survival
DILI
drug-induced liver injury
DIN
drug induced nephrotoxicity
DLBCL
diffuse large b-cell lymphoma
DLI
DMC
donor lymphocyte infusions
Data monitoring committee
DMSO
dimethyl sulfoxide
DNA
deoxyribonucleic acid
DOR
duration of response
DRESS
drug reaction with eosinophilia and systemic symptoms
EAS
efficacy analysis set
EBV
Epstein-bar virus
EC
ethics committee
ECG
electrocardiogram
ECHO
echocardiography
eCRF
electronic case report form
EDC
electronic data capture
EDTA
ethylenediaminetetraacetic acid
EEG
electroencephalogram
EFS
event-free-survival
EMA
European medicines agency
EOS
end of study
eSource
electronic source
EU
Europe
FAB
French-American-British
FACT
Foundation for the Accreditation of Cellular Therapy
FAS
full analysis set
FDA
Food and Drug Administration
FDG
fluorodeoxyglucose
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FFPE
formalin-fixed, paraffin-embedded
FL
follicular lymphoma
FNA
fine needle aspiration
FPFV
first patient first visit
GCB
germinal-center B-cell-like
GCP
good clinical practice
GGT
gamma-glutamyl transferase
GM-CSF
granulocyte macrophage-colony stimulating factor
GVHD
graft-versus-host disease
GTD
greatest transverse diameter
GZL
HbcAb
HbsAb
gray zone lymphoma
Hepatitis B core antibody
Hepatitis B surface antibody
HbsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HGBL
high-grade B-cell lymphoma
HIV
human immunodeficiency virus
HLA
histocompatibility antigens
HSC
hematopoietic stem cell
HSCT
hematopoietic stem cell transplant
HSV
herpes simplex virus
IB
investigator’s brochure
ICANS
Immune effector Cell-Associated Neurotoxicity Syndrome
ICE
Immune effector Cell-associated Encephalopathy 
ICF
informed consent form
ICH
International Council for Harmonisation
ICN
ifosfamide, carboplatin and novantrone
ICU
intensive care unit
ID
identification
IEC
independent ethics committee
IFN-γ
Interferon gamma
IGH
immunoglobulin heavy
IL
interleukin
IN
investigator notification
IND
investigational new drug
INR
International Normalized Ratio
IPNHLRC
International Pediatric non-Hodgkin Lymphoma Response Criteria
IRB
institutional review board
IRT
interactive response technology
IT
intrathecal therapy
ITP
thrombocytopenic purpura
IUD
intrauterine device
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IUS
intrauterine system
i.v./IV
Intravenous
IVIG
Intravenous immunoglobulin
JACIE
Joint Accreditation Committee of the ISCT and the EBMT
JC
John Cunningham
KM
Kaplan-Meier
LD
lymphodepleting
LDi
longest transverse diameter of a lesion
LDH
lactate dehydrogenase
LFT
liver function test
LISA
lentivirus insertion site analysis
LLOQ
lower limit of quantification
LMB
Lymphome Malins de Burkitt
LSS
lymphoma specific survival
LTFU
long-term follow-up
LTR
long terminal repeats
LVEF
left ventricular ejection fraction
MAS
macrophage activation syndrome
MCL
mantle cell lymphoma
MedDRA
medical dictionary for regulatory activities
mg
milligram(s)
MHC
major histocompatibility complex
MI
myocardial infarction
MMc
maternal microchimerism
MR
minor response
MRA
magnetic resonance angiogram
MRD
minimal residual disease
MRI
magnetic resonance imaging
MUGA
multigated acquisition
NCI
National Cancer Institute
NHL
non-Hodgkin’s lymphoma
NMR
no metabolic response
NR
no response
NYHA
New York Heart Association
ORR
overall response rate
OS
overall survival
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction/protein-creatinine ratio
PD
progressive disease/pharmacodynamics
PE
physical exam
PET
positron emission tomography
PFS
progression free survival
PIP
pediatric investigation plan
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PK
pharmacokinetic(s)
PMBCL
primary mediastinal B-cell lymphoma
PMD
progressive metabolic disease
PMR
partial metabolic response
PPD
product of perpendicular diameters
PR
partial response
PT
prothrombin time
PTLD
post-transplant lymphoproliferative disorders
QC
quality control
Q.D.
once a day
QMS
quality management system
qPCR
quantitative polymerase chain reaction
R-ICE
rituximab, ifosfamide, carboplatin, and etoposide
r/r
relapse/refractory
RAP
report and analysis plan
RBC
red blood cell(s)
RCL
replication competent lentivirus
RD
relapsed disease
RFS
relapse free survival
RNA
ribonucleic acid
R Value
ALT/ALP x ULN
SAE
serious adverse event
SAP
statistical analysis plan
SC
steering committee
SCID-X1
X-linked severe combined immunodeficiency
sCR
serum creatinine
SCT
stem cell transplant
SD
standard deviation
SDi
shortest axis perpendicular to LDi
SOP
standard operating procedure
SPD
sum of the product of the perpendicular diameters for multiple lesions
SUSAR
suspected unexpected serious adverse reactions
SUV
standard uptake value
TBIL
total bilirubin
TCR
T-cell receptors
TLS
tumor lysis syndrome
TNC
total nucleated cell
TNF
tumor necrosis factor
TTCR
time to complete response
TTP
time to progression
TTR
time to response
ULN
upper limit of normal
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ULQ
upper limit of quantification
UNK
unknown
US
United States
UTI
urinary tract infection
VH
heavy chain variable domain
VL
light chain variable domain
VSV-G
vesicular stomatitis virus glycoprotein
WAS
Wiskott-Aldrich syndrome
WBC
white blood cell
WHO
World Health Organization
WoC
withdrawal of consent
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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (eg: any 
background therapy)
Baseline efficacy 
assessment
If multiple assessments are performed prior to infusion/randomization then 
the one closest temporally prior to infusion will serve as baseline 
assessment.
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, etc. taken from a study subject
Cohort
A specific group of subjects fulfilling certain criteria and generally treated at 
the same time
Dosage
Dose of the study treatment given to the subject in a time unit
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of 
care.
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last subject 
infused or at a later point in time as defined by the protocol.
Final Enrollment
Point/time of subject entry into the study when the following have been 
confirmed:
A. ICF signed
B. Local subject eligibility completed
C. Leukapheresis material reviewed and accepted for manufacturing
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of each study treatment package
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(concomitant or rescue therapy)
Part
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in subjects with established disease 
and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (eg: Screening, Treatment, and Follow-
up) which are described in the Protocol. Periods define the study phases 
and will be used in clinical trial database setup and eventually in analysis
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time 
all study drug administration is discontinued and no further assessments 
are planned
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
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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
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject.
Study treatment
Any single drug or combination of drugs or intervention administered to the 
subject as part of the required study procedures.
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and 
should be used to identify the subject throughout the study for all data 
collected, sample labels, etc.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study
Withdrawal of study 
consent
Withdrawal of consent is defined as when a subject 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 study related contact, and 
does not allow analysis of already collected biologic material.
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Amendment 1
Amendment rationale
At the time of this protocol amendment (January 2020), 24 sites have been initiated, and 8
patients have been enrolled in study.
The protocol is being amended to accommodate the below listed key changes, to align with the 
approved Pediatric Investigation Plan (PIP) modification and to align with the tisagenlecleucel 
program language updates and corrections and clarifications to statements based on feedback 
received from the sites/ethics committees.  
This protocol amendment aims to make the following key changes:
1. Update of inclusion criteria to allow patients between 18 and 25 years of age to be 
considered for study as B-NHL in the adolescent and young adult population is believed to 
be more similar to that seen in pediatric patients. Pediatric patients with Burkitt lymphoma 
have the same biological features and clinical behavior to at least or equal to 25 years of 
age (Bouska et al 2017); the expression of cytogenetic and molecular markers in DLBCL 
that are associated with a poorer prognosis most strongly increases between 24 and 36 
years of age (Klapper et al 2012); and the immunophenotype of PMBCL in young adult 
patients showed a similar pattern that seen in childhood (Oschilles et al 2011).
2. Update of inclusion criteria to allow Burkitt leukemia to be considered for study. Burkitt 
lymphoma and Burkitt leukemia have identical cytogenetic aberrations, surface markers 
and molecular genetics. These two subsets are treated under the same chemotherapy 
regimen and share the same prognosis (Patte et al 2001, Cairo et al 2007).
3. Addition of a Data Monitoring Committee (DMC) for safety monitoring based on 
feedback from European Medicines Agency (EMA).
4. Updates were made to the CRS management algorithm (removal of high dose 
corticosteroids for high grade CRS) to align with the [Investigator’s Brochure] and current 
practices within the CAR-T cell community.
5. New neurotoxicity grading based on immune effector cell-associated neurotoxicity 
syndrome (ICANS).
6. Added new allowance for prior history of Hepatitis B or C as long as lack of active disease 
is established.
7. Removal of ALC and absolute CD3+ T cell requirements from the inclusion criteria. 
These count requirements are needed only prior to leukapheresis, and many patients 
enrolling on the trial will have historical leukapheresis products.
8. To further ensure patient safety, added pre-infusion criteria 11 to ensure women of child-
bearing potential have pregnancy testing.
9. For patients with poor clinical condition and/or low body weight, PK and immunogenicity 
related samples should only be collected if additional blood sampling does not result in an 
important concern such as interference with the medical management or clinical risk for 
the patient.
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IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/ 
Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the informed consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Changes to Protocol
1. List of abbreviations: Updated with new terms.
2. Protocol Summary: Updated to align with changes made in other sections of protocol.
3. Figure 1-1: Footnote updated to reflect newer references.  CTL019 Investigator’s 
Brochure updated to Tisagenlecleucel Investigator’s Brochure here and throughout 
protocol.
4. Section 3: Study design updated to align with approved Pediatric Investigation Plan (PIP) 
modification, allow for more than one bag of cells to be administered if needed, describe 
staggered infusions of Burkitt leukemia patients and clarify End of Study.
5. Section 4.1.1: Reference to medications restrictions (Section 6.2.2) added.
6. Section 4.2: Clarification of dosing provided.
7. Section 4.5.1.1: Updated Cytokine Release Syndrome (CRS)/Macrophage Activation 
Syndrome (MAS) to align with CTL019 program language for management and grading
a. Table 4-1: Neurologic symptoms removed
b. Table 4-2: Table added with updated CRS grading 
8. Section 4.5.1.2: Updated neurological adverse reactions to align with CTL019 program 
language for grading and assessment
a. Table 4-3: Table added with ICANS Grading
b. Table 4-4: Table added with Encephalopathy Assessment
c. Table 4-5: Table added with ICE Score 
9. Section 4.5.1.5.1: Updated Viral reactivation to align with CTL019 program language.
10. Section 4.5.1.7: Removed PML from Prolonged depletion of normal B cell and hypo- or 
agammaglobulinemia to align with CTL019 program language
11. Section 4.5.2.2: Investigational Product Handling Manual updated to Novartis Product 
Handling Manual for Clinical Trials: CAR-T Product. Updated throughout protocol.
12. Section 4.5.2.3: Updated New or secondary malignancies to align with CTL019 program 
language
14. Section 4.5.2.6: Removed Neurological events (late) section as this information is covered 
in 4.5.1.2. Subsequent section numbers updated accordingly.
15. Section 4.5.2.7: Added Transmission of infectious agents to align with CTL019 program 
language.
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16. Section 4.5.2.8: Added Decrease in cell viability due to inappropriate handling of the 
product to align with CTL019 program language.
17. Section 4.5.3.1: Removed Maternal CD 19 CAR T cells details in this section to align with 
CTL019 program language
18. Section 5: Updated Population to align with PIP modification.
19. Section 5.1: 
a. Inclusion criteria 2: Updated to allow for inclusion of patients with Burkitt leukemia.
b. Inclusion criteria 3: Updated to allow for inclusion of patients ≤25 years old.
c. Inclusion criteria 5: Updated to allow for inclusion of Burkitt leukemia patients who 
have only bone marrow involvement.
d. Inclusion criteria 7: Removed ALC and absolute CD3+ T cell requirements.
20. Section 5.2: 
a. Exclusion criteria 6: Infection language updated to align with CTL019 program 
language.
b. Exclusion criteria 7: Removed 'or prior' and changed the Appendix 2 to Appendix 3 to 
align with CTL019 program language.
c. Exclusion criteria 13: Updated to align with CTL019 program language.
d. Exclusion criteria 17: Updated to align with CTL019 program language.
e. Exclusion criteria 18: Updated to align with CTL019 program language.
21. Section 6.1.2: Removal of 'single' and 'infusion' to clarify dosing.
22. Section 6.1.3: 
a. Clarified pre-infusion criteria 8 as patients are likely to have some mild toxicities 
following lymphodepletion.
b. Added pre-infusion criteria 11 to ensure women of child-bearing potential have 
pregnancy testing.
23. Section 6.1.4: 
a. Tumor lysis syndrome (TLS): other suggested lab testing added. Reference to 
management Section 6.6.2.4 added.
b. Cytokine Release Syndrome: updated to align with CTL019 program language.
24. Section 6.1.5.1: Reference to medications restrictions (Section 6.2.2) added.
25. Section 6.1.6: Clarified timing of tisagenlecleucel administration.
26. Section 6.2.1: Added CTL019 program language to describe collection of concomitant 
therapies.
27. Section 6.2.2: 
a. Medication restrictions prior to leukapheresis updated to allow for steroids and low 
dose chemotherapy >72 hours prior to leukapheresis to stabilize disease.  
b. Medication restrictions prior to and post tisagenlecleucel infusion updated to provide 
wash-out of >8 weeks for cranial radiation.
c. Removed ‘Investigational Leukapheresis, Cryopreservation and Scheduling Manual’ 
and updated to [Novartis Leukapheresis, Cryopreservation, and Scheduling Manual 
for Clinical Trials: CAR-T Product]. This update was also made throughout 
remainder of protocol.
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d. Removed ‘Short acting granulocyte colony stimulating factor (G-CSF) should not be 
given within 72 hours prior to tisagenlecleucel infusion and long acting G-CSF should 
not be given within 10 days prior to tisagenlecleucel infusion.
28. Section 6.6.2.1: Added language to ensure timely access to additional doses of 
tocilizumab and reference to Tocilizumab USPI added.
a. Added wording for additional assessments and/ or hospitalization if requested by HA 
or EC/IRB
b. Table 6-1 – Table 6-2: Updated to align to the CTL019 program for CRS 
management and grading. Table entitled ‘Definition of high dose vasopressors’
29. Section 6.6.2.2: Neurological AE section updated to align to the CTL019 program 
language
30. Section 6.6.2.7: Removed language for neurologist consult in the context of progressive 
multifocal leukoencephalopathy (PML) since PML is not an identified risk.
31. Section 6.7: Removed reference to Appendix 2 and throughout the remainder of the 
document since this Appendix is now removed.
32. Section 6.7.1: Clarified timing of tisagenlecleucel administration. Tisagenlecleucel 
disposal and destruction language added to align with CTL019 program template.
33. Table 8-1: Assessment Schedule:
a. Screening window changed from ‘W-16 to W-12’ to ‘W-16 to W-1’
b. Removed D2, D7, D14 and D21 heights.
c. Flow cytometry leukapheresis changed to Local from Central.
d. Local cytokine testing removed.
e. Removed monthly urine pregnancy tests and clarified need for pre-lymphodepletion 
serum testing.
f.
Removed urinalysis on day of infusion.
g. Removed CMV and EBV testing.
h. Frequency of bone marrow aspirate or biopsy added for Burkitt leukemia and updated 
for patients with bone marrow involvement.
i.
Added IVIG, ICANS grading and ICE Score.
j.
Updated schedule for Cytokines.
l.
Screening Tisagenlecleucel PK on bone marrow and CSF removed. PK by flow 
cytometry added to assessment schedule. Footnote added to table for clarification on 
exempted patients.
m. Addition of EOS column.
n. Clarification of Month 12 requirement for Tisagenlecleucel PK flow cytometry 
(peripheral blood).
34. Section 8.1: Clarified acceptable windows for Standard of Care testing to be used as part 
of Screening. Other updates made for accuracy.
35. Section 8.1.2: Clarified that leukapheresis material must be collected at a Novartis 
certified leukapheresis center.
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36. Section 8.1.3: Added ‘In such cases, a rescreening CRF must be filled in to ensure the 
subject’s original ID can be linked to the subject’s new ID.’
37. Table 8-2: Clarified lesions being assessed with color photography during 
treatment/follow-up as being skin lesions. Table also updated with wording for Burkitt 
leukemia
38. Section 8.3.2: Clarified timing of bone marrow and CSF assessments.
39. Table 8-3: 
a. Removed reference to Appendix 1 as this is an error.
b. Weight and height assessments clarified.
40. Table 8-4: Updated with most recent version of Lansky Scale.
41. Table 8-5: Removal of labs that are no longer required or were repeated within table. 
Added flow cytometry on leukapheresis product.
42. Section 8.4.4.1: Updated ECG section to align with CTL019 program language.
43. Section 8.5.1: Clarification provided regarding subjects exempt from PK and 
immunogenicity sampling.
44. Section 8.5.1.2: Added ‘For patients with poor clinical condition and/or low body weight, 
blood samples for PK and immunogenicity analysis should only be collected if an 
additional blood sampling does not result in an important concern such as interference 
with the medical management or clinical risk for the patient’
a. Table 8-7: Updated tables to limit volumes drawn, remove screening samples, and 
clarify sampling for subjects ≤15kg.
45. Table 8-16: Updated window for Enrollment in Peripheral blood for serum cytokine 
analyses to be consistent with rest of protocol. 
 
46. Section 9.1.1: Manufacturing failure listed as reason for Study Discontinuation. Details of 
how manufacturing failure will be handled added.
47. Section 9.1.2: Updated to include lost to follow-up as a reason for discontinuation.
48. Section 9.1.5: Clarified possible reasons for Early study termination by sponsor.
49. Section 9.2: Removed death as reason for EOS assessment(s) to be performed. Removed 
details of assessments to be performed on long-term follow-up study. Clarified that 
subjects who withdraw consent would be offered long-term follow-up study entry.
50. Section 10.1.1: Criteria for Adverse Events version updated to 5.0. Update made 
throughout the remainder of protocol. Updates made to align with CTL019 program 
language.
51. Section 10.1.2: Updates made to include collection of specific instances of disease 
progression as SAEs as well as other updates to align with CTL019 program language.
52. Section 10.1.3: Appendix number updated from ‘Appendix 3’ to ‘Appendix 4’
53. Section 10.1.5: Appendix number updated from ‘Appendix 3’ to ‘Appendix 4’
54. Section 10.1.6: Pregnancy reporting updated to provide guidance for follow-up of live 
births.
 
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56. Section 10.2.4: DMC to monitor safety is added to the study.
57. Section 12.1.4: Clarified the definition of the Efficacy Analysis Set to ensure it aligns with 
primary and secondary objectives.
58. Section 12.4.4.1: Definition of age subgroups updated.
59. Section 12.5.1.1 - Section 12.5.1.4: Removal of "Event documented after at least two 
missing tumor assessments" as censoring reason in order to capture all events and to align 
at a program level, based on feedback from Norwegian Health Authority.
60. Section 12.5.2.3: Clarification of wording regarding safety post tisagenlecleucel infusion.
61. Section 12.8.1: Added the sample size requirement for subjects <18 years for subgroup 
analysis of the primary endpoint.
62. Section 15: References updated.
63. Section 16.1.3.2: Screening requirements added for subjects with diagnosis of Burkitt 
leukemia.
64. Section 16.1.3.5: Measurable disease defined for subjects with Burkitt leukemia.
65. Section 16.1.4.2.2: Updated to reflect inclusion of Burkitt leukemia patients and need for 
more frequent bone marrow assessments in these subjects.
66. Section 16.1.4.3.4: Spleen involvement section was updated to align with definitions of 
Response Criteria (Table 16-3).
67. Previous named Section 16.2 Appendix 2: Non-Mobilized Leukapheresis and
Cryopreservation Recommendations and Required Product Targets removed as section 
duplicates information in Novartis Leukapheresis, Cryopreservation, and Scheduling 
Manual for Clinical Trials: CAR-T Product. Subsequent Section/Appendix numbers and 
Table numbers updated accordingly. References to effected Section/Appendix numbers 
and Tables updated throughout the protocol.
68. Section 16.2: Updated with new eligibility algorithms for Hepatitis B and C.
69. Table 16-7 and Table 16-8: Updated to align with CTL019 program template.
70. Table 16-13: In text table numbers updated and reference added.
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Protocol Summary
Protocol number
CCTL019C2202
Full Title
A Phase II, single arm, multicenter open label trial to determine the safety and 
efficacy of tisagenlecleucel in pediatric subjects with relapsed or refractory 
mature B-cell non-Hodgkin lymphoma (NHL)
Brief title
A Phase II, single arm, multicenter open label trial to determine the safety and 
efficacy of tisagenlecleucel in children and adolescents with non-Hodgkin 
lymphoma (NHL)
Sponsor and 
Clinical Phase
Novartis, Phase II
Investigation 
type
Biological/Vaccine
Study type
Interventional
Purpose and 
rationale
The purpose of the study is to assess the efficacy and safety of tisagenlecleucel 
in children and adolescents with r/r B-cell NHL. For pediatric subjects who have 
recurrent or refractory (r/r) B-cell NHL, survival rates are dismal, only ~20-50% 
subjects are alive at 2 years with overall response rate (ORR) of 20-30% after 
conventional salvage chemotherapy.
Primary 
Objective(s)
Evaluate the efficacy of tisagenlecleucel therapy as measured by ORR and 
determined by local investigator assessments in subjects with aggressive r/r B-
cell NHL
(
 
Secondary 
Objectives
!
Evaluate the duration of response (DOR) in subjects with aggressive r/r B-cell 
NHL
!
Evaluate event free survival (EFS) in subjects with aggressive r/r B-cell NHL
!
Evaluate relapse free survival (RFS) in subjects with aggressive r/r B-cell 
NHL
!
Evaluate progression free survival (PFS) in subjects with aggressive r/r B-cell 
NHL
!
Evaluate overall survival (OS) in subjects with aggressive r/r B-cell NHL
!
Evaluate the safety of tisagenlecleucel therapy
!
Characterize the in vivo cellular kinetics (levels, expansion, persistence) of 
tisagenlecleucel cells into target tissues (blood, bone marrow, lymph nodes, 
cerebral spinal fluid and other tissues if available), as measured by qPCR in 
relation to safety and efficacy
!
Characterize the presence of pre-existing and treatment induced 
immunogenicity and impact on cellular kinetics and response
!
Assess the proportion of subjects who proceed to transplant post-
tisagenlecleucel therapy until end of study (EOS)
!
Retrospective assessment of potential CRS predictive models considering 
also data from other CTL019 trials
Study design
A Phase II, single arm, multicenter, open label study to determine the safety and 
efficacy of tisagenlecleucel in pediatric subjects less than 18 years of age (and 
young adults aged equal or less than 25 years) and weighing at least 6 kg with 
CD19+ r/r mature B-cell NHL, who have relapsed after one or more prior 
therapies (can include allogeneic and autologous HSCT) or have primary 
refractory disease (i.e. have not achieved a CR or PR after first line therapy), with 
the following sequential phases: Consent, Screening, Pre-treatment, Treatment 
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and Follow-up. Efficacy will be assessed until relapse, progression, death, lost to 
follow up, withdrawal of consent or EOS; safety will be monitored throughout the 
duration of the study. After EOS, subjects will be asked to continue in a post-
study long-term follow-up (LTFU) under a separate destination protocol 
[CCTL019A2205B], for up to 15 years post-infusion.
Population
The target patient population participating in the study will include male and 
female pediatric patients less than 18 years of age (and young adults aged equal 
or less than 25 years) and weighing at least 6 kg with CD19+ r/r mature B-cell 
NHL, including broad histological aggressive subtypes based on the World Health 
Organization (WHO) classification (Swerdlow et al 2016), such as Burkitt 
lymphoma/Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), primary 
mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), as well as 
the indolent subtype of follicular lymphoma (FL) who have relapsed after one or 
more prior therapies or are primary refractory (have not achieved a complete 
response (CR) or partial response (PR) after the first line of therapy). Patients 
who have progressed after prior hematopoietic stem cell transplant (HSCT) are 
allowed to participate in the study.
It is planned to enroll approximately 35 pediatric patients with an aim to have 26 
infused and evaluable patients with aggressive subtypes available for the primary 
analysis. In addition, pediatric patients with follicular lymphoma will be enrolled 
until the 26 patients with aggressive subtypes have been infused and are 
available for primary analysis.
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1.
Signed informed consent and assent forms if applicable must be obtained 
prior to participation in the study
2.
Histologically confirmed (local evaluation) mature B-cell non-Hodgkin 
lymphoma (B-cell NHL) including the following subtypes; Burkitt 
lymphoma/Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), 
primary mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), 
and follicular lymphoma (FL)
Note: Patients with B-cell NHL associated with Nijmegen breakage syndrome 
will be allowed.
a.
Sufficient formalin-fixed, paraffin-embedded (FFPE) tumor sample must 
be available for correlative analyses. A recent tumor sample obtained for 
the purpose of the study must be submitted, however if not clinically 
feasible, an archival tumor biopsy from the most recent relapse may be 
submitted instead. Excisional biopsies should be submitted wherever 
possible; in cases where this is not possible a core needle biopsy is 
allowed. Fine needle aspiration (FNA) is not suitable.
3.
Patients ≤25 years of age and weighing at least 6 kg at the time of screening
4.
Patients who have relapsed after one or more prior therapies (can include 
allogeneic and autologous hematopoietic stem cell transplant) or are primary 
refractory (have not achieved a CR or PR after the first line of therapy)
5.
Measurable disease by radiological criteria in all patients at the time of 
screening. Patients with Burkitt leukemia who don’t meet radiological criteria 
must have bone marrow involvement of >25% by local assessment of bone 
marrow aspirate and/or biopsy. For details refer to Appendix 1.
6.
Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status 
≥60.
7.
Adequate bone marrow reserve without transfusions (transfusion >2 weeks 
prior to laboratory assessment is allowed) defined as:
a.
Absolute neutrophil count (ANC) >1000/mm3
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b.
Platelets ≥50000//mm3
c.
Hemoglobin ≥8.0 g/dl
8.
Adequate organ function:
a.
a serum creatinine (sCR) based on gender/age as follows:
Maximum Serum Creatinine (mg/dL)
Age
Male
Female
1 to <2 years
0.6
0.6
2 to <6 years
0.8
0.8
6 to <10 years
1.0
1.0
10 to <13 years
1.2
1.2
13 to <16 years
1.5
1.4
≥16 years
1.7
1.4
b.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤5 times the upper limit of normal (ULN) for age
c.
Total bilirubin <2 mg/dL (for Gilbert’s Syndrome patients total bilirubin <4 
mg/dL)
d.
Adequate pulmonary function
i.
Oxygen saturation of >91% on room air
ii.
No or mild dyspnea (≤Grade 1)
9.
Must have a leukapheresis material of non-mobilized cells accepted for 
manufacturing. Note: Leukapheresis material will not be shipped to or 
assessed for acceptance by the manufacturing site until documented 
confirmation of all other eligibility criteria is received.
Exclusion 
criteria
Patients meeting any of the following criteria are not eligible for inclusion in this 
study.
1.
Prior gene therapy or engineered T cell therapy
2.
Prior treatment with any anti-CD19 therapy
3.
Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to 
screening and ≤4 months prior to infusion
4.
Presence of grade 2 to 4 acute or extensive chronic graft-versus-host 
disease (GVHD) in patients who received prior allogeneic HSCT Appendix 6.
5.
Prior diagnosis of malignancy other than study indication, and not disease 
free for 5 years
6.
Clinically significant active infection confirmed by clinical evidence, imaging, 
or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
7.
Presence of active hepatitis B or C as indicated by serology. Repeat serology 
is required if the interval between serology performed at screening and 
tisagenlecleucel infusion exceeds 8 weeks. For detailed criteria see Appendix 
2.
8.
Human Immunodeficiency Virus (HIV) positive test. Repeat serology is 
required if the interval between serology performed at screening and 
tisagenlecleucel infusion exceeds 8 weeks
9.
Active neurological autoimmune or inflammatory disorders not related to B 
cell NHL (eg: Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
10. Active central nervous system (CNS) involvement by malignancy. Note:
Patients with history of CNS disease that have been effectively treated will be 
eligible
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11. Patients with B-cell NHL in the context of post-transplant lymphoproliferative 
disorders (PTLD) associated lymphomas
12. Patients with concomitant genetic syndromes associated with bone marrow 
failure status such as patients with Fanconi anemia, Kostmann syndrome, 
Shwachman syndrome or any other known bone marrow failure syndrome. 
Note: Patients with Down syndrome will not be excluded.
13. Known hypersensitivity to the excipients of tisagenlecleucel or to any other 
drug product as advised for administration in the study protocol (e.g. 
lymphodepleting agents, tocilizumab)
14. Cardiac disorder defined as:
a.
Cardiac or cardiac repolarization abnormality, including any of the 
following:
i.
History of myocardial infarction (MI), angina pectoris, or coronary 
artery bypass graft (CABG) within 6 months prior to starting study 
treatment
ii.
Clinically significant cardiac arrhythmias (eg: ventricular tachycardia), 
complete left bundle branch block, high-grade atrioventricular (AV) 
block (eg: bifascicular block, Mobitz type II and third degree AV 
block)
b.
Left ventricular ejection fraction (LVEF) <45% as determined by 
echocardiography (ECHO) or magnetic resonance angiogram (MRA) or 
multigated acquisition (MUGA)
c.
New York Heart Association (NYHA) functional class III or IV (Chavey et 
al 2001)
15. Subjects enrolled in this study are not permitted to participate in additional 
parallel investigational drug or device studies
16. Pregnant or nursing (lactating) women.
Note: Women of child-bearing potential (WOCBP) must have a negative 
pregnancy test performed at screening, within 24 hours prior to 
leukapheresis, lymphodepletion, tisagenlecleucel infusion and at EOS
17. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception from enrollment into this study through at least 12 
months after the tisagenlecleucel infusion and until chimeric antigen receptor 
(CAR) T-cells are no longer present by qPCR on two consecutive tests. 
qPCR test results will be available upon request.
18. Sexually active males who do not agree to use a condom during intercourse 
from enrollment into this study through at least 12 months after the 
tisagenlecleucel infusion and until CAR-T-cells are no longer present by 
qPCR on two consecutive tests. qPCR test results will be available upon 
request.
Investigational
treatment
The investigational treatment is an intravenous (iv) tisagenlecleucel infusion with 
a proposed dose range of 0.2 to 5 x 106 CAR-positive viable T cells per kg body 
weight (subjects ≤50 kg) or 0.1 to 2.5 x 108 CAR-positive viable T cells 
(subjects >50 kg).
Efficacy 
assessments
!
Radiologic imaging
!
Bone marrow biopsy or aspirate
!
Cerebral spinal fluid (CSF) cytology
!
Physical exam findings/cytology/biopsy evaluation
Pharmacokinetic 
assessments
!
Tisagenlecleucel cellular kinetics by qPCR and flow cytometry
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Key safety 
assessments
!
Physical examination
!
Vital signs
!
Adverse events (AE)
!
Clinical laboratory evaluations
!
Physical development
!
Performance status
Data analysis
!
The primary efficacy analysis will be based on all evaluable subjects with 
aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel.
!
 
