A Phase II, Open Label, Multi-center Trial to Determine the Efficacy and Safety of Tisagenlecleucel Re-infusion in Pediatric and Adolescent Young Adult (AYA) Patients With Acute Lymphoblastic Leukemia Experiencing Loss of B Cell Aplasia
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Sponsor: Novartis Pharmaceuticals



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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...............................................................................................................12
Amendment 1 ....................................................................................................................14
Protocol summary..............................................................................................................19
1
Introduction .......................................................................................................................22
1.1
Background............................................................................................................22
1.1.1
Overview of disease, epidemiology and current treatment...................22
1.1.2
Historical experience with viral gene therapies ....................................22
1.1.3
Overview of tisagenlecleucel................................................................23
1.1.4
Non-clinical experience ........................................................................24
1.1.5
Clinical experience................................................................................24
1.2
Purpose ..................................................................................................................25
2
Objectives and endpoints...................................................................................................26
3
Study design ......................................................................................................................27
4
Rationale............................................................................................................................28
4.1
Rationale for study design .....................................................................................28
4.1.1
Rationale for lymphodepletion..............................................................28
4.1.2
Rationale for choice of background therapy.........................................29
4.2
Rationale for dose/regimen and duration of treatment ..........................................29
4.3
Rationale for choice of control drugs ....................................................................29
4.4
Purpose and timing of interim analyses.................................................................29
4.5
Risks and benefits..................................................................................................29
4.5.1
Identified safety risks ............................................................................30
4.5.2
Potential safety risks .............................................................................37
4.5.3
Cerebral edema......................................................................................37
4.5.4
Other risks .............................................................................................40
5
Population..........................................................................................................................41
5.1
Inclusion criteria ....................................................................................................41
5.2
Exclusion criteria...................................................................................................41
6
Treatment...........................................................................................................................44
6.1
Study treatment......................................................................................................44
6.1.1
Investigational and Control Drugs ........................................................44

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6.1.2
Pre-infusion evaluation .........................................................................45
6.1.3
Additional safety procedures prior to tisagenlecleucel infusion...........46
6.1.4
Additional study treatments ..................................................................47
6.1.5
Treatment arms/group ...........................................................................47
6.1.6
Guidelines for continuation of treatment ..............................................47
6.1.7
Treatment duration................................................................................48
6.1.8
Tisagenlecleucel dosing regimen ..........................................................48
6.2
Other treatment (s).................................................................................................48
6.2.1
Concomitant therapy.............................................................................48
6.2.2
Prohibited medication and non-drug therapies .....................................49
6.2.3
Rescue medication ................................................................................50
6.3
Subject numbering, treatment assignment.............................................................50
6.3.1
Subject numbering ................................................................................50
6.3.2
Treatment assignment ...........................................................................50
6.4
Treatment blinding.................................................................................................50
6.5
Dose escalation and dose modification..................................................................50
6.5.1
Dose modifications................................................................................50
6.5.2
Follow-up for toxicities.........................................................................51
6.6
Additional treatment guidance...............................................................................51
6.6.1
Treatment compliance...........................................................................51
6.6.2
Recommended treatment of adverse events..........................................51
6.6.3
Emergency breaking of assigned treatment code..................................56
6.7
Preparation and dispensation.................................................................................56
6.7.1
Handling of Tisagenlecleucel................................................................57
6.7.2
Handling of additional treatment ..........................................................57
7
Informed consent procedures ............................................................................................57
8
Visit schedule and assessments .........................................................................................58
8.1
Study Flow.............................................................................................................61
8.1.1
Screening...............................................................................................61
8.1.2
Enrollment.............................................................................................61
8.1.3
Leukapheresis........................................................................................61
8.1.4
Information to be collected on screening failures.................................61
8.1.5
Treatment ..............................................................................................61
8.1.6
Survival follow-up ................................................................................63
8.2
Subject demographics/other baseline characteristics.............................................63
8.2.1
Demographics .......................................................................................63

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8.2.2
Baseline characteristics.........................................................................64
8.3
Efficacy..................................................................................................................64
8.3.1
Efficacy assessments.............................................................................64
8.4
Safety.....................................................................................................................64
8.4.1
Laboratory evaluations..........................................................................66
8.4.2
Electrocardiogram (ECG) .....................................................................67
8.4.3
Other safety evaluations........................................................................67
8.4.4
Appropriateness of safety measurements..............................................67
8.5
Additional assessments..........................................................................................67
8.5.1
Clinical Outcome Assessments (COAs) ...............................................67
8.5.2
Pharmacokinetics ..................................................................................68
8.5.3
Biomarkers............................................................................................69
8.5.4
Imaging .................................................................................................70
8.5.5
Other Assessments ................................................................................70
9
Study discontinuation and completion ..............................................................................70
9.1
Discontinuation......................................................................................................70
9.1.1
Discontinuation of study .......................................................................70
9.1.2
Withdrawal of informed consent...........................................................71
9.1.3
Lost to follow-up...................................................................................72
9.1.4
Early study termination by the sponsor.................................................72
9.2
Study completion and post-study treatment ..........................................................73
10 Safety monitoring and reporting........................................................................................73
10.1
Definition of adverse events and reporting requirements......................................73
10.1.1
Adverse events ......................................................................................73
10.1.2
Serious adverse events ..........................................................................75
10.1.3
SAE reporting........................................................................................76
10.1.4
Adverse events of special reporting requirements ................................76
10.1.5
Duration of adverse event reporting......................................................76
10.1.6
Pregnancy reporting ..............................................................................77
10.1.7
Reporting of Tisagenlecleucel errors including misuse/abuse..............77
10.2
Additional Safety Monitoring................................................................................78
10.2.1
Liver safety monitoring.........................................................................78
10.2.2
Renal safety monitoring........................................................................78
10.2.3
Data Monitoring Committee .................................................................79
10.2.4
Steering Committee...............................................................................79
10.2.5
Follow up of Secondary Malignancy....................................................79

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11 Data collection and database management........................................................................79
11.1
Data collection.......................................................................................................79
11.2
Database management and quality control............................................................80
11.3
Site monitoring ......................................................................................................80
12 Data analysis and statistical methods ................................................................................81
12.1
Analysis sets ..........................................................................................................81
12.1.1
Screened Set..........................................................................................81
12.1.2
Enrolled Set...........................................................................................81
12.1.3
Full Analysis Set ...................................................................................81
12.1.4
Safety Set ..............................................................................................81
12.1.5
Per-Protocol Set ....................................................................................82
12.1.6
Cellular kinetic analysis set...................................................................82
12.1.7
Pharmacokinetic analyses set................................................................82
12.2
Subject demographics and other baseline characteristics......................................82
12.3
Treatments .............................................................................................................82
12.4
Transfusion during the study will be listed. In addition, whether patients have 
received anti-cytokine medications for the management of CRS will be 
summarized.Analysis of the primary endpoint(s)..................................................83
12.4.1
Definition of primary endpoint(s).........................................................83
12.4.2
Statistical model, hypothesis, and method of analysis..........................83
12.4.3
Handling of missing values/censoring/discontinuations.......................83
12.4.4
Sensitivity and Supportive analyses......................................................83
12.5
Analysis of secondary endpoints ...........................................................................84
12.5.1
Overall Remission rate (ORR)..............................................................84
12.5.2
Event free survival (EFS)......................................................................84
12.5.3
Overall survival (OS)............................................................................85
12.5.4
Safety endpoints....................................................................................85
12.5.5
Pharmacokinetics ..................................................................................86
12.5.6
Biomarkers............................................................................................87
12.5.7
PK/PD relationships..............................................................................87
12.5.8
Patient reported outcomes.....................................................................87
87
12.7
Interim analyses.....................................................................................................87
12.8
Sample size calculation..........................................................................................87
13 Ethical considerations and administrative procedures ......................................................87
13.1
Regulatory and ethical compliance........................................................................87
13.2
Responsibilities of the investigator and IRB/IEC..................................................87

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13.3
Publication of study protocol and results...............................................................88
13.4
Quality Control and Quality Assurance.................................................................88
14 Protocol adherence ............................................................................................................88
14.1
Protocol amendments.............................................................................................89
15 References .........................................................................................................................90
16 Appendices ........................................................................................................................96
16.1
Appendix 1: Eligibility based on serologic markers for hepatitis B and C: ..........96
16.2
Appendix 2: Tisagenlecleucel modified data reporting – Treatment and 
Follow Up Phase....................................................................................................97
Appendix 3: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................101
Appendix 4: Specific Renal Alert Criteria and Actions and Event Follow-up ...............104
List of tables
Table 2-1
Objectives and related endpoints ..........................................................26
Table 4-1
Clinical signs and symptoms associated with CRS (Lee et al 2014)....31
Table 4-2
Cytokine Release Syndrome Grading (Lee et al 2014).........................31
Table 4-3
Immune effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) Grading for children (Lee et al, 2019)...................................33
Table 4-4
Encephalopathy Assessment for Children Age <12 Years Using the 
Cornell Assessment of Pediatric Delirium (Lee et al, 2019) ................34
Table 6-1
Drug Supply ..........................................................................................44
Table 6-2
CRS management..................................................................................52
Table 6-3
Definition of High Dose Vasopressors .................................................53
Table 8-1
Assessment Schedule ............................................................................59
Table 8-2
Assessments & Specifications...............................................................64
Table 8-3
Karnofsky/Lansky Performance Scales ................................................65
Table 8-4
Laboratory Assessments........................................................................66
Table 8-5
CTL019 pharmacokinetics by q-PCR in peripheral blood collection 
log..........................................................................................................68
69
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................77
Table 16-1
Adverse event reporting........................................................................98
Table 16-2
Concomitant Medication and Laboratory Reporting ............................98
Table 16-3
Liver Event and Laboratory Trigger Definitions ................................101
Table 16-4
Follow Up Requirements for Liver Events and Laboratory Triggers.101
Table 16-5
Specific Renal Alert Criteria and Actions...........................................104

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Table 16-6
Follow up of renal events....................................................................105
List of figures
Figure 1-1
Tisagenlecleucel chimeric antigen receptor design...............................24
Figure 3-1
Study Design .........................................................................................28

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List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALB
Albumin
ALC
Absolute Lymphocyte Count
ALL 
Acute Lymphoblastic Leukemia
ALP
Alkaline phosphatase
ALT 
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/SGPT
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/SGOT
ATG 
Anti-thymocyte globulin
ATC
Anatomical Therapeutic Chemical
AYA
Adolescent Young Adult
B-ALL
B cell lineage acute lymphoblastic leukemia
BM
Bone Marrow
BMT
Bone Marrow Transplantation
BUN
Blood Urea Nitrogen
CAR
Chimeric Antigen Receptor
CBC 
Complete Blood Count
CCGs
CRF Completion Guidelines
CD
Cluster of Differentiation
CD137
4-1BB costimulatory molecule
CFR 
Code of Federal Regulations
CI
Confidence Interval
CIBMTR
Center for International Blood and Marrow Transplant Research
CIF
Cumulative Incidence Function
CKAS
Celluar Kinetic Analysis Set
CLL 
Chronic Lymphocytic Leukemia
Cmax
Maximum concentration
CMO&PS
Chief Medical Office and Patient Safety
CNS
Central Nervous System
CRF/eCRF
Case Report/Record Form; the terms CRF/eCRF can be applied to either 
EDC or Paper
CR
Complete remission
CRES
CART-cell-related-encephalopathy
Cri
Complete remission with incomplete blood count recovery
CRO
Contract Research Organization
CRP
C-Reactive Protein
CRS 
Cytokine Release Syndrome
CSF
Cerebral Spinal Fluid
CSP
Clinical Study Protocol
CSR 
Clinical Study Report
CT
Computed Tomography

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CTC 
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTL 
Cytotoxic T Lymphocyte
CTL019 cells
CD 19 redirected autologous T cells (also called CART19 cells)
DOR 
Duration of Response
DLBCL
Diffuse Large B Cell Lymphoma
DMC
Data Monitoring Committee
DMSO
Dimethylsulfoxyde
DNA 
Deoxyribonucleic Acid
DRESS
Drug Reaction with eosinophilia and systemic syndromes
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECHO 
Echocardiogram
EDC
Electronic Data Capture
EFS
Event Free Survival
EMA 
European Medicines Agency
ENS
Enrolled Set
EOS
End of Study
EOT
End of Treatment and Primary Follow-Up
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFP
Fresh Frozen Plasma
FL
Follicular Lymphoma
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor
GFR 
Glomerular Filtration 
GGT
Gamma-glutamyltransferase.
GI
Gastrointestinal
GM-CSF
Granulocyte Macrophage-Colony Stimulating Factor
GVHD
Graft versus Host Disease
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICANS
Immune effector Cell-Associated Neurotoxicity Syndrome
ICE
Immune effector Cell-associated Encephalopathy
ICF
Informed Consent Form
ICH 
International Conference on Harmonization
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
IL6R
Interleukin 6 receptor

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IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IUD/IUS
Intrauterine Device/Intrauterine System
i.v.
Intravenous(ly)
KM
Kaplan Meier
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LISA
Lentivirus insertion site analysis
LLOQ
Lower Limit of Quantification
LOQ
Limit of Quantification
LP
Lumbar Puncture
LPLV
Last Patient Last Visit
LVEF
Left Ventricular Ejection Fraction
MAP 
Master Analysis Plan
MAS 
Macrophage Activation Syndrome
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Authorities
MHC 
Major Histocompatibility Complex
MMC
Maternal microchimerism
MRD 
Minimal Residual Disease
MRA
Magnetic Resonance Angiography
MRI 
Magnetic Resonance Imaging
MRT
Mean Residence Time
MUGA
Multiple Uptake Gated Acquisition
NCCN
National Comprehensive Cancer Network
NE
Norepinephrine Equivalent
NR
No Response
ORR
Overall Remission Rate
OS
Overall Survival
pALL
Pediatric Acute Lymphoblastic Leukemia
PB
Peripheral Blood
PE
Physical examination
PCR 
Polymerase Chain Reaction
PD
Pharmacodynamics
pH
Hydrogen ion concentration; a measure of the acidity or basicity of an 
aqueous solution
PI
Principal Investigator
PK
Pharmacokinetics
PKAS
Pharmacokinetic Analysis Set
PML
Progressive multifocal leukoencephalopathy

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PPS 
Per-Protocol Set
PR
Partial Remission
PT
Prothrombin Time
q-PCR
Quantitative Polymerase Chain Reaction
RCL 
Replication Competent Lentivirus
RDC 
Remote Data Capture
RMP
Risk Management Plan
r/r
Relapsed or refractory
SAE
Serious Adverse Event
SC
Steering Committee
scFv
Single chain Fv fragment of an antibody
SCT 
Stem Cell Transplantation
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Event
TNF
Tumor Necrosis Factor
TLS 
Tumor Lysis Syndrome
TCR 
T Cell Receptor
TCR-zeta
Signaling domain found in the intracellular region of the TCR zeta, gamma 
and epsilon chains
ULN
Upper Limit of Normal
VASST
Vasopressin and Septic Shock Trial
VH
Heavy Chain Variable Domain
VL
Light Chain Variable Domain
VSV-G
Vesicular Stomatitis Virus, Glycoprotein
WBC
White Blood Cell
WOCBP
Women of child bearing potential

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Baseline efficacy 
assessment
If multiple assessments are performed prior to re-infusion/randomization then the 
one closest temporally prior to re-infusion will serve as baseline assessment
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject 
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day)
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 study
The end of the study is defined as the last visit of the last subject 
Final Enrollment
The point at which a patient meets all inclusion/exclusion criteria and the patient’s 
additional dose of tisagenlecleucel is confirmed
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant 
Investigational 
drug/treatment
The drug whose properties are being tested in the study
MAP
Master Analysis Plan documents project standards in the statistical methods which 
will be used within the individual clinical trial SRAP documentation
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. 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
Personal data
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes subject identifier information, 
study information and biological samples. 
Premature 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
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.

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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 (WoC)
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer and does not allow any further collection of 
personal data 

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Amendment 1
Amendment 1 (23-Jun-2020)
Amendment rationale 
At the time of this protocol amendment, (June 2020), the study is in start-up phase. 0 sites have 
been initiated and 0 patients have been screened. 
The protocol is amended to clarify that tisagenlecleucel is not an investigational treatment. 
Participants in the trial will be prescribed commercial tisagenlecleucel by a physician and it will 
be administered in the course of medical practice. The trial is still considered interventional 
because of the required laboratory assessments and bone marrow assessments. This amendment 
is also intended to ease the participation burden on the patients by reducing the number of 
required patient visits, and implement clarifications to the original protocol. No changes were 
made as a result of a safety event.
This protocol amendment aims to make the following key changes:
1. Clarification that participants in this trial will receive commercial tisagenlecleucel, 
prescribed by the treating physician in the course of medical practice. This clarification 
is essential because the doses for re-infusion were previously manufactured for each 
individual patient as commercial product and the physician can request this additional 
dose at any time from Novartis.
2. Removed Pre-treatment and Day -1 visits from the schedule of assessments and 
references to them in Section 3. Day -1 assessments will now occur on Day 1, prior to 
patient’s re-infusion. 
3. Clarifies original protocol by requiring a bone marrow aspirate or biopsy at screening 
and at Day 28. Bone marrow aspirate or biopsy will be optional, performed if clinically 
indicated, at Month 3, Month 6 and Month 12. 
4. Clarifies original protocol by adding HIV, Hepatitis B and C testing, and Serum 
immunoglobulin level testing to Table 8-1. These items were required by the original 
protocol but were not listed in the Assessment Schedule. 
5. Modified Section 9.1.1 from discontinuation of study treatment to discontinuation of 
study. Tisagenlecleucel is not being provided as a study drug, and decisions to stop or 
continue treatment will occur outside of this trial. This section now describes criteria 
and procedures for discontinuing from the study. 
6. Removed references to Independent Review Committee (IRC), because an IRC was not 
established for this trial. 
7. Updated Section 8.5.3 to remove the biomarker assessments that are not being 
performed.
8. Corrected typo in the primary endpoint, to show that B cell aplasia is measured by 
circulating B lymphocytes (< 50/µL), not (>50/µL).