!
The safety analysis will include all subjects with r/r B-cell NHL who received 
an infusion of tisagenlecleucel.
The primary efficacy and safety analysis will be conducted when all evaluable 
subjects with aggressive r/r B-cell NHL have been infused and followed for at 
least 6 months from tisagenlecleucel infusion or discontinued early as well as at 
least 50% of those subjects have a follow-up of at least 9 months from 
tisagenlecleucel infusion or discontinued early.
Key words
Tisagenlecleucel, r/r B-cell NHL, pediatric patients, BL, DLBCL, PMBCL, GZL, 
FL, leukapheresis, lymphodepleting chemotherapy (LD)
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1
Introduction
1.1
Background
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1.1
Overview of disease pathogenesis, epidemiology and classification
Lymphomas most commonly occur during the second decade of life, with a median age at 
diagnosis of 10 years 8 months, and is rare in infants (≤1 percent). The incidence increases with 
age as lymphomas account for approximately 4, 14, 22, and 25 percent of neoplasms in children 
1 to 4, 5 to 9, 10 to 14, and 15 to 19 years of age, respectively (Kaatsch 2010). Non-Hodgkin 
lymphoma (NHL), a heterogeneous group of lymphoid malignancies, is the fourth most 
common malignancy diagnosed in children and accounts for approximately 7% of all childhood 
cancers in the developed world (Kaatsch 2010, Minard-Colin et al 2015). In the United States, 
approximately 750-800 new cases of childhood NHL are diagnosed annually with an estimated 
incidence of 10 to 20 cases per million people per year (Percy et al 1999). There is a male 
predominance, with the exception of primary mediastinal B-cell lymphoma, in which the 
incidence is similar among males and females. Childhood NHL is more common in whites than 
African Americans (Percy et al 1999, Attias et al 2009).
In adults, NHL typically presents as a low or intermediate grade disease, however, childhood 
NHL is usually an aggressive, poorly differentiated, disseminated disease, often invading 
extranodal sites, the bone marrow (BM), and central nervous system (CNS) in advanced stages. 
In order to determine the optimal management in childhood NHL, the grade and extent of 
disease must be established. The WHO classification for tumors of hematopoietic and lymphoid 
tissue (Campo et al 2011, Swerdlow et al 2016) represents the established guidelines for the 
diagnosis of malignant lymphomas and is based on the recognition of distinct diseases 
according to a combination of morphologic, immunophenotypic, genetic, molecular, and 
clinical features. About 90% of childhood NHL can be categorized as mature B-cell neoplasms, 
precursor lymphoid neoplasms of B- or T-cell lineage, and mature T-cell and NK-cell 
neoplasms. Among these categories, NHL is the most common, accounting for up to 60% of all 
newly diagnosed lymphomas in childhood and adolescence (Sandlund et al 1996, Burkhardt et 
al 2005).
Aggressive mature B-cell NHL consists mainly of Burkitt lymphoma (BL), diffuse large B-cell 
lymphoma (DLBCL), and primary mediastinal large B-cell lymphoma (PMBCL). Pediatric 
follicular lymphoma (FL) is an indolent lymphoma which acts as a paradigm for the 
management of all indolent subtypes of NHL. Gray zone lymphomas are defined as lymphoid 
malignancies that cannot be reliably classified into a single disease entity after all available 
morphologic, immunophenotypic, and molecular investigations have been performed. The 2008 
WHO classification proposed 2 gray zone lesions: (1) B-cell lymphoma, unclassifiable (BCLU), 
with features intermediate between DLBCL and BL and (2) B-cell lymphoma, unclassifiable, 
with features intermediate between DLBCL and classical Hodgkin lymphoma. In the 2016 
revision to the WHO classification system, the category of BCLU with features intermediate 
between DLBCL and BL was eliminated, and all large B-cell lymphomas with c-myc and BCL2
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and/or BCL6 gene rearrangements have been identified as a distinct entity: high-grade B-cell 
lymphoma (HGBL) with rearrangement of c-myc and BCL2 and/or BCL6. While there are 
numerous subtypes within the various categories of mature B-cell NHL, the treatment paradigm 
consists of more intensive regimens utilized for more aggressive disease as determined by stage 
and grade (Minard-Colin et al 2015).
Among the aggressive B-cell lymphomas, Burkitt lymphoma (BL) is the predominant 
malignancy, with the sporadic variant accounting for 40% of all childhood NHL in Western 
Europe and the United States (Mosse and Weck 2010). Tumor cells typically exhibit a mature 
B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase (Tdt) 
and CD5, but do express surface immunoglobulin, (with either kappa or lambda light chains) 
and B-cell markers such as CD19, CD20, and CD10 (Minard-Colin et al 2015).
Burkitt lymphoma is characterized by translocation of the c-myc oncogene on chromosome 
8q24 to one of the immunoglobulin gene loci regulatory elements (ie, IGH, IGK or IGL), 
resulting in the inappropriate overexpression of c-myc and malignant cell proliferation. The 
most common translocation associated with BL is t(8;14), resulting in translocation of c-myc to 
the IGm (mu) heavy chain gene (IGH) locus on chromosome 14q32, seen is approximately 80% 
of all BL cases. Less commonly, translocations between c-myc and the gene for either the kappa 
or lambda light chain, t(2;8) and t(8;22), respectively, can occur (Miles et al 2016). The 2016 
WHO classification includes a distinct entity for the small subset of BL cases without MYC
translocations, designated “Burkitt-like lymphoma with 11q aberration”. While the clinical 
course appears to be similar to BL, lymphomas belonging to this subtype differ from BL in that 
they have a more complex karyotype, cytological pleomorphism and lower levels of MYC 
expression (Campo et al 2011).
Sporadic BL typically arises in the abdomen, lymphatic tissue of Waldeyer ring and head-neck 
region, although jaw involvement rarely occurs. Other sites of involvement include testes, bone, 
skin, pleural and peritoneal spaces. In advanced stages, BL presents with circulating lymphoma 
cells, bone marrow and CNS involvement, conferring a poorer prognosis. There has been 
considerable variability among staging systems in the classification of advanced disease in BL. 
Historically thought to represent different disease entities, the French-American-British (FAB) 
classification system categorized BL as small non-cleaved cell lymphoma or L3 acute 
lymphoblastic leukemia (ALL), depending on the presence of solid tumor/nodal mass or >25% 
bone marrow involvement, respectively. The WHO classification system recognized both 
phases as single disease entity, mature B cell neoplasm with subtype of Burkitt lymphoma or 
Burkitt cell leukemia, depending on the site of disease burden (Mosse and Weck 2010, Campo 
et al 2011). The recently revised International Pediatric Non-Hodgkin Lymphoma Staging 
System (Rosolen et al 2015) based on the initial St. Jude classification (Murphy 1980) describes 
stage IV BL as lymphoma with ≥5% to ≤25% bone marrow involvement and/or CNS 
involvement; >25% bone marrow involvement is defined as L3 ALL. Regardless of the 
classification system, treatment strategies are based on risk stratification and patients with bone 
marrow involvement are treated with regimens designed for BL (Woessmann et al 2005).
DLBCL in children and adolescents is a mature B-cell neoplasm, accounting for 10%-20% of 
childhood NHL; occurring with more frequency and aggressiveness during adolescence than 
during the first decade of life (Allen et al 2015). Immunophenotyping profile shows two 
different molecular patterns of DLBCL; activated B-cell-like (ABC) and germinal-center 
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B-cell-like (GCB). Whereas the adult DLBCL is frequently associated with the non-GCB
phenotype, approximately two thirds of pediatric DLBCLs express the GCB molecular pattern 
with CD10 and BCL-6 positivity, which in part, may contribute to the better overall survival 
rates in children compared to adults (Oschlies et al 2006, Worch et al 2013). Furthermore, the 
t(14;18) rearrangements of the IGH and the BCL2 genes commonly seen in adults is rarely seen 
in children and adolescent cases of DLBCL (Oschlies et al 2006). Instead, about 15% of a subset 
of pediatric DLBCL cases compared to 2% of adult cases, had a translocation that juxtaposed 
the IRF4 oncogene next to one of the immunoglobulin loci, and this abnormality seemed to 
confer a better outcome (Salaverria et al 2011). Many of the DLBCL patients, particularly those 
younger than 14 years have a genetic profile similar to BL, characterized by a high frequency 
of abnormalities at the MYC locus (chromosome 8q24), including MYC rearrangement and 
overexpression; however, DLBCLs rarely have a proliferation index >95% (Miles et al 2008,  
Klapper et al 2008, Deffenbacher et al 2012). Of note, ID3-TCF3 pathway alterations associated 
with BL/B-cell leukemia (B-AL), were not observed in DLBCL (Miles et al 2016).
In DLBCL patients, CNS and/or bone marrow involvement is uncommon but when present 
CNS disease usually manifests as intracranial masses and is associated with poor prognosis 
(Salzburg et al 2007, El-Mallawany and Cairo 2015). Lymphomatous primary CNS disease 
without systemic involvement is uncommon in immunocompetent pediatric cases but more 
commonly seen with inherited or acquired immunodeficiency (Abla et al 2011).
Primary mediastinal (thymic) B-cell lymphoma (PMBCL), which is a separate entity from 
DLBCL, has histological and genetic features resembling the adult form, and accounts for 
approximately 2% childhood NHL cases (Oschlies et al 2011, Dunleavy and Wilson 2015). 
PMBCL is associated with chromosomal aberrations in chromosomes 9p and 2p, involving 
JAK2 and c-rel, respectively, and is often associated with inactivation of SOCS1 (Oschlies et al 
2011, Bea et al 2005). These mediastinal tumors can be locally invasive and while dissemination 
outside the thoracic cavity can occur, CNS and bone marrow involvement are rare (Jaffe et al 
2008).
According to the 2008 WHO classification of lymphomas (Campo et al 2011), pediatric FL is 
an indolent low-grade mature B-cell lymphoma affecting 1-2% of all pediatric lymphomas 
(Quintanilla-Martinez et al 2016, Liu et al 2013). Follicular lymphoma in children although 
morphologically similar to adult FL, displays significant differences from adult form in 
incidence, pathology and in expression of genetic markers. While adult FL is characterized by 
IGH-BCL2; t(14;18) (q32;q21) gene rearrangement and Bcl-2 overexpression, this is 
uncommon in children and when present is associated with an aggressive disease, unresponsive 
to treatment. FL in children has male predominance and is usually localized in the lymph nodes 
in the neck or tonsils, or may also present with extranodal involvement, and has an excellent 
prognosis with rare disease relapse and longer median survival rates with current therapies 
(Sandlund and Perkins 2015).
1.1.1.2
Current therapies and unmet medical need
Treatment in pediatric B-cell NHL consists of stage- and histology-directed multi-agent 
chemotherapy, with more intensive regimens utilized for more aggressive disease 
(Minard-Colin et al 2015). Although there are clinical and biological differences between BL
and DLBCL, there is significant clinico-pathologic overlap among the mature B-cell NHL seen 
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in children, adolescents, and young adults. As such, similar treatment regimens have been used 
to treat both BL and large B-cell histologies, with no difference in outcome based on tumor 
histology, with the exception of PMBCL which has exhibited inferior outcomes (Gerrard et al 
2013).
Outcomes for pediatric BL and DLBCL have greatly improved with intensive, short duration, 
pulsed courses of multi-agent chemotherapy, adapted to the disease stage (Reiter et al 1999,  
Woessmann et al 2005, Cairo et al 2007, Gerrard et al 2008, Minard-Colin et al 2015, Sandlund 
2015). Newly diagnosed pediatric B-cell NHL patients are cured in the vast majority of cases, 
with rates approaching 80-90%, with standard available therapies (Minard-Colin et al 2015). 
However, there remains a high unmet medical need for patients with relapsed or refractory 
mature B-cell NHL (r/r B-cell NHL), as salvage therapies including hematopoietic stem cell 
transplant (HSCT), rituximab-based therapies and intensive chemotherapy regimens, offer 
limited clinical benefit and no therapies are currently accepted as the standard of care. Outcomes 
for this patient population are generally poor, with 5 year survival rates approaching 10-30% 
(Cairo et al 2007, Barth et al 2013, Minard-Colin et al 2015, Minard et al 2016).
A study conducted by the Children’s Oncology Group (COG) evaluated the combination of 
rituximab, ifosfamide, carboplatin, and etoposide (R-ICE) in r/r B-cell NHL. Twelve of 
20 patients (60%) achieved partial or complete responses, the majority of whom (8/12, 67%) 
were alive at Follow-up of 13 to 30 months. Five of these 8 patients also received HSCT (Griffin 
et al 2009). However, patients who did not achieve a response (40%) to this treatment had a 
dismal prognosis with median overall survival of 2.5 months, highlighting the significant unmet 
medical need in this patient population for improved therapeutic options.
Hematopoietic stem cell transplant (HSCT) offers some survival benefit for r/r B-cell NHL 
patients able to achieve remission. The 5-year EFS patients who received either allogeneic 
(n=90) or autologous HSCT (n=92) after achieving a complete remission post conventional 
chemotherapy was 50-52% for DLBCL and 27-31% for BL (Gross et al 2010). However, 
chemo-resistance is a major problem, making remission difficult to achieve and therefore 
making patients ineligible for transplant (Bradley and Cairo 2008).
In a retrospective 10-year multicenter study from the United Kingdom, of the 33 children with 
r/r mature B-cell NHL, 9 patients (27.3%) survived, with a median Follow-up of 4.3 years. 
Patients who responded to either two cycles of CYVE (high-dose cytarabine and etoposide) or 
ICE (ifosfamide, carboplatin, and etoposide), each in combination with four doses of rituximab, 
followed by auto-HSCT had better survival outcomes compared to patients who were primary 
refractory or had early relapses. The investigators considered the possibility that the children 
who survived were those who remained well enough to tolerate and respond to immuno-
chemotherapy followed by transplantation (Anoop et al 2012).
In a retrospective review of 1,322 pediatric B-cell NHL patients prospectively enrolled in the 
LMB-89, LMB-96, and LMB-2001 trials between July 1989 and March 2007, 67 patients were 
identified as having relapsed disease, defined as any tumor progression after having achieved a 
CR. In all 3 studies, the salvage therapy at relapse was determined based on the patient’s initial 
disease stage and treatment regimen: patients with completely resected stage I and abdominal 
stage II (Group A), and patients with more advanced disease excluding stage IV with CNS 
involvement and mature B-cell leukemia (B-AL) (Group B), received CYVE with or without 
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high dose methotrexate; patients with stage IV with CNS involvement and B-AL (Group C) 
received VENOMID (vindesine, novantrone, methylprednisolone, ifosfamide), ICN 
(ifosfamide, carboplatin and novantrone) or ICE (ifosfamide, carboplatin, etoposide, and triple 
intrathecal therapy). Rituximab was added to the salvage therapy regimen for some patients 
after 1996. The overall response rate (ORR) was 65% (2 of 3 in group A, 19 of 29 in group B 
and 3 of 5 in group C achieved a CR/PR). Five-year OS was only 29.9% with a median Follow-
up of 6.4 years (OS in groups A, B and C were 66.7%, 34.2%, and 17.4%, respectively). In 
responding patients, high-dose chemotherapy with stem cell transplant (SCT) improved 
survival, with both allogeneic and autologous transplant being equally effective, (OS of 38% 
and 49% respectively). However, patients not responding to initial salvage chemotherapy did 
not benefit from a further transplant. Also, rituximab addition did not offer significant survival 
benefit. Variables associated with improved survival rates were; single site of disease at relapse, 
large cell histology, initial low-risk disease (ie, group A or group B constituting stage I, II or III 
patients with normal lactate dehydrogenase (LDH)), and sustained remission >6 months, in a 
multivariate analysis of results (Jourdain et al 2015).
The Japanese Pediatric Leukemia/Lymphoma Study Group conducted a phase II study using R-
ICE (n=22) or other rituximab based regimens (n=3) as ﬁrst line salvage treatment in patients 
with r/r B-cell NHL (Osumi et al 2016). The 5-year OS in all patients receiving salvage therapy 
(n-33) was 48.5% with a median Follow-up of 5.9 years. The ORR (CR/PR) was 73% in patients 
treated with R-ICE regimen and a majority of them proceeded to receive HSCT. However, viral 
infections associated with allogeneic HSCT resulted in 4 deaths. Investigators considered that 
compromised immune function with B-cell aplasia resulting from prior rituximab therapy may 
have caused these fatal toxicities.
Consensus on the usefulness of rituximab and HSCT in pediatric patients with relapsed mature 
B-cell NHL has not been reached as only a handful of studies with modest responses are 
reported so far.
Considering the limited treatment options and poor prognosis for patients with r/r B-cell NHL, 
novel approaches are warranted to address the unmet need in this patient population for 
therapies that can achieve improved responses and overall survival.
1.1.2
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 possibly eliminate the patient’s malignant 
cells. In particular, chimeric antigen receptor (CAR)-based approach involves engineering T 
cells with sequences that encode antibody-based antigen recognition moieties linked to 
signaling domains. Unlike T-cell receptors (TCR), 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 
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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 (CART-19), a second generation CAR, 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 
lymphocytes transfected with a chimeric antigen receptor to combine the effector functions of 
T lymphocytes 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 and Pallavicini 2001).
Figure 1-1
Tisagenlecleucel chimeric antigen receptor design
Recent clinical trials of tisagenlecleucel in r/r chronic lymphoblastic leukemia (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 2019). 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 [Tisagenlecleucel Investigator’s Brochure].
Abbreviation: antigen presenting cell (APC), CAR-T cell lymphocytes (CTL)
1.1.3
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, 
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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, 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).
1.1.4
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
Investigational New Drug (IND) studies [Z2101I] and [B2002I]. In addition, there is 1
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 [Tisagenlecleucel Investigator’s Brochure].
Clinical Cellular Kinetics
In adult r/r DLBCL subjects 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 subjects demonstrated expansion of 
transgene levels. Neither subject 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 (Mueller et al 2017).
The initial expansion of tisagenlecleucel and its prolonged persistence is required for initial as 
well as sustained disease response as was shown in pediatric and young adult ALL.
1.1.4.1
Clinical efficacy
Tisagenlecleucel is approved by the United States (US) Food and Drug Administration (FDA) 
for the treatment of subjects up to 25 years with B-cell precursor acute lymphoblastic leukemia 
(ALL) that is refractory or in second or later relapse [Kymriah FDA 2017] and for the treatment 
of adult patients with relapsed or refractory (r/r) large B-cell lymphoma after two or more lines 
of systemic therapy including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, 
high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma [Kymriah FDA 
2018].
Tisagenlecleucel is currently under evaluation by the European Medicines Agency (EMA) and 
other agencies for the treatment of adult subjects with refractory or relapsed DLBCL who are 
ineligible for autologous stem cell transplant, and for the treatment of pediatric and young adult 
subjects (up to 25 years) with refractory or relapsed B-cell ALL.
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Efficacy in r/r pediatric and young adult ALL
Out of the 63 tisagenlecleucel-infused subjects, 52 (83%) achieved CR/Cri (complete remission 
with incomplete blood count recovery) within 3 months after infusion, and all of them were 
minimum residual disease (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
Two clinical trials with tisagenlecleucel in DLBCL subjects failing or not being candidates to
HSCT are ongoing:
!
CTL019A2101J (NCT02030834) (Schuster et al 2017a): this is a single-arm, 
single-institution trial ongoing at University of Pennsylvania. Patients with CD19+ 
DLBCL or FL with no curative treatment options, who relapsed, or had residual disease 
after autologous stem cell transplant (ASCT), or were not eligible for autologous or 
allogeneic HSCT, are eligible for trial. Patients had to have partial response or stable 
disease to most recent therapy. The 6-month ORR in DLBCL subjects was 50% 
(7/14 subjects), with CR achieved in 6 subjects (43%; 95% confidence interval (CI): 18-
71%). Sustained remissions were achieved, and at a median Follow-up of 28.6 months, 
86% of subjects with DLBCL who had a response (95% CI, 33 to 98) had maintained the 
response.
!
CTL019C2201 (NCT02445428) (JULIET trial) (Schuster et al 2017b): this is a Novartis 
sponsored ongoing single-arm, multicenter trial. As of March 2017 cut-off, 99 subjects 
received a single dose of tisagenlecleucel. Median time from infusion to data cut-off was 
3.7 months. Median age was 56 years (range 22-76). Fifty percent of the subjects received 
at least 3 prior lines of therapy, including 47% prior ASCT. Primary efficacy analysis 
based on 81 subjects showed clinically meaningful and durable responses including 53% 
overall response rate (ORR 37%, 30% CR). Median duration of response (DOR) and OS 
were not reached and most subjects achieving CR at Month 3 have remained in CR at data 
cut-off.
1.1.4.2
Clinical Safety
Section 4.5 outlines expected and potential toxicities related to tisagenlecleucel, most of which 
occur within 8 weeks of infusion.
Safety in r/r ALL
In subjects with r/r 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 subjects who received tisagenlecleucel, 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-cell NHL
In the recently approved CAR-T cell therapy for adult r/r DLBCL [Kymriah FDA 2018] based 
on study [CTL019C2201], among the 99 subjects 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 subjects required tocilizumab and 11% of subjects required 
corticosteroids
There were 16 subjects who died after tisagenlecleucel infusion. Three subjects died within 
30 days of tisagenlecleucel infusion due to DLBCL; 13 subjects 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 profile 
observed in study C2201 was well characterized and manageable with close monitoring and 
established treatment algorithm (Schuster et al 2017b).
In study [CTL019A2101J], 36 subjects (20 DLBCL, 14 FL, and 2 mantle cell lymphoma (MCL)) 
were treated with tisagenlecleucel. There was one death (possibly related to tisagenlecleucel) 
in a subject with FL who died 234 days after tisagenlecleucel infusion in pathological CR
(Schuster et al 2017a).
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) [BLA Clinical 
Review Memorandum Yescarta 2017].
For further information refer to the [Tisagenlecleucel Investigator’s Brochure].
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 subjects with r/r ALL and in 4 adult 
subjects 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 qPCR detectable in any of the subject samples at time points up to 2 years 
following infusion (7 subjects from UPCC03712 trial; 16 subjects form UPCC04409 trial, 
11 subjects from CHP959 trial).
1.2
Purpose
For the 10-20% of pediatric subjects who have r/r B-cell NHL, survival rates are dismal, only 
~20-50% subjects are alive at 2 years with ORR of 20-30% after conventional salvage 
chemotherapy. Patients who respond to rituximab based chemotherapy (R-ICE), benefit from a 
subsequent transplant and achieve modest survival advantage (~30-50% EFS at 5 years). 
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However, those patients who are r/r to R-ICE (~40%) are not candidates for a transplant and 
have median overall survival of only 2.5 months. The purpose of the study is to assess the 
efficacy and safety of tisagenlecleucel in children, adolescents and young adults with r/r B-cell 
NHL.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoints(s) for primary objective(s)
Evaluate the efficacy of tisagenlecleucel 
therapy as measured by ORR and determined 
by local investigator assessments in subjects 
with aggressive r/r B-cell NHL
Overall response rate (ORR), which includes 
complete response (CR) and partial response (PR)
determined by local investigator assessments.
Secondary Objective(s)
Endpoints(s) for secondary objective(s)
Evaluate the duration of response (DOR) in 
subjects with aggressive r/r B-cell NHL
DOR is defined as the time from the date of first 
documented disease response (CR or PR) as 
determined by local investigator assessments to the 
date of first documented progression or death due to 
underlying cancer.
Evaluate event free survival (EFS) in subjects 
with aggressive r/r B-cell NHL
EFS is defined as the time from date of first 
tisagenlecleucel infusion to the earliest date of death 
from any cause, disease progression as determined 
by local investigator assessments, or starting new 
anticancer therapy for underlying cancer, excluding 
HSCT.
Evaluate relapse free survival (RFS) in 
subjects with aggressive r/r B-cell NHL
RFS is defined as the time from the date of first 
documented disease response (CR or PR) as 
determined by local investigator assessments to the 
date of first documented disease progression or 
death due to any cause.
Evaluate progression free survival (PFS) in 
subjects with aggressive r/r B-cell NHL
PFS is defined as the time from the date of first 
tisagenlecleucel infusion to the date of first 
documented disease progression as determined by 
local investigator assessments or death due to any 
cause
Evaluate overall survival (OS) in subjects with 
aggressive r/r B-cell NHL
OS is defined as the time from date of first 
tisagenlecleucel infusion to the date of death due to 
any cause.
Evaluate the safety of tisagenlecleucel 
therapy
Physical examination, vital signs, adverse events, 
laboratory abnormalities, performance status and as 
applicable physical development
Characterize the in vivo cellular kinetics 
(levels, expansion, persistence) of 
tisagenlecleucel cells into target tissues 
(blood, bone marrow, lymph nodes, cerebral 
spinal fluid and other tissues if available), as 
measured by qPCR in relation to safety and 
efficacy
Cellular kinetics parameters: Cmax, Tmax, AUCs, 
Clast, Tlast, and/or other relevant parameters in 
peripheral blood, bone marrow, lymph nodes,
cerebrospinal fluid and other tissues as appropriate, 
Month 3 (±14 days) response, safety endpoint (CRS 
grade).
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Objective(s)
Endpoint(s)
Characterize the presence of pre-existing and 
treatment induced immunogenicity and impact 
on cellular kinetics and response
Levels of pre-existing and treatment induced 
immunogenicity, cellular kinetic parameters, and 
efficacy (Month 3 (±14 days) response)
Assess the proportion of subjects who 
proceed to transplant post-tisagenlecleucel 
therapy until end of study (EOS)
Number of subjects that proceed to SCT after 
tisagenlecleucel infusion until EOS will be described
Retrospective assessment of potential CRS 
predictive models considering also data from 
other CTL019 trials
Assess the ability for early prediction of cytokine 
release syndrome utilizing clinical and biomarker data
3
Study design
This Phase II, single arm, multicenter, open label study to determine the safety and efficacy of 
tisagenlecleucel in pediatric subjects less than 18 years of age (and young adults aged equal or 
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less than 25 years) and weighing at least 6 kg with CD19+ r/r mature B-cell NHL, who have 
relapsed after one or more prior therapies (can include allogeneic and autologous HSCT) or 
have primary refractory disease (i.e. have not achieved a CR or PR after first line therapy), will 
have the following sequential phases for all subjects (Section 8):
!
Consent
!
Screening
!
Leukapheresis collection
!
Pre-treatment
!
Tisagenlecleucel manufacturing
!
Lymphodepleting (LD) chemotherapy (as applicable)
!
Treatment and Follow-up
Screening begins after signing the study Informed Consent Form (ICF). Leukapheresis 
collection can begin after signing the consent. Non-mobilized leukapheresis material collected 
from the subject prior to study entry (historical) may be usable for tisagenlecleucel 
manufacturing if collected at an appropriately certified leukapheresis center and is of acceptable 
quality. Final enrollment is defined as the point at which a subject meets all inclusion/exclusion 
criteria and the subject’s leukapheresis material is received and accepted for manufacturing. If 
the subject’s leukapheresis collection is deemed unacceptable, the subject will screen fail. 
However, the subjects may be re-screened or re-apheresed as detailed under Section 8.1.
Pre-treatment phase will begin at enrollment until Day -1 (pre-infusion visit) and includes 
manufacturing of tisagenlecleucel. 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. This 
phase may also include bridging therapy of investigator’s choice (if needed may be continued 
from screening through pre-treatment phase), and LD chemotherapy, which is completed 2 to 
14 days before tisagenlecleucel infusion.
Treatment and Follow-up phase will include tisagenlecleucel infusion (Day 1) and the infused 
subjects will be followed according to the Assessment Schedule (Table 8-1) until end of study 
(EOS). The investigational treatment contains 0.2 to 5 x 106 CAR-positive viable T-cells per 
kg body weight (subjects ≤50 kg) or 0.1 to 2.5 x 108 CAR-positive viable T-cells (subjects >50 
kg) via an intravenous infusion. Subjects will be infused with the maximum cell dose within 
this range that can be individually manufactured. Efficacy assessments will be based on 
International Pediatric Non-Hodgkin Lymphoma Response Criteria (Sandlund et al 2015).
End of Study (EOS) is when all subjects complete the protocol defined 2-year treatment and 
follow-up phase and/or discontinue early. After end of study, all subjects will be asked to 
continue in a post-study long-term follow-up (LTFU) under a separate destination protocol 
[CCTL019A2205B], for up to 15 years post-infusion. Under this protocol, Follow-up for the 
lentiviral vector safety will continue as per the following health authority guidelines: FDA 
(2006a), FDA (2006b), European Medicines Agency (EMA) (2008) and EMA (2009).
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Figure 3-1
Study Design
a Aggressive B-cell NHL subtypes (BL, DLBCL, PMBCL, GZL; N=26), in addition FL subjects may also 
be treated; age ≤25 years; r/r to one or more lines of prior therapies
b Previous leukapheresis collection or during screening
c Administered as applicable, fludarabine (30 mg/m2 i.v. daily for 4 days) and cyclophosphamide 
(500 mg/m2 i.v. daily for 2 days starting with the first dose of fludarabine)
d Subjects that discontinue treatment and follow-up phase early (post-infusion but prior to M24 visit)
will continue in Annual Follow-up or Survival Follow-up until End of Study (until all subjects who 
receive tisagenlecleucel complete 2 years of post-treatment phase or discontinue early).
e Conducted under a separate destination protocol
Efficacy will be evaluated by the investigator using computerized tomography/magnetic 
resonance imaging (CT/MRI) and positron emission tomography (PET)-CT or PET-MRI based 
on International Pediatric Non-Hodgkin Lymphoma (Sandlund et al 2015) response criteria 
clarified by Novartis for pediatric population (Appendix 1). Baseline disease assessment will 
be performed locally, at screening and repeated within two weeks prior to infusion. If local 
Health Authorities require the use of specific imaging modalities (eg: MRI) and/or a different 
imaging schedule for disease response assessment purposes, a decision will be made on a case 
by case basis upon discussion between Novartis and the Investigator. Imaging will be performed 
at Day 28 (as clinically indicated), Months 3, 6, 9, 12, 18, 24 post infusion and yearly thereafter 
or as clinically indicated until relapse or disease progression, death, lost to Follow-up, 
withdrawal of consent or EOS. Safety will be collected as per investigator assessment (as per 
Assessment Schedule in Table 8-1).
A post-study LTFU for tisagenlecleucel safety will continue under a separate destination 
protocol [CCTL019A2205B] per the following health authority guidelines: FDA (2006a), FDA 
(2006b), European Medicines Agency (EMA) (2008) and EMA (2009).
For the purpose of close safety monitoring of subjects in particular those with aggressive disease 
subtypes and for safely onboarding new sites, a staggered approach will be utilized at each site 
and will occur as follows:
!
First subject infusion, wait 14 days
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!
Second subject infusion, wait 14 days
!
Third subject infusion
Following completion of this staggered infusion of the first three subjects, the site may infuse 
subsequent subjects without staggering.
Additional staggering will apply at the study level for subjects with a diagnosis of Burkitt 
leukemia at study entry and this will occur as follows:
!
First Burkitt leukemia subject infusion on study, wait 14 days
!
Second Burkitt leukemia subject infusion, wait 14 days
!
Third Burkitt leukemia subject infusion
Following completion of this staggered infusion of the first three subjects with Burkitt leukemia, 
subsequent subjects will be treated in the study without staggering.
4
Rationale
4.1
Rationale for study design
This study is part of an agreed Pediatric Investigation Plan (PIP). The single-arm study design 
and sample size is justified by the rarity of r/r B-cell NHL subject population, poor prognosis, 
lack of approved effective therapies in this setting and limited recruitment to selected and 
specially trained tisagenlecleucel infusion centers.
Subject population will include aggressive subtypes of B-cell NHL. Therefore, subjects will be 
allowed to receive “bridging therapy” of investigator’s choice to adequately manage their 
rapidly progressing underlying disease while they are screened for the study and/or after 
enrollment. Subjects with follicular lymphoma will be also included in the study. After
assessment of eligibility, subjects qualifying for the study will be enrolled and are allowed to 
start lymphodepleting chemotherapy as recommended in protocol. Within 2-14 days of 
completion of lymphodepleting chemotherapy, tisagenlecleucel will be infused.
The efficacy of tisagenlecleucel will be evaluated through the primary endpoint of ORR which 
includes complete response (CR) and partial response (PR) as determined by local assessment. 
The choice of ORR as the primary endpoint is based on evidence that ORR is a standard 
outcome measurement in NHL (Cheson et al 2007).
Safety will be monitored in this trial closely in the first 1 month following tisagenlecleucel 
infusion and then every 3 months during the first year post-tisagenlecleucel infusion followed 
by semiannual assessment during the second year and annually thereafter until the EOS.
During the annual Follow-up phase of the study following Month 12 post tisagenlecleucel 
infusions only protocol defined AEs and adverse events of special interest (AESI) will be 
collected (Appendix 3). The frequency of safety monitoring and AESI are based on the clinical 
safety experience made in previous tisagenlecleucel studies.
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4.1.1
Rationale for choice of bridging therapy
There are no standard treatment regimens recommended for the management of aggressive r/r 
B-cell NHL. Therefore, subjects will be allowed to receive bridging therapy per investigator’s 
discretion. Medication restrictions prior to leukapheresis are provided in Section 6.2.2. It is 
recommended to complete bridging therapy 2 weeks before tisagenlecleucel infusion to allow 
for resolution of any toxicities.
4.2
Rationale for dose/regimen and duration of treatment
There is currently no clinical experience dosing pediatric B-cell NHL subjects with 
tisagenlecleucel. The recommended dose in this trial is based on experience from studies in 
pediatric ALL subjects. Clinical responses were observed across the wide range of 
CAR-positive cells infused including the lowest dose tested clinically. The dose-response, dose-
safety, and dose-cellular kinetics analyses were performed using the data obtained from 
pediatric and young adult subjects with relapse/refractory ALL (B2202 and B2205J) 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 CTL019C2202.
!
Dose-response and dose-exposure: Across the dose range studied, dose and exposure were 
independent.
!
Dose-safety: The probability of any grade neurologic events and time to resolution of 
cytopenia were not impacted by dose. There was a 1.6 fold 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 
CRS for dose of 5.0×108 cells and 6.0×108 cells were comparable, ie, 0.389 and 0.462, 
respectively. In addition, CRS is generally manageable in the study with the steps outlined 
in the CRS algorithm (Table 6-1).
Based on the totality of evidence from dose-safety, dose-efficacy, and exposure-response 
analyses, and the positive benefit risk ratio observed across the full range of doses, the dose 
specification mentioned as below will be utilized for Study CTL019C2202.
One of two possible CAR-positive viable T cell dose ranges will be prepared for the subject 
determined by the subject’s weight during the leukapheresis visit or at baseline as follows:
!
Subjects ≤50 kg: 0.2 to 5.0 x 106 autologous CAR-positive viable T cells per kg body 
weight
!
Subjects >50 kg: 0.1 to 2.5 x 108 autologous CAR-positive viable T cells
Patients will be infused with the maximum cell dose within this range that can be individually 
manufactured.
Due to subject specific characteristics, batches outside of the manufacturing specification 
and/or the protocol recommended dose range may be produced. These batches will be evaluated 
to determine if they can be made available to the subject on a case by case basis, and these doses 
can be administered based on the benefit/risk assessment by the treating physician.
Please see [Tisagenlecleucel
Investigator’s Brochure]
for further information on 
tisagenlecleucel dose selection in preclinical and clinical studies.
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4.3
Rationale for lymphodepletion
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T-cell 
proliferation (Dummer et al 2002), a recent 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 and Bevan 1999, Surh and Sprent 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 and Ahmed 
2001, Van Stipdonk et al 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 interleukin (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 the addition of 
fludarabine to cyclophosphamide increased CAR-T cell expansion and persistence and 
improved disease free survival rates in adult subjects 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 subjects received lymphodepleting chemotherapy. 
Ninety-seven of these 99 subjects received fludarabine and cyclophosphamide.
4.4
Purpose and timing of interim analyses
Not applicable.
4.5
Risks and benefits
Appropriate eligibility criteria Section 5 are included in this protocol. Recommended guidelines 
for prophylactic or supportive management of study-drug induced AEs are provided in Section 
6.6.2.
Tisagenlecleucel administered to over 500 subjects in clinical trials across the dose ranges tested 
has a well characterized safety profile in pediatric and young adult subjects. Even though there 
is currently no clinical experience treating pediatric B-cell NHL subjects with tisagenlecleucel, 
3 pediatric and young adult r/r B-ALL studies and adult r/r DLBCL study have demonstrated a 
positive risk/benefit profile population. Therefore, it is expected that the potential benefit of 
tisagenlecleucel therapy in the pediatric B-cell NHL population in this study [CCTL019 C2202]
may outweigh the potential risks. The long-term risks will also be monitored for up to 15 years 
post tisagenlecleucel in LTFU study [CCTL019A2205B] per health authority requirements.
Appropriate eligibility criteria and specific dose-limiting toxicity definitions are included in this 
protocol. Recommended guidelines for prophylactic or supportive management of study-drug 
induced AEs are provided in Section 6.6.2.
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The risk to subjects in this trial may 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 
[Tisagenlecleucel Investigator’s Brochure]. In addition, stopping rules and monitoring by the 
Steering Committee (SC) are included in this protocol Section 10.2.5. There may be unforeseen 
risks with tisagenlecleucel which could be serious or potentially life threatening.
Safety risks that have been identified with the use of tisagenlecleucel or are considered 
potentially associated with tisagenlecleucel are briefly outlined below.
4.5.1
Identified safety risks
4.5.1.1
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 
interferon gamma (IFN-γ), IL-6, tumor necrosis factor (TNF), ferritin, CRP, and IL-10. Severe 
and life-threatening events have been observed in subjects 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 4-1) and is 
graded according to the Lee Criteria (Table 4-2). Macrophage activation syndrome (MAS) is 
also associated with CRS as manifested by liver function test (LFT) abnormalities, cytopenias, 
and coagulopathy.
Life-threatening and fatal outcomes associated with CRS and severe concomitant infections 
have been observed in pediatric and adult subjects treated with tisagenlecleucel.
The onset of CRS should be retrospectively defined as the date of the first sign or symptom 
consistent with CRS. The resolution date of CRS should generally be declared resolved once 
fever, oxygen, and pressor requirements have resolved. Patients that receive anti-cytokine 
therapy or antipyretics may quickly resolve fever, however CRS should be considered ongoing 
even in the absence of fever until improvement of hemodynamic status and/or hypoxia with 
resolution of pressor and/or oxygen requirements. Concurrent or subsequent neurotoxicity is 
considered as a separate event (See section 4.5.1.2) and does not affect the grading or resolution 
of CRS. For example, necessity of intubation in those patients having a degree of neurotoxicity 
(e.g presence of seizure) where there is a concern for their ability to maintain a patent airway 
should not influence the grading or resolution of CRS (Lee et al 2019).
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Table 4-1
Clinical signs and symptoms associated with CRS (modified from 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
Table 4-2
Cytokine Release Syndrome Grading (Lee et al 2014)
Grade
Toxicity
Grade 1
Symptoms are not life threatening and require symptomatic treatment only, 
e.g., fever, nausea, fatigue, headache, myalgia, malaise
Grade 2
Symptoms require and respond to moderate intervention
Oxygen requirement <40% or
Hypotension responsive to fluids or low dose of one vasopressor or
Grade 2 organ toxicity
Grade 3
Symptoms require and respond to aggressive intervention
Oxygen requirement ≥40% or
Hypotension requiring high dose* or multiple vasopressors or
Grade 3 organ toxicity or grade 4 transaminitis
Grade 4
Life-threatening symptoms
Requirement for ventilator support or
Grade 4 organ toxicity (excluding transaminitis)
Grade 5
Death
*High dose vasopressor doses are shown in Table 6-2
A therapeutic strategy for the management of CRS is provided in Section 6.6.2.1 that should be 
followed.
4.5.1.2
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 
majority of neurological events were observed within 8 weeks following tisagenlecleucel 
infusion and were transient, however a delayed onset (ie, >8 weeks) may occur.
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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.
Early neurological events are the second most-common adverse reaction associated with CAR-
T therapies. In attempt to standardize the assessment of these events, the CARTOX working 
group has suggested the name CART-cell- related- encephalopathy syndrome (CRES) (Neelapu 
et al 2018). This syndrome is described as a toxic encephalopathy with a wide range of variable 
symptoms such as aphasia, confusion, delirium, tremors, occasionally seizures and rarely life-
threatening cerebral edema. The manifestation of CRES is biphasic, with the first phase 
occurring concurrently with CRS symptoms typically within the first 5 days after CAR-T-cell 
therapy, and the second phase after CRS subsides. Delayed neurological events with seizures 
or episodes of confusion 3-4 weeks following CAR-T-cell therapy have been reported to occur 
in approximately 10% of patients.
Although encephalopathy is a dominant feature of neurotoxicity following treatment with CAR-
T cell therapy, there are other neurologic symptoms that should be taken into account. The 
American Society for Transplantation and Cellular Therapy (ASTCT) recently defined the term 
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) as “a disorder 
characterized by a pathologic process involving the central nervous system following any 
immune therapy that results in the activation or engagement of endogenous or infused T cells 
and/or other immune effector cells. Symptoms or signs can be progressive and may include 
aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, 
seizures, and cerebral edema” (Lee et al 2019). A grading system was developed in order to 
characterize this syndrome (Table 4-4). For patients ≤12 years, the ICANS grading requires 
assessment of interactions via the Cornell Assessment of Pediatric Delirium (CAPD) (Table 4-
5), whereas for patients > 12 years, it incorporates key aspects of the mini-mental status exam 
via the Immune effector Cell-associated Encephalopathy (ICE) score (Table 4-6).
In clinical trials, the majority of neurological events following tisagenlecleucel infusion were 
observed within 8 weeks, however, neurological events with later onset > 8 weeks and not in 
the context of CRS have also been reported. Most neurological events observed within 8 weeks 
were transient or self-limiting in nature. Frequently, encephalopathy, confusional state and 
delirium were observed. Other manifestations include a multifarious set of signs and symptoms 
including seizures, aphasia, speech disorder, and tremor. Some of the events are severe and may 
have a life-threatening outcome.
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 and prior history of CNS leukemia and history of other 
prior CNS diseases. 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.
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The causality assessment of neurological events in subjects 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.
Table 4-3
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
Grading (Lee et al, 2019)
Neurotoxicity 
Domain
Grade 1
Grade 2
Grade 3
Grade 4
ICE Score for 
age >12yr^
7-9
3-6
0-2
0 (patient is unarousable
and unable to perform ICE)
CAPD score for 
age ≤12yr
<9
<9
≥9 
Unable to perform CAPD
Depressed level 
of 
consciousness 
(any age)v
Awakens 
spontaneously
Awakens to 
voice
Awakens only to 
tactile stimulus
Patient is unarousable or 
requires vigorous or 
repetitive tactile stimuli to 
arouse. Stupor or coma
Seizure (any 
age)
N/A
N/A
Any clinical seizure 
focal or generalized 
that resolves 
rapidly; or Non-
convulsive seizures 
on EEG that 
resolve with 
intervention
Life-threatening prolonged 
seizure (>5 min); or 
Repetitive clinical or 
electrical seizures without 
return to baseline in 
between. 
Motor weakness 
(any age)§
N/A 
N/A 
N/A
Deep focal motor weakness 
such as hemiparesis or 
paraparesis
Elevated ICP / 
Cerebral edema
N/A
N/A
Focal/local edema 
on neuroimaging#
Diffuse cerebral edema on 
neuroimaging; Decerebrate 
or decorticate posturing; or 
Cranial nerve VI palsy; or 
Papilledema; or Cushing's 
triad
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor 
findings, raised ICP/cerebral edema) not attributable to any other cause. For example, a patient with an 
ICE score of 3 who has a generalized seizure is classified as having Grade 3 ICANS. 
^ A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is 
awake with global aphasia. But a patient with an ICE score of 0 may be classified as having 
Grade 4 ICANS if the patient is unarousable.
v Depressed level of consciousness should be attributable to no other cause (e.g. no sedating 
medication)
§ Tremors and myoclonus associated with immune effector cell therapies may be graded 
according to CTCAE v5.0 but they do not influence ICANS grading.
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# Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity 
feature and is excluded from ICANS grading. It may be graded according to CTCAE v5.0.
CAPD: Cornell Assessment of Pediatric Delirium
Table 4-4
Encephalopathy Assessment for Children Age ≤12 Years Using the 
Cornell Assessment of Pediatric Delirium (CAPD) (Lee et al, 2019)
Answer the following based on 
interactions with the child over the 
course of the shift
Never
4
Rarely
3
Sometimes
2
Often
1
Always
0
1. Does the child make eye contact with 
the caregiver?
2. Are the child’s actions purposeful?
3. Is the child aware of his/her 
surroundings?
4. Does the child communicate needs 
and wants?
Never
0
Rarely
1
Sometimes
2
Often
3
Always
4
5. Is the child restless?
6. Is the child inconsolable?
7. Is the child underactive – very little 
movement while awake?
8. Does it take the child a long time to 
respond to interactions?
Table 4-5
Immune effector Cell-associated Encephalopathy (ICE) score for 
Subjects Age >12 years (Lee et al, 2019)
Category
Test
Scoring
Orientation
Orientation to year, month, city, hospital
4 points total (1 point each)
Naming
Ability to name 3 objects (e.g. point to 
clock, pen, button)
3 points total (1 point each)
Following 
Commands
Ability to follow simple commands (e.g. 
“Show me 2 fingers” or “Close your eyes 
and stick out your tongue”)
1 point
Writing
Ability to write a standard sentence (e.g. 
“Our national bird is the bald eagle”)
1 point
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Category
Test
Scoring
Attention
Ability to count backwards from 100 by 10
1 point
For the management of neurological events see Section 6.6.2.2.
4.5.1.3
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 <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 al 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.
Subjects will have typically received lymphodepleting chemotherapy that is completed a few 
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 6.6.2.3.
4.5.1.4
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 
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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 
grade 3 in Common Terminology Criteria for Adverse Events (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 6.6.2.4.
4.5.1.5
Infections
There is an increased risk and severity of infections in patients with longer and more intense 
immunosuppression. Subjects treated with tisagenlecleucel are at risk of infection for several 
reasons:
!
B-cell depletion is known to be associated with hypogammaglobulinemia that also 
contributes to the risk.
!
Underlying bone marrow disease or dysfunction further increases the risk of infections
!
Subjects with prolonged and profound immunosuppression may be at enhanced risk for 
more frequent and severe opportunistic infections. This may result from preceding 
anti-cancer treatment, such as radiation or chemotherapy, and lymphodepleting 
chemotherapy prior to treatment with tisagenlecleucel causing severe neutropenia and/or 
B-cell depletion from tisagenlecleucel.
Serious infections were observed in subjects after tisagenlecleucel infusion, some of which were 
life- threatening or fatal.
4.5.1.5.1 Viral reactivation
Patients with active hepatitis B or active hepatitis C have been excluded from clinical studies 
with tisagenlecleucel, because of the potential risk of viral reactivation and the risk of fulminant 
hepatitis, hepatic failure and fatal outcome. Patients who are HIV positive have also been 
excluded, because of the possible effect on HIV viral suppression. 
In addition, there is currently no experience with manufacturing tisagenlecleucel for patients 
testing positive for HBV, HCV and HIV. Patients are to be screened for any active HBV, HCV 
or HIV infection prior to leukapheresis.
Subjects with active hepatitis B or hepatitis C or with 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 6.6.2.5.
4.5.1.6
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 
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endogenous) in addition to B cell aplasia that may favor a production of auto-antibodies binding 
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 white blood cell (WBC)
count >1000 cells/μL, febrile neutropenia is seen in subjects 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 6.6.2.6.
4.5.1.7
Prolonged depletion of normal B cells and hypo- or 
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 subjects. 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.
Given that a typical T-lymphocyte may have a lifespan of 40 years, tisagenlecleucel may 
potentially be detectable in a subject for a very prolonged period and prolonged depletion of B-
cells may occur, in particular in the subset of subjects who continue to demonstrate a tumor 
response. Long term data are currently not available.
A therapeutic strategy for the management of B cell depletion with resulting 
hypo-gammaglobulinemia is provided in Section 6.6.2.7.
4.5.1.8
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.
Subjects 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.
A therapeutic strategy for the management of hematopoietic cytopenias is provided in
Section 6.6.2.8.
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4.5.2
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.
4.5.2.1
Cerebral edema (fatal)
No fatal cerebral edemas have been reported within three weeks following tisagenlecleucel 
infusion in the clinical development program or the post-marketing setting to date that would 
resemble five fatal events reported for JCAR015 in the ROCKET study. JCAR015 presents a 
very different construct of an anti-CD19 CAR-T cell product compared to tisagenlecleucel.
These five fatal cases of cerebral edema were characterized by a rapid evolution soon after 
JCAR015 infusion, appeared to be resistant to anti-cytokine treatment, and ensued brain death 
within 1-2 days after diagnosis. Following a retrospective exploratory analysis of these five 
cases, it is believed that these fatal cerebral edemas emerged from rapid T-cell expansion 
associated with the specific CAR-T cell product construct that determines the kinetics of T-cell 
expansion after infusion together with other risk factors such as high baseline blood levels of 
IL-15 (Gilbert 2017). Key findings of this retrospective analysis of the JCAR015 cases with 
fatal cerebral edema showed that all five patients experienced rapid, early expansion of their 
CAR-T cells within a week of being infused (rather than the typical time frame of 12-14 days), 
high levels of the CD8+ subtype and, consequently, a sharp spike in cytokines such as IL-2 and 
TNFα. Autopsy results from two of the patients showed a breakdown of the blood-brain barrier, 
possibly due to inflammatory cytokine surge. Potential baseline risk factors included age 
younger than 30 years, Philadelphia chromosome negativity, subset of disease (ie, B-ALL), 
fewer prior regimens, higher levels of IL15 and decreased levels of platelets (Gust et al 2017).
Since the five fatal cases after exposure to the JCAR015 product have become known, another 
patient with fatal cerebral edema was reported in the ZUMA-1 trial following KTE-019 infusion 
that may be worthwhile to mention for completeness. This patient progressed to CRS grade 4 
refractory to tocilizumab and dexamethasone on Day 4, developed cerebral edema that was
refractory to siltuximab and mannitol on Day 9, and died on Day 11 (Turtle et al 2017). The 
clinical course of this case treated with KTE-019 may not be comparable with those 5 cases 
treated with JCAR015, which is further supported by a retrospective analysis of baseline 
cytokine and chemokine levels in serum and cerebrospinal fluid suggesting significant pre-
existing underlying inflammatory condition providing an alternate explanation [BLA Clinical 
Review Memorandum Yescarta 2017].
4.5.2.2
Replication competent lentivirus (RCL) production
Replication-competent 
lentivirus 
(RCL) 
could 
theoretically
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 subject.
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 subjects will only receive cell products that meet RCL release 
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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 subjects
and their close contact(s), and therefore, monitoring for RCL will be conducted during the 
course of the trial (see [Novartis Product Handling Manual for Clinical Trials: CAR-T Products]
for a description of the assays). Since the probability and characteristics of an RCL are unknown, 
no regulatory guideline for the management of RCL positive subjects exist to date.
As per guidance for gene therapy medicinal products, subjects exposed to tisagenlecleucel will 
be monitored for 15 years following last treatment for vectors persistence and RCL within the 
LTFU study.
The Management of this potential risk is addressed in Section 6.6.2.9.
4.5.2.3
New or secondary malignancies (including vector insertion site 
oligo/monoclonality)
Secondary malignancies in cancer patients, i.e., newly occurring malignancies other than the 