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Section 4.5: Deleted two paragraphs that were duplicate of two previous paragraphs in the 
section.
Section 5.1: Revised Inclusion Criteria #1 to indicate that all patients must have an additional 
dose of unexpired, commercial tisagenlecleucel available and prescribed by a physician in the 
course of medical practice.
Section 5.1: Revised Inclusion Criteria #6 to update the definition of loss of B cell aplasia to 
require only one measurement for patients, (previously 2 were required for patients with 
absolute count≥ 50/µL but less then 200/µL ), which can be either absolute B lymphocyte count 
≥ 50/µL or PB B lymphocyte ≥ 10% of the total lymphocytes.
Section 5.2: Updated Exclusion Criteria #7 to clarify that it is 72 hours prior to tisagenlecleucel 
infusion.
Section 6.1: Updated section to indicate that the tisagenlecleucel is not considered study 
treatment. The product will be released commercially to the treating physician when it is 
prescribed in the course of medical practice. 
Table 6-1: Moved table from section 6.1.1 to section 6.1. Updated contents of table to reflect 
the use of commercial tisagenlecleucel which is prescribed by the treating physician in the 
course of medical practice.
Section 6.1.1: Updated section to indicate it is not applicable.
Section 6.1.8: Updated section to indicate the dose range is the approved dose range.
Section 6.2.2: Updated paragraph on Medication restrictions prior to leukapheresis to indicate 
Not Applicable.
Section 6.7: Removed sentence indicating each site will be supplied with study drug.
Section 6.7.1: Modified section title to Handling of Tisagenlecleucel
Section 6.7.1: Updated section to indicate the investigator will maintain a record of the 
commercial tisagenlecleucel administered to study participants in a drug accountability log. 
Section 6.7.1: Updated the tisagenlecleucel disposal and destruction section to indicate that the 
package insert for commercial Kymriah should be referenced.
Table 8-1 and Section 8.1: Revised as follows:
–
Updated Periods in row one to Screening, Treatment and End of Study. 
–
Revised Visit Names in row 2 to Screening, Enrollment, assessment period and End of 
Study. 
–
Removed pre-treatment visit and Day -1 visit and columns for pre-treatment visit 
assessments and D-1 assessments.
–
Moved assessments previously required on D-1 to D1
–
Added HIV & Hepatitis B and C testing, Serum immunoglobulin levels (IgG, IgA, IgM) 
to Screening visit. 

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–
Added Bone Marrow Aspirate or Biopsy as a required procedure to Screening visit and 
D28 visit, and as an optional procedure to M3, M6 and M12 visits.
–
Revised procedure CTL019 infusion to Re-infusion of prescribed, commercially 
available tisagenlecleucel
Section 8.1.5: Removed requirement to collect labs of special interest for all patients that 
experience a CRS. 
Section 8.2.2: Added Prior antineoplastic therapies and MRD status to baseline characteristics
Section 8.3.1: Removed the data review by Independent Review Committee (IRC).
Section 8.4: Added CNS evaluation description to the Physical examination specifications.
Table 8-4: Added HIV & Hepatitis B & C testing and Serum immunoglobulin levels (IgG, IgA, 
IgM). Clarified that pregnancy test can be either serum or urine at D28, M3 and M6.
Table 8-6: Updated Day for the pre-dose sample to D1. 
Section 8.5.3: Removed biomarker assessments that are not being performed in this trial.
Section 9.1.1: Revised Section to indicate requirements for discontinuing from study
Section 9.2: Clarified the definition of end of study.
Section 10.1.7: Updated section title to Reporting of Tisagenlecleucel errors including 
misuse/abuse. Added statement indicating that this section will remain applicable.
Section 11.2: Removed sentence referring to emergency code breaks as not applicable to this 
trial.
Section 12: Updated to indicate:
–
The primary analysis of the study (primary, secondary 
 objectives) will 
occur after all patients complete the Month 12 visit or prematurely discontinue from the 
study.
–
Interim analyses may be performed every six months for publication purpose.
Section 12.1.5: Clarified text defining the Per-Protocol Set. 
Section 12.3: Clarified that the safety set will be used for the analyses described in this section.
Section 12.4.1: Updated primary endpoint to align with section 2. 
Section 12.4.2: Updated primary efficacy analysis methods.
Section 12.4.3: Added statement that patients who proceed to HSCT while in remission after 
reinfusion will be censored at the time of HSCT.
Section 12.4.3: Added Statement that the volume of data generated due to the COVID-19 
pandemic may also be assessed and sensitivity analyses will be performed, if deemed 
appropriate. 
Section 12.4.4: Added statement indicating the impact of COVID-19 will be explored and as 
appropriate, a sensitivity analysis of the primary endpoint may be performed to assess the 
impact to the study. 

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Section 12.4.4.1: Clarified the fifth bullet by adding Patients with a loss of B cell aplasia.
Section 12.5: Clarifications to the wording to align with Section 2.
Section 12.5.1: Removed MRD negativity to align with Section 2.
Section 12.5.3: Created section for overall survival.
Section 12.5.4.2: Added definition of treatment emergent adverse events and clarified how AEs 
will be summarized.
Section 12.5.4.3: Removed urinary laboratory tests from the summaries that will be generated.
Section 12.5.4.5: Updated section to remove statement indicating malignant and normal B cell 
populations will be listed and summarized by patient and time point and removed the reference 
to section 10.6.1.
Section 12.5.5: Added clarification regarding the Pharmacokinetic Analysis Set and removed 
statement that the CKAS set will be used for the analysis of 
 biomarkers.
Section 12.5.6: Updated Section to Not Applicable and deleted duplicate text that already 
appears in Section 12.5.4.5.
Section 12.6: Corrected hyperlink and Section reference.
Section 12.7: Removed duplicate text.
References: Added missing citations.
Changes to the remainder of the document include grammatical corrects/clarifications of minor 
inconsistencies.
Where appropriate, the words study treatment and CTL019 have been replaced by 
Tisagenlecleucel throughout the document. 

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Protocol summary
Protocol number
CTL019BUS03
Full Title
A phase II, open label, multi-center trial to determine the efficacy and safety of 
tisagenlecleucel re-infusion in Pediatric and Adolescent Young Adult (AYA) 
patients with acute lymphoblastic leukemia experiencing loss of B cell aplasia
Brief title
Study of efficacy and safety of reinfusion of tisagenlecleucel in pediatric and 
young adult patients with Acute Lymphoblastic Leukemia 
Sponsor and 
Clinical Phase
Novartis 
Phase II
Multi-center
Investigation 
type
Biological
Study type
Interventional: Any research study that prospectively assigns human participants 
to one or more health-related interventions to evaluate the effects on health 
outcomes. Interventions include but are not restricted to drugs, cells and other 
biological products, surgical procedures, radiological procedures, devices, 
behavioral treatments, process-of-care changes, preventive care, etc. [WHO 
Definition]
Purpose and 
rationale
Reinfusion of one or more additional doses of tisagenlecleucel can restore B-
cell aplasia in some patients with early evidence of poor or short persistence of 
CD19-directed CAR-T cells and improve durable remission rates. (Maude 
2016)
Frequently, tisagenlecleucel manufacturing will yield more than one dose. If a 
patient who was previously treated with tisagenlecleucel presents with 
evidence of B-cell recovery within 12 months following first infusion and has an 
additional cryopreserved tisagenlecleucel dose, reinfusion of one dose can be 
performed with the aim to restore B-cell aplasia and potentially prolong 
remission and leukemia control
Primary 
Objective(s) 
Evaluate the incidence of B cell aplasia after re-infusion of tisagenlecleucel
Secondary 
Objectives
Evaluate the efficacy of reinfusion of tisagenlecleucel for loss of B cell aplasia 
as measured by overall remission rate (ORR) 12 months after tisagenlecleucel 
reinfusion, which includes CR and CR with incomplete blood count recovery 
(CRi) as determined by investigator assessment for pALL patients
Evaluate event free survival (EFS)
Evaluate Overall survival (OS)
Evaluate the safety of reinfusion of tisagenlecleucel reinfusion therapy.
Study design
This is a multi-center Phase II study investigating the efficacy and safety of 
reinfusion of tisagenlecleucel in pediatric and young adult patients with ALL who 
were previously treated with tisagenlecleucel and experience B cell recovery. 
The study will be comprised of 54 patients with 49 evaluable pediatric and young 
adult patients up to and including 25 years of age who have been previously 
infused with commercial tisagenlecleucel once and have an additional dose of 
commercial tisagenlecleucel available and prescribed in the course of medical 
practice.
Population
Patients up to and including 25 years of age with B-cell precursor acute 
lymphoblastic leukemia (ALL) who have been treated with commercial