primary malignancy (e.g., T-cell and non-T-cell hematological malignancies, solid tumors), can 
be increased as a result of both previous chemotherapy and radiation therapy exposure and 
partly due to increased rates within families (Freidman et al 2010). The rate of new malignancy 
detection following tisagenlecleucel therapy will need to take into account these additional 
confounding risk factors.
Transduction of a patient’s T cells with the lentiviral vector could lead to insertional 
mutagenesis resulting in an uncontrolled T-cell proliferation and an oncogenic effect that could 
result in a T-cell and may be non-T-cell malignancies. 
Ruella et al (2018) reported a B-cell ALL patient treated in an early clinical study at the 
University of Pennsylvania (Penn) / Children’s Hospital of Philadelphia with CTL019 as 
manufactured by Penn. The patient showed an initial response to treatment and relapsed 9 
months after infusion with CD19-negative leukemia cell that aberrantly expressed the anti-
CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during 
CAR-T cell manufacture at Penn and its product bound in cis to the CD19 epitope on the surface 
of leukemic cells, masking it from recognition by and conferring resistance to the CAR-T. 
The Novartis manufacturing process for tisagenlecleucel is designed to significantly reduce the 
probability of contaminating B cells in the T cell culture. Therefore, the risk of CAR 
transduction of B cells as observed at the early CTL019 study at Penn and described in the 
publication by Ruella et al (2018) can be considered low with the current Novartis 
manufacturing process.
Tisagenlecleucel uses third generation self-inactivating lentiviral vector. Insertional 
mutagenesis was addressed in two lentivirus insertion site analysis (LISA) studies where 12 
batches of tisagenlecleucel ready for infusion and two batches of product manufactured from 
healthy donor cells were analyzed. The results indicate that there was no preferential integration 
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near genes of concern, no preferential sites of integration (hottest lesion), 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 et al 2002, Dudley et al 2005).
The management of this potential risk is addressed in Section 6.6.2.10.
4.5.2.4
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). Prior chemotherapy 
and radiation also contribute to the risk.
No AEs associated with this potential were observed in tisagenlecleucel clinical trials.
4.5.2.5
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.
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4.5.2.6
Graft versus host disease (GVHD)
The chance of graft versus host disease (GVHD) occurring in subjects is low, but it is a potential
risk with tisagenlecleucel therapy in subjects 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 
subjects with grade 3 GVHD and none with grade 4) (Porter et al 2006). Of 18 ALL subjects 
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 6.6.2.11.
4.5.2.7
Transmission of infectious agents
Transmission of infectious agents could lead to new infections and reactivation of pre-existing 
viral disease (e.g., HBV, HCV, or HIV), respectively, in close contacts including personnel 
involved in the tisagenlecleucel manufacturing process, health care providers involved in 
leukapheresis and administering tisagenlecleucel or the patients treated with tisagenlecleucel. 
Multiple steps are required to produce tisagenlecleucel CAR-T-cells, involving leukapheresis 
to obtain patient autologous starting material, enrichment and activation, gene transduction via 
lentiviral vector and expansion. Transmission of infectious material via product could 
potentially derive from the patient’s own leukapheresis material prepared from autologous 
blood, other material including the tisagenlecleucel viral vector required to manufacture 
tisagenlecleucel, through contamination during the manufacturing process or inadequate 
storage. Due to the nature of the product (i.e., cells), there is no possibility to introduce terminal 
sterilization or dedicated viral removal and inactivation steps. Stringent precautions to prevent 
introduction of viral adventitious agents and to ensure microbial safety of tisagenlecleucel are 
in place in compliance with principles of good manufacturing practices and regulatory 
guidelines.
The risk associated with tisagenlecleucel is considered low. 
4.5.2.8
Decrease in cell viability due to inappropriate handling of the product
Inappropriate handling of the manufactured product including transport, storage in addition to 
thawing and standing time prior to infusion may result in a decrease of viable cells. This may 
impact the efficacy and safety of tisagenlecleucel. Qualified center personnel must follow 
appropriate protocols for product handling to receive, thaw, and infuse the finished 
tisagenlecleucel product. Please refer to the [Novartis Leukapheresis, Cryopreservation, and 
Scheduling Manual for Clinical Trials: CAR-T Product]. 
4.5.3
Other risks
4.5.3.1
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 
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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.
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 subject 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.
5
Population
The target patient population participating in the study will include male and female, pediatric 
patients (<18 years of age, weighing at least 6 kg) as well as adolescent and young adult patients 
(≤25 years of age) with CD19+ r/r mature B-cell NHL, including broad histological aggressive 
subtypes based on the WHO classification (Swerdlow et al 2016), such as BL, DLBCL, PMBCL, 
GZL and FL who have relapsed after one or more prior therapies or are primary refractory (have 
not achieved a CR or PR after the first line of therapy). Patients who have progressed after prior 
allogeneic and autologous HSCT are allowed to participate in the study.
It is planned to enroll approximately 35 patients with an aim to have 26 infused and evaluable
patients (of these at least 18 subjects less than 18 years of age) with aggressive subtypes of r/r 
B-cell NHL available for the primary analysis. There is no pre-specified target for the number 
of pediatric FL patients to be treated because it is an extremely rare disease type. However 
enrollment in this subtype will be open until 26 patients with the aggressive subtypes have been 
infused and are evaluable for primary analysis. It is anticipated that the life expectancy of 
enrolled patients is at least 12 weeks or more.
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The investigator or designee must ensure that only patients who meet all the following inclusion
and none of the exclusion criteria at screening and prior to infusion are offered treatment in the 
study.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent and assent forms if applicable must be obtained prior to 
participation in the study.
2. Histologically confirmed (local evaluation) mature B-cell non-Hodgkin lymphoma (B-cell 
NHL) including the following subtypes; Burkitt Lymphoma and Burkitt Leukemia (L3 B-
ALL) (BL), Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal B-Cell 
Lymphoma (PMBCL), Gray Zone lymphoma (GZL), and Follicular Lymphoma (FL).
Note: Patients with B-cell NHL associated with Nijmegen breakage syndrome will be 
allowed.
a. Sufficient formalin-fixed, paraffin-embedded (FFPE) tumor sample must be available 
for correlative analyses. A recent tumor sample obtained for the purpose of the study 
must be submitted, however if not clinically feasible, an archival tumor biopsy from 
the most recent relapse or other historical sample may be submitted instead. 
Excisional biopsies should be submitted wherever possible; in cases where this is not 
possible a core needle biopsy is allowed. Fine needle aspiration (FNA) is not suitable.
3. Patients ≤25 years of age and weighing at least 6 kg at the time of screening.
4. Patients who have relapsed after one or more prior therapies (can include allogeneic and 
autologous hematopoietic stem cell transplant) or are primary refractory (have not 
achieved a CR or PR after the first line of therapy).
5. Measurable disease by radiological criteria in all patients at the time of screening. Patients 
with Burkitt leukemia who don’t meet radiological criteria must have bone marrow 
involvement of >25%. For details refer to Appendix 1.
6. Karnofsky (age ≥16 years) or Lansky (age <16 years) performance status ≥60.
7. Adequate bone marrow reserve without transfusions defined as:
a. Absolute neutrophil count (ANC) >1000/mm3
b. Platelets ≥50000//mm3
c. Hemoglobin ≥8.0 g/dl
Note: These criteria do not apply for subjects with Burkitt leukemia.
8. Adequate organ function:
a. a serum creatinine (sCR) based on gender/age as follows:
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Maximum Serum Creatinine (mg/dL)
Age
Male
Female
1 to <2 years
0.6
0.6
2 to <6 years
0.8
0.8
6 to <10 years
1.0
1.0
10 to <13 years
1.2
1.2
13 to <16 years
1.5
1.4
≥16 years
1.7
1.4
b. AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤5 times the 
upper limit of normal (ULN) for age.
c. Total bilirubin <2 mg/dL (for Gilbert’s Syndrome patients total bilirubin <4 mg/dL).
d. Adequate pulmonary function
i.
Oxygen saturation of >91% on room air.
ii. No or mild dyspnea (≤Grade 1)
9. Must have a leukapheresis material of non-mobilized cells accepted for manufacturing. 
Note: Leukapheresis material will not be shipped to or assessed for acceptance by the 
manufacturing site until documented confirmation of all other eligibility criteria is 
received.
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Prior gene therapy or engineered T cell therapy
2. Prior treatment with any anti-CD19 therapy
3. Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to screening and 
≤4 months prior to infusion
4. Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in 
patients who received prior allogeneic HSCT Appendix 6.
5. Prior diagnosis of malignancy other than study indication, and not disease free for 5 years
6. Clinically significant active infection confirmed by clinical evidence, imaging, or positive 
laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
7. Presence of active hepatitis B or C as indicated by serology. Repeat serology is required if 
the interval between serology performed at screening and tisagenlecleucel infusion 
exceeds 8 weeks. For detailed criteria see Appendix 2.
8. Human Immunodeficiency Virus (HIV) positive test. Repeat serology is required if the 
interval between serology performed at screening and tisagenlecleucel infusion exceeds 
8 weeks
9. Active neurological autoimmune or inflammatory disorders (eg: Guillain-Barre syndrome, 
Amyotrophic Lateral Sclerosis)
10. Active CNS involvement by malignancy. Note: Patients with history of CNS disease that 
have been effectively treated will be eligible.
11. Patients with B-cell NHL in the context of post-transplant lymphoproliferative disorders 
(PTLD) associated lymphomas.
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12. Patients with concomitant genetic syndromes associated with bone marrow failure status
such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any 
other known bone marrow failure syndrome. Note: Patients with Down syndrome will not 
be excluded.
13. Known hypersensitivity to the excipients of tisagenlecleucel or to any other drug product 
as advised for administration in the study protocol (e.g. lymphodepleting agents, 
tocilizumab)
14. Cardiac disorder defined as:
a. Cardiac or cardiac repolarization abnormality, including any of the following:
i.
History of myocardial infarction (MI), angina pectoris, or coronary artery bypass 
graft (CABG) within 6 months prior to starting study treatment
ii. Clinically significant cardiac arrhythmias (eg: ventricular tachycardia), complete 
left bundle branch block, high-grade AV block (eg: bifascicular block, Mobitz 
type II and third degree AV block)
b. LVEF <45% as determined by ECHO or MRA or MUGA
c. NYHA functional class III or IV (Chavey et al 2001)
15. Subjects enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies
16. Pregnant or nursing (lactating) women.
Note: Women of child-bearing potential (WOCBP) must have a negative pregnancy 
test performed at screening, within 24 hours prior to leukapheresis, lymphodepletion, 
tisagenlecleucel infusion and at EOS.
17. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception from 
enrollment into this study through at least 12 months after the tisagenlecleucel infusion 
and until CAR-T cells are no longer present by qPCR on two consecutive tests. qPCR test 
results will be available upon request. Highly effective contraception methods include:
!
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (eg: 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 bilateral tubal ligation at least six weeks before 
enrollment. 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 subjects on the 
study, the vasectomized male partner should be the sole partner for that subject
!
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.
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Additional considerations:
!
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 (eg: age appropriate history of vasomotor symptoms) or have had surgical 
bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral 
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.
Note: If local regulations deviate from the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF.
18. Sexually active males who do not agree to use a condom during intercourse from 
enrollment through at least 12 months after the tisagenlecleucel infusion and until CAR-T 
cells are no longer present by qPCR on two consecutive tests. qPCR test results will be 
available upon request.
Note: 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.
6
Treatment
6.1
Study treatment
Study treatments will include lymphodepleting chemotherapy (if given) and tisagenlecleucel 
(investigational drug).
6.1.1
Investigational drugs
Tisagenlecleucel is an autologous cellular immunotherapy product that is comprised of CD3+ T 
cells that have undergone ex vivo T cell activation, genetic 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 subject 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. The 
transduced cells are expanded ex vivo. At the end of the culture, the 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.
For details please refer to the [Novartis Product Handling Manual for Clinical Trials: CAR-T 
Products] and the current version of the [Investigator Brochure].
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6.1.2
Tisagenlecleucel dosing regimen
The investigational treatment is intravenous tisagenlecleucel with a proposed dose range of 0.2 
to 5 x 106 CAR-positive viable T cells per kg body weight (subjects ≤50 kg) or 0.1 to 2.5 x 108
CAR-positive viable T cells (subjects >50 kg).
In rare cases tisagenlecleucel may present with out-of- specification results from the release 
testing. Where the administration of the product is necessary to avoid an immediate significant 
hazard to the subject and taking into account the alternative options for the subject and the 
consequences of not receiving tisagenlecleucel, the supply of the product may be justified upon 
request from the treating physician. Tisagenlecleucel will then be provided based on the 
evaluation of the risks and the confirmation of the treating physician to accept the product.
6.1.3
Pre-infusion evaluation
If the time since any assessment completed at screening for clinical eligibility has exceeded its 
required specified window (as detailed in Section 8.1), the assessment must be repeated prior 
to tisagenlecleucel infusion. If the period of delay is more than 4 weeks from completing 
lymphodepletion and there is no significant cytopenia (see Section 6.1.5.2), lymphodepletion 
should be repeated, and these criteria will need to be re-checked prior to tisagenlecleucel 
infusion.
If any of the following criteria is met, tisagenlecleucel infusion must be delayed until resolution:
1. Rapidly progressing or uncontrolled B-cell NHL
2. Active and/or uncontrolled TLS despite medical intervention
3. Active CNS involvement by malignancy
4. Laboratory abnormalities that, in the opinion of the investigator, may impact subject 
safety or the subjects’ ability to receive tisagenlecleucel.
5. Following clinical abnormalities:
!
Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 
91% or presence of progressive radiographic abnormalities on chest x-ray
!
Cardiac arrhythmia not controlled with medical management
!
Hypotension requiring pressor support
!
Active infection, as evidenced by positive blood cultures for bacteria, fungi, or 
polymerase chain reaction (PCR) positivity for viral DNA in blood within 72 hours of 
tisagenlecleucel cell infusion, or clinical or radiographic evidence
!
Active graft versus host disease (GVHD) Appendix 6.
6. Allogeneic hematopoietic stem cell transplant (HSCT) ≤4 months prior to tisagenlecleucel 
infusion
7. A significant change in clinical status that would, in the opinion of the investigator, 
increase the risk of adverse events associated with tisagenlecleucel
8. Significant toxicities from chemotherapy (including lymphodepletion) that would, in the 
opinion of the investigator, increase the risk of adverse events associated with 
tisagenlecleucel.
9. Prohibited medications and non-drug therapies as described in Section 6.2.2.
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10. Positive influenza test within 10 days prior to tisagenlecleucel infusion (please refer to
Table 8-1). If the subject 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 subject 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 subject is asymptomatic. For 
subjects residing in the United States, Canada, Europe and Japan, influenza testing is 
required during the months of October through May (inclusive). For subjects residing in 
the southern hemisphere such as Australia, influenza testing is required during the months 
of April through November (inclusive). For subjects with significant international travel, 
both calendar intervals above may need to be considered.
11. Women of child-bearing potential must have a negative serum pregnancy test performed 
within 24 hours prior to tisagenlecleucel infusion.
6.1.4
Additional safety procedures prior to tisagenlecleucel infusion
Tumor lysis syndrome (TLS)
The risk of TLS is dependent on disease burden. Subjects will be closely monitored both before 
and after lymphodepleting chemotherapy and the tisagenlecleucel infusion, including blood 
tests for potassium, creatinine, calcium, phosphorous, and uric acid. Subjects with elevated uric 
acid or high tumor burden will receive prophylactic allopurinol, or a non-allopurinol alternative 
(eg: febuxostat).
For further recommendations regarding the management of TLS, please refer to Section 6.6.2.4.
Infections
Infection prophylaxis should follow local guidelines dictated only by the preceding
lymphodepleting chemotherapy.
Cytokine Release Syndrome
A minimum of two doses of tocilizumab per subject for use in the event of cytokine release 
syndrome and emergency equipment must be available on site prior to infusion. Treatment 
centers should have timely access to additional doses of tocilizumab (see Section 6.6.2.1 
/Cytokine Release Syndrome (CRS) for details). See full Prescribing Information to use 
tocilizumab safely and effectively [local Actemra Prescribing Information].
Premedication
Side effects from T cell infusions can include fever, chills and/or nausea. All subjects should 
be pre-medicated with acetaminophen (paracetamol) and diphenhydramine or another 
H1 antihistamine approximately 30 to 60 minutes prior to infusion. These medications can be 
repeated every 6 hours as needed. Non-steroidal anti-inflammatory medication may be 
prescribed if the subject continues to have fever not relieved with acetaminophen (paracetamol).
Steroids should NOT be used for premedication. It is recommended that subjects should NOT 
receive systemic corticosteroids other than physiologic replacement, except for serious
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emergency, since this may have an adverse effect on tisagenlecleucel cell expansion and 
function.
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. Subjects should be evaluated and carefully 
monitored until complete resolution of signs and symptoms. Subject or subject’s caregiver 
should monitor the subject’s temperature twice a day for the first 3-4 weeks. Subjects are 
required to stay near the treatment site for the first 4 weeks. The subject or subject’s caregiver 
should be instructed to call the investigator promptly with any signs of fever for possible 
hospitalization.
Supportive care:
Local guidelines will be followed for the supportive care of 
immunosuppressed and chemotherapy treated subjects. All blood products administered should 
be irradiated. For details about prohibited concomitant medications and non-drug therapies 
please refer to Section 6.2.2.
6.1.5
Additional treatments
6.1.5.1
Bridging therapy
While awaiting completion of tisagenlecleucel product manufacturing, those subjects who may 
need additional (bridging) therapy to control their disease, based on the extent of the disease 
burden and per investigator’s discretion, may receive appropriate treatment. Medication 
restrictions prior to leukapheresis are provided in Section 6.2.2. It is recommended that bridging 
therapy be completed 2 weeks prior to tisagenlecleucel infusion.
6.1.5.2
Lymphodepleting chemotherapy
Prior to tisagenlecleucel infusion, each subject should undergo lymphodepletion, unless the 
subject has a significant cytopenia (eg: WBC <1000 cells/μL, absolute lymphocyte count 
<200/μL) 
or 
any 
condition 
that, 
in 
the 
investigator’s 
opinion, 
precludes 
lymphodepletion. Female subjects of childbearing potential must have a negative serum 
pregnancy test within 24 hours prior to the start of lymphodepleting therapy (if >8 weeks from 
the last test). If the subject does not require lymphodepleting therapy, she should still have a 
negative serum pregnancy test at the required visit that takes place within 24 hours prior to 
tisagenlecleucel infusion.
Lymphodepletion should start such that tisagenlecleucel will be infused 2 to 14 days after 
completion of lymphodepletion depending on the lymphodepleting regimen. Lymphodepletion 
may be repeated in case tisagenlecleucel has been delayed by more than 4 weeks (see Section 
6.1.3. The preferred regimen is as follows:
!
Fludarabine (30 mg/m2 intravenously (i.v.) daily for 4 days)
!
Cyclophosphamide (500 mg/m2 i.v. daily for 2 days starting with the first dose of 
fludarabine)
Side effects of fludarabine include severe neurological events of seizure, agitation, blindness, 
coma and death. Instances of life-threatening and sometimes fatal autoimmune phenomena such 
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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. Fludarabine may also severely decrease bone 
marrow function (fludarabine full prescribing information).
Cyclophosphamide can cause 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. High 
doses of cyclophosphamide led in a few instances to severe, and sometimes fatal, congestive 
heart failure after the first 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 a subject has a history of grade 4 hemorrhagic cystitis with cyclophosphamide or of resistance 
to a cyclophosphamide-containing regimen, then the following regimen should be used:
!
Cytarabine (500 mg/m2 i.v. daily for 2 days) and
!
Etoposide (150 mg/m2 i.v. daily x 3 days starting with the first dose of cytarabine)
Refer to the prescription information for toxicities associated with cytarabine and etoposide.
6.1.6
Treatment duration
A single dose of tisagenlecleucel will be given within 30 minutes after thawing of the product. 
For more details please refer to [Novartis Product Handling Manual for Clinical Trials: CAR-
T Products].
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Collection of therapy within 30 days of screening
Clinically significant prescription and nonprescription medication, excluding vitamins, and 
herbal and nutritional supplements, procedure-related (inpatient or outpatient) medications and 
therapy taken by the subject during the 30 days prior to screening will be recorded. 
Collection of concomitant therapy from screening to end of study
At every visit following the screening visit up to the end of the study, concomitant medications 
and therapy will be recorded in the medical record on the appropriate CRF. During selected trial 
phases, concomitant medication collection will be modified as outlined in Appendix 3: 
Tisagenlecleucel modified data reporting 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. 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
on the appropriate Case Report Forms (CRF).
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Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
enrolling a subject or allowing a new medication to be started. If the subject is already enrolled, 
contact Novartis to determine if the subject should continue participation in the study.
6.2.1.1
Modified data capture of concomitant treatments for inpatient/in 
hospital events
A significant number of tisagenlecleucel treated subjects will require multiple days of inpatient 
and/or intensive care unit (ICU) care within 28 days after tisagenlecleucel infusion. These AEs 
are mostly due to CRS and MAS, although there may be also contribution from the preceding 
lymphodepleting chemotherapy (eg: events such as febrile neutropenia or hematopoietic 
cytopenias). Cytokine release syndrome/MAS toxicity is an ‘on-target’ effect of the 
tisagenlecleucel cell expansion, activation and tumor cell killing.
A typical inpatient or ICU day can generate hundreds of data points and many therapeutic dose 
changes throughout a given day. These inpatient events and days are not scheduled protocol 
defined visits, although they are anticipated to occur in some subjects. Revised inpatient data 
capture will be utilized for this study to systematically collect subsets of subject data to describe 
the management of safety events associated with tisagenlecleucel therapy for the purpose of:
!
Adequately informing physicians and subjects of the expected risks of tisagenlecleucel 
and the recommended interventions to manage these risks
!
Health authority submission
This is done through a targeted collection of concomitant medications and laboratory data and 
CRS eCRF pages specifically designed to capture tisagenlecleucel related toxicity, severity, 
seriousness, causality, interventions and response/resolution following intervention. Details can 
be found in the CRF Completion Guidelines (CCGs).
6.2.1.2
Permitted concomitant therapy requiring caution and/or action
The subject 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.
6.2.2
Prohibited medications and non-drug therapies
Medication restrictions prior to leukapheresis
The subject must be asked to notify the investigational site about any new medications he/she 
takes after the start of the study drug. 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. 
Subjects may receive the following medications prior to leukapheresis in order to stabilize the 
disease:
1. Therapeutic doses of steroids may be given for up to 1 week but must be stopped >72 
hours prior to leukapheresis.
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2. Low-dose daily chemotherapy may be given for up to 1 week but must be stopped > 72 
hours prior to leukapheresis.
For all other medication restrictions before leukapheresis, please refer to the recent [Novartis 
Leukapheresis, Cryopreservation, and Scheduling Manual for Clinical Trials: CAR-T Product].
Medication restrictions prior to and post 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: <12 mg/m2/day hydrocortisone 
or equivalent.
2. Steroids or other immunosuppressant drugs are not recommended to be used as 
pre-medication for tisagenlecleucel therapy 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 (eg: rituximab) should not be used within 
2 weeks prior to tisagenlecleucel infusion
4. CNS disease prophylaxis or intrathecal therapy must be stopped >1 week prior to 
tisagenlecleucel infusion (eg: intrathecal methotrexate)
5. Radiation therapy must be stopped >2 weeks prior to tisagenlecleucel infusion. Cranial 
radiation must be stopped >8 weeks prior to tisagenlecleucel infusion.
6. Live vaccines must not be used in tisagenlecleucel recipients for at least 6 weeks prior to 
lymphodepletion and during tisagenlecleucel treatment until immune recovery following 
treatment with tisagenlecleucel.
7. Granulocyte macrophage-colony stimulating factor (GM-CSF) has the potential to worsen 
CRS symptoms and are not recommended during the first 3 weeks after tisagenlecleucel 
infusion or until CRS has resolved.
8. Antiproliferative therapies, other than lymphodepletion including low dose daily or 
weekly maintenance chemotherapy should not be used within 2 weeks prior to infusion.
!
Short acting drugs used to treat primary disease (eg: hydroxyurea, tyrosine kinase 
inhibitors) must be stopped >72 hours prior to tisagenlecleucel.
9. GVHD therapies: In subjects with allogeneic HSCT, any systemic drug used for GVHD 
prophylaxis must be stopped >2 weeks prior to tisagenlecleucel infusion to confirm that 
GVHD recurrence is not observed (eg: calcineurin inhibitors, methotrexate or other 
chemotherapy drugs, mycophenolyate, rapamycin, thalidomide, or immunosuppressive 
antibodies such as rituximab, anti-TNF, anti-IL6 or anti-IL6R, systemic steroids)
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
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Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the subject to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject. If the subject fails to start treatment for any reason, the 
reason will be entered into the appropriate CRF page. For detailed screening and enrollment 
procedures, related to the use of Interactive Response Technology (IRT), please refer to the
[IRT User Manual].
6.4
Treatment Blinding
Not applicable.
6.5
Dose escalation and dose modification
Not applicable as subjects will receive a single intravenous (i.v.) infusion of CAR-positive 
viable T cells.
6.5.1
Follow-up for toxicities
6.5.1.1
Follow-up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with total bilirubin (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 subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further Follow-up as outlined 
below:
!
For subjects 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 subjects 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 alkaline phosphatase (ALP) elevation >2.0 x ULN with ALT/ALP x ULN (R value) <2 in 
subjects without bone metastasis, or elevation of ALP liver fraction in subjects 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 subjects 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 
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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 and direct 
bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/International 
Normalized Ratio (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 (eg: biliary 
tract) may be warranted.
4. Obtain pharmacokinetic (PK) sample, as close as possible to last dose of tisagenlecleucel, 
if PK analysis is performed in the study.
5. Additional testing for other hepatotropic viral infection (cytomegalovirus (CMV), Epstein-
bar virus (EBV) or Herpes simplex virus (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 
significant”, thus, met the definition of serious adverse event (SAE) and reported as SAE using 
the term “potential drug-induced liver injury”. All events should be followed up with the 
outcome clearly documented
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Novartis has established methods to ensure full traceability between the subject’s autologous 
leukapheresis and the tisagenlecleucel product in line with the requirements outlined in 
21 CFR1271.250, 21CFR1271.290, Regulation Ethics committee (EC) 1394/2007, the 
Directive 2004/23/EC as well as the rules and principles of the European (EU) “Detailed 
guidelines on good clinical practice specific to advanced therapy medicinal products”. 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 Cell and Gene 
Therapies Unit Product Quality Department. A unique subject identifier will be used in order 
to maintain the chain of identity between the autologous leukapheresis material and the 
tisagenlecleucel batch, and the link between subject identity and unique subject identifier will 
be confirmed prior to infusion. The [Novartis Product Handling Manual for Clinical Trials: 
CAR-T Products] 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.
The investigator or designee must maintain an accurate record of the drug receipt logs and Drug 
Accountability Forms. Drug accountability will be reviewed by the field monitor during site 
visits and prior to the completion of the study. At study close-out, and, as appropriate during 
the course of the study, the investigator will return a copy of the completed drug accountability 
forms to the Novartis monitor or to the Novartis address provided in the investigator folder at 
each site.
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6.6.2
Recommended treatment of adverse events
Subjects infused with tisagenlecleucel are at risk of developing a number of AE that are related 
either to tisagenlecleucel itself, other therapies (eg: immunochemotherapy) and conditions 
concurrent with the subject’s primary disease. Following tisagenlecleucel infusion, subjects 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.
6.6.2.1
Cytokine release syndrome (CRS)
Ensure that at least two doses tocilizumab per subject are available on site prior to infusion of 
tisagenlecleucel. Hospitals should have timely access to additional doses of tocilizumab. 
Supportive care, tocilizumab, and corticosteroids have been used for effective management of 
CRS. Prompt responses to tocilizumab have been seen in most subjects. For further information 
relating to the administration of tocilizumab in the treatment and management of CRS 
symptoms, including warnings, precautions, and relevant ADRs, please refer to local 
prescribing information [Actemra USPI].
Identify cytokine release syndrome (CRS) based on clinical presentation (see Section 4.5.1.1). 
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 
subjects for signs or symptoms of CRS for at least 4 weeks after treatment with tisagenlecleucel. 
Counsel subjects to seek immediate medical attention should signs or symptoms of CRS occur 
at any time. Myeloid growth factors, particularly GM-CSF, are not recommended during the 
first 3 weeks after tisagenlecleucel infusion or until CRS has resolved.
At the first sign of CRS, immediately evaluate subject for hospitalization and institute treatment 
with supportive care, tocilizumab and/or corticosteroids as indicated.
A detailed treatment algorithm for the management of CRS (Lee et al 2014) is presented below 
in Table 6-1 and Table 6-2. The CRS management algorithm is a guideline and the investigator 
may use discretion or modify the treatment approach as needed for an individual subject. 
If requested by HA or EC/IRB or based on local practice, more frequent monitoring assessment 
and/or hospitalization can be implemented by the physicians.
Subjects will be required to remain proximal to the treating site for the first 4 weeks.
Table 6-1
CRS management
CRS severity 
Symptomatic 
treatment
Tocilizumab 
Corticosteroids
Mild symptoms requiring 
symptomatic treatment 
only e.g. low fever, 
fatigue, anorexia, etc.
Exclude other causes 
(e.g. infection) and treat 
specific symptoms with 
e.g. antipyretics, anti-
emetics, anti-
analgesics, etc.
Not applicable
Not applicable
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CRS severity 
Symptomatic 
treatment
Tocilizumab 
Corticosteroids
If neutropenic, 
administer antibiotics 
per local guidelines
Symptoms requiring 
moderate intervention:
- high fever
- hypoxia
- mild hypotension
Antipyretics, oxygen, 
intravenous fluids 
and/or low dose 
vasopressors as 
needed.
If no improvement after 
symptomatic treatment 
administer tocilizumab i.v. 
over 1 hour:   
- 8 mg/kg (max. 800 mg)    
   if body weight  ≥ 30 kg 
- 12 mg/kg if body weight    
   <30 kg  
If no improvement,  repeat 
every 8 hours (max total of 4 
doses)*
If no improvement within 
12-18 hours of 
tocilizumab, administer 
a daily dose of 2 mg/kg 
i.v. methylprednisolone 
(or equivalent) until 
vasopressor and oxygen 
no longer need, then 
taper.*
Symptoms requiring 
aggressive intervention: 
-hypoxia requiring      
high-flow oxygen 
  supplementation or
- hypotension requiring 
  high-dose or multiple 
  vasopressors
High-flow oxygen
Intravenous fluids and 
high-dose 
vasopressor/s
Treat other organ 
toxicities as per local 
guidelines
Life-threatening
symptoms: 
- hemodynamic                     
  instability despite i.v. 
   fluids and vasopressors
- worsening respiratory     
  distress
- rapid clinical 
  deterioration
Mechanical ventilation
Intravenous fluids and 
high-dose 
vasopressor/s
Treat other organ 
toxicities as per local 
guidelines
* If no improvement after tocilizumab and steroids, consider other anti-cytokine and anti-T-cell therapies. These 
therapies may include siltuximab (11 mg/kg i.v. over 1 hour), high doses of steroids (e.g. high dose 
methylprednisolone or equivalent steroid dose according to local ICU practice) cyclophosphamide, anti-thymocyte 
globulin (ATG) or alemtuzumab.
Table 6-2
Definition of high dose vasopressors
Vasopressor
Dose to be given for ≥ 3 hours
Weight-based dosing¥
Flat dosing§
Norepinephrine monotherapy
≥ 0.20 mcg/kg/min 
≥ 20 mcg/min
Dopamine monotherapy
≥ 10 mcg/kg/min
≥ 1000 mcg/min
Phenylephrine monotherapy
≥ 2 mcg/kg/min 
≥ 200 mcg/min
Epinephrine monotherapy
≥ 0.1 mcg/kg/min 
≥ 10 mcg/min
If on vasopressin
Vasopressin + norepinephrine 
equivalent (NE) of 
≥0.1 mcg/kg/mina
Vasopressin + NE ≥ 10 
mcg/minb
If on combination 
vasopressors (not 
vasopressin)
NE of ≥ 0.2 mcg/kg/mina
NE of ≥ 20 mcg/minb
§If institutional practice is to use flat dosing.
¥Weight-based dosing was extrapolated by dividing the flat dosing of a vasopressor by 100.
Vasopressin and Septic Shock Trial (VASST) norepinephrine equivalent equation:
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aNE dose (weight-based dosing) = [norepinephrine (mcg/kg/minute)] + [dopamine (mcg/kg/minute) / 2] + 
[epinephrine (mcg/kg/minute)] + [phenylephrine (mcg/kg/minute) / 10] bNE dose = [norepinephrine (mcg/min)] 
+ [dopamine (mcg/kg/min) ÷ 2] + [epinephrine (mcg/min)] + [phenylephrine (mcg/min) ÷10]
Source: Adapted from Lee et al 2014, Lee et al 2015, Russell et al 2008, Porter et al 2015 and Chimeric Antigen 
Receptor (CAR) Cell Therapy Toxicity Assessment and Management – Pediatric, dated 30-Jan-2018.
Other anti-cytokine therapies may also be considered upon their availability, if the subject does 
not respond to tocilizumab. If the subject 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 4.5.1.1. Cases of transient left ventricular dysfunction, as assessed by ECHO, have been 
reported in some subjects 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.
As the time-course and rapidity of CRS development varies among subjects, additional 
unscheduled blood samples may be collected as needed, if clinically feasible. Frequent 
monitoring of serum CRP, ferritin and cytokines should be considered during the clinical course 
of CRS of any severity (eg: 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 ferritin, CRP and serum cytokine levels should NOT be used for 
clinical management decisions related to the treatment of CRS.
6.6.2.2
Neurological adverse events (early or late)
Neurologic events, primarily reflective of encephalopathy and delirium, may occur after
tisagenlecleucel infusion. These present clinically as signs and symptoms of varying severity
such as confusion, disorientation, agitation, aphasia, somnolence and tremors. In severe cases 
seizures, motor weakness, incontinence, impaired consciousness, increased intracranial
pressure, and cerebral edema may be concurrent to, following the resolution or in the absence
of CRS. Subjects should be monitored for neurologic events, diagnostically worked-up and
managed depending on the underlying pathophysiology and in accordance to local standard of
care.
Evaluation:
!
Thorough neurological examination, with frequent monitoring and determination of 
CTCAE grading as well as ASTCT Consensus ICANS Grading (Table 4-4).
!
Diagnostic work up to evaluate potential secondary causes:
!
Brain imaging (CT scan and/or MRI): to exclude intracranial hemorrhage, disease
relapse, evidence suggestive of infection or cerebral edema.
!
Lumbar puncture for CSF evaluation, if clinically indicated
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!
Chemistry laboratory testing
!
Electroencephalogram (EEG)
Management:
!
If the neurological event is concurrent with CRS refer to CRS algorithm table for
treatment recommendation (Table 6-1).
!
Consider anti-seizure medications (eg: Levetiracetam) for patient at high risk (prior
history of seizure) or administer in the presence of seizure.
!
For encephalopathy, delirium or associated events: appropriate treatment and supportive
care should be implemented as per local standard of care. In worsening events, consider a
short course of steroids (Neelapu et al 2018, Teachey et al 2018).
6.6.2.3
Hypersensitivity including acute infusion reactions
Subjects should be monitored for signs and symptoms of hypersensitivity following initiation 
of tisagenlecleucel infusion and treated appropriately. Tisagenlecleucel is contraindicated in 
subjects 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 subjects 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.
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. Subjects should be evaluated and carefully 
monitored until complete resolution of signs and symptoms.
6.6.2.4
Tumor lysis syndrome (TLS)
Subjects 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, subjects 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 (eg: febuxostat), and 
increased oral/i.v. hydration prior to lymphodepleting chemotherapy and 
tisagenlecleucel infusion should be given in subjects 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)
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!
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 (eg: 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.
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).
6.6.2.5
Infections
Subjects with active, uncontrolled infection should not start tisagenlecleucel treatment until the 
infection is resolved.
Subjects 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 (eg: 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 
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at least 6 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 subjects 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.
6.6.2.6
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 subject should be evaluated for infection (Section 4.5.1.5) and CRS (Section 4.5.1.1) 
and managed appropriately with fluids, antibiotics, and supportive care, if applicable.
In the event that the subject develops sepsis or systemic bacteremia following tisagenlecleucel 
cell infusion, appropriate cultures and medical management should be initiated. If a 
contaminated tisagenlecleucel product is suspected, the product can be retested for sterility 
using archived samples that are stored at the manufacturing site.
6.6.2.7
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. Immunoglobulin levels in newborns of mothers treated with tisagenlecleucel 
should also be assessed and managed as per standard of care.
6.6.2.8
Hematopoietic cytopenias lasting greater than or equal to 28 days
Myeloid growth factors, particularly GM-CSF, have the potential to worsen CRS symptoms 
and are not recommended during the first 3 weeks after tisagenlecleucel infusion or until CRS 
has resolved.
Haematopoietic cytopenias should be managed with standard measures of observation, blood 
product support, growth factors and/or antibiotics as indicated and per local standard of care.
6.6.2.9
Replication competent lentivirus (RCL) production
If a positive RCL assay result is obtained from a subject blood specimen, (eg: as detected by 
Vesicular Stomatitis Virus Glycoprotein (VSV-G) quantitative PCR), the Investigator will be 
informed and the subject rescheduled for a retest of the DNA test. The subject must be isolated 
until an understanding of how to manage the subject becomes clear. Some considerations are:
!
Intensive Follow-up of the subject in consultation with gene therapy experts, study 
investigators, and Health Authorities
!
Inform local and country specific public health officials
!
Identify sexual partners and provide appropriate counseling and intervention
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6.6.2.10 New or secondary malignancies including vector insertion site 
oligo/monoclonality)
If uncontrolled T-cell proliferation occurs (eg: expansion of T cells in the absence of CD19 
antigen), subjects may be treated with corticosteroids such as methylprednisolone 
(2 mg/kg/d i.v.) or chemotherapy, such as high dose cyclophosphamide. Investigators should 
further discuss this with the sponsor. Toxicity associated with allogeneic or autologous T cell 
infusions has been managed with a course of pharmacologic immunosuppression. T cell 
associated toxicity has been reported to respond to systemic corticosteroids (Lamers et al 2006).
This theoretical toxicity is distinct from the toxicity associated with a CRS that develops during 
T-cell proliferation upon exposure to CD19 expressing cells. CRS associated with T-cell 
expansion is managed with anti-cytokine therapy, not immunosuppressants.
6.6.2.11 Graft versus host disease (GVHD)
Graft versus host disease can be severe but can be controlled with steroids and other 
immunosuppressants as per local standard of care.
6.7
Preparation and dispensation
Manufacturing of tisagenlecleucel cells will occur at the Novartis manufacturing facilities in 
Morris Plains, NJ, USA, Fraunhofer Institute, Leipzig, Germany or at contract manufacturing 
organizations (CMOs).
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 [Novartis Leukapheresis, 
Cryopreservation, and Scheduling Manual for Clinical Trials: CAR-T] and the [Novartis 
Product Handling Manual for Clinical Trials: CAR-T Products].
6.7.1
Handling of study treatment
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.
A study physician MUST evaluate the subject just prior to infusion to ensure the subject meets 
tisagenlecleucel infusion criteria. Coordination of the timing of thaw of tisagenlecleucel product 
and infusion will be done. The tisagenlecleucel product will be thawed using either a water bath 
or dry thaw method. Prior to infusion, confirmation of the subject’s identity with the subject 
identifiers on the infusion bag will be done. Once thawed, tisagenlecleucel product may be 
stored at room temperature (20°C to 25°C) and administered as an intravenous infusion within 
30 minutes from thawing.
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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 subject except for the medication number.
Tisagenlecleucel can be infused both in an inpatient or outpatient facility per investigator’s 
discretion. Factors such as, but not limited to, subject’s disease status and general health 
condition, proximity to infusion facility, and ability to monitor and report any post-infusion 
symptoms as advised by investigator or site personnel, should be considered in determining 
inpatient/outpatient infusion. Due to lack of experience in treating B-cell NHL in pediatric 
subjects with tisagenlecleucel, it is recommended to infuse subjects in an inpatient setting.
Trained study staff will administer the tisagenlecleucel infusion using precautions for 
immunosuppressed subjects. Protective isolation should follow institutional standards and 
policies. Emergency medical equipment should be available during the infusion in case the 
subject has a significant reaction to the infusion such as anaphylaxis or severe hypotension.
The tisagenlecleucel dose will be administered via a single intravenous infusion. Depending on 
the volume of the tisagenlecleucel product, it will be given either as an i.v. infusion through a 
latex free i.v. tubing WITHOUT a leukocyte filter (approximately 10-20 mL per minute 
adjusted as appropriate for smaller children and smaller volumes) or as an i.v. push via a syringe 
(for smaller volumes). It is recommended that the infusion/i.v. push be completed within 30 
minutes of thawing the cryopreserved product in order to preserve maximum cell viability. 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 repeated at 2 hours. If vital signs are unsatisfactory and unstable, continue to 
monitor the subject until vital sign stabilization.
All used infusion supplies, including the infusion bag and tubing, must be disposed of according 
to local institutional standard operating procedures. For further details on product storage, 
preparation, thawing and administration, please refer to the specific guidance provided in the 
[Novartis Product Handling Manual for Clinical Trials: CAR-T Products].
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.
Tisagenlecleucel disposal and destruction
Tisagenlecleucel cell product may require disposal for a variety of reasons, including but not 
limited to: 1) Mislabeled product; 2) Condition of patient prohibits infusion; and/or 3) Patient 
refuses infusion. Disposal of unused tisagenlecleucel product must be approved by Novartis 
study team. Upon Novartis approval, tisagenlecleucel may be disposed of according to local 
laws/ institutional SOP. 
Any used infusion supplies, including the infusion bag(s) and tubing, must be disposed of 
according to local institutional standard operating procedures.
Reconciliation of 
tisagenlecleucel cell product shipped, administered, and remaining, is performed by Novartis 
(or designee). All tisagenlecleucel cell product dispositions will be documented in the study 
files. At study close-out, and as appropriate during the course of the study, the investigator will 
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return a copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.
Please refer to the recent [Novartis Product Handling Manual for Clinical Trials: CAR-T 
Products].
6.7.2
Handling of additional treatment
Additional treatments will be handled according to local guidelines.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject 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 (eg: all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH Good clinical practice (GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed 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 subject 
informed consent and should be discussed with the subject 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 (IN) 
or an aggregate safety finding. New information might require an update to the informed 
consent and then must be discussed with the subject.
Women of child bearing potential 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.
Male subjects 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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8
Visit schedule and assessments
Assessment schedule lists all of the assessments when they are performed. All data obtained 
from these assessments must be supported in the subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study by withdrawing 
consent for any reason should be scheduled within 2 weeks for a visit or as soon as possible, at 
which time all of the assessments listed for the final visit will be performed. At this final visit, 
all dispensed investigational product should be reconciled, and the adverse event and 
concomitant medications recorded on the CRF.
In each 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 subject’s source 
documentation. The tables indicate which assessments produce data to be entered into the 
clinical database (X) or remain in source documents only (S) (“Category” column). No CRF 
will be used as a source document.
The following assessments will be performed as per the Assessment Schedule (Table 8-1):
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Table 8-1
Assessment Schedule
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Obtain Informed 
Consent
X
Interactive Web 
Response System 
(IWRS)/Interactive
Response Technology 
(IRT)
S
S; 
clinica
l 
eligibil
ity and 
leukap
heresi
s 
accept
ance
S
S
S
S
Subject History
Demography
X
Inclusion/exclusion 
criteria
X
Medical History and 
Concomitant disease
X
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Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Diagnosis and extent 
of cancer at initial 
presentation
X
Prior antineoplastic 
therapy
X
Concomitant 
antineoplastic therapy
X
X
X
Donor chimerism 
(local; only if received 
prior allogeneic SCT 
or if unknown)
X
Cytogenetics (local 
lab)
X
Prior/concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IVIG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Tumor tissue-lymph 
node/extranodal
(archival paraffin 
blocks/slides or fresh 
tumor from 
biopsy/resection, for 
efficacy/biomarkers/P
K assessments)
X
X; 
residual 
tumor 
biopsy if 
availabl
e
At relapse
Tumor 
immunophenotyping 
See Section 8.1 for 
details
X
At relapse
Physical assessments
Physical examination 
(PE); pregnancy 
assessment as 
applicable
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Performance status 
assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
X
X
X
X
X
X
X
X
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Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Tanner staging (only 
for subjects <18 years 
old; stop once Tanner 
5 is reached)
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECHO/MUGA/
MRA
X
ECG
X
X
Pulse oximetry
X
X
Intervention
Leukapheresis
X
Lymphodepleting 
Chemotherapy
X
Tisagenlecleucel pre-
infusion criteria
S
S
Tisagenlecleucel 
infusion
X
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Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Antineoplastic 
therapies after 
tisagenlecleucel 
infusion or study 
discontinuation
X
As appropriate
Laboratory assessments
Hematology (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Local flow cytometry 
leukapheresis (fresh 
product)
X
Local lab tests of 
special interest in 
case of CRS (ferritin, 
CRP and coagulation 
factors)
X; During CRS only, refer to Section 6.6.2.1.
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Pregnancy tests 
(serum test required at 
screening, pre-
leukapheresis,pre-
lymphodepletion, pre-
infusion and at EOS;
Urine test at other 
time points (local lab))
and menstrual status
S
S 
(within 
24 
hours 
prior 
to  first 
dose)
S
(within 
24 
hours 
prior 
to 
infusio
n)
S
S
S
S
S
S
S
S
S
Urinalysis (local lab)
S
S
S
Viral serology ( HIV, 
Hepatitis B & C testing 
(HCV) (local lab)
X 
(repea
t 
Hepati
tis and 
HIV 
serolo
gy 
if >8 
weeks 
from 
infusio
n)
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Influenza A and B 
testing (local lab)
X 
(within 
10 
days 
prior 
to 
infusio
n)
Coagulation (PT, 
activated partial 
thromboplastin time 
(aPTT), INR, 
fibrinogen, D-dimer) 
(local lab)
X
X
X
X
X
X
Serum 
immunoglobulin levels 
(IgG, IgA, IgM) (local 
lab)
X
X
X
X
X
X
X
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Efficacy and disease assessments (Refer to Table 8-2, Appendix 1)
Local overall disease 
assessment
X
X
after 
compl
etion 
of 
bridgin
g 
therap
y
X
(as 
clinicall
y 
indicate
d)
X
X
X
X
X
X
X
X
CT/MRI - Neck, Chest, 
Abdomen, Pelvis
X 
(within 
8 
weeks 
prior 
to 
screen
ing for 
eligibili
ty)
X
within 
2 
weeks 
prior 
to 
infusio
n
X
(as 
clinicall
y 
indicate
d)
X
X
X
X
X
X
X
X
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
PET-CT with contrast 
enhanced diagnostic 
CT/PET-MRI - Neck, 
Chest, Abdomen, 
Pelvis
X
(if no 
CT/M
RI 
availa
ble)
X
As clinically indicated, if CT/MRI is not available
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Bone marrow (BM) 
aspirate or biopsy 
(local)
X 
(within 
8 
weeks 
of 
screen
ing)
X
(if BM 
involv
ement 
at 
screen
ing or 
as 
clinical
ly 
indicat
ed; 
within 
2 
weeks 
prior 
to 
infusio
n
X
(if BM 
involve
ment at 
baselin
e OR as 
clinicall
y 
indicate
d)
At the time of radiological CR/PR/MR/NR 
in subjects with bone marrow disease at 
baseline
or
as clinically indicated
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Bone marrow (BM) 
aspirate or biopsy 
(local) for subjects 
with Burkitt Leukemia
X 
(within 
8 
weeks 
of 
screen
ing)
X 
X 
X 
X 
X 
X 
At the time of 
radiological 
CR/PR/MR/NR 
or
as clinically indicated
CSF cytology (by 
lumbar puncture; 
local)
X
X
As clinically indicated
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
CT/MRI Brain
X 
(within 
8 
weeks 
prior 
to 
screen
ing as 
clinical
ly 
indicat
ed)
X 
(within 
2 
weeks 
prior 
to 
infusio
n as 
clinical
ly 
indicat
ed)
X
As clinically indicated
Color Photography 
(only in case of any 
skin lesions; with 
scale/ruler) (local)
X 
(within 
8 
weeks 
prior 
to 
screen
ing)
X
within 
2 
weeks 
prior 
to 
infusio
n
X
(as 
clinicall
y 
indicate
d)
X
X
X
X
X
X
X
X
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Biomarker (central lab) and safety assessments
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X; 
AE
SI
onl
y
X
ICANS Consensus 
Scoring & CAPD/ICE 
score 
X
At the first sign or symptom of neurologic toxicity, the ICANS grade 
should be determined (as part of or outside the scheduled physical 
examination). If the patient experiences suspected worsening of the 
event, the grade should be reassessed and the worst grade should be 
recorded.
Immunogenicity, 
Humoral (serum)*
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
X
(not 
requir
ed for 
subjec
t ≤15
kg)
X
X
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
(not 
require
d for 
subject 
≤15 
kg)
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
(not 
requi
red 
for 
subje
ct 
≤15 
kg)
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
At relapse
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Immunogenicity, 
Cellular (Peripheral 
Blood)*
X
(1 sample at 
enrollment/pre-
chemotherapy)
X
X
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
(not 
require
d for 
subject 
≤15 
kg)
X
X
(not 
requi
red
for 
subje
ct 
≤15 
kg)
X
(not 
requir
ed for 
subjec
t ≤15 
kg
At relapse
Cytokines (serum)
X
X
X
X
X
X
X
X
X
X
Serum (Rituximab) (if 
applicable)*
X
CRS assessments by 
peripheral blood 
(Tisagenlecleucel 
qPCR, serum 
biomarkers, 
anti-cytokine therapy)
X
As clinically indicated dependent upon the presence and time-course of CRS and administration of anti-
cytokine therapies. 
 