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tisagenlecleucel once and have an additional dose available and prescribed to 
them in the course of medical practice. 
Key Inclusion 
criteria
•
Must have an additional unexpired dose of commercial tisagenlecleucel 
available which is prescribed by a physician in the course of medical practice
•
Patients who were previously treated with commercial tisagenlecleucel and 
present with evidence of B-cell recovery as defined by:
–
Peripheral blood (PB) absolute B lymphocyte count ≥ 50/µL, OR
–
PB B lymphocyte ≥ 10% of the total lymphocytes 
Key Exclusion 
criteria

Prior gene therapy other than tisagenlecleucel

Prior adoptive T cell therapy other than tisagenlecleucel

Active CNS involvement by malignancy

Active or latent hepatitis B or active hepatitis C (test within 8 weeks of 
screening), or any uncontrolled infection at screening

HIV positive test within 8 weeks of screening. False positivity should be 
excluded by antigen detection tests or nucleic acid tests that have been 
shown not to cross react with tisagenlecleucel vector.
Study treatment
Not applicable. A second dose (for re-infusion) of commercial tisagenlecleucel 
is not considered a study treatment because it is released commercially when 
prescribed by the treating physician in the course of medical practice.
Efficacy 
assessments

B and T-cells by Flow Cytometry 

CTL019 Pharmacokinetics by qPCR
Pharmacokinetic 
assessments 

CTL019 Pharmacokinetics by qPCR
Key safety 
assessments
All patients treated with tisagenlecleucel will be monitored for specific toxicities 
for 15 years following reinfusion, irrespective of their response to 
tisagenlecleucel
Data analysis
This study is an exploratory study to evaluate the incidence of B cell aplasia 
after reinfusion of tisagenlecleucel.
Sample size was based on an exact test for single proportion to test the null 
hypothesis H0: p<=0.10. Where p is the percent of patients who establish B-
cell aplasia during 12 months. If the true rate p>= 0.25, then with an one sided 
alpha level of 2.5% and at least 80% power, a minimum of 49 evaluable 
patients will be required for the study. Considering drop-out rate of 10%, a total 
of approximately 54 patients will be enrolled into the study.
Primary analysis will be performed using the Full Analysis Set. For primary 
analysis, the proportion of patients who establish B-cell aplasia during 12 
months will be presented together with an exact 95% Clopper-Pearson 
confidence interval. The null hypothesis will be rejected if the lower limit of the 
95% confidence interval is greater than 0.10, demonstrating improvement after 
reinfusion. 
All secondary 
variables will be summarized descriptively.
Categorical data will be presented in frequencies and percentages. For 
continuous data descriptive statistics (mean, standard deviation, median, 25th
and 75th percentiles, min and max) will be provided. Kaplan Meier’s estimates 

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will also be reported for the time to event variables. Summarized safety data 
will also be presented. 
Key words
Acute lymphoblastic leukemia, tisagenlecleucel, CTL019, reinfusion

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1
Introduction
1.1
Background
1.1.1
Overview of disease, epidemiology and current treatment
Acute lymphoblastic leukemia (ALL) is a hematological malignancy characterized by the 
proliferation of immature lymphoid cells in the bone marrow, blood, and other organs (Jabbour 
et al 2005). 
ALL is primarily a disease of children, adolescents, and young adults. ALL is the most common 
childhood cancer, accounting for about 80% of all leukemia cases in children and approximately 
26% of cancer diagnoses among children from birth to 14 years of age (Ward et al 2014). 
According to SEER projections for 2017, approximately 5,970 new cases of ALL (both adults 
and children) will be diagnosed in the US (httpsseer cancergov/statfacts/html/alylhtml). The 
most recent SEER analysis of prevalence estimated that there were 81,837 patients living with 
ALL in the US in 2014. 
The median age at diagnosis is 15 years old, and 56% of new cases from 2010 to 2014 were 
diagnosed in patients younger than 20 years of age. 
Among children, B-cell lineage ALL constitutes approximately 88% of leukemia cases. 
Pediatric B-cell ALL (pALL) has remained the primary cause of pediatric cancer mortality in 
the past 30 years, even though the mortality rate has been declining
(httpsseer
cancergov/statfacts/html/alylhtml). 
Current treatment for B cell malignancies include combinations of chemotherapy, radiation 
therapy, bone marrow transplantation, or peripheral blood and cord blood stem cell 
transplantation (SCT). Initial chemotherapy is typically administered over a 2 to 3 year period. 
With current first line multi-agent treatment regimens, the long term remission among children 
with ALL is greater than 80%. Fifteen to 20% of patients who achieve an initial remission will 
experience disease relapse. Although this can occur at any time after diagnosis, the majority of 
relapses occur within 2 years of initial treatment (Nguyen et al 2008). 
Most patients (>85%) with relapsed ALL will achieve a second remission (Borwitz et al 2015); 
however, the challenge remains to maintain remission. Most children who relapse once will 
relapse again, and will ultimately succumb to their disease. Leukemia is still the leading cause 
of death in pediatric oncology (Borwitz et al 2015). Although no standard definition exists, ALL 
is considered refractory if a complete remission (CR) is not attained within 1-2 cycles of 
chemotherapy from the initial or relapse diagnosis. Refractory ALL in adults or children has a 
dismal prognosis and these are not candidates for SCT. Thus relapsed or refractory (r/r) ALL 
patients, both adult and pediatric, have significant unmet medical need (Maude et al 2018).
1.1.2
Historical experience with viral gene therapies
Retroviral vectors are highly effective gene delivery vehicles for inserting the foreign genetic 
material into the host cell. 
Lentiviral vectors, a major subset of retroviral vectors, demonstrate distinct integration patterns 
compared to other retroviral vectors, which have been the predominant vector to date for gene 

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transfer studies. The integration pattern of lentiviral vectors tends to be inside active 
transcription units as opposed to upstream in the locus control region where the insertion would 
have a greater chance of up-regulating gene expression. In addition, lentiviral vectors have no 
enhancer activity in their LTR regions and have lower levels of poly-A read-through, all factors, 
which may improve gene transfer safety (Zaiss et al 2002). Thus, lentiviral vectors appear a 
safer alternative to retroviral vectors, which is supported by animal models (Montini et al 2006). 
Lentiviral vector trials have demonstrated more polyclonal patterns of vector insertion (Cartier 
et al 2009, Biffi et al 2011), with the exception of the first patient reported from a thalassemia 
trial (Cavazzana-Calvo et al 2010). Importantly, despite a very high transduction efficiency 
achieved using lentiviral vectors, molecular clonality studies have not indicated any reasons for 
concern, to date, in published clinical trials (Schambach et al 2013). 
For further information refer to the [tisagenlecleucel Investigator’s Brochure].
1.1.3
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-based approach involves engineering T-cells with 
sequences that encode antibody-based antigen recognition moieties linked to signaling domains. 
Unlike T-cell receptors (TCR), chimeric antigen receptors (CARs) allow the T-cells to 
specifically target and destroy tumor cells in a Major Histocompatibility Complex (MHC) 
independent manner (Mellman et al 2011). 
A promising target antigen for B-cell malignancies is CD19, a cell-surface protein whose 
expression is restricted to B-cells and their precursors (Sadelain et al 2003, Porter et al 2011), 
with no expression on hematopoietic stem cells or non-B cell tissues. It is a member of the 
immunoglobulin (Ig) superfamily and a component of a cell surface signal transduction 
complex that regulates signal transduction through the B-cell receptor (Fearon et al 2000). Mice 
lacking CD19 have decreased number of B-cells in peripheral lymphoid tissues, decreased B-
cell response to oral vaccines and mitogens, and decreased serum Ig levels (Fearon et al 2000). 
First generation CARs contain the TCR activation signal domain consisting of TCRζ. Second 
generation CARs contain costimulatory signaling domains as well: either CD28 or 4-1BB. The 
3rd generation CARs contain further advancements such as double costimulatory modules 
comprised of CD28, 4-1BB plus TCRζ (June 2007, June et al 2009, Kohn et al 2011). 
Tisagenlecleucel (CART-19), a second generation CAR T cell therapy, is an adoptive cellular 
immunotherapy that uses the autologous peripheral blood T cells that have been genetically 
modified ex vivo to target CD19 on the surface of B-cells. As shown in Figure 1-1, the CAR 
approach uses genetically programmed T cells transfected with chimeric receptor genes to 
combine the effector functions of T cells with the ability of antibodies to recognize predefined 
surface antigens with high specificity in a non-MHC restricted manner (Gross et al 1989, 
Pinthus et al 2003). These receptors have the ability to recognize intact membrane proteins 
independent of antigen processing. The tumor antigen binding function of CAR is usually 
accomplished by the inclusion of a single chain variable fragment (scFv) antibody, containing 
the heavy chain variable domain (VH) and light chain variable domain (VL) joined by a peptide 
linker of about 15 residues in length (Mullaney et al 2001).

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Figure 1-1
Tisagenlecleucel chimeric antigen receptor design
Recent clinical trials of tisagenlecleucel in r/r CLL, r/r ALL, and r/r B cell lymphomas 
(including follicular lymphoma (FL)) have shown promising and durable anti-tumor efficacy 
(Porter et al 2011, Grupp et al 2013, Maude et al 2014, Maude el al 2018, Schuster et al. 2017). 
Consequently, tisagenlecleucel appears to be a therapeutic alternative for patients with B cell 
malignancies (including FL) refractory to the current therapies. For further information refer to 
the [tisagenlecleucel Investigator’s Brochure].
1.1.4
Non-clinical experience
Extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent 
tumor models (Calogero et al 2000, Clay et al 2002, Hombach et al 2002, Pule et al 2003, 
Sadelain 2003, Clay et al 2002, Hombach et al 2002, Pule et al 2003, Sadelain 2003). Others 
have used electroporation or retroviral vectors to create CAR T cells and have shown in vivo 
safety and efficacy of adoptively transferred T cells in immunodeficient mouse models 
(Willemsen et al 2000, Roessig et al 2002, Brentjens et al 2003, Cooper et al 2003, Serrano et 
al 2006). The incorporation of costimulatory signaling modules such as CD28 and 4-1BB in 
second generation CARs increases potency of the engineered T cells in pre-clinical studies 
(Finney et al 1998, Krause et al 1998, Eshhar et al 2001, Maher et al 2002, Finney et al 2004, 
Friedmann-Morvinski et al 2005, Brentjens et al 2010,). The pre-clinical data supporting CAR 
T cell persistence, expansion and anti-tumor efficacy have been published (Gross and Eshhar 
1992, Milone et al 2009).
1.1.5
Clinical experience
Tisagenlecleucel is investigated in several B-cell malignancies including r/r ALL, r/r diffuse 
large B-cell lymphoma (DLBCL), r/r CLL, and FL. Available data showed encouraging anti-
tumor efficacy with manageable toxicity (Grupp 2013, Porter 2011, Schuster 2017, Chong 2016, 
Maude 2018).

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For more details please refer to the [tisagenlecleucel Investigator’s Brochure].
1.1.5.1
Clinical efficacy
Tisagenlecleucel has been approved by the US FDA for the treatment of patients up to 25 years 
with B-cell precursor ALL that is refractory or in second or later relapse and for adult patients 
with r/r large B-cell lymphoma after two or more lines of systemic therapy including DLBCL
not otherwise specified, high grade B-cell lymphoma and DLBCL arising from follicular 
lymphoma [Kymriah Package Insert]. European Medicine Agency (EMA) has approved 
tisagenlecleucel for the treatment of pediatric and young adult patients up to 25 years of age 
with B-cell ALL that is refractory, in relapse post-transplant or in second or later relapse, and 
of adult patients with r/r DLBCL after two or more lines of systemic therapy [EU SmPC 2018]. 
Efficacy in r/r pediatric and young adult ALL
The efficacy of tisagenlecleucel was demonstrated in a multi-center, global phase II study 
(B2202; ELIANA). In this trial, 75 children and young adults with r/r B cell ALL received an 
infusion of tisagenlecleucel. At enrollment, patients had a median age of 11 years, a median of 
3 previous therapies (range, 1 to 8); 46 patients (61%) had undergone previous allogeneic HSCT. 
The overall remission rate (CR/CRi) was 81%; 45 patients (60%) had complete remission (CR), 
and 16 (21%) had complete remission with incomplete hematologic recovery (CRi). All patients 
who had a best overall response of CR or CRi were negative for minimal residual disease. The 
rate of relapse-free survival among patients with a response to treatment was 59% at 12 months. 
The majority of patients (89%) did not receive an allogeneic stem cell transplant after 
tisagenlecleucel. Updated data demonstrated a 24-month overall survival rate of 66%.(Maude 
et al 2018).
1.1.5.2
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 patients with refractory or relapsed B-cell precursor ALL, CRS was observed in 77% (21% 
Grade 3, 25% Grade 4). The median time to onset of CRS in this population was 3 days after 
infusion (range, 1 to 22). Neurologic events were reported in 40% of the patients (13% grade 3 
and no grade 4). The most common other adverse events of any grade were infection (43%), 
pyrexia (40%), decreased appetite (39%), febrile neutropenia (35%), prolonged cytopenia (not 
resolved by day 28, 37%) and headache (36%). Tumor lysis syndrome was reported in 
4% (Maude et al 2018).
1.2
Purpose
B-cell aplasia, which can be monitored by measuring CD19 positive B-cells by flow cytometry, 
is an expected on-target toxicity of successful CD19-directed CAR T-cell therapy. B-cell 
aplasia occurred in all the patients who had a response, and as long as CAR-modified T cells 
persist, B-cell aplasia continues. Therefore, B-cell aplasia provides what appears to be a highly 
accurate pharmacodynamic marker of tisagenlecleucel persistence (Maude 2014).

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Tisagenlecleucel can produce potent, sustained responses in children and young adult patients 
with relapsed/refractory ALL. In the Eliana study, sustained remissions were associated with 
the persistence of tisagenlecleucel and B-cell aplasia (a surrogate marker for persistence), 
suggesting continued effector function. Some patients had tisagenlecleucel persistence of up to 
2 years. The probability of tisagenlecleucel persistence at 6 months was 68% (95% CI: 50% to 
92%) (Maude 2018). Yet a subset of patients do not respond or relapse due to poor CAR-T cell 
expansion and limited persistence. In Eliana 22% of patients had early B-cell recovery (within 
6 months of tisagenlecleucel infusion). Early B cell recovery reflects poor tisagenlecleucel 
persistence and was associated with higher risk of relapse (Maude 2018).
Reinfusion of one or more additional doses of tisagenlecleucel can restore B-cell aplasia in 
some patients with early evidence of poor or short persistence and improve durable remission 
rates (Maude 2016) reported on retreatment or reinfusion with murine (CTL019 / 
tisagenlecleucel) or humanized (CTL119) CD19-directed CAR T cells. Of 55 patients in CR at 
1 month after CTL019 infusion (55/59 CR), 3 patients received a repeat infusion of murine 
CTL019 for CD19+ relapse and 17 for poor persistence at 3 and/or 6 months after initial 
infusion (Maude 2016). Remission was achieved in 1/3 children treated for CD19+ relapse. Of 
3 patients reinfused for CD19+ MRD, 1 progressed to CD19+ relapse, 1 became MRD- but had 
B cell recovery, and 1 had reduced MRD. Reinfusion induced B-cell aplasia for a second time 
in 1/7 children treated for B cell recovery, while 6/7 children reinfused for CD19+ hematogones 
demonstrated continued B-cell aplasia 6-21 months after repeat infusion. Of this group, 6 
remained in remission 9-24 months after initial infusion, and 1 experienced a CD19- relapse. 
Eight children previously treated with CAR T-cells (CTL019, n = 5; other, n = 3) were treated 
on a phase 1 study of humanized CTL119 for B cell recovery (n = 3), CD19+ relapse (n = 4), 
or no response to prior CAR T-cells (n = 1). Cytokine release syndrome (CRS), seen in 4 
patients, did not require vasopressor or respiratory support. Responses were seen in 4/8 patients 
with an ongoing CR of 7 months in 1 patient. 2/4 responding patients were previously resistant 
to reinfusion of murine CTL019.
Frequently, tisagenlecleucel manufacturing will yield more than one dose. If a patient who was 
previously treated with tisagenlecleucel presents with loss of B-cell aplasia, reinfusion may
restore B-cell aplasia and potentially prolong remission and leukemia control.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints 
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoint(s) for primary objective(s) 

Evaluate the incidence of B cell aplasia
after reinfusion of tisagenlecleucel

Proportion of patients who establish B cell aplasia within 
12 months of reinfusion, as measured by circulating B 
lymphocytes (< 50/µL) and presence of CTL019 cells by 
qPCR in the peripheral blood.
Secondary Objective(s)
Endpoint(s) for secondary objective(s)

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Objective(s)
Endpoint(s)

Evaluate the efficacy of reinfusion of 
tisagenlecleucel for loss of B cell aplasia 
as measured by overall remission rate 
(ORR) 12 months after tisagenlecleucel 
reinfusion, which includes CR and CR with 
incomplete blood count recovery (CRi) as 
determined by investigator assessment for 
pALL patients

Evaluate event free survival (EFS)

Evaluate Overall survival (OS)

Evaluate the safety of tisagenlecleucel 
reinfusion therapy 

Proportion of patients with ORR (= CR + CRi) per 
Investigator assessment in pALL patients during 12 
months post-reinfusion

EFS, i.e. the time from date of tisagenlecleucel 
reinfusion to the earliest of relapse, treatment failure, or 
death

OS, i.e. the time from date of tisagenlecleucel re-infusion 
to the date of death due to any reason

Safety parameters including adverse events and 
laboratory abnormalities
3
Study design
A phase II, open label, multi-center trial to determine the efficacy and safety of tisagenlecleucel
re-infusion in pediatric and AYA patients with acute lymphoblastic leukemia experiencing loss 
of B-cell aplasia. The patient population for this study will be comprised of 49 evaluable 
patients up to and including 25 years of age who have been previously infused with commercial 
tisagenlecleucel and have an additional dose of commercial tisagenlecleucel available and 
prescribed by a physician in the course of medical practice
Additionally these patients must have loss of B-cell aplasia defined as: 