PPD
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Tisagenlecleucel 
Cellular Kinetics by 
qPCR (peripheral 
blood)*
X
X
(not 
require
d for 
subject 
≤15 
kg)
X
X
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
X
X
X
(not 
requi
red
for 
subj
ect 
≤15 
kg)
X
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
(not 
requi
red
for 
subje
ct 
≤15 
kg)
X
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
At relapse
Tisagenlecleucel 
Cellular Kinetics by 
Flow cytometry 
(peripheral blood)*
X
(1 sample at 
enrollment/pre-chem
otherapy)
X
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
X
(not 
requir
ed for 
subje
ct ≤15 
kg)
X
X
X
X
(not 
requi
red 
for 
subj
ect 
≤15 
kg)
X
(not 
require
d for 
subject 
≤15 
kg)
X
(not 
requir
ed for 
subjec
t ≤15 
kg)
At relapse
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Tisagenlecleucel 
Cellular Kinetics by 
qPCR (bone marrow)*
X
At relapse or as clinically 
indicated: M6, M9, M12, M18 
and M24 collections are 
recommended (only if 
disease present in bone 
marrow at baseline)
Tisagenlecleucel 
Cellular Kinetics by 
Flow cytometry (bone 
marrow)*
X
As clinically indicated
Tisagenlecleucel 
Cellular Kinetics by 
qPCR in CSF*
X
As clinically indicated
Correlative studies (central lab)
Leukapheresis sample 
for correlative studies
X
Tisagenlecleucel cell 
product sample for 
correlative studies
X
Survival
X; Q3M ±28d until EOS
X
X
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
Period
Screening
Pre-treatment
Treatment and Follow-up
Visit Name
Enrollment
Lymphodepleting
Chemotherapy
Pre-infusion
Infusion
Follow-up (until EOS)
Day/Week/Month
W-16 
to
W-1
W-12 
to
W-1
D-14 
to D-2
D-1 
+1d
D1
D2 D4 ±1d D7 ±1d
D11 
±1d
D14 
±3d
D17 
±3d
D21 
±3d
D28
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±28d
M18
±28d
M24
±28d
An
n 
ual 
Fol
low
-up
EOS
Disposition
X; EOS
(post-infusion, all assessments required at M24 are expected to be completed)
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
* For patients with poor clinical condition and/or low body weight, PK and immunogenicity sample should only be collected if it does not interfere with the medical 
management of the patient or does not put the patient at an unnecessary safety risk.
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
8.1
Screening
An IRB/EC approved informed consent form (ICF) must be signed before any study specific 
screening procedures. Screening assessments to determine eligibility should be performed as 
per the assessment schedule detailed in Table 8-1. Procedures performed prior to ICF as part of 
routine standard of care may be considered for eligibility, if performed within allowed windows 
outlined in this section of the protocol.
Screening procedure(s) that do not satisfy the eligibility criteria may be 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 eligibility criteria as specified in Section 5. Re-leukapheresis 
is also allowed in case the leukapheresis material is not accepted for manufacturing or if 
manufacturing has failed. In these cases, the subject may not have to re-consent, and the original 
subject identification (ID) number assigned by the investigator will be used.
Subjects who have signed an informed consent will be registered in the IRT system and undergo 
a routine lymphoma staging workup including all screening assessments outlined in Table 8-1.
The assessments below do not need to be repeated if performed in the context of the 
leukapheresis procedure or if performed as part of clinical routine prior to 4 weeks of signing 
the ICF:
!
Local flow cytometry leukapheresis
!
Serum immunoglobulin levels (IgG, IgA, IgM)
!
Donor Chimerism (within 3 months of screening, prior allogeneic SCT patients only, or if 
unknown)
Laboratory parameters or other screening parameters may be retested within the screening 
period for an individual subject.
In the event that the time between routine standard of care testing or initial screening assessment 
and the enrollment exceeds 8 weeks, the following must be repeated:
!
ECHO/MUGA/MRA
!
Viral serology (HIV, HbsAg, HBsAb, HBcAb, hepatitis C virus (HCV)) ribonucleic 
acid (RNA). If HIV screening test is positive then a confirmatory HIV test is required 
to be performed as per current local guidelines (see Appendix 2 for interpretation of 
Hepatitis B and Hepatitis C results)
!
Performance status assessment
!
Complete Blood Count with differential and Platelet Count, Chemistry Panel, 
Coagulation Panel
!
Urinalysis
!
Pregnancy Test (as applicable)
In the event that the time between routine standard of care testing or initial screening assessment 
and enrollment exceeds 12 weeks, the below screening procedures must be repeated in addition 
to the above:
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Oncology Clinical Trial Protocol (Version 01) Clean
Protocol No. CCTL019C2202
!
Physical Examination (PE) including height, weight, vital signs, extramedullary disease 
assessment and CNS symptom assessment
!
Pulse oximetry
!
Imaging (CT/MRI or PET-CT or fluorodeoxyglucose 18F (FDG)-PET)
!
CSF cytology as clinically indicated
!
Bone marrow aspirate and/or biopsy (if clinically indicated or diagnosis of Burkitt 
leukemia)
!
CNS Brain Imaging (CT/MRI) (if clinically indicated)
8.1.1
Subject demographics/other baseline characteristics
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
8.1.1.1
Demographics
The following demographic data will be collected:
!
Age
!
Gender
!
Race
!
Ethnicity
8.1.1.2
Baseline characteristics
The following baseline characteristics will be collected:
!
Primary disease
!
Medical history, concomitant conditions
!
Prior medication
!
Prognostic factors
8.1.2
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 
possible manufacturing failure.
Once leukapheresis is collected, information on the subject’s leukapheresis material including 
sample sentinel vials collected from leukapheresis (when available) will be sent to Novartis 
manufacturing separately or together with leukapheresis material. Final enrollment is defined 
as the point at which the subject meets all clinical inclusion/exclusion criteria, and the subject’s 
leukapheresis material is received and accepted for manufacturing.
At the investigator’s discretion and taking into consideration the subject’s expected length of 
survival and the manufacturing process, additional leukapheresis collections may be performed. 
It is recommended not to exceed a maximum of two apheresis procedures/attempts within a 14 
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day window. It is at the investigator’s discretion whether the subject should continue with the 
procedure or be rescheduled for an additional procedure/attempt.
Cryopreserved non-mobilized leukapheresis materials collected prior to study entry (historical) 
may be usable for tisagenlecleucel manufacturing if collected at a Novartis certified 
leukapheresis center and if the product is accepted for manufacturing. Historical product 
collected prior to the last allogeneic SCT would not be accepted.
For subjects who will undergo leukapheresis collection on study after signing ICF, specific 
recommended criteria must be met prior to the procedure. Please refer to the Leukapheresis Key 
Requirements within the most recent [Novartis Leukapheresis, Cryopreservation, and 
Scheduling Manual for Clinical Trials: CAR-T Product] for more detailed instructions on 
optimal timing of leukapheresis collection, prohibited concomitant drugs, and the 
recommended procurement, handling and shipment procedures of the leukapheresis samples to 
the designated manufacturing facility.
8.1.3
Re-screening
Re-screening is allowed, at the discretion of the investigator, for subjects who screen fail or 
discontinue from the study prior to infusion.
A new ICF must be signed if the investigator chooses to re-screen the subject, and the 
re-screened subject will be assigned a new subject ID. In such cases, a rescreening CRF must 
be filled in to ensure the subject’s original ID can be linked to the subject’s new ID. All required 
screening activities must be performed when the subject is re-screened for participation in the 
study. Once the number of subjects screened and enrolled is likely to ensure target enrollment, 
the Sponsor may close the study to further screening. In this case, the subjects who screen failed 
will not be permitted to re-screen.
8.1.3.1
Information to be collected on screening failures
For subjects that fail screening, the following information will be captured on appropriate Case 
Report Form:
!
Informed Consent Information
!
Demography
!
Inclusion/Exclusion Criteria
!
Leukapheresis (if applicable)
!
The reason for screen failure
!
Adverse Events (if applicable) that meet reporting criteria in Appendix 3.
!
Death (if applicable)
!
Withdrawal of Consent (if applicable)
No other data will be entered into the clinical database for subjects who are not enrolled.
8.2
Enrollment
Following informed consent, information on the subject’s leukapheresis material including 
sample sentinel vials collected from leukapheresis (when available) will be sent to Novartis 
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manufacturing facility separately or together with leukapheresis material. Enrollment is defined 
as the point at which a subject meets all clinical eligibility criteria and the subject’s 
leukapheresis material is received and accepted for manufacturing. Once assigned, the Subject 
Number must not be re-used for any other subject. If a screened subject is not enrolled, the 
specific reason will be entered into the electronic Data Capture (EDC) system. Clinical 
eligibility (entered by site) and Enrollment upon product acceptance (entered by manufacturing 
facility) will be captured in the Interactive Response Technology (IRT) system. If a subject is 
re-screened, re-enrollment will also be recorded using the IRT system. If repeat screening 
procedures are needed after the initial clinical eligibility has been recorded in IRT, confirmation 
of new clinical eligibility must be captured in the IRT system. For detailed enrollment 
procedures related to the use of IRT, please refer to the [IRT User Manual].
8.3
Efficacy
Efficacy/Pharmacodynamics (PD) are measured per assessments described below.
8.3.1
Efficacy assessments
Eligibility will be determined by the local staging assessment by required radiology images and 
other assessments obtained during screening by the investigator. The decision regarding subject 
management will also remain with the local investigator.
Disease characterization at baseline and evaluation of efficacy during study rely on the 
following:
!
Imaging
!
Bone marrow biopsy or aspirate
!
CSF cytology
!
Physical exam findings/cytology/biopsy evaluation
Efficacy assessments will be performed locally at the site as indicated in Table 8-2, and as 
clinically indicated until relapse, disease progression, death, lost to Follow-up, withdrawal of 
consent or end of study. Efficacy evaluations will be based on the International Pediatric NHL 
Response Criteria (Sandlund et al 2015) as detailed in Appendix 1. The latest efficacy 
assessment after bridging therapy and prior to infusion will be used as baseline. Any imaging 
assessment obtained after infusion cannot be considered baseline/pre-infusion images.
Radiological imaging will be centrally collected and checked for quality by an imaging 
Contract Research Organization (CRO) designated by Novartis. The results of the local 
evaluations will be used for primary and secondary analysis purposes. The local investigator’s 
assessment will also be used for treatment decision making. Central review of the imaging 
data may be performed if deemed necessary.
Information regarding prior interventions (eg: radiotherapy), pre-existing radiographic findings 
that mimic metastatic disease at screening/baseline, physical exam finding (eg: skin lesions, 
etc.), cytology results and on-study procedures (eg: bone marrow biopsy, etc.) may be 
transmitted to the imaging CRO from the clinical database.
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Table 8-2
Efficacy Assessment Collection Plan
Procedure
Screening
Baseline
During Treatment/Follow-up
CT or MRI Neck, 
Chest, Abdomen, 
Pelvis
Mandated to 
determine study 
eligibility and must 
be performed within 
8 weeks prior to 
screening (allowed 
if part of clinical 
routine).
After the 
completion of 
bridging therapy 
and within 2 
weeks prior to 
infusion (only if 
PET-CT with 
diagnostic CT or 
PET-MRI is not 
available)
At Month 3 (±14 days) (only if 
PET-CT with diagnostic CT or 
PET-MRI is not available); 
Mandated at Months 6, 9 
(±14 days), Months 12, 18, 24 
(±28 days) and annually 
thereafter or as clinically 
indicated until relapse, 
progression, death, lost to 
Follow-up or withdrawal of 
consent or EOS.
As clinically indicated at Day 28 
(±7 days); due to the mechanism 
of action of tisagenlecleucel, the 
Day 28 (±7 days) assessment 
should be interpreted in context 
of other clinical parameters that 
suggest true progression rather 
than pseudoprogression due to 
inflammatory changes and tumor 
swelling
PET-CT with contrast 
enhanced diagnostic 
CT or PET-MRI -
Neck, Chest, 
Abdomen, Pelvis
N/A
Recommended;
within 2 weeks 
prior to infusion of 
tisagenlecleucel 
product, if no 
CT/MRI available
Recommended; at Month 3 (±14 
days) or as clinically indicted, if 
CT/MRI is not available
Once CR is confirmed (prior to or 
after Month 3 (±14 days) PET 
imaging is not required (CT only)
Dedicated PET
N/A
Recommended; if 
no PET-CT or 
PET-MRI available 
within 2 weeks 
prior to infusion of 
tisagenlecleucel 
product
Recommended; at Month 3 (±14 
days) (if no PET-CT/ PET-MRI 
available), or as clinically 
indicted.
Once CR is confirmed (prior to or 
after Month 3 (±14 days) PET 
imaging is not required (CT only)
Bone marrow aspirate 
or biopsy
Mandated within 8 
weeks prior to 
screening
Mandated if 
diagnosis of 
Burkitt leukemia, 
bone marrow 
involvement at 
screening, or as 
clinically indicated; 
done within 2 
weeks prior to 
infusion
Mandated at Month 3 (±14 days) 
and at time of radiological 
CR/PR/MR/NR in subjects with 
baseline bone marrow disease 
and at other times as clinically 
indicated
For Burkitt leukemia: Mandated 
at Day 28 (±7 days), Month 3 
(±14 days), Month 6 (±14 days), 
Month 9 (±14 days) and Month 
12 (±28 days) and then as 
clinically indicated.
CSF Cytology
Mandated
NA
As clinically indicated
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Procedure
Screening
Baseline
During Treatment/Follow-up
CT/MRI Brain
As clinically 
indicated within 8
weeks prior to 
screening
If clinically 
indicated within 2
weeks prior to 
infusion
As clinically indicated
Color photography 
(with scale/ruler)
For any skin 
lesions present; 
within 8 weeks prior 
to screening
For any skin 
lesions present; 
within 2 weeks 
prior to infusion
If skin lesions were documented 
at baseline, follow same 
schedule as CT/MRI of Neck, 
Chest, Abdomen, Pelvis
Tumor biopsy (FFPE)
Mandated from the 
time of diagnosis 
and/or at recent 
relapse prior to 
study entry
Recommended at Month 3 (±14 
days) and required at relapse
Physical Exam
Mandated
Mandated
Mandated
Other Biopsy
As clinically 
indicated
As clinically 
indicated
As clinically indicated
8.3.1.1
Baseline imaging assessments
Imaging assessments are as described in Table 8-2 and should be performed at the time points 
specified. Imaging assessments will be performed at screening preferably within 4 weeks prior 
to tisagenlecleucel infusion and will be used to determine eligibility. Any imaging assessments 
already completed during the regular work-up of the subject within 8 weeks prior to the 
screening visit, including before signing the main study ICF, can be considered as the screening
images for this study to determine eligibility. After completion of bridging therapy and within 
2 weeks prior to tisagenlecleucel infusion, imaging will be repeated (see Table 8-2) to establish 
baseline disease status. Any imaging assessments obtained after infusion cannot be considered 
baseline images.
A PET-CT with diagnostic CT/PET-MRI (or PET-CT without diagnostic CT + dedicated 
diagnostic CT or dedicated PET when PET-CT with diagnostic CT/PET-MRI not available) is 
recommended to be performed within 2 weeks prior to the scheduled tisagenlecleucel infusion. 
One of the following scanning scenarios are to occur prior to infusion and on study when PET 
imaging may be obtained:
1. PET-CT with diagnostic CT
2. PET-CT with non-diagnostic CT + dedicated diagnostic CT
3. Dedicated diagnostic CT + dedicated FDG PET
Refer to Appendix 1 for details regarding imaging requirements.
If a subject 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 chest (MRI of chest is not 
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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 neck,
abdomen and pelvis should be performed.
A MRI or CT of the brain must be performed at screening/baseline as clinically indicated and 
must be repeated within 2 weeks prior to tisagenlecleucel infusion as clinically indicated. 
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 at screening as a result of a physical exam these are to be documented 
via the efficacy criteria, color photography should be acquired using a digital camera in clear 
focus, including a scale/ruler, in such a way that the size of the lesion(s) can be determined from 
the photograph.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
8.3.1.2
Post-baseline imaging assessments
Imaging assessments as described in Table 8-2 should be performed at the time points specified 
preferably using the same imaging modality used at baseline. CT/MRI imaging assessments for 
response evaluation may be performed on day 28 (±7 days) as clinically indicated post 
tisagenlecleucel infusion and will be repeated at Months 3, 6, 9, (±14 days) and at Months 12, 
18, 24 (±28 days) and yearly thereafter or as clinically indicated until disease progression, death, 
lost to Follow-up, withdrawal of consent or EOS. PET/CT imaging is recommended to be 
performed at Month 3 (±14 days). Assessments should be scheduled using the infusion date as 
the reference date (not the date of the previous tumor assessment).
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion for suspicion of PD or to support the efficacy evaluations for a subject, 
as necessary. 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 assessed under a single evaluation.
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment.
For subjects who discontinue post-treatment phase for reasons other than documented disease 
progression, death, lost to Follow-up, or withdrawal of consent, tumor assessments must 
continue to be performed until documented disease progression (per investigator), death, lost to 
Follow-up, withdrawal of consent or EOS; every 3 months in the first year, every 6 months in 
the second year and annually thereafter.
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All study imaging (including any protocol required off-schedule imaging studies) should be 
submitted to the designated imaging CRO for quality control.
8.3.2
Other efficacy assessments
Bone marrow biopsy and/or aspirate and CSF by lumbar puncture must be performed within 
8 weeks prior to screening and bone marrow biopsy/aspirate must be repeated 2 weeks prior to 
tisagenlecleucel infusion if there is bone marrow involvement at screening. In subjects with 
bone marrow involvement at baseline, biopsy or aspirate (of adequate quality) should be 
obtained at the time of disease response by imaging to confirm a response of CR, NR, MR or 
PR.
Tumor biopsy and histological as well as any molecular disease characterization is performed 
locally at screening. 
 
 
Tumor biopsy is also recommended by 
International Pediatric Lymphoma response criteria at Month 3 (±14 days) to confirm CR and 
is required at relapse, particularly if PET shows residual metabolically active tissue to rule out 
interference of CTL019 activity with PET results.
Physical Examination (PE) including extramedullary disease assessment and CNS symptoms 
assessment are performed at screening, pre-infusion (Day -1) and at scheduled visits post-
infusion.
8.3.3
Appropriateness of efficacy assessments
CT/MRI are well established disease monitoring imaging methods in pediatric lymphomas even 
though PET-CT with diagnostic CT or PET-MRI is considered to have superior diagnostic 
accuracy compared to standard imaging methods in adult lymphoma. Subjects are exposed to 
higher doses of ionizing radiation with PET-CT with diagnostic CT, which is exacerbated by 
multiple imaging time points during efficacy assessments. Furthermore, even small doses of 
radiation exposure may pose increasing risk of secondary malignancies and this is more likely 
in children (Sandlund et al 2015). CT-MRI are therefore appropriate modalities for response 
assessments in these pediatric population. PET-CT with diagnostic CT is recommended with 
less frequency; at baseline and at Month 3 (±14 days) to confirm disease response.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section (Section 10.1).
Safety will be monitored by physical examination, vital signs, physical development, 
performance status, assessing immunogenicity against tisagenlecleucel, lab abnormalities as 
well as collecting adverse events at every visit.
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Table 8-3
Physical Assessments
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate CRF that captures 
medical history. Significant findings which begin or worsen after informed consent and 
meet the definition of an Adverse Event must be recorded on the Adverse Event CRF 
page.
Vital signs
Vital signs include temperature, blood pressure, pulse measurements, respiratory 
rate, and pulse oxygen.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg)) will be 
measured via a consistent method at each assessment, when possible.
8.4.1
Tanner staging (only for subjects <18 years old)
Tanner staging for subjects less than 18 years of age will be updated semiannually until 
M24 visit and annually thereafter. If a subject is classified as Tanner Stage 5 at screening or at 
any point during the trial, no further Tanner staging will be required for the remainder of the 
trial. Female subject reproductive status (menstrual status and pregnancy information) will be 
updated at Months 3, 6, 9, 12, 18 and 24, then annually thereafter.
8.4.1.1
Males
Genitalia stages
Stage 1: Pre-adolescent. Testes, scrotum, and penis are of about the same size and proportion 
as in early childhood.
Stage 2: The scrotum and testes have enlarged and there is a change in the texture of the scrotal 
skin. There is also some reddening of the scrotal skin.
Stage 3: Growth of the penis has occurred, at first mainly in length but with some increase in 
breadth. There has been further growth of testes and scrotum.
Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and 
scrotum further enlarged. There is also further darkening of the scrotal skin.
Stage 5: Genitalia adult in size and shape. No further enlargement takes place after Stage 5 is 
reached.
Pubic hair stages
Stage 1: Pre-adolescent. The vellus over the pubes is not further developed than that over the 
abdominal wall, ie, no pubic hair.
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Stage 2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, 
appearing chiefly at the base of the penis.
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the 
junction of the pubes.
Stage 4: Hair is now adult in type, but the area covered by it is still considerably smaller than 
in most adults. There is no spread to the medial surface of the thighs.
Stage 5: Hair distribution is adult in quantity and type and is described in the inverse triangle. 
Hair can be spread to the medial surface of the thighs.
8.4.1.2
Females
Breast stages
Stage 1: Pre-adolescent; elevation of papilla only.
Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, enlargement of 
areola diameter.
Stage 3: Further enlargement of breast and areola, with no separation of their contours.
Stage 4: Projection of areola and papilla to form a secondary mound above the level of the 
breast.
Stage 5: Mature stage; projection of papilla only, due to recession of the areola to the general 
contour of the breast.
Pubic hair stages
Stage 1: Pre-adolescent; the vellus over the pubes is not further developed than that over the 
anterior abdominal wall, no pubic hair.
Stage 2. Sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, 
appearing chiefly along the labia.
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the 
junction of the pubes.
Stage 4: Hair is now adult in type, but the area covered by it is still considerably smaller than 
in most adults. There is no spread to the medial surface of the thighs.
Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically feminine 
pattern. Spread to the medial surface of the thighs, but not up the linea alba or elsewhere above 
the base of the inverse triangle.
8.4.2
Performance status
Karnofsky or Lansky Performance status scale will be used as described in Table 8-4.
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Table 8-4
Karnofsky/Lansky Performance Scales
Karnofsky Scale (age ≥16 years)
Lansky Scale (age <16 years)
Able to carry on normal activity and to work; no 
special care needed.
Able to carry on normal activity; no special care is 
needed
100
Normal no complaints; no evidence of 
disease
100
Fully active, normal
90
Able to carry on normal activity; minor 
signs or symptoms of disease
90
Minor restrictions with strenuous physical 
activity
80
Normal activity with effort; some signs or 
symptoms of disease
80
Active, but gets tired more quickly
Unable to work; able to live at home and care for 
most personal needs; varying amount of 
assistance needed.
Mild to moderate restriction
70
Cares for self; unable to carry on normal 
activity or to do active work
70
Both greater restrictions of, and less time 
spent in active play
60
Requires occasional assistance, but is 
able to care for most of his personal needs
60
Up and around, but minimal active play; 
keeps busy with quieter activities 
50
Requires considerable assistance and 
frequent medical care
50
Lying around much of the day, but gets 
dressed; no active play; participates in all 
quite play and activities 
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
Moderate to severe restriction
40
Disabled; requires special care and 
assistance
40
Mostly in bed; participates in quiet 
activities
30
Severely disabled; hospital admission is 
indicated although death not imminent
30
Stuck in bed; needs help even for quiet 
play 
20
Very sick; hospital admission necessary; 
active supportive treatment necessary
20
Often sleeping; play is entirely limited to 
very passive activities
10
Moribund; fatal processes progressing 
rapidly
10
Does not play nor get out of bed
0
Dead
0
Unresponsive
8.4.3
Laboratory evaluations
Screening and other laboratory assessments will be performed according to Table 8-1, Table 8-
5 and Table 8-6. Additional assessments should be performed between visits as clinically 
required to follow AEs or tisagenlecleucel expected events and for detailed modified data 
capture for inpatient/in hospital events. For all laboratory assessments and electrocardiogram 
(ECG) that occur on Day 1, these should be performed prior to tisagenlecleucel infusion unless 
indicated otherwise.
The Investigator will evaluate the clinical significance of each applicable laboratory value 
outside of the reference range. This decision shall be based upon the nature and degree of the 
observed abnormality. Values which are considered clinically significant and/or study related 
to tisagenlecleucel will be noted. The Investigator may choose to repeat any abnormal result, in 
order to rule out laboratory error.
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With respect to laboratory assessments listed within this protocol, please refer to the 
[Laboratory Manual] for more detailed instructions for the collection, handling, and shipment 
of PK and biomarker samples.
Table 8-5
Laboratory Assessments (local)
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin Concentration (MCHC), 
MCV (Mean Corpuscular Volume), Platelets, Red blood cells, White blood cells with 
complete differential (Basophils, Eosinophils, Lymphocytes, Atypical Lymphocytes, 
Monocytes, Neutrophils, Lymphoblasts, and Other)
Chemistry
Glucose (fasting or non-fasting), Blood Urea Nitrogen (BUN) or Urea, Creatinine, 
Sodium, Potassium, Calcium, Magnesium, Phosphorus, Chloride, Total Protein, 
Albumin, Bilirubin (total and direct), Alkaline Phosphatase (ALP), Aspartate 
Aminotransferase (AST), Alanine Aminotransferase (ALT), Lactate Dehydrogenase 
(LDH), Ferritin, C-reactive Protein (CRP) and Uric Acid.
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocyte 
esterases, Nitrite, pH, Protein, Specific Gravity)
If macroscopic panel is abnormal then perform microscopic panel (Red Blood Cells, 
White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Coagulation
Prothrombin time (PT) or International normalized ratio (INR), activated Partial 
thromboplastin time (aPTT), fibrinogen, and D-dimer
Viral Serology
Rapid Influenza A & B, Hepatitis C Virus (HCV) RNA qualitative test or antibody, 
Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (HbcAb) (anti-HBc), 
Hepatitis B surface antibody (anti-HBs), HIV (if an initial HIV screening test is 
positive then a confirmatory HIV test is required to be performed as per current local 
guidelines)
CSF
White Blood Cells, Presence or absence of lymphoblasts, Red Blood cells, Glucose, 
Protein
Additional tests
Serum immunoglobulin levels (IgG, IgA, IgM), peripheral blood, donor chimerism 
(prior allogeneic SCT subjects only, or if unknown), bone marrow morphologic blast 
cell counts, flow cytometry on leukapheresis product
Pregnancy 
Test
Serum/Urine pregnancy test (refer to Table 8-1). Pregnancy test performed at 
screening, within 24 hours prior to leukapheresis, lymphodepleting chemotherapy, 
and tisagenlecleucel infusion and at EOS.
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Table 8-6
Laboratory Assessments (central)
Test Category
Test Name
Flow cytometry 
(Screening and at 
relapse)
B cells, tumor cell immunophenotyping, CD19 assessment
Tumor clonal typing
Deep sequencing (peripheral blood and bone marrow aspirate)
Tisagenlecleucel 
assessments
Tisagenlecleucel cellular kinetics by qPCR and/or flow cytometry (peripheral 
blood and bone marrow aspirate), 
 