Peripheral blood (PB) absolute B lymphocyte count ≥ 50/µL, OR

PB B lymphocyte ≥ 10% of the total lymphocytes 
Efficacy in this setting will be defined as establishing B cell aplasia.
The efficacy of the following sub populations will also be evaluated:
1. Patients with a loss of B-cell Aplasia within 9 months of first infusion AND are MRD (+) 
at time of enrollment
2. Patients with a loss of B cell aplasia very early (<3months), early (≤3 to <6months) and 
later (≥6 months) following first infusion
The study will have the following sequential phases for all patients: Screening (Section 8.1.1), 
Treatment and Follow-up (Section 8.1.5). The total duration of the study is about 12 months. 
After tisagenlecleucel re-infusion, efficacy will be assessed at months 1, 3, 6, and 12. Safety 
will be assessed throughout the study. 
The end of the study will be when all patients complete a month 12 visit unless discontinuing 
prior as outlined in Section 9.1. The patient may voluntarily withdraw from the study for any 
reason, at any time. Patients who receive commercial tisagenlecleucel must be followed for up 
to 15 years post-infusion. Patients can be followed under the Center for International Blood and 
Marrow Transplant Research (CIBMTR) cellular therapy registry if consented for participation. 
For patients who do not provide consent for participation in the Center for International Blood 

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and Marrow Transplant Research (CIBMTR) registry, AEs will need to be reported as outlined 
in Table 16-1 per the Safety Reporting guidelines of 15 years or until the patient enrolls in the 
registry.
Figure 3-1
Study Design
4
Rationale
4.1
Rationale for study design
4.1.1
Rationale for lymphodepletion
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T-cell 
proliferation (Dummer et al 2002), a finding that naive T-cells begin to proliferate and 
differentiate into memory-like T-cells when total numbers of naive T-cells are reduced below a 
certain threshold (Goldrath 1999, Surh 2000). Host lymphodepletion may enhance the 
effectiveness of adoptively transferred T-cells (Dummer et al 2002). Homeostatic T-cell 
proliferation can lead to activation of certain immune cell subsets (King et al 2004), providing 
a clue to improved anti-tumor responses. T-cells can undergo up to seven rounds of cell division 
after being deprived of contact with antigen presenting cells (Kaech 2001, van Stipdonk 2001).
Lymphodepletion eliminates regulatory T-cells and other competing elements of the immune 
system that act as “cytokine sinks”, enhancing the availability of cytokines such as IL-7 and IL-
15 (Klebanoff et al 2005). Data indicates that the increased anti-tumor 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 lymohodepleting 
regimen with CD19 CAR-T cell therapies. It has been demonstrated that addition of fludarabine 
to cyclophosphamide increases CAR-T cell expansion and persistence and improves disease 
free survival rates in adult patients with r/r B-ALL (Turtle et al 2016).
In previous and ongoing studies with tisagenlecleucel most of the patients received 
lymphodepleting therapy with fludarabine and cyclophophamide and around 20% of DLBCL 
patients received bendamustine.

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4.1.2
Rationale for choice of background therapy
Please refer to Section 1.1
4.2
Rationale for dose/regimen and duration of treatment
The approved dose range for tisagenlecleucel is: 

0.2 to 5.0×106 CAR positive viable T cells / kg for patients < 50 kg or 

to 2.5×108 CAR-positive viable T cells for patients > 50 kg. 
[Refer to the Kymriah Product Information]
Please see [tisagenlecleucel Investigator’s Brochure] for further information on tisagenlecleucel 
dosing in preclinical and clinical studies.
4.3
Rationale for choice of control drugs 
Not applicable 
4.4
Purpose and timing of interim analyses
No formal interim analysis will be performed for this study. As required, interim analyses may 
be performed every six months for publication purpose. 
Please refer to Section 12.7 Interim Analysis.
4.5
Risks and benefits
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as specific 
dose modification and stopping rules, are included in this protocol. Recommended guidelines 
for prophylactic or supportive management of tisagenlecleucel induced AEs are provided in 
Appendix Table 16-1.
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring. [Refer to the Kymriah Product 
Information]
As of 26-Mar-2019, tisagenlecleucel has been administered to over 579 patients in clinical trials 
across the dose ranges tested, and has a well characterized safety profile in pediatric and young 
adult patients. Overall, it is anticipated that the benefits of tisagenlecleucel therapy, including 
complete and long-term remissions when compared to the current standards of care, will 
outweigh the risks in this study.
Safety risks that have been identified with the use of tisagenlecleucel or are considered 
potentially associated with tisagenlecleucel are briefly outlined below.
Poor tisagenlecleucel persistence and early loss of B-cell aplasia within 6 months of 
tisagenlecleucel infusion are associated with higher risk of relapse. Patients with early B-cell 
recovery usually proceed to other experimental CAR-T cell therapies or allogeneic 
hematopoietic stem cell transplant (allo-SCT). Allo-SCT is associated with significant 
morbidity and mortality, particularly in patients who had received prior allo-SCT. Additionally, 

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subsequent allo-SCT may not be feasible in some patients because of the lack of a suitable 
donor or ineligibility due to co-morbidities (Crotta 2017).
Reinfusion of one or more additional dose/s of tisagenlecleucel can restore B cell aplasia in 
some patients with early evidence of poor persistence or B-cell recovery (by extending 
persistence) and improve durable remission rates (Maude 2016). If successful, patients may not 
require subsequent therapies and/or allo-SCT. 
Data from clinical trials revealed that the baseline pre-infusion disease burden correlates with 
the severity of CRS; a higher disease burden was significantly associated with severe CRS
(Maude 2014). Patients with B-cell recovery without evidence of overt disease relapse are at 
lower risk for severe CRS and other complications with tisagenlecleucel reinfusion. Although, 
in the setting of overt relapse, the risk of severe CRS is increased, consistent with reported 
incidence in the safety section.
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 such as IFNg, IL-6 and TNF are released by 
activated T cells or activated monocytes/macrophages. Cytokine release syndrome, including 
fatal or life-threatening events, has been frequently observed after tisagenlecleucel infusion, in 
particular if associated with concomitant infections. In almost all cases, development of 
cytokine release syndrome occurred between 1 to 10 days (median onset 3 days) after 
tisagenlecleucel infusion. The median time to resolution of cytokine release syndrome was 7 
days.
CRS shows a wide range of clinical signs and symptoms (Table 4-2) and is graded according 
to the Lee Criteria (Table 4-1) (Lee et al. 2014). In the setting of more severe CRS following 
CAR-T-cell therapy, AEs of macrophage activation syndrome (MAS) and hemophagocytic 
lymphohistiocytosis (HLH) have also been reported. Both HLH and MAS have similar clinical 
manifestations as CRS, irrespective of the underlying cause, and encompass a group of severe 
immunological disorders characterized by hyperactivation of macrophages and lymphocytes, 
pro-inflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-
mediated multiorgan failure (Neelapu et al 2018). Patients, who experienced severe CRS, 
showed a clinical phenotype that resembles MAS or HLH including high fever, multi-organ 
dysfunction or CNS disturbances that is further evidenced by similar laboratory findings of 
abnormal macrophage activation, high serum levels of ferritin, lactate dehydrogenase and 
soluble CD25, low fibrinogen, and cytokine profile. Thus, HLH/MAS might not only belong to 
a similar spectrum of hyper-inflammatory disorders as CRS, but could be interpreted as 
manifestations of CRS of higher severity (Teachey et al 2018).
Risk factors for severe CRS in pediatric and young adult B-ALL patients are high pre-infusion 
tumor burden, uncontrolled or accelerating tumor burden following lymphodepleting 
chemotherapy, active infection and early onset of fever or CRS following tisagenlecleucel 
infusion. 

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In pediatric ALL and adult DLBCL patients, high tumor burden is a risk factor for developing 
severe CRS. In the ongoing clinical study B2202 in pediatric and young adult B-cell ALL 
(N=75), CRS was reported in 77% of patients (47% with Grade 3 or 4). Two deaths occurred 
within 30 days of tisagenlecleucel infusion: one patient died with CRS and progressive 
leukaemia and the second patient had resolving CRS with abdominal compartment syndrome, 
coagulopathy and renal failure when death occurred due to an intracranial haemorrhage. In the 
ongoing DLBCL clinical study C2201 (N=111), CRS was reported in 58% of patients, (22% 
with Grade 3 or 4).
Table 4-1
Clinical signs and symptoms associated with CRS (Lee et al 2014)
Organ system
Symptoms
Constitutional
Fever ± rigors, malaise, fatigue, anorexia, myalgia, arthralgia, nausea, vomiting, 
headache
Skin
Rash
Gastrointestinal
Nausea, vomiting, diarrhea
Respiratory
Tachypnea, hypoxemia
Cardiovascular
Tachycardia, widened pulse pressure, hypotension, increased cardiac output 
(early), potentially diminished cardiac output (late)
Coagulation
Elevated D-dimer, hypofibrinogenemia ± bleeding
Renal
Azotemia
Hepatic
Transaminitis, hyperbilirubinemia
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 6-3 
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 adverse reactions
Neurological events, including events indicative of encephalopathy and delirium of non-
infectious origin, have been observed in patients following various types of T cell directed 

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therapy including tisagenlecleucel and other CAR-T cell therapies of other institutions. The 
pathophysiology for neurological events, in particular in case of late events, 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 obvious predictors of 
neurologic toxicity. Confounders, such as preceding or newly induced anti-cancer treatment 
regimens, might be involved.
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 cytokine release syndrome (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 Blood and Marrow Transplantation (ASBMT) 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 4-3) which incorporates key aspects of the mini-mental status 
exam via the Immune effector Cell-associated Encephalopathy (ICE) score (Table 4-4).
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 events after tisagenlecleucel infusion can be concurrent with 
CRS, following resolution of CRS or in the absence 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. Delayed onset of neurological events may also occur as 
CRS is resolving or after CRS has completely resolved.