Cytokines
Cytokine panel including IL-6, IL-6R, IL-10, TNF-α, IFN-γ (peripheral blood, 
CSF)
RCL (VSV-G)
Vesicular Stomatitis Virus Glycoprotein (VSV-G) qPCR (peripheral blood)
Immunogenicity
Prevalence and Incidence of immunogenicity against tisagenlecleucel 
(peripheral blood and serum)
 
 
 
 
8.4.4
Cardiac assessments
8.4.4.1
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed and evaluated locally as described in Table 8-1.
!
at screening
!
Day 1 (pre-infusion)
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator.
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate CRF page.
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate.
8.4.4.2
Cardiac imaging - MRA (magnetic resonance angiography), MUGA 
(multiple gated acquisition) scan or echocardiogram
A MRA, MUGA or ECHO scan is required to be completed at screening. Clinically significant 
abnormalities present when the subject signed the informed consent should be reported as 
Medical History on the appropriate CRF page. New or worsened clinically significant findings 
occurring after informed consent must be recorded as an Adverse Events on the CRF page.
8.4.5
Pregnancy
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, 
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male participants should not donate sperm for at least 12 months after the tisagenlecleucel 
infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests.
All women of child-bearing potential will have pregnancy testing. A pregnancy test must be 
performed within 24 hours prior to leukapheresis, lymphodepletion, and tisagenlecleucel
infusion and at EOS. Serum pregnancy tests are required during screening (prior to 
lymphodepleting chemotherapy, serum/urine pregnancy test is acceptable) until prior to the 
tisagenlecleucel infusion and at EOS. Following tisagenlecleucel infusion, women of child-
bearing potential will have serum or urine pregnancy tests performed (either at their scheduled 
visits or at-home using a urine pregnancy test kit provided) monthly up to Month 12 and until 
CAR-T cells are no longer present by qPCR on two consecutive tests. Additional pregnancy 
testing might be performed if requested by local requirements. For details on the frequency of 
pregnancy testing please refer to Table 8-1.
For all pregnancy tests performed at home, the site personnel will Follow-up with the subject 
via telephone call to collect the date and the test results and document the information in the 
subject’s source documents.
Every effort must be made for the women of child bearing potential to return to the site for the 
final serum pregnancy test at the EOS. However, if the subject is unable to return to the site, 
then the subject will administer a urine pregnancy test at home using a kit 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 as per Section 10.1.6.
To ensure subject safety, each pregnancy occurring once the subject has been infused with 
tisagenlecleucel 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.
For monitoring and management of immunoglobulin levels in newborns of mothers treated with 
tisagenlecleucel see Section 6.6.2.7.
Pregnancy should be recorded on a Clinical Trial Pregnancy Report Form and reported by the 
investigator to the oncology 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 for any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
For more information about the effects of tisagenlecleucel on reproduction please refer to the 
recent [Investigator Brochure].
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8.4.6
Other safety evaluations
For details regarding biomarker and PK evaluations to assess safety, please refer to Section 8.5.
8.4.7
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
Humoral immunogenicity to tisagenlecleucel and detectable RCL will be assessed as described
Table 8-1.
8.5.1
Pharmacokinetics
For patients with poor clinical condition and/or low body weight, blood samples for PK and 
immunogenicity analysis should only be collected if an additional blood sampling does not 
result in an important concern such as interference with the medical management or clinical 
risk for the patient.
PK samples will be collected at the visits defined in the assessment schedule. Follow 
instructions outlined in the [Laboratory Manual] regarding sample collection, numbering, 
processing and shipment. See the potential use of residual samples for more information.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data.
The number of samples/blood draws and total blood volume collected will not exceed those 
stated in the protocol.
Pharmacokinetic (PK) samples will be obtained and evaluated in all subjects.
Tisagenlecleucel PK and cellular kinetics will be used interchangeably throughout the protocol.
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Table 8-7
Tisagenlecleucel pharmacokinetics by qPCR in peripheral blood 
collection log
Treatment 
Period or 
Cycle
Day
Scheduled Time Point*
Dose 
Reference 
ID
PK1
Sample 
No.
Sample 
Volume**
1
W-12 to D-1 
Enrollment/Pre-
Chemotherapy
101
901
3 mL
1
D4±1d
D4
101
902
3 mL
1
D7±1d
D7§
101
903
3 mL
1
D11 ±1d
D11§
101
904
3 mL
1
D14±3d
D14
101
905
3 mL
1
D21±3d
D21
101
906
3 mL
1
D28±7d
D28§
101
907
3 mL
1
M3±14d
M3§
101
908
3 mL
1
M6±14d
M6§
101
909
3 mL
1
M9±14d
M9
101
910
3 mL
1
M12±28d
M12§
101
911
3 mL
1
M18±28d
M18
101
912
3 mL
1
M24±28d
M24§
101
913
3 mL
1
M36±28d
M36
101
914
3 mL
1
M48±28d
M48
101
915
3 mL
1
Unscheduled (PK 
samples related to 
CRS)***
101
1001
3 mL
1
Unscheduled (PK 
samples at 
relapse)****
101
2001
3 mL
1
Unscheduled (PK 
samples related to 
safety events)
101
3001
3 mL
* All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
** All subject sample volumes subject to adjustment for size and subject condition.
*** Additional unscheduled samples may be collected as needed dependent upon individual subject 
differences in the clinical time-course of CRS and administration of anti-cytokine therapy, if clinically 
feasible. Unscheduled PK sample collections related to CRS will cease once PK sample collections 
related to anti-cytokine therapy commence, if applicable.
**** In the event subject relapses, an unscheduled PK sample should be collected along with 
corresponding immunogenicity sample
Note: Tumor clonal typing by deep sequencing analysis (peripheral blood) is performed from these 
same samples. RCL by VSV-G qPCR is performed at the relevant time points using DNA extracted 
from these samples.
§ for subjects ≤15 kg body weight, only these marked samples will be collected
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Table 8-8
Tisagenlecleucel pharmacokinetics by flow cytometry in peripheral 
blood collection
Treatment 
Period or 
Cycle
Day
Scheduled Time Point*
Dose 
Reference 
ID
PK2
Sample 
No.
Sample 
Volume
1
W-12 to D-1 
Enrollment/Pre-
Chemotherapy
Pre-dose
101
201
2 mL
1
D7±1d
D7§
101
202
2 mL
1
D11±1d
D11
101
203
2 mL
1
D14±3d
D14
101
204
2 mL
1
D17±3d
D17
101
205
2 mL
1
D28±7d
D28§
101
206
2 mL
1
M3±14d
M3§
101
207
2 mL
1
M6±14d
M6§
101
208
2 mL
1
M9±14d
M9
101
209
2 mL
1
M12±28d
M12
101
210
2 mL
1
M18±28d
M18
101
211
2 mL
1
Unscheduled (PK 
samples related to 
CRS)**
101
4001
2 mL
1
Unscheduled (PK 
sample at 
relapse)***
101
5001
2 mL
* All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
** Additional unscheduled samples may be collected as needed dependent upon individual subject 
differences in the clinical time-course of CRS, if clinically feasible.
*** In the event subject relapses, an unscheduled PK sample should be collected along with 
corresponding immunogenicity sample
§ for subjects ≤15 kg body weight, only these marked samples will be collected
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Table 8-9
Tisagenlecleucel pharmacokinetics by qPCR in bone marrow aspirate 
collection log
Treatment 
Period or 
Cycle
Day
Scheduled Time Point*
Dose 
Reference 
ID
PK3
Sample 
No.
Sample 
Volume**
1
M3±14d
M3
101
302
2 mL
1
Unscheduled (PK 
sample at 
relapse)
101
7001
2 mL
1
Unscheduled (eg: 
related to safety 
events)
101
8001
2 mL
* All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
** All subject sample volumes subject to adjustment for size and subject condition.
Note: Tumor clonal typing by deep sequencing analysis (bone marrow aspirate) may be performed 
from these same samples.
Table 8-10
Tisagenlecleucel pharmacokinetics by flow cytometry in bone marrow 
aspirate collection log
Treatment 
Period or 
Cycle
Day
Scheduled Time Point*
Dose 
Reference 
ID
PK4
Sample 
No.
Sample 
Volume**
￼
1
Unscheduled
(PK sample at 
relapse)
101
9001
2 mL
1
Unscheduled 
(eg: related to 
safety events)
101
1101
2 mL /collection
*All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
** All subject sample volumes subject to adjustment for size and subject condition.
Table 8-11
Tisagenlecleucel pharmacokinetics by qPCR in CSF collection log
Treatment 
Period or 
Cycle
Day
Scheduled Time Point*
Dose 
Reference 
ID
PK5
Sample 
No.
Sample 
Volume
1
Unscheduled
101
2101
4-6 mL
* All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
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Table 8-12
Immunogenicity (humoral) serum sample collection log
Treatment 
Period or 
Cycle
Day
Scheduled Time 
Point*
Dose 
Reference 
ID
IG1 
Sample 
No.
Sample 
Volume
1
W-12 to D-1 
Enrollment/Pre-
Chemotherapy
Pre-dose
101
601
3 mL
1
D-14 to D-2
Lymphodepleting 
chemotherapy
Pre-dose§
101
602
1
D14±3d§
D14
101
603
3 mL
1
D28±7d
D28§
101
604
3 mL
1
M3±14d
M3§
101
605
3 mL
1
M6±14d
M6
101
606
3 mL
1
M12±28d
M12
101
607
3 mL
1
M18±28d
M18
101
608
3 mL
1
M24±28d
M24
101
609
3 mL
1
Unscheduled (at 
relapse)**
101
3101
3 mL
1
Unscheduled (eg: 
related to safety 
events)
101
4101
3 mL /collection
* All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified.
** In the event subject relapses, an unscheduled immunogenicity sample should be collected along 
with corresponding PK samples
§ for subjects ≤15 kg body weight, only these marked samples will be collected
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Table 8-13
Immunogenicity (cellular) peripheral blood sample collection log
Treatment 
Period or
Cycle
Day
Scheduled Time Point*
Dose 
Reference 
ID
IG2 
Sample 
No.
Sample 
Volume**
1
W-12 to D-1 
Enrollment/Pre-
Chemotherapy
Pre-dose§
101
701
10 mL
1
D28±7d
D28§
101
702
10 mL
1
M3±14d
M3§
101
703
10 mL
1
M6±14d
M6
101
704
10 mL
1
M12±28d
M12
101
705
10 mL
1
M18±28d
M18§
101
706
10 mL
1
M24±28d
M24
101
707
10 mL
1
Unscheduled (at 
relapse)**
101
5101
10 mL
1
Unscheduled 
(eg: related to 
safety events)
101
6101
10 mL
/collection
* All measurement times are relative to date of tisagenlecleucel infusion unless otherwise specified
** All subject sample volumes subject to adjustment for size and subject condition.
*** In the event subject relapses, an unscheduled immunogenicity sample should be collected along 
with corresponding PK sample.
§ for subjects ≤15 kg body weight, only these marked samples will be collected
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Table 8-15
Rituximab PK
Cycle
Day*
Scheduled time point 
relative to time post 
CTL019 dosing
Dose 
Refere
nce ID
PK7 Sample No. 
(Rituximab)
Blood Volume 
(mL)
1
D-1
Pre-dose
101
801
3
* Day and scheduled time point are relative to the date of CTL019 infusion
8.5.1.1
Analytical method
The assays to be utilized for various PK/biomarker assessments include qPCR assay to detect 
CTL019/4-1BB+ cells (transgene copies/microgram DNA) in peripheral blood and other tissues 
and flow cytometric analysis to detect tisagenlecleucel positive cells. Details regarding 
collection and processing of the samples used in these assays will be provided in the [Central 
Laboratory Manual].
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8.5.1.2
Pharmacokinetic blood collection and handling
For patients with poor clinical condition and/or low body weight, blood samples for PK and 
immunogenicity analysis should only be collected if an additional blood sampling does not 
result in an important concern such as interference with the medical management or clinical 
risk for the patient.
PK samples will be collected at the visits defined in the assessment schedule. Refer to the 
[Laboratory Manual] for detailed instructions for the collection, handling, and shipment of PK 
samples. See the potential use of residual samples for more information.
8.5.2
Biomarkers
Sample(s) will be collected at the time point(s) defined in the assessment schedule.
Follow instructions for sample collection, numbering, processing and shipment provided in the 
[Laboratory manual].
Biomarker analyses will focus on:
 
2. Correlation analysis of biomarker measurements performed pre- and post-infusion with 
key outcomes of efficacy and safety such as CRS
 
 
 
 
 
 
 
 
 
 
 
 
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8.5.3
Imaging
The methods for assessment and recording are specified in Table 8-2 and Appendix 1.
8.5.4
Other Assessments
No additional tests will be performed on subjects entered into this study.
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study, prior to tisagenlecleucel infusion
Study treatment (eg: tisagenlecleucel infusion, lymphodepletion, and other therapies used in 
combination with tisagenlecleucel) may be discontinued if, in the investigator’s opinion, its 
continuation would be detrimental to the patient's safety.
Subjects who discontinue before tisagenlecleucel infusion should NOT be considered 
discontinued from the study before they return for the End-of-Study (EOS) assessments, as 
appropriate. The EOS assessment visit should be completed within 2 weeks of the decision to 
discontinue the study. If they fail to return for these assessments, every effort (eg: telephone, 
email, or letter) should be made to contact them.
The investigator must also contact the IRT to register the subject’s end of study.
Study treatment must be discontinued under the following circumstances:
!
Death
!
Subject/guardian/investigator decision
!
Disease progression
!
Pregnancy
!
Use of prohibited treatment, against recommendations in the prohibited treatment
Section 6.2.2.
!
Any situation in which study participation might result in a safety risk to the subject
!
Adverse events or any laboratory abnormalities that in the judgment of the investigator, 
prevents the subject from continuing participation in the study
!
Manufacturing failure
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of the study 
treatment and record this information.
If a manufacturing failure occurs, the investigator may decide to repeat the leukapheresis for 
re-manufacturing. The clinical and operational aspects in case of manufacturing failures are 
described in protocol section 8.1. The bridging and patient stabilization treatment administered 
between the screening and the tisagenlecleucel infusion are described in Section 6.1 and Section 
6.2.     
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If there is no additional cryopreserved material from the original leukapheresis collection to be 
sent, then, at the investigator’s discretion and taking into consideration the subject’s expected 
length of survival and the manufacturing process, additional leukapheresis collections may be 
performed. It is recommended not to exceed a maximum of two apheresis procedures/attempts 
within a 14 day window. In these cases, the subject may not have to reconsent, and the original 
subject identification (ID) number assigned will be used.  
Section 8.1 lists the procedures that would need to be repeated if the time between initial 
screening assessments and the enrollment exceeds 8 weeks or 12 weeks. 
A subject who discontinues from the study prior to infusion can be re-screened. In this situation, 
a new ICF must be signed, and all required screening activities must be performed for 
participation in the study. In such cases, a rescreening CRF must be completed to ensure the 
subject’s original ID can be linked to the subject’s new ID.
A patient who had first manufacturing failure and the investigator’s and/or subject’s decision is 
not to pursue a second manufacturing, or if a subject fails two manufacturing attempts, the
patient will be considered as enrolled in the trial and the discontinuation reason will be 
manufacturing failure. Those patients will be part of the enrolled analysis set. 
9.1.2
Discontinuation from study, post-tisagenlecleucel infusion
Subjects who receive study treatment but decide to discontinue prematurely during Follow-up 
phase should NOT be considered to have completed the study (EOS) UNLESS the reason is 
death, lost to follow-up, or withdrawal of consent (see Section 9.1.3). In such cases, the 
investigator must contact the IRT to register the subject’s EOS.
Subjects who decide to discontinue the follow-up phase post-infusion, prior to M24 visit for 
other reasons, should return for the annual assessments indicated in the Follow-up phase of 
assessment schedule (Table 8-1) until death, lost to Follow-up, withdrawal of consent, or EOS, 
whichever occurs first. In case of disease progression, no further imaging or response 
assessments are required.
Any new anti-cancer therapy treatment including HSCT must be recorded as part of the Follow-
up assessments.
If the subject cannot or is unwilling to attend any visit(s) for any reason, the site staff should 
maintain contact (telephone, e-mail, letter, etc.) with the subject, or with a person pre-designated 
by the subject, to obtain survival status once every 3 months until death, lost to Follow-up, 
withdrawal of consent, or EOS (Section 9.2), whichever occurs first.
9.1.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a subject:
Does not want to participate in the study anymore
AND
Does not want any further visits or assessments
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AND
Does not want any further study related contacts
AND
Novartis/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’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.
In this situation, the investigator should make a reasonable effort (eg: telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
No further assessments may be conducted, and the data that would have been collected at 
subsequent visits will be considered missing.
The investigator must contact the IRT to register the subject’s end of study.
Further attempts to contact the subject 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 subject’s study withdrawal should be made as detailed in the 
assessment Table 8-1.
After subject’s withdrawal of consent, depending on the regional/country/local laws and 
requirements, Novartis may continue to retain and use all research results (data) and any
biological samples that have already been collected for storage and future analyses.
9.1.4
Lost to Follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, eg: dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to Follow-up until due 
diligence has been completed or until the end of the study.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. 
Reasons for early termination:
!
Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study
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!
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
!
Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, the subject should be seen as soon as possible (within 2 
weeks as indicated in Section 9.2) and the same assessments should be performed as described 
in Section 8 for a discontinued or withdrawn subject. 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 subject’s interests. For subjects who have received the tisagenlecleucel 
infusion, a long term post-study Follow-up for lentiviral vector 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.
9.1.5.1
Criteria for stopping or pausing the study
The study will be stopped or paused, and health authorities notified if:
!
Any subject develops detectable replication competent lentivirus (RCL) during the study
!
The Sponsor, SC, or any regulatory body decides for any reason that subject safety may be 
compromised by continuing the study
!
The Sponsor decides to discontinue the development of the intervention to be used in this 
study
The study may be paused while waiting for the notification of the Health Authorities and the 
SC for investigation and a possible protocol amendment if any subject experiences any of the 
following events within three weeks of the tisagenlecleucel cell infusion:
!
Life-threatening (grade 4) toxicity that is unmanageable, unexpected, unrelated to 
preceding chemotherapy and considered attributable to protocol therapy. Identified safety 
risks expected to be associated with tisagenlecleucel include CRS, neurological events, 
hypersensitivity, TLS, infections, febrile neutropenia, prolonged depletion of normal 
B-cells cytopenias associated with hypo- or agammaglobulinemia, and prolonged 
hematopoietic cytopenias (see Section 4.5.1). In this setting, high fevers, hypotension, 
hypoxia, disseminated intravascular coagulation, encephalopathy (eg: lethargy, confusion, 
aphasia, seizure), ICU admission, dialysis and mechanical ventilation may occur. The 
expected risks can also result in grade 4 hepatotoxicity, nephrotoxicity and cardiotoxicity.
!
Death suspected to be related to tisagenlecleucel therapy
9.2
End of study and long term Follow-up
The end of study (EOS) assessments for each subject is completed within 2 weeks of a subject’s
premature withdrawal of consent or when all infused and evaluable subjects with aggressive B-
cell NHL have completed Month 24 evaluation or discontinued early. A final Clinical Study 
Report (CSR) will be produced once all subjects complete the study.
The primary efficacy and safety analysis will also be conducted when all evaluable subjects 
with aggressive r/r B-cell NHL have been infused and followed for at least 6 months from study 
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day 1 or discontinued early, as well as at least 50% of those infused subjects have a follow-up 
of at least 9 months. In addition, all subjects who complete the study will be enrolled in a 
separate LTFU protocol [CCTL019A2205B] at the time of EOS (a separate informed consent 
form will be provided for this protocol). Any subject who prematurely withdraws consent from 
the study will be given the option to enroll in the LTFU protocol at the time of withdrawal of 
consent from this study.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (eg: any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject 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 subject 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 subject at each visit 
during the study. Adverse events also may be detected when they are volunteered by the subject 
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 
Adverse Event.
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 10.1.2):
1. Adverse events will be assessed and graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0, with the exception of CRS, which will 
follow Section 6.6.2.1. 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 (ie, 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 
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both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single subject.
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 10.1.2 for definition of 
SAE) and which seriousness criteria have been met.
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include treatment interruption or withdrawal.
6. Its outcome, ie, its recovery status or whether it was fatal.
If the event worsens, the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 AEs only, if improvement to a lower 
grade is determined a new entry for this event should be reported in the eCRF 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 eCRF.
Adverse events (including laboratory 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.
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (eg: 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.
Adverse events separate from the progression of malignancy (eg: deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will 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 
[Tisagenlecleucel Investigator's Brochure].
Abnormal laboratory values or test results constitute AEs 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 subjects with 
the underlying disease.
Detailed AE reporting requirements during the periods of screening, pre-treatment, treatment, 
follow-up and post-treatment are outlined in Table 16-7.
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Detailed information regarding CRS adverse events (e.g. oxygen requirements, vasopressor 
usage) will also be collected to allow for assessment using alternative CRS grading scales (e.g.
Lee et al 2019).  
10.1.2
Serious adverse events
An 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 subject 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, unless 
hospitalization is for:
!
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 subject’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, e.g.: defined as an event that jeopardizes the subject 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 subject 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 
(secondary malignancies, not disease progression of the study indication) will be assessed as 
serious under “medically significant”.
Progression of the underlying malignancy with fatal outcome must be reported as a SAE within 
24 hours of awareness, if the following criteria are met: 
!
Death within 30 days after tisagenlecleucel infusion, irrespective of causality to 
tisagenlecleucel
!
Deaths beyond 30 days after tisagnelecleucel infusion, if there is at least a possible 
causality to tisagenlecleucel
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Non-fatal disease progression should not be reported as AE.
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.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject 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. Additional SAE reporting 
requirements, including those for the periods of screening, pre-treatment, Follow-up and 
post-treatment, are also outlined in Appendix 3. 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 
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.
For subjects who sign the main study ICF, SAE collection starts at time of main study informed 
consent whether the subject is a screen failure or not.
10.1.4
Adverse events of special reporting requirements
If specifically requested by a local Health Authority, expedited reporting of pre-specified AEs 
will occur.
10.1.5
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.
10.1.6
Pregnancy reporting
To ensure subject 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 
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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 should be recorded and reported by the investigator on the Clinical Trial Pregnancy 
Report Form 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 on the SAE Report Form.
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 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.
10.1.7
Reporting of study treatment errors including misuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
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 10-1
Guidance for capturing the study treatment errors
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.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject 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 AE/SAE):
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!
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 16-9 for complete definitions of liver laboratory triggers and liver events.
Every liver event defined in Table 16-9 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 16-10. Repeat liver chemistry tests (ALT, AST, TBIL, ALB,
PT/INR, ALP and GGT) to confirm elevation.
!
These liver chemistry repeats should be performed using the local laboratory used by the 
site. If a liver event is subsequently reported, any local liver chemistry tests previously 
conducted that are associated with this event should have results recorded on the 
appropriate CRF
If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.
!
Hospitalization of the subject if appropriate
!
Causality assessment of the liver event
!
Thorough Follow-up of the liver event, which can include the following based on 
investigator’s discretion:
!
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, 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.
10.2.2
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, 
urinary tract infection (UTI), extreme exercise, or trauma)
Renal event findings must be confirmed 24-48 hours after the first assessment.
Every renal laboratory trigger or renal event as defined in Table 16-11 should be followed up 
by the investigator or designated personnel at the trial site as summarized in Appendix 5.
10.2.3
Follow-up of secondary malignancy
For subjects treated with tisagenlecleucel, treating physicians/health care providers should 
contact Novartis if the subject develops a secondary malignancy. Upon clinical confirmation of 
a secondary malignancy, blood samples should be collected for cellular kinetic analyses by 
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qPCR and flow cytometry. Two tubes of blood are requested: 10 mL sample of peripheral blood 
mononuclear cells (PBMCs) in a sodium heparin collection tube and 6 mL of blood in an 
ethylenediaminetetraacetic acid (EDTA) tube. 
 
 
 Additional 
details for sample handling and shipping are outlined in the [Laboratory Manual].
10.2.4
Data Monitoring Committee
An independent DMC will assess safety data, and critical efficacy variables at regular intervals.
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC.
10.2.5
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, and Novartis representatives. The SC will review safety and efficacy data, and ensure 
transparent management of the study according to the protocol through recommending and 
approving modifications as circumstances require. The SC will review protocol amendments as 
appropriate. Together with the Novartis clinical trial team, the SC will also develop 
recommendations for publications of study results including authorship rules. The details of the 
role of the SC will be defined in a Steering Committee charter.
11
Data Collection and Database management
11.1
Data collection
Data not requiring a separate written record will be defined in the protocol and the assessment 
schedule and can be recorded directly on the CRFs. All other data captured for this study will 
have an external originating source (either written or electronic) with the CRF not being 
considered as source.
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, allow modification and/or verification of 
the entered data by the investigator staff. Designated investigator staff can refer to CCGs (CRF 
Completion Guidelines) as a guidance document for data entry in CRF.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (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 subject 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.
11.2
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 (ATC)
classification system. Medical history/current medical conditions and adverse events will be 
coded using the medical dictionary for regulatory activities (MedDRA) terminology.
Subject IDs and visit occurrences will be tracked using an Interactive Response Technology 
(IRT). The system will be supplied by a vendor, who will also manage the database. The data 
will be sent electronically to Novartis (or a designated CRO) at specific timelines.
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.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis
delegated CRO representative will review the protocol and data capture requirements 
(ie, electronic source (eSource), direct data entry (DDE) or electronic case report form (eCRFs))
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 subject 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/clinical research associate (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 subject 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 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
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, 
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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 
subjects will be disclosed.
12
Data analysis and statistical methods
Majority of infused subjects will have aggressive r/r B-cell NHL. The aggressive r/r B-cell NHL 
is defined as subjects with subtypes BL, DLBCL, PMBCL and GZL. Due to rarity of FL in 
pediatric population, it is anticipated that only a very limited number of subjects will be enrolled. 
The primary interest is to estimate the efficacy of tisagenlecleucel therapy in subjects with 
aggressive r/r B-cell NHL who have measurable disease at baseline (baseline assessment prior 
to infusion for patients on bridging therapy should be done after completion of bridging therapy). 
The primary efficacy analysis will be based on all evaluable subjects with aggressive r/r B-cell 
NHL. The efficacy from subjects with FL will be listed separately. The safety analysis will 
include all subjects with r/r B-cell NHL. The primary efficacy and safety analysis will be 
conducted when all evaluable subjects with aggressive r/r B-cell NHL have been infused and 
followed for at least 6 months from study day 1 or discontinued early as well as at least 50% of 
those subjects have a Follow-up of at least 9 months. Infused subjects with follicular lymphoma 
will be listed descriptively. A final Clinical Study Report (CSR) will be produced once all 
subjects complete the study.
Any data analysis carried out independently by any investigators should be submitted to 
Novartis before publication or presentation.
12.1
Analysis sets
The analysis sets to be used are defined as below. Subjects with aggressive r/r B-cell NHL in 
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 pharmacokinetics analysis.
12.1.1
Screened Set
The Screened Set comprises all subjects who have signed informed consent and screened in the 
study.
12.1.2
Enrolled Set
The enrolled set comprises all subjects who are enrolled in this study. Enrollment is defined as 
the point at which the subject meets all inclusion/exclusion criteria, and the subjects’ 
leukapheresis material is received and accepted for manufacturing.
12.1.3
Full Analysis Set
The Full Analysis Set (FAS) comprises all subjects who received an infusion of tisagenlecleucel.
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12.1.4
Efficacy Analysis Set
The Efficacy Analysis Set (EAS) includes all subjects with aggressive r/r B-cell NHL who 
received infusion of tisagenlecleucel and had measurable disease at baseline.
12.1.5
Safety Set
The Safety Set comprises all subjects who received an infusion of tisagenlecleucel. In this study 
the Safety Set contains the same subjects as the FAS.
12.1.6
Cellular kinetic analysis set
The tisagenlecleucel cellular kinetic analysis set (CKAS) consists of subjects in FAS who 
provide an evaluable cellular kinetic profile (at least one valid cellular kinetic parameter). The 
CKAS will be used for summaries (tables and figures) of cellular kinetic data.
Note that subjects may be removed from the estimation of certain cellular kinetic parameters 
on an individual basis depending on the number of available samples. These subjects will be 
identified at the time of the analyses.
 
12.1.8
Other analysis sets
Not applicable.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data will be listed by subject and/or summarized descriptively 
by subjects with aggressive relapsed/refractory (r/r) B-cell NHL and follicular lymphoma 
separately for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class, preferred term, and subjects with aggressive r/r B-cell NHL and follicular 
lymphoma separately.
12.3
Treatments
The total cells infused (cells) and total tisagenlecleucel transduced viable T cells infused (cells) 
will be listed and summarized by subjects with aggressive r/r B-cell NHL and follicular 
lymphoma separately using descriptive statistics. Subjects will be grouped into the following 
categories:
!
Below the prescribed dose range
!
Within the prescribed range
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!
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 subject and summarized by the Anatomical Therapeutic Chemical 
(ATC) term. Transfusion during the study will be listed. In addition, whether subjects have 
received anti-cytokine medications for the management of CRS will be summarized.
12.4
Analysis of the primary endpoint(s)
The primary aim of the study is to evaluate the efficacy of tisagenlecleucel therapy as measured 
by overall response rate (ORR), which includes Complete Response (CR) and Partial Response 
(PR) based on local investigator assessments in subjects with aggressive r/r B-cell NHL who 
have measurable disease at baseline (baseline assessment prior to infusion for patients on 
bridging therapy should be done after completion of bridging therapy).
12.4.1
Definition of primary endpoint(s)
The primary endpoint is the overall response rate (ORR) as determined by local investigator 
assessment in subjects with aggressive r/r B-cell NHL. The ORR is defined as the proportion 
of subjects with a best overall disease response of CR or PR, where the best overall disease 
response is defined as the best disease response recorded from tisagenlecleucel infusion until 
progressive disease or start of new anticancer therapy, whichever comes first. The primary 
endpoint analysis will be performed on EAS comprising aggressive r/r B-cell NHL subjects. 
The overall response assessment is based on International Pediatric Non-Hodgkin Lymphoma 
classification response criteria (Sandlund et al 2015).
A subject will have a best overall disease response of CR if they had CR, as overall disease 
response for at least one of the assessments.
A subject will have a best overall disease response of PR if at least one overall response of PR 
is available (and the subject would not qualify for CR).
A subject will have a best overall response of MR if at least one overall disease response of MR 
is available (and the subject does not qualify for CR or PR).
A best overall disease response of NR will be declared when at least one NR assessment is 
available earliest at 4 weeks after tisagenlecleucel infusion (and the subject would not qualify 
for CR, PR or MR).
A subject will have a best overall disease response of PD if the progressive disease was observed 
less than 28 weeks after tisagenlecleucel infusion (and the subject does not qualify for CR, PR, 
MR or NR).
If a subject does not qualify for CR, PR, MR, NR or PD, then their best disease response will 
be Unknown (UNK).
See Appendix 1 for details of disease response criteria.
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12.4.2
Statistical model, hypothesis, and method of analysis
The ORR along with the 95% Exact Clopper-Pearson confidence intervals will be summarized 
in subjects with aggressive r/r B-cell NHL in the EAS. The results of FL subjects (a very rare 
and indolent subtype) will be reported separately in a descriptive manner.
12.4.3
Handling of missing values/censoring/discontinuations
Subjects in this study who are of unknown clinical response will be treated as non-responders.
12.4.4
Sensitivity and supportive analyses
The primary analysis will also be performed on the Enrolled Set, FAS and on subjects who 
received a dose no less than the target dose range using the same methodology.
12.4.4.1 Subgroup analysis
Subgroup analyses of the primary endpoint will be performed on the following based on the 
subject’s baseline status:
!
Age: <18 years, ≥18 years
!
Gender: male, female
!
Race: White, Asian, Other
!
Ethnicity: Hispanic or Latino, Other
!
Disease subtypes including BL, DLBCL, PMBCL, GZL
!
Prior response status: Primary refractory, relapse without SCT, relapse after SCT
!
Use of prior rituximab: Yes or No
!
Stage of disease at baseline: I/II, III/IV
Subgroup analyses will only be performed if at least 5 subjects are present in each subgroup. 
Some grouping of classes will be considered if there are too few subjects in some subgroups.
12.5
Analysis of secondary endpoints
The secondary objectives in this study include evaluating duration of response (DOR), event 
free survival (EFS), relapse free survival (RFS), progression free survival (PFS), overall 
survival (OS) and safety. Due to rarity of incidence, it is expected that a very limited number 
of subjects with FL will be enrolled. DOR, EFS, RFS, PFS and OS will be analyzed only in 
subjects with aggressive r/r B-cell NHL. Kaplan-Meier (KM) analyses will be performed if 
adequate number of events are observed. DOR, EFS, RFS, PFS and OS for subjects with FL 
will be listed. Local investigator assessment will be used for secondary endpoints that involve 
disease response.
12.5.1
Efficacy and/or pharmacodynamic endpoint(s)
12.5.1.1 Duration of response (DOR)
Duration of response (DOR) applies only to subjects 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 
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PR) whichever occurs first, to the date of first documented relapse or death due to underlying 
cancer (at time of primary endpoint analysis).
In case a subject does not have progression or death due to underlying cancer 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
!
New anticancer therapy (also see below for handling HSCT)
!
Adequate assessments no longer available
Distribution of DOR will be estimated using the KM method in which death due to reason other 
than underlying cancer will be censored. DOR will be only summarized among subjects with 
aggressive r/r B-cell NHL.
As HSCT is an important treatment option in responding subjects, it is appropriate to consider 
the date of HSCT as censoring date, instead of censoring at the last tumor assessment date. If a 
subject received HSCT after a CR or PR, relapse or survival status after HSCT will be recorded 
on the corresponding Follow-up eCRFs. In such cases, the date of relapse or death (if due to 
underlying cancer) after HSCT will be used for the calculation of DOR as a sensitivity analysis.
In addition, the DOR may be separately summarized for subjects in aggressive r/r B-cell NHL
with best overall response of CR and those with best overall response of PR.
12.5.1.2 Event free survival (EFS)
Event free survival (EFS) is the time from date of first tisagenlecleucel infusion to the earliest
date of the following:
!
Death from any cause
!
Disease progression as determined by local investigator assessments
!
New anticancer therapy for underlying cancer, excluding HSCT (at time of primary 
endpoint analysis)
In case a subject does not have any of the above events prior to data cutoff, EFS is censored at 
the last adequate response assessment date on or prior to the earliest censoring event (except 
for HSCT). The censoring reason could be:
!
Ongoing without event
!
Lost to Follow-up
!
Withdrew consent
!
HSCT (see below for handling of HSCT)
!
Adequate assessments no longer available
In the main analysis of EFS, subjects who proceed to HSCT after tisagenlecleucel infusion will 
be censored at the time of HSCT. In addition, a sensitivity analysis of EFS will be performed 
without censoring for HSCT.
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The distribution function of EFS will be estimated using the KM method. The median EFS 
along with 95% confidence intervals will be presented if appropriate.
EFS will be only analyzed among subjects with aggressive r/r B-cell NHL.
12.5.1.3 Relapse free survival (RFS)
Relapse free survival applies only to subjects 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, 
whichever occurs first) to the date of first documented relapse or death due to any cause (at time 
of primary endpoint analysis).
In case a subject does not have progression or death due to any cause prior to data cutoff, RFS 
will be censored at the date of the last adequate disease 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 HSCT)
!
Adequate assessment no longer available
In the main analysis of RFS, subjects who proceed to HSCT after tisagenlecleucel infusion will 
be censored at the time of HSCT. In addition, a sensitivity analysis of RFS will be performed 
without censoring HSCT, if there is at least 1 subject with HSCT after tisagenlecleucel infusion 
while in remission.
RFS will be assessed only in subjects with the best overall response of CR or PR. The 
distribution function of RFS will be estimated using the KM method. The median RFS along 
with 95% confidence intervals will be presented if appropriate. RFS will be only analyzed 
among subjects with aggressive r/r B-cell NHL.
12.5.1.4 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 as determined by local 
investigator assessment or death due to any cause (at time of primary endpoint analysis). If a 
subject has not had an event, PFS is censored at the date of the last adequate assessment.
In case a subject 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)
!
Adequate assessments no longer available
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In the main analysis of PFS, subjects 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.
PFS will be estimated using the KM method and the median PFS as well as proportion of 
subjects without event at 3, 6, 9, and 12 months will be presented along with 95% confidence 
interval. PFS will be only analyzed among subjects with aggressive r/r B-cell NHL.
12.5.1.5 Overall survival (OS)
Overall survival is the time from date of first tisagenlecleucel infusion to the date of death due 
to any cause (at time of primary endpoint analysis).
Subjects not known to have died at the data cut-off date are censored at their last contact date, 
which is defined as the latest date they were known to be alive. Subjects were followed for 
survival also in case of HSCT. OS will be summarized censoring for SCT as sensitivity analysis.
The distribution function of OS will be estimated using the KM method. The median OS along 
with 95% confidence intervals will be presented if appropriate. OS will be only analyzed among 
subjects with aggressive r/r B-cell NHL.
12.5.2
Safety endpoints
12.5.2.1 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 aggressive r/r B-cell NHL and follicular lymphoma separately and 
combined in Safety set.
The overall observation period for safety endpoint analysis will be divided into three mutually 
exclusive segments:
!
Pre-treatment period: from day of subject’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 applies to subjects who received 
lymphodepleting chemotherapy): from the first day of lymphodepleting chemotherapy to 
the day before infusion of tisagenlecleucel, for subjects who received infusion, or to the 
earlier of date of discontinuation and 30 days after last dose of lymphodepleting 
chemotherapy for subjects who didn’t receive infusion of tisagenlecleucel.
!
Post-infusion period: starting at day of tisagenlecleucel infusion until EOS.
12.5.2.2 Adverse events (AEs)
Reporting of adverse events will be based on the most current Medical Dictionary for 
Regulatory Activities (MedDRA) and Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.
Adverse events that begin or worsen after informed consent should be recorded in the subject’s 
source documents. New or worsening adverse events prior to starting study treatment (ie, 
lymphodepleting chemotherapy or the pre-infusion visit if the lymphodepleting chemotherapy 
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is not given) or are not required to be recorded in the CRF unless it is an AE meeting criteria or 
SAE meeting criteria. Once the subject begins 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 started or worsened during the 
post-infusion period, ie, the tisagenlecleucel treatment-emergent AEs. In addition, AEs that 
started or worsened during the lymphodepleting period will be summarized for all subjects who 
received lymphodepleting chemotherapy. All safety data (including those from the pre-
treatment period) will be listed along with the period of the starting date of AE.
The incidence of tisagenlecleucel treatment-emergent adverse events (new or worsening during
the post-infusion period) will be summarized by primary system organ class, preferred term, 
seriousness, severity (based on CTCAE grades), and relation to study treatment. A subject with 
multiple CTCAE grades for an AE will be summarized under the maximum CTCAE grade 
recorded for the event. The frequency of AEs of grade 3 or above will be summarized together.
Deaths and serious adverse events will be listed by subject and tabulated by primary system 
organ class and preferred term.
12.5.2.3 Adverse events of special interest (AESI)
The current search criteria of AESI are based on limited experience from ongoing clinical 
studies without an accurate assessment of causality. AESI and the search criteria of AESI will 
be updated prior to reporting. For the safety post tisagenlecleucel infusion, AESIs will be 
summarized by drug relationship, group term, preferred term, maximum grade, and timing of 
onset: Within 8 weeks post first tisagenlecleucel infusion, 8 weeks to 1 year post first 
tisagenlecleucel infusion, >1 year post first tisagenlecleucel infusion, and any time post first 
tisagenlecleucel infusion..
12.5.2.4 Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities will be flagged.
12.5.2.5 Performance status and tanner staging
All performance status and tanner staging data will be listed.
12.5.2.6 Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) CTCAE version 5.0. The calculation of CTCAE grades will be based on the observed 
laboratory values only, clinical assessments will not be taken into account. For laboratory tests 
covered by CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or 
higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following summaries will be generated separately for hematology and biochemistry and 
laboratory tests:
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!
shift tables using CTCAE grades to compare baseline to the worst post-infusion value
!
for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high)
All laboratory data will be listed with valued flagged to show the corresponding common 
terminology criteria (CTC) grades and the classifications relative to the laboratory reference 
ranges.
 
 
12.5.2.7 Immunogenicity
The humoral immunogenicity assay measures the antibody titers specific to the tisagenlecleucel 
molecule prior to and following infusion. Data will be further fractionated to determine 
proportion of subjects who make transient versus sustained antibody responses. The cellular 
immunogenicity assay assesses the presence of T lymphocytes activated by the tisagenlecleucel 
protein. Data will be reported as summary statistics of pre and post-dose levels of activated T 
lymphocytes. 
 
 Further details will be provided in the statistical analysis plan (SAP).
12.5.2.8 Percentage of subjects who undergo HSCT after tisagenlecleucel 
therapy
The percentage of subjects who undergo HSCT after tisagenlecleucel infusion among all 
subjects in FAS will be summarized along with exact 95% CI into the following subgroups.
!
While in remission
!
After relapse
12.5.2.9 Cytokine release syndrome
Clinical and biomarker data from tisagenlecleucel studies will be analyzed to potentially 
identify an early predictive model which reflects the risk of developing severe cytokine release 
syndrome. Only parameters that can be potentially utilized in clinical setting by treating 
physicians will be considered for the model development.
12.5.3
Pharmacokinetics
Tisagenlecleucel transgene and CAR transgene will be used interchangeably throughout the 
document. The tisagenlecleucel cells, as quantitated by flow cytometry, refers to the CAR 
positive T cells.
Tisagenlecleucel concentrations in peripheral blood (and bone marrow and CSF if available) 
will be listed, graphed and summarized by time points as assessed by the following:
!
CAR transgene levels as measured by qPCR
!
CAR-positive T cells measured by flow cytometry of CD3-positive
 
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The cellular kinetic parameters listed in Table 12-1 along with other relevant cellular kinetic 
parameters will be estimated, if feasible, from the individual concentration versus time profiles 
using a non-compartmental approach within the modeling program Phoenix® (Pharsight, 
Mountain View, CA) and reported by Month 3 (±14 days) response category.
Table 12-1
Non-compartmental pharmacokinetic parameters
Parameter
Definition
AUC 0-28d 
and/or
AUC 0-84d
The AUC from time zero to day 28 and/or day 84 and or other disease 
assessment days, in peripheral blood (%×*days or days×*copies/μg)
Cmax
The maximum (peak) observed in peripheral blood or other body fluid drug 
concentration after single dose administration (% or copies/μg)
Tmax
The time to reach maximum (peak) peripheral blood or other body fluid drug 
concentration after single dose administration (days)
T1/2
The half-life associated with the elimination phase slope of a semi logarithmic 
concentration-time curve (days) in peripheral blood
Clast
The last observed quantifiable concentration in peripheral blood (% or copies/μg)
Tlast
The time of last observed quantifiable concentration in peripheral blood (days)
 
 
 
 
 
 
 