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In pediatric and young adult B-cell ALL patients, manifestations of encephalopathy and/or 
delirium occurred in 40% of patients (13% were Grade 3; no grade 4 were observed) within 8 
weeks after tisagenlecleucel infusion. In DLBCL patients, manifestations of encephalopathy 
and/or delirium occurred in 21% of patients (12% were Grade 3 or 4) within 8 weeks after 
tisagenlecleucel infusion.
The causality assessment of neurological events in patients treated with tisagenlecleucel can be 
confounded, as CNS toxicity can be associated with chemotherapy used for lymphodepletion 
and the presence of co-morbid conditions such as CRS, fever and infections.
Table 4-3
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
Grading for children (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, and 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)

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§ Tremors and myoclonus associated with immune effector cell therapies may be graded according to 
CTCAE v5.0 but they do not influence ICANS grading.
# 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 (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?
For the management of neurological adverse reactions see Section 6.6.2.2
4.5.1.3
Infections
There is an increased risk and severity of infections in patients with longer and more intense 
immunosuppression. Patients treated with tisagenlecleucel are at risk of infection for several 
reasons: 

Underlying bone marrow disease or dysfunction increases the risk of infections. 

Patient with prolonged and profound immunosuppression are 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.

B-cell depletion is known to be associated with hypo- or agammaglobulinemia that 
contributes to the risk.

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Serious infections were observed in patients after tisagenlecleucel infusion, some of which were 
life-threatening or fatal.
4.5.1.3.1 Viral Reactivation
Patients with active hepatitis B or active hepatitis C or HIV positive have been excluded from 
clinical studies with tisagenlecleucel. Patients with prior hepatitis B or C have the potential risk 
of viral reactivation and the risk of fulminant hepatitis, hepatic failure and fatal outcome. 
Subjects with active or prior hepatitis B, hepatitis C or HIV confirmed by serology will not be 
enrolled in the study; for detailed exclusion criteria see Section 5.2, for serology assessment see
Table 16-1 
A therapeutic strategy for the management of infections 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 
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 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
Prolonged depletion of normal B cells/agammaglobulinemia
Since normal B-cells express CD19, B-cell aplasia is an expected on-target toxicity of a 
successful CD19-directed CAR T cell therapy, and a useful surrogate reflecting the persistence 
of CAR T cells and effectiveness of treatment. B-cell aplasia is observed in all responding 
patients. 
Loss of B-cells can result in hypo- or agammaglobulinemia, potentially rendering the patients 
more susceptible to infections, especially with encapsulated organisms; and viral reactivation 
such as herpes viruses or rarely in progressive multifocal leukoencephalopathy (PML).
Given that a typical T-cell may have a lifespan of 40 years, tisagenlecleucel may potentially be 
detectable in a patient for a very prolonged period and prolonged depletion of B-cells may occur, 
in particular in the subset of patients who continue to demonstrate a tumor response. Long term 
data are currently not available. 

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The AEs observed after tisagenlecleucel infusion were managed well by treatment with 
immunoglobulins. 
A therapeutic strategy for the management of B-cell depletion with resulting hypo-
gammaglobulinemia is provided in Section 15.
4.5.1.6
Hematopoietic cytopenias not resolved by Day 28
Hematopoietic cytopenias are an on-target effect after tisagenlecleucel infusion and 
tisagenlecleucel activity also targeting normal B-cells. Prolonged hematocytopenias not 
resolved by Day 28 are considered a consequence. The etiology of the cytopenias may be either 
the CAR-T-cell therapy per se or prior anti-cancer treatment, such as chemotherapy (i.e., 
multiple lines and cycles), radiation, and lymphodepleting chemotherapy or a combination 
(Brudno and Kochenderfer 2016), exerting cytotoxic effects. Prolonged neutropenia has been 
associated with increased risk of infection. A therapeutic strategy for the management of 
hematopoietic cytopenias is provided in Section 6.6.2.2. 
4.5.1.7
Febrile neutropenia
Febrile neutropenia and associated events such as grade 3 or grade 4 decreased neutrophil 
counts with elevated temperature were reported in clinical studies with tisagenlecleucel. The 
use of chemotherapy is known to be associated with the risk of neutropenia and if severe, with 
febrile neutropenia. The risk of neutropenia depends on various factors such as type and dose 
of chemotherapy used, age, gender, performance status and baseline hematology lab data. As 
lymphodepleting therapy is used in all patients with a WBC count > 1000 cells/μL, febrile 
neutropenia is seen in patients treated with tisagenlecleucel regimen. Also, as lymphodepleting 
therapy is given close to the infusion of tisagenlecleucel (within two weeks), therefore, 
overlapping toxicities can be expected.
A therapeutic strategy for the management of febrile neutropenia is provided in Section 6.6.2.7.
4.5.1.8
Hypersensitivity including acute infusion reactions
Hypersensitivity reactions may also occur due to the excipients (such as dimethyl sulfoxide 
(DMSO) or dextran 40) of the infused solution in which the cells are dispersed. Clinically, 
hypersensitivity reactions can be classified as 'immediate' or 'delayed' depending on their onset 
after drug administration (Corominas et al 2014; Limsuwan and Demoly 2010). In principle, 
immediate reactions including acute infusion reactions occur within less than 1 hour after drug 
administration and may present in a wide range of symptoms such as fever, chills, nausea, 
urticaria, angioedema, rhinitis, conjunctivitis, dyspnea, bronchospasm, tachycardia, 
hypotension, anaphylaxis or anaphylactic shock. Delayed hypersensitivity reactions appear 
after more than 1 hour and up to several days after drug exposure and could include variable 
cutaneous symptoms such as late-occurring urticaria, maculopapular eruptions, fixed drug 
eruptions, vasculitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, or drug reaction 
with eosinophilia and systemic symptoms (DRESS) (Averbeck et 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.

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A therapeutic strategy for the management of hypersensitivity including acute infusion 
reactions is provided in Section 6.6.2.8.
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.
4.5.3
Cerebral edema
Fatal cases of cerebral edema, soon after infusion with rapid evolution, have been reported with 
CAR-T cell therapies other than tisagenlecleucel (CTL019); in five subjects in the ROCKET
study evaluating JCAR015 for the treatment of ALL and in one subject in the Zuma-1 study 
evaluating KTE-19 for the treatment of CLL. The subject in the ZUMA-1 study is described as 
becoming febrile on Day 1 and progressing from Grade 3 to Grade 4 CRS, refractory to 
tocilizumab and dexamethasone, by Day 4. Cerebral edema developed on Day 9, was refractory 
to siltuximab and mannitol, and led to death on Day 11 (Turtle et al 2017).
No fatal cerebral edemas have been reported following tisagenlecleucel infusion in the clinical 
development program or the post-marketing setting to date that would resemble five fatal events 
reported for JCAR015.
4.5.3.1
Generation of replication competent lentivirus (RCL) 
Replication-competent lentivirus (RCL) may be generated during tisagenlecleucel 
manufacturing using a lentiviral vector to encode anti-CD19 CAR or subsequently after 
introduction of vector transduced viable T cells into the patient. 
However, an RCL resulting from manufacturing is highly unlikely since elements are 
incorporated in the design of the vector system that minimize vector recombination and 
generation of RCL. Furthermore, the vector used to transduce the product undergoes sensitive 
assays for detection of RCL thus patients will only receive cell products that meet RCL release 
criteria considered sufficient to confirm the absence of RCL in tisagenlecleucel and the 
negligible probability of de novo generation of any RCL.As per guidance for gene therapy 
medicinal products, patients exposed to tisagenlecleucel will be monitored for 15 years 
following last treatment for vectors persistence. RCL is not specifically being evaluated in the 
CIBMTR or EBMT Cellular Therapy Registry (Novartis Study CCTL019B2401) for long term 
follow up; however, pharmacovigilance for potential consequences (e.g. malignancies, 
autoimmune diseases) will be reported.
The management of this potential risk is addressed in Section 6.6.
4.5.3.2
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 (Friedman et al 2010). The rate of new malignancy 

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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 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 (UPenn) / Children’s Hospital of Philadelphia with CTL019 as 
manufactured by UPenn. 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. can be considered low with the current Novartis manufacturing 
process.
Tisagenlecleucel uses third generation self-inactivating lentiviral vector to safeguard against 
the potential oncogenic effects. Insertional mutagenesis was evaluated in two lentivirus 
insertion site analysis (LISA) studies where 12 batches of manufactured patient product ready 
for infusion and two batches of product manufactured from healthy donor cells were analyzed. 
The results indicate that there was no preferential integration near genes of concern, no 
preferential sites of integration (hot spots), and no preferential outgrowth of cells harboring 
integration sites of concern.
Tisagenlecleucel is based on autologous, fully differentiated T cells and therefore the 
carcinogenicity risk is considered to be low in comparison to genetic modification or repair 
such as HSC gene therapy. In a recent review of CAR-T cell therapies, Bonifant et al (2016) as 
well as Mohanlal et al (2016) discussed that to date no cases of malignant transformation have 
been reported for genetic modification of T cells and that there currently is no evidence for 
vector-induced immortalization, clonal expansion, or enrichment for integration sites near 
genes implicated in growth control or transformation. This is supported by the results of the 
lentivirus insertion site analysis (LISA) studies performed during the development of 
tisagenlecleucel.
Theoretically, CAR-positive viable T cells could proliferate without control of normal 
homeostatic mechanisms. In pre-clinical studies (Milone et al 2009) and clinical experience to 
date (Porter et al 2011, Grupp et al 2013, Maude et al 2014), CAR-positive viable T cells have 
only proliferated in response to physiologic signals or upon exposure to CD19 antigen. In the 
context of tisagenlecleucel therapy, it is expected that the T cells will proliferate in response to 
signals from the CD19 expressing malignant tumor and normal B cells. This could be either 
harmful depending on the extent of proliferation or beneficial, since clonal dominance of 
adoptively transferred T cells has been associated with tumor reduction in adoptive transfer 
trials (Dudley 2002, Dudley 2005). 

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The management of this potential risk is addressed in Section 6.6
4.5.3.3
New occurrence or exacerbation of an autoimmune disorder
An emerging number and variety of autoimmune diseases following after anti-cancer treatment 
including immunotherapy are reported, ranging from asymptomatic immunological alterations 
to life-threatening systemic autoimmune diseases (Pérez-De-Lis et al 2017). However, specific 
etiopathogenic mechanisms that could clearly link the induced autoimmune disorder with the 
immunological pathways altered by the anti-cancer treatments are not well understood. 
Persistent immune abnormalities after treatment with chemotherapy, development of auto-
antibodies and neoantigens are proposed to be crucial in the pathogenesis of autoimmune 
diseases post anti-cancer treatment (Descotes and Gouraud 2008, Chang and Gershwin 2010, 
Amos et al 2011).
The risk of autoimmune reaction with tisagenlecleucel is low since CD19 is not present on most 
normal tissue other than normal B-cells. New occurrence or exacerbation of an autoimmune 
disorder has not been observed with tisagenlecleucel thus far. 
4.5.3.4
Hematologic disorders (incl. aplastic anemia and bone marrow failure)
There is potential risk of a hematologic disorder such as 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.
4.5.3.5
Aggravation of graft versus host disease (GVHD)
The chance of graft versus host disease (GVHD) occurring in patients after tisagenlecleucel
infusion is low, but there is a potential risk of aggravation of preexisting GVHD in patients with 
mixed chimerism of host and donor hematopoietic cells due to prior allogeneic HSCT. A study 
of activated donor lymphocyte infusions (ex vivo activated cells collected from the donor and 
grown in the same fashion as tisagenlecleucel but without the CAR introduction) did not show 
high rates of GVHD (2/18 patients with grade 3 GVHD and none with grade 4) (Porter et al 
2006). Of 18 ALL patients treated with autologous tisagenlecleucel therapy who had relapsed 
after prior allogeneic HSCT with residual mixed chimerism, none have developed GVHD after 
autologous tisagenlecleucel infusion (Maude et al 2014). Long term data are currently limited.
For the management of GVHD see Section 6.6.2.11 
4.5.3.6
Transmission of infections agents
Transmission of infections 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 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 

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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. 
4.5.3.7
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 [Kymriah Package Insert].
4.5.4
Other risks
4.5.4.1
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. The human placenta forms an 
incomplete barrier for blood cells, allowing bidirectional passage of nucleated blood cells. 
Circulating maternal cells transfer to the fetus during pregnancy, where they may integrate with 
the fetal immune and organ systems, creating a state of maternal microchimerism (MMc) 
(Loubiere et al 2006, Stevens 2016). Hence, there is a potential risk that immunologically active 
maternal tisagenlecleucel positive T-cells may cross the placenta. Currently, the potential 
impact of tisagenlecleucel on the offspring’s B-cells such as inducing B-cell lymphocytopenia 
or other potential toxicities such as effects on the development of autoimmune disease (see 
below) is not known.
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.

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5
Population
The target population consists of pediatric and adolescent young adult patients up to and 
including 25 years of age with B-cell ALL who have been previously infused once with 
tisagenlecleucel and have a loss of B-cell aplasia. Approximately 54 subjects will be enrolled 
to allow 49 subjects treated. 
The investigator or designee must ensure that only subjects 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
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Must have an additional dose of unexpired, commercial tisagenlecleucel available and 
prescribed by a physician in the course of medical practice. 
2. Signed informed consent must be obtained prior to participation in the study.
3. Age up to and including 25 years at the time of ICF signature 
4. Patients must have CD-19+ Leukemia
5. Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at 
screening
6. Patients who were previously treated with commercial tisagenlecleucel and present with 
evidence of B-cell recovery as defined by: 
a. Peripheral blood (PB) absolute B lymphocyte count ≥ 50/µL, OR
b. PB B lymphocyte ≥10% of the total lymphocytes 
7. Subjects must meet the following hematological values without transfusion at Screening:

Absolute neutrophil count (ANC) ≥ 1,000/mm3 (≥ 1×109/L)

Absolute lymphocyte count (ALC) > 300/mm3 (> 0.3×109/L) 

Absolute number of CD3+ T cells > 150/mm3 (> 0.15×109/L)

Platelets ≥ 50 000/mm3 (≥ 50×109/L)

Hemoglobin ≥ 8.0 g/dl (≥ 4.9 mmol/L)
8. A serum creatinine of ≤ 1.5 times ULN or eGFR ≥ 60 mL/min/1.73 m2
9. Adequate pulmonary function defined as:

No or mild dyspnea (≤ Grade 1)

Oxygen saturation measured by pulse oximetry > 90% on room air
10. Liver function tests including the following:

ALT or AST ≤ 5 times the ULN

Total bilirubin < 2mg/dl (with the exception of subjects with Gilbert’s syndrome. 
Subjects with Gilbert’s syndrome may be included if their total bilirubin is < 4mg/dl). 
5.2
Exclusion criteria
Subjects eligible for this study must not meet any of the following criteria:
1. Prior gene therapy other than tisagenlecleucel

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2. Prior adoptive T cell therapy other than tisagenlecleucel
3. Active CNS involvement by malignancy
4. Systemic chemotherapy or radiotherapy within 2 weeks prior to enrolment or tyrosine kinase 
inhibitors (for patients with Philadelphia chromosome positive ALL) within 1 week prior to 
enrolment.
Notes: 

Non-hematologic toxicity from prior treatment must be resolved to CTCAE grade 1 
or better. 

The use of hydroxyurea is permitted for temporary control of WBC elevations in 
patients with aggressive disease both prior and during the first 7 days after enrolment.

The use of corticosteroids within one week prior to enrolment is also allowed
5. Presence of active or prior hepatitis B or C as indicated by serology (for detailed criteria see 
Table 16-2). Serology must be repeated, if the interval between testing at Screening and 
tisagenlecleucel infusion exceeds 8 weeks.
6. HIV positivity as indicated by serology. Serology must be repeated, if the interval between 
testing at screening and tisagenlecleucel infusion exceeds 8 weeks.
7. Clinically significant acute infection confirmed by clinical evidence, imaging, or positive 
laboratory tests within 72 hrs prior to tisagenlecleucel infusion (e.g., blood cultures, PCR 
for DNA/RNA, etc.).
8. Previous or concurrent malignancy except for curatively treated non-melanoma skin cancers, 
in situ carcinoma (e.g. cervix, breast, bladder, prostate), and cancers in complete remission 
for at least 3 years and without evidence of recurrence.
9. Pregnant or nursing (lactating) women. NOTE: Women of child-bearing potential must have 
a negative serum pregnancy test performed within 24 hours before lymphodepletion (if 
performed) and prior to tisagenlecleucel infusion.
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they agree to use 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 (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject

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
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 enrollment into this study.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six 
weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow up hormone level assessment is she considered not 
of child bearing potential.
NOTE: If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
11. Sexually active males must 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. 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. 
12. Known hypersensitivity to the excipients of tisagenlecleucel or to any product to be given 
to the patient as per the study protocol (e.g. tocilizumab and lymphodepleting agents)
13. Any study procedure (e.g., lumbar puncture) that, in the investigator’s judgment and/or 
according to clinical standards, is a contraindication