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12.7
Interim analyses
Not Applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
It is planned to enroll approximately 35 subjects with an aim to infuse at least 26 evaluable 
subjects with aggressive r/r B-cell NHL (BL, DLBCL, PMBCL and GZL) for the primary ORR 
analysis. The primary objective of the study is to estimate response rate and therefore the sample 
size is not based on power calculation. Among 26 subjects with aggressive r/r B-cell NHL, ORR 
will be descriptively summarized with the point estimate along with 95% exact CIs. With a 
sample size of 26 subjects, the 95% exact CI assuming various observed response rates are 
displayed in Table 12-2.
Table 12-2
95% exact confidence interval assuming various observed response 
rates
Observed response rate (%)
95% exact CI (%)
38 (10/26)
20.2, 59.4
50 (13/26)
29.9, 70.1
62 (16/26)
40.6, 79.8
In addition, it is planned to ensure that there are at least 18 infused pediatric subjects with 
aggressive r/r B-cell NHL for the subgroup analysis of subjects <18 years. There is no pre-
specified target for the number of FL subjects to be treated because it is an extremely rare and 
indolent disease. However enrollment in this subtype will be open until at least 26 subjects,
including at least 18 pediatric subjects, with the aggressive subtypes for primary analysis have 
been treated.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed 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.
13.2
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, subject recruitment procedures (eg:
advertisements) and any other written information to be provided to subjects. 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 
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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.
13.3
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 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 (eg: 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.
13.4
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 standard operating procedures (SOPs), and are performed according to 
written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 and health authorities, where required, it cannot be implemented.
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14.1
Protocol Amendments
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 prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject 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.
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16
Appendices
16.1
Appendix 1: Guidelines for efficacy evaluation in pediatric non-
Hodgkin lymphoma studies
16.1.1
Introduction
The purpose of this document is to provide working definitions and rules to evaluate efficacy 
in pediatric patients with non-Hodgkin lymphoma (NHL), in studies conducted by Novartis. 
This document is based on the consensus of a multidisciplinary international (North America, 
Europe, and Australia) collaboration of experts in pediatric oncology, hematopathology, 
radiology, and NHL biology held in 2009 and 2012 at the Third and Fourth International 
Symposia respectively, on Childhood, Adolescent and Young Adult NHL, the International 
pediatric non-Hodgkin lymphoma response criteria (Sandlund et al 2015) and the Lugano 
Classification (Barrington et al 2014, Cheson et al 2007, Cheson et al 2014).
16.1.2
Methodology and Definitions
16.1.2.1 Computed tomography (CT)/Magnetic resonance imaging (MRI)
For optimal evaluation of patients, the same methods of assessment and technique should be 
used to characterize each identified and reported lesion at baseline/pre-infusion and during 
Follow-up. Contrast-enhanced CT or MRI 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 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 neck, abdomen and pelvis (MRI of the chest is not 
recommended due to respiratory artifacts). MRI is the preferred imaging modality for 
evaluating central nervous system (CNS) disease. CT scan is superior for assessing the lungs, 
and MRI is superior for assessing the marrow.
16.1.2.2 Fluorodeoxyglucose-Positron emission tomography (FDG-PET)
PET scans should cover the whole body from base of skull to mid-thigh. Examinations should 
be consistent across all time points when performed 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, duration of fasting, and glucose level 
should be collected for each time point. The PET images should be converted to standardized 
uptake value (SUV) maps to support comparison across time points and to standardize viewing 
conditions.
16.1.2.3 PET-CT
Hybrid PET-CT with diagnostic CT scanners may be used to acquire PET and CT images if the 
CT produced by the scanner is of diagnostic quality, and includes i.v. contrast. Non-diagnostic 
CT images acquired for attenuation purposes during PET-CT are NOT acceptable as the only 
CT scan for the time point.
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If the diagnostic CT and PET are acquired on the same day, it is strongly recommended that the 
PET is performed prior to the CT with IV contrast as to not compromise PET results. Thus, one 
of the three following imaging methodologies is possible in a lymphoma study:
Table 16-1
Possible imaging methodologies in lymphoma study
1
PET-CT with diagnostic CT
2
PET-CT with non-diagnostic CT + dedicated diagnostic CT
3
Dedicated diagnostic CT + dedicated FDG PET
16.1.2.4 PET-MRI
Hybrid PET-MRI whole body with contrast enhancement may be acquired instead of a PET-CT 
scan, in a manner similar to PET-CT. A PET-MRI with MRI coverage of the neck, chest, 
abdomen and pelvis plus a CT of the chest should be obtained (MRI of the chest is not 
recommended due to respiratory artifacts), Section 16.1.2.3.
16.1.2.5 Handling Changes in Imaging Technique
The same imaging modality should be used at baseline and all subsequent assessments to allow 
for consistency across assessments and to reduce the risk of false and unknown responses based 
on differences in imaging modalities.
If a change in the imaging modality has occurred during the study (eg: a switch from CT to 
MRI, a switch from i.v. contrast to non-contrast, or a switch from a diagnostic quality CT to an 
attenuation correction CT), the reviewer will determine whether this change in technique affects 
tumor evaluation. If, in the opinion of the reviewer, there are too many differences in the exams, 
resulting into non-evaluation of disease burden identified at baseline, the response will be 
unknown (UNK), unless there is clear evidence of progression.
Note: for time points that do not require PET imaging this rule does not apply (e.g. evaluation 
1 includes a CT neck, chest, abdomen, pelvis vs evaluation 2 includes PET imaging and a CT 
neck, chest, abdomen, pelvis). The radiological response that does not include PET imaging 
should not be assessed as UNK due to the missing PET, Section 16.1.4.4.1 and Table 16-2.
16.1.3
Definitions
16.1.3.1 Disease stage
Extent and involvement by lymphoma is determined by the investigator at screening and 
described by the disease stage. Stage is an important prognostic factor and can also influence 
treatment decisions.
16.1.3.2 Screening
Measurable disease by radiological criteria within 8 weeks of screening visit must be 
established locally by investigator to meet eligibility and enrollment criteria for study. For 
patients with Burkitt leukemia, measurable disease by bone marrow assessment is sufficient if 
radiological criteria are not met.
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16.1.3.3 Baseline/Pre-Infusion
Baseline examination should be as close as possible to the date of randomization/start of 
treatment, preferably within 2 weeks prior to date of randomization/start of treatment and after 
completion of any bridging therapy. Patients with no measurable disease at baseline will 
continue efficacy Follow-up as per the protocol visit evaluation schedule and maintenance of 
complete response (CR), or progressive disease (PD) will be assessed at post-infusion time 
points.
16.1.3.4 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)
16.1.3.5 Measurable Disease
All anatomic measurements should be taken in two perpendicular dimensions and recorded in 
metric notation. Throughout this document, a lesion will be called measurable if:
!
It can be measured accurately in 2 perpendicular dimensions: longest diameter (LDi) (also 
known as transverse diameter), and short diameter (SDi), which is the longest short 
diameter perpendicular to LDi (also known as perpendicular diameter). The LDi and SDi 
must be measured on the same slice.
!
For patients ≥12 years of age:
!
For a nodal lesion, LDi must be >15 mm, regardless of SDi
!
For an extranodal lesion, both LDi and SDi must be >10 mm
!
For patients <12 years of age who do not meet the above criteria, measurable disease 
will be determined by the investigator, based on what threshold of measurements 
would be considered abnormal at baseline in this age group.
Note: The baseline threshold established by the investigator must be documented in the 
source document and the CRF and should be applied to all subsequent assessments of 
measurable and non-measurable disease described in this document.
A lymph node not meeting the measurability criteria but with LDi >15 mm (eg: 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 neither a measurable nor a non-measurable nodal lesion for FDG-avid histologies.
All lesions visible on PET but not on CT/MRI will be treated as non-measurable.
Patients with Burkitt leukemia must have >25% bone marrow involvement by disease if 
radiological criteria are not met.
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16.1.3.6 Bulky Disease
Bulky disease will not be classified as a separate entity and shall be captured by means of 
response criteria and sum of the product of the perpendicular diameters for multiple lesions 
(SPD).
16.1.3.7 Non-Measurable Disease
Non-measurable disease refers to all other lesions, including small lesions (eg: longest diameter 
<10 mm with CT/MRI or pathological lymph nodes with 10 to <15 mm short axis), as well as 
truly non-measurable lesions eg: blastic bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, lymphangitis cutis/pulmonis, abdominal masses/abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques.
16.1.3.8 Index Lesions/Target Lesions. Index or target lesions are considered 
the same and will be referred to as index lesions in the document
!
Up to 6 of the largest nodes, nodal masses or other lymphomatous lesions including 
extranodal disease measurable in two diameters (LDi and SDi)
!
Should represent overall disease burden and include mediastinal and retroperitoneal 
disease, if involved
16.1.3.9 Non-index/Non-target Lesions. Non-index or non-target lesions are 
considered the same and will be referred to as non-index lesions in 
the document
!
All measurable disease not selected as index lesions but are consistent with lymphoma
!
All non-measurable disease
16.1.3.10 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 non-measurable lesion attributable to lymphoma (eg: ascites, pleural effusion)
16.1.4
Efficacy assessments
16.1.4.1 Eligibility
In general, patients should have at least one measurable nodal lesion (>15 mm in the long axis) 
or at least one measurable extranodal lesion (with both LDi and SDi >10 mm).
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16.1.4.2 Methods of disease assessment
16.1.4.2.1
PET Combined with Diagnostic CT Scan
The integration of PET into more frequently acquired CT evaluation may 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 Table 8-1 and Table 8-
2. PET scans should be performed at pre-specified times during and/or after treatment. PET 
may also be acquired to confirm CT and PD results. Response assessments made after a change 
in imaging modality should be queried to confirm the change in the modality and the response 
assessment provided.
In order to calculate the sum of the product of the perpendicular diameters (SPD) of all index 
lesions, the appropriate dimensions of the lesions 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 
(eg: 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 (ie, borders of the lesion are 
confounded by 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 a single lesion, 
report the overall diameters to one of the lesions and assign 0 mm × 0 mm to each of the other 
previously measured lesions. Subsequently, the product of the perpendicular diameters (PPD)
of the confluent mass should be used to assess response. Disease progression is indicated by an 
increase of more than 25% in the PPD of the confluent mass compared with nadir of the sum of 
the product of perpendicular diameters (SPD) of the individual nodes.
If a lesion splits into several discrete lesions, the individual product of the perpendicular 
diameters (PPDs) of each discrete lesion should be summed together to represent the PPD of 
the entire 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).
16.1.4.2.2
Bone marrow assessment
Bone marrow evaluation by biopsy or aspirate (if adequate quality and volume), should be 
performed for all patients at screening, locally by investigator. All patients with lymphomatous 
bone marrow involvement at screening and as clinically indicated, should undergo additional 
bone marrow assessments, by biopsy or aspirate, 2 weeks prior to infusion (baseline) to reassess 
disease burden and post-infusion, to confirm any radiological response. Bone marrow 
biopsy/aspirate results will take precedence over bone marrow assessment reported by imaging 
for overall disease assessments. After confirmation of CR by bone marrow assessment (for 
patients with diagnosis other than Burkitt leukemia), further bone marrow assessments are not 
required and should be performed as clinically indicated by the investigator. Patients who have 
negative bone marrow involvement at screening are not required subsequent assessments unless 
clinically indicated.
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Patients with Burkitt leukemia are required to have bone marrow assessments performed at day 
28, month 3, month 6, month 9, and month 12 visits, and then as clinically indicated.
16.1.4.2.3
CSF Assessment
Cerebrospinal fluid (CSF) evaluated by lumbar puncture in all patients at screening. Patients 
with CSF involvement at screening should be excluded from study participation (Protocol 
Section 5). CSF assessments should be conducted at any time while on study as clinically 
indicated by the investigator.
16.1.4.2.4
Physical examination
Cutaneous lesions must be histologically confirmed for lymphomatous involvement (the 
investigational site must document the histological confirmation (yes or no) on the 
corresponding CRF) and submit photograph(s) including a scale/ruler ((color photography 
using digital camera). Response assessment of cutaneous lesions will be performed and results 
will be recorded on the corresponding CRF at baseline and at the time of each radiological 
assessment.
16.1.4.3 Documentation of disease
For the evaluation of disease at baseline and throughout the study, the following assessments 
should be recorded.
16.1.4.3.1
FDG Update
FDG uptake in nodal and extranodal site that is suggestive of lymphoma will be assessed using
five-point scale PET Five Point Scale (5PS).
16.1.4.3.2
Index lesions
A minimum of one measurable index lesion and 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 selected index 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 lesions should be selected on the basis of their size and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically).
Index nodal lesions
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 different
regions of the body including mediastinal and retroperitoneal areas of disease whenever these 
sites are involved.
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Index extranodal lesions
Extranodal lesions in organ such as lung, liver and kidney may be included up to six index 
lesions to be assessed throughout the study if attributable to lymphoma. Lymphomatous 
involvement of non-FDG avid lesions, and cutaneous lesions should be assessed histologically. 
If such lesions are measurable and histological assessment is consistent with lymphoma, then 
they may be selected as index lesions.
16.1.4.3.3
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 extra nodal lesions
Measurable extranodal lesions not selected as index lesions and all non-measurable disease 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.
16.1.4.3.4
Spleen Involvement
The spleen will be assessed qualitatively for enlargement on the basis of CT and/or MRI scans, 
however no measurements will be recorded unless index lesions are noted. Assessment of 
spleen size should be performed before start of treatment and if present should be assessed at 
baseline. The spleen involvement should be reassessed on study as “Enlarged”, “Normalization 
(normal size for nodal lesions or absent for extra-nodal lesions)”, “Neither normalization nor 
unequivocal progression”, “Unequivocal progression” or “Not assessed”. Enlarged spleen, not 
attributable to lymphoma will not prevent a CR if rest of the disease burden has disappeared.
Discrete intrasplenic lesions should be followed as index, non-index and new extranodal lesions, 
and splenic enlargement should be followed as non-index and new extranodal lesions.
16.1.4.3.5
Liver involvement
Given variability in physical habitus and the impact of numerous medical conditions, liver size 
by physical examination or CT scan is not considered a reliable measure of quantifying hepatic 
involvement by lymphoma, hence organomegaly alone is not sufficient to support 
lymphomatous involvement of the liver in this trial. Diffusely increased or focal uptake, with 
or without focal or disseminated nodules, supports liver involvement. Intrahepatic lesions 
should be followed as index or non-index lesions throughout the trial.
16.1.4.3.6
CSF Involvement
CSF involvement should be documented in the CRF as “Yes” or “No” at each lumbar puncture.
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16.1.4.3.7
Bone marrow involvement
Lymphomatous involvement of bone marrow should be documented in the CRF as “Yes” or 
“No” at each bone marrow assessment by biopsy and/or aspiration.
16.1.4.3.8
PET 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 (Barrington et al 2014). The 5PS scores the most intense 
uptake in a site of disease (Table 16-2).
Table 16-2
Five Point Scale (5PS) to determine FDG uptake
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 of 3 will be considered negative
* 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 at least 2 times greater than the maximum SUV in 
the liver. The 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).
16.1.4.4 Response Evaluation
The efficacy variables in the statistical analysis are based on overall disease response
(Table 16-4), which is a combined evaluation of response based on all components of 
radiological, bone marrow, CSF and clinical findings, and is determined at each post-baseline 
assessment. The radiological, bone marrow biopsy/aspirate, CSF, and additional clinical 
assessments are evaluated as defined in the International pediatric non-Hodgkin lymphoma 
response criteria [IPNHLRC] and the Lugano 2014 criteria (Table 16-3) and overall disease 
response is then determined by taking into account all the above criteria (Table 16-4).
16.1.4.4.1
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/MRI response based on anatomical measurements of index/non-index/new lesions. 
The possible response outcomes are complete response (CR), partial response (PR), minor 
response (MR), no response (NR), progressive disease (PD) or unknown (UNK) as 
defined in Table 16-3.
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 
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(PMR), no metabolic response (NMR), progressive metabolic disease (PMD) and 
unknown (UNK), as defined in Table 16-3.
3. Overall radiological response combines CT/MRI response with PET response. The 
outcomes include CR, PR, MR, NR, PD and UNK. For time points when both CT and 
PET are available, if PET and CT responses are inconsistent for a given time point, PET 
response will take precedence. If at a particular time point, only a CT/MRI assessment is 
performed, the PET response obtained at a different time point (previous or subsequent to 
the current time point being assessed) may be taken into account to determine the overall 
radiological response.
Note: Chest x-ray and ultrasound should not be used to measure tumor lesions.
When only CT/MRI imaging is available, only the CT/MRI response will be determined.
When CT/MRI and PET imaging is available all response assessments (CT/MRI response, PET 
response and the overall radiological response) will be possible, when PET imaging is not 
available only CT/MRI based response will be possible. The metabolic response designation 
will only be applied for the radiological response when PET imaging is available, the CT/MRI 
response and overall disease response will consist of the standard response conventions.
Example: A CT response of PR at the same assessment as a PET response of CMR will 
constitute an overall radiological response of CR, and - a subsequent time point with CT only 
and CT response of CR. The overall radiological response of CR is possible when PET imaging 
is not available if there is no change in anatomical location or a prior PET scan showed a CR.
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Table 16-3
Definitions of response criteria
Overall Response 
Criteria
CT/MRI based response
PET-based response 
(Only when PET 
imaging is available)
Biopsy/ Aspirate/
other 
assessments
CNS disease 
on CSF when 
available
New 
Disease
Bone marrow 
(BM)
Complete 
Response 
(All of the 
following)
CR
CR (Disappearance of all 
index and non-index 
disease by CT/MRI)
Spleen: Normalizeda
†5PS of 1, 2, or 3 
without residual mass 
on 5PS (CMR)
Resected residual 
mass that is 
pathologically 
(morphologically) 
negative for 
disease
Negative
None
Negative
CRb
PR/SD/NN (Residual mass 
present on CT/MRI)
Spleen: Normalizeda
†5PS of 1, 2, or 3 with 
residual mass on 5PS 
(CMR)
Residual mass 
has no 
morphologic 
evidence of 
disease from 
limited or core 
biopsy
Negative
None
Negative
CRu
PR/SD/NN (Residual mass 
present on CT/MRI)
Spleen: Normalizeda
†5PS of 1, 2, or 3 with 
residual mass on 
5PS(CMR)
N/A
Negative
None
Negative
Partial Response 
(All of the 
following)
Index: ≥50% decrease from 
baseline in SPD of all index 
lesions (Morphologic 
detection of disease in a 
biopsy sample of the mass 
may be present)
Non-Index: Non-PD
Spleen: Non-PD
†5PS of 4 or 5 with 
reduced uptake 
compared to baseline 
with respect to SUV 
intensity or extent. This 
may apply to the specific 
hottest lesion and/or 
overall. It is expected 
that there will be residual 
mass(es) present (PMR)
N/A
Negative
None
Persistent 
morphologic 
detection of 
disease in the BM 
if it was present at 
baseline; 
however, there 
should be a >50% 
reduction in the 
percentage of 
lymphoma cells
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Overall Response 
Criteria
CT/MRI based response
PET-based response 
(Only when PET 
imaging is available)
Biopsy/ Aspirate/
other 
assessments
CNS disease 
on CSF when 
available
New 
Disease
Bone marrow 
(BM)
Minor Response 
(All of the 
following)
Index: Decrease in 
SPD >25% but <50% on 
CT or MRI
Non-Index: Non-PD
Spleen: Non-PD
†5PS of or 4 or 5 with 
reduced lesion uptake 
compared with baseline 
with respect to SUV 
intensity or extent (PMR) 
OR †5PS of 4 or 5 with 
no significant change in 
FDG uptake from 
baseline (NMR)
N/A
Negative
None
Morphologic 
evidence of 
disease, if present 
at baseline; 
however, there 
should be 25% to 
50% reduction in 
percentage of 
lymphoma cells
No Response (All 
of the following)
No criteria for CR, PR, MR 
or PD are met
†5PS of 4 or 5 with no 
significant change in 
FDG uptake from 
baseline (NMR)
N/A
Negative
None
Do not meet CR, 
PR, MR, or PD 
criteria
Progressive 
Disease (At least 
one of the 
following)
Index: >25% increase in 
SPD on CT or MRI
Non-Index: Unequivocal 
progression
Spleen: Unequivocal 
Progression
†5PS of 4 or 5 with 
increased uptake 
compared to the visually 
determined nadir with 
respect to SUV intensity 
or extent OR New FDG-
avid foci consistent with 
lymphoma (PMD)
New/recurrent 
Disease, Positive 
for lymphoma
Development 
of 
new/recurrent 
morphologic 
evidence of 
disease in CSF
Present, 
attributable 
to 
lymphoma
New/recurrent 
morphologic 
evidence of 
disease in BM
Note: 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.
a Enlarged spleen, not attributable to lymphoma will not prevent a CR if rest of the disease burden has disappeared.
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16.1.4.5 Overall Disease Response
Overall disease response is determined based on a consolidated approach, taking into account 
results from combined radiological assessment, bone marrow biopsy and/or aspirate, and other 
clinical findings that may be available, at each time point. Disease status at screening, baseline 
and efficacy during the study will be evaluated using the following:
!
Radiological Imaging
!
Bone marrow biopsy or aspirate
!
CSF cytology
!
Physical exam findings/cytology/biopsy evaluation
Of note, patients with lymphoma involvement detected in the baseline bone marrow 
biopsy/aspirate require a subsequent bone marrow biopsy/aspirate to be considered for overall 
disease response. Radiologic assessment of bone marrow involvement alone is not sufficient to 
consider a patient negative for bone marrow involvement in cases where there is lymphoma 
involvement of bone marrow at baseline. For example, if the combined radiological response 
assessment at Month 3 (±14 days) is CR/CMR (implying that PET-based bone marrow 
involvement at Month 3 (±14 days) was negative), the overall disease response would be a CR 
only when there is documentation of a bone marrow biopsy negative for lymphoma involvement. 
The same principle applies to CSF involvement. For example, if the combined radiological 
response is PR, but CSF results of a lumbar puncture at the same time point indicates new CSF 
involvement, the overall disease response would be PD.
Disease status at screening, baseline and overall disease response at each post-baseline 
assessment should be captured on the CRF, along with the date of assessment/response.
Clinical progression must be based on documented physical exam/clinical findings; 
confirmation by imaging and/or biopsy is recommended, but not mandatory.
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Table 16-4
Overall Disease Response
Oncology Assessments of Complete Response (CR)
Requires ALL of the following:
CT/MRI-based or Combined 
CT/MRI and PET 5 Point Scale 
Assessment
Bone Marrow 
biopsy/aspirate
Physical Exam 
Lesions; 
Cytology/Biopsy 
evaluation
CSF
CR/CMR
!
If bone marrow 
was positive at 
baseline, it has 
to be normal by 
morphology at 
post-infusion 
assessment.
!
If bone marrow 
was negative at 
baseline, bone 
marrow 
confirmation at 
post-infusion is 
not required.
NOTE: Bone marrow 
evaluation by 
aspirate/biopsy must 
be performed within a 
± 4 week window of 
imaging studies in 
order to be applied to 
the response 
assessment
None, or normalized/ 
disappeared if present 
previously;
Any lesions of 
undetermined 
malignancy on CT/MRI 
should be benign by 
clinical results. 
Cytology/biopsy results 
should not demonstrate 
any evidence of 
disease.
NOTE: Cytology/biopsy 
evaluation status must 
be performed within a 
± 4 week window of 
imaging studies in order 
to be applied to the 
response assessment
Morphologically 
free of disease, 
when 
applicable
Oncology Assessments of Partial Response (PR)
Requires that one of the following assessment combination across each row is true:
CT/MRI-based or Combined 
CT/MRI and PET 5 Point Scale 
Assessment
Bone Marrow 
biopsy/aspirate
Physical Exam 
Lesions; 
Cytology/Biopsy 
evaluation
CSF
PR/PMR
CR/PR, when 
applicable
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with 
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
CR/CMR
PR, when applicable
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with 
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
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Oncology Assessments of Minor Response (MR)
Requires that one of the following assessment combination across each row is true:
CT/MRI-based or Combined 
CT/MRI and PET 5 Point Scale 
Assessment
Bone Marrow
biopsy/aspirate
Physical Exam 
Lesions; 
Cytology/Biopsy 
evaluation
CSF
MR and non-PD by PET when 
available
CR/PR/MR, when 
applicable
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with 
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
CR/CMR/PR/PMR
MR, when applicable
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
Oncology Assessments of No Response (NR)
Requires that one of the following assessment combination across each row is true:
CT/MRI-based or Combined 
CT/MRI and PET 5 Point Scale 
Assessment
Bone Marrow
biopsy/aspirate
Physical Exam 
Lesions; 
Cytology/Biopsy 
evaluation
CSF
NR/NMR
CR/PR/MR, when 
applicable
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with 
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
CR/CMR/PR/PMR/MR/NMR
NR, when applicable
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with 
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
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Oncology Assessment of Unknown (UNK)
Requires that one of the following assessment combination across each row is true:
CT/MRI-based or Combined 
CT/MRI and PET 5 Point Scale 
Assessment
Bone Marrow
biopsy/aspirate
Physical Exam 
Lesions; 
Cytology/Biopsy 
evaluation
CSF
UNK/not done
CR/PR/MR/NR, when 
applicable
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with 
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
CR/CMR/PR/PMR/MR/NR/NMR
UNK/not done post-
infusion, when 
morphological 
evidence of disease 
at baseline AND not 
consistent with 
progression
No new unequivocal 
lesions, and previously 
reported lesions not 
consistent with 
progression;
Not consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
CR/CMR/PR/PMR/MR/NR/NMR
CR/PR/MR/NR, when 
applicable
UNK/not done post-
infusion, when 
evidence of disease at 
baseline AND not 
consistent with 
progression
Morphologically 
free of disease, 
when 
applicable
Oncology Assessments of Progressive Disease (PD)
Requires at least ONE of the following:
CT/MRI-based or Combined 
CT/MRI and PET 5 Point Scale 
Assessment
Bone Marrow
biopsy/aspirate
Physical Exam 
Lesions; 
Cytology/Biopsy 
evaluation
CSF
PD/PMD
New or recurrent 
involvement
New unequivocal lesion 
or previously reported 
lesions consistent with 
progression
New 
involvement
16.1.4.6 Efficacy analysis definitions
16.1.4.6.1
Best overall disease response
The best overall response (BOR) is the best overall disease response recorded from date of 
randomization/start of treatment until progressive disease or start of new anticancer therapy, 
whichever comes first.
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).
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A patient will have a best overall response of MR if at least one overall disease response of MR 
is available (and the patient does not qualify for CR or PR).
A best overall response of NR will be declared when at least one overall disease response of 
NR is available at least 6 weeks after start of treatment (and the patient does not qualify for CR, 
PR or MR). If a different minimum follow-up period for NR is more appropriate (eg: 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 start 
of treatment and the second scheduled post-baseline assessment (and the patient does not 
qualify for CR, PR, MR or NR).
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 start of treatment. If PD is observed 
after this maximum Follow-up period, and the patient does not qualify for CR, PR, MR or NR, 
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.
If a subject does not qualify for CR, PR, MR, NR or PD, then their best disease response will 
be Unknown (UNK).
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.
16.1.4.6.2
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 in Section 16.1.4.6.3.
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, survival will be 
censored at the date of last contact.
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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, progression-free 
survival is censored at the date of the last adequate assessment as defined in Section 16.1.4.6.3.
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 or death due to lymphoma. If a patient has 
not had an event, time to progression is censored at the date of the last adequate assessment.
Duration of response
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 the first documented overall disease response
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 whose best overall disease response was 
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 (ie, first patient first visit (FPFV) to last patient last visit (LPLV)
used for the analysis) for patients who had a PFS event (ie, 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.
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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 16.1.4.6.3.
Relapse free survival
Relapse free survival (RFS) applies only to patients whose best overall disease response was 
CR or PR. It is defined as the time from the date of the first documented overall disease response 
of CR or PR to the date of first documented progression or death due to any reason. If a patient 
has not had an event, RFS is censored at the date of the last adequate assessment.
16.1.4.6.3
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 (eg: PET-CT, CT, or MRI), bone marrow 
biopsy, CSF and additional biopsy assessment if overall disease response at that 
assessment is CR/PR/MR/NR/UNK
!
the earliest date of all measurements including radiological assessment (eg: PET-CT, CT, 
or MRI), bone marrow biopsy, CSF and additional biopsy assessments if overall disease 
response at that assessment is PD
Start dates
For all “time to event” variables other than the duration of response and relapse free survival 
variables, the date of randomization/start of treatment will be used as the start date. For the 
calculation of duration of response and relapse free survival 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 and 
relapse free survival.
End dates
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.
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!
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 16.1.5.2)
!
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, MR or NR 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).
16.1.4.6.4
Censoring and sensitivity analyses
Censoring reasons
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 16-5) will be 
calculated for each time to event variable based on the information reported.
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Table 16-5
Censoring reasons
Time to event variables
Possible censoring reasons
OS
!
Alive
!
Lost to Follow-up
PFS, EFS, TTP, RFS and 
DOR
!
Ongoing without event
!
Lost to Follow-up
!
Withdrew consent
!
Death due to reason other than underlying cancer (only used for TTP 
and DOR)
!
New anti-cancer therapy added (except for EFS optional)
!
Event documented after two or more missing response assessments
!
Adequate assessment no longer available1
LSS
!
Alive
!
Lost to Follow-up
!
Death due to reason other than lymphoma
1 Adequate assessment is defined in Section 16.1.4.6.3. 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 16-6), as 
well as addressing the issues of missing response assessments during the study. The protocol 
Section 12 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 16.1.4.6, and using the draft FDA guideline on 
endpoints (FDA Guideline Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics-May 2007) as a reference, the following analyses can be considered:
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Table 16-6
Options for event dates used in PFS, EFS, TTP, DOR, RFS
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
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 16.1.4.6.3.
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, ie,
!
(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.
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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 eg: 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), ie, 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, example:
!
By assigning the dates for censoring and events only at scheduled visit dates. The latter 
could be handled by replacing in Table 16-6 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 report and analysis plan 
(RAP) documentation.
16.1.5
Data handling and programming conventions
The following rules should be used and specified in the RAP documentation:
16.1.5.1 Calculation of ‘time to event’ variables
Time to event = end date – start date + 1 (in days)
When no post-baseline assessments are available, the date of randomization/start of treatment 
will be used as end date (duration = 1 day) when time is to be censored at last assessment, 
ie, time to event variables can never be negative.
16.1.5.2 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 (eg: vital signs assessment, performance status assessment, efficacy 
assessment, laboratory, PK.)
!
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
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16.1.5.2.1
Date of new anti-cancer therapy
The date of new anti-cancer therapy is the date of the 1st new antineoplastic therapy (including 
medicine, radiotherapy and surgery reported in the further antineoplastic therapy pages or from 
other sources (eg: HSCT page).
16.1.5.2.2
Incomplete assessment dates
All investigation dates (eg: 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 16.1.4.6.3). If all measurement dates have no day 
recorded, the 1st of the month is used.
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.
16.1.5.2.3
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.
16.1.6
References (available upon request)
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; 32:3048-58.
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; 32:3059-67.
Cheson BD, Pfistner B, Juweid ME, et al (2007) Revised response criteria for malignant 
lymphoma. J Clin Oncol; 25:579-86.
FDA Guideline (2007) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Sandlund JT, Guillerman RP, Perkins SL, et al (2015) International Pediatric Non-Hodgkin 
Lymphoma Response Criteria. J Clin Oncology; 33(18):2106-11.
16.1.7
Additional Information
16.1.7.1 Adaptation for use in maintenance/adjuvant settings
For study populations without measurable disease at baseline (eg: 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).
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16.1.7.2 Relapsed Disease (RD)
Any of the following meets the definition of RD:
!
Any new nodal lesion >15 mm in any axis (ie, 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
!
≥25% 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 (ie, complete disappearance of extranodal mass or and ≤15 mm long axis 
for nodal mass), then reappearance of an extranodal lesion at the same site or increase of 
the 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
16.1.7.3 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, disease-free survival is censored at the date of the last adequate 
assessment. Similar censoring rules and reasons as the ones used for PFS can be applied.
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16.2
Appendix 2: Eligibility based on serologic markers for hepatitis B 
and C
Hepatitis B
1. Test for Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (HBsAb) and 
Hepatitis B core antibody (HBcAb).
2. If all of these three tests are negative, the patient is eligible.
3. If HBsAb only is positive:
a. The patient is eligible in the absence of signs of hepatitis (e.g. increase of AST/ALT).
b. Test for HBV DNA in presences of signs of hepatitis (e.g. increase of AST/ALT).
4. If HBsAg is positive, the patient is NOT eligible.
5. If HBsAg is negative but either HBcAb or both HBcAB and HBsAb are positive, test for 
HBV DNA.
a. If HBV DNA is positive, the patient is NOT eligible.
b. If HBV DNA is negative, the patient is eligible.
Hepatitis C
1. Test for Hepatitis C virus antibody (HCV Ab).
2. If HBV Ab is negative, the patient is eligible.
3. If HCV Ab is positive, test for HCV RNA.
a. If HCV RNA is negative, the patient is eligible.
b. If HCV RNA is positive, the patient is NOT eligible.
Patients with a history of Hepatitis B or C should be managed according to the current 
guidance from the American Society of Clinical Oncology (Hwang et al 2015) and HCV 
Guidance from the American Association for the Study of Liver Disease-Infectious Diseases 
Society of America (2014-2018).
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16.3
Appendix 3: Tisagenlecleucel modified data reporting
This guidance is used to determine whether or not an AE (non-serious, serious), 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 10.1.2, 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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Table 16-7
Adverse event reporting
Signed ICF 
through start of 
lymphodepleting  
chemotherapy  or 
pre-infusion visit
Start of 
lymphodepleting 
chemotherapy or 
pre-infusion visit 
through Month 12 
post 
tisagenlecleucel 
infusion
> Month 12 visit through End Of Study
AEs 
(non-
serious 
and 
serious)
All infections
All laboratory 
abnormalities 
deemed clinically 
significant by the 
investigator
All clinical AEs 
grade ≥3
All SAEs and 
deaths
All AEs related to 
a study procedure
All AEs leading to 
study 
discontinuation
All AEs(i.e., non-
serious AEs and 
SAEs) including 
laboratory 
abnormalities 
deemed clinically 
significant by the 
investigator 
irrespective of 
causality
Any non-serious AEs ≥ Grade 3 and any SAEs irrespective of Grade with at least a possible 
causal relationship to tisagenlecleucel
The following AEs (i.e., non-serious AE and SAEs, if not otherwise specified) should be 
reported to Novartis regardless of causality:
AEs with fatal outcome
Events related to a study procedure
Serious neurologic disorder
Serious or opportunistic infections, that fulfill any of the following criteria:
!
Require anti-infective treatment 
!
Lead to significant disability or hospitalization 
!
Need for surgical or other intervention
Hepatitis B reactivation
Progressive multifocal leucoencephalopathy (PML)
Prolonged depletion of normal B cells/ Agammaglobulinemia
New occurrence or exacerbation of an autoimmune disorder
Hematological disorders (incl. aplastic anemia and bone marrow failure)
Positive RCL test result
New secondary T-cell or non T-cell malignancy other than the primary underlying malignancy
Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a location 
near a known human oncogene
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Table 16-8 
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 through EOS)
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 
All
Modified:
Related to an AE (non-serious and serious) 
defined as reportable for this period
Antineoplastic 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 through EOS)
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient
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:
Record all antibiotics starting from day of infusion, even if 
given prophylactically
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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 through EOS)
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient
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 clinically relevant results (scheduled or 
unscheduled) for all AEs defined as reportable in 
Table 16-7 
Record all other laboratory values if they are ≥ 
Grade 3 (not part of LTFU Study) 
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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16.4
Appendix 4: Liver event and laboratory trigger definitions and 
Follow-up requirements
Table 16-9
Liver Event and Laboratory Trigger Definitions
Definition/threshold
Liver laboratory triggers
3 x ULN ALT/AST ≤5 x ULN
1.5 x ULN <TBIL ≤2 x ULN
Liver events
ALT or AST >5 × ULN
ALP >2 × ULN (in the absence of known bone 
pathology)
TBIL >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 TBIL >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 
TBIL: total bilirubin; ULN: upper limit of normal
Table 16-10
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 (eg: conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBIL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
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Criteria
Actions required
Follow-up monitoring
ALT or AST
>8 × ULN
Discontinue the study treatment 
immediately (if applicable)
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing 
factors (eg: conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBIL, 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 (eg: conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBIL, 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 
drug (if applicable)
Establish causality
Record the AE and contributing 
factors (eg: conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBIL, 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 (eg: conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBIL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
>3 to ≤5 × ULN (subject 
is asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate 
close observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks
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 (eg: conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
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Criteria
Actions required
Follow-up monitoring
TBIL (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 (eg: conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBIL, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
Test for hemolysis (eg: reticulocytes, 
haptoglobin, unconjugated [indirect] 
bilirubin)
>1.5 to ≤2 × ULN 
(subject is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate 
close observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice
Discontinue the study treatment 
immediately (if applicable)
Hospitalize the subject
Establish causality
Record the AE and contributing 
factors (eg: conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBIL, 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 (eg: conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
a Elevated ALT/AST >3 × ULN and TBIL >2 × ULN but without notable increase in ALP to >2 × ULN
b (General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia
c Resolution 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.
* 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 
TBIL: total bilirubin; ULN: upper limit of normal
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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16.5
Appendix 5: Specific renal alert criteria and actions and event 
Follow-up
Table 16-11
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 24h-48h if possible
!
Consider drug interruption or discontinuation unless 
other causes are diagnosed and corrected
!
Consider subject hospitalization and specialized 
treatment
New onset dipstick proteinuria ≥3+ OR
(Spot) urinary protein-creatinine ratio 
(PCR) ≥1g/g (or ≥100 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 sCr
!
Exclude infection, trauma, bleeding from the distal 
urinary tract/bladder, menstruation
!
Consider bleeding disorder
+ Corresponds to Kidney Disease, Improving Global Outcomes (KDIGO) criteria for Acute Kidney Injury
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Table 16-12
Follow-up renal events
Assess, document and record in the appropriate CRF
!
Urine dipstick and sediment microscopy evidence of Drug Induced Nephrotoxicity (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 subject 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
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16.6
Appendix 6: Graft versus host disease (GVHD)
Chronic GVHD is an immune-mediated disorder that may occur following allogeneic SCT. 
Manifestations include scleroderma, dry eyes, dry mouth, lichenoid oral changes, bronchiolitis 
obliterans, vanishing bile ducts, or weight loss. It is to be diagnosed specifically rather than 
diagnosed when acute GVHD-like syndromes develop late (beyond day +100) after any 
transplant or donor leukocyte infusion.
As part of the exclusion criteria for this protocol Section 5 regarding GVHD, the grading & 
staging assessment of acute GVHD will follow the criteria described below in Table 16-13, and 
the definition of chronic GVHD will follow the criteria described in Table 16-14.
Table 16-13
Staging and grading of acute Graft-Versus-Host Disease (adapted 
from Harris et al, 2016)
Extent of organ involvement
Skin
Liver
Gut
Stage
1
Rash on <25% of skina
Total bilirubin 2-3 mg/dLb
Diarrhea >500 mL/dayc or 
persistent nausead
2
Rash on 25-50% of skin
Total bilirubin 3-6 mg/dL
Diarrhea >1,000 mL/day
3
Rash >50% of skin
Total bilirubin 6-15 mg/dL
Diarrhea >1,500 mL/day
4
Generalized erythroderma 
with bullous formation
Total bilirubin >15 mg/dL
Severe abdominal pain 
with or without ileus
Gradee
I
Stage 1-2
None
None
II
Stage 3 or
Stage 1 or
Stage 1
III
Stage 2-3 or
Stage 2-4
IVf
Stage 4 or
Stage 4
a Use “rule of nines” or burn chart to determine extent of rash.
b Range given as total bilirubin. Downgrade by 1 stage if an additional cause of elevated bilirubin has 
been documented.
c Volume of diarrhea applies to adults. For pediatric subjects, the volume of diarrhea should be based 
on body surface area. Gut staging for pediatric subjects was not discussed at the Consensus 
Conference. Downgrade by 1 stage if an additional cause of diarrhea has been documented.
d Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
e Criteria for grading given as a minimum degree of organ involvement required to confer that grade.
f Grade IV may also include lesser organ involvement but with extreme decrease in performance 
status.
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Table 16-14
Definition of chronic Graft-Versus-Host-Disease
Definite and Possible Manifestations of Chronic GVHD
Organ System
Definite Manifestations of 
Chronic GVHD
Possible Manifestations of 
Chronic GVHD
Skin
Scleroderma (superficial or 
fasciitis), lichen planus, vitiligo, 
scarring alopecia, hyperkeratosis 
pilaris, contractures from skin 
immobility, nail bed dysplasia
Eczematoid rash, dry skin, 
maculopapular rash, 
hyperpigmentation, hair loss
Mucous membranes
Lichen planus, non-infectious 
ulcers, corneal erosions/non-
infectious conjunctivitis
Xerostomia, keratoconjunctivitis sicca
Gastrointestinal (GI) 
tract
Esophageal strictures, steatorrhea
Anorexia, malabsorption, weight loss, 
diarrhea, abdominal pain
Liver
None
Elevation of alkaline phosphatase, 
transaminitis, cholangitis, 
hyperbilirubinemia
Genitourinary (GU)
Vaginal stricture, lichen planus
Non-infectious vaginitis, vaginal 
atrophy
Musculo-
skeletal/Serosa
Non-specific arthritis, myositis, 
myasthenia, polyserositis, 
contractures from joint 
immobilization
Arthralgia
Hematologic
None
Thrombocytopenia, eosinophilia, 
autoimmune cytopenias
Lung
Bronchiolitis obliterans
Bronchiolitis obliterans with organizing 
pneumonia, interstitial pneumonitis
At any time point post-transplant, if there are ANY definite symptoms (column 2) then the symptoms 
should be identified as chronic GVHD.
At any time point post-transplant, if there are any possible symptoms (column 3) but no definite 
symptoms, then it is at the physicians’ discretion to identify as either acute or chronic GVHD.
Acute and chronic GVHD cannot be present at the same time. Thus if #1 is fulfilled, then all 
manifestations of GVHD should be identified as chronic GVHD.
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Limited Chronic GVHD
!
Localized skin involvement and/or liver dysfunction OR
!
Involvement of only one target organ
Extensive Chronic GVHD
!
Generalized skin involvement ≥50% of body surface area OR
!
Localized skin involvement and/or liver dysfunction plus at least one of the following:
!
Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis
!
Eye involvement (Schirmer’s test with <5 mm wetting)
!
Involvement of minor salivary glands or oral mucosa on lip biopsy
!
Involvement of any other target organs OR
!
Involvement of at least two target organs
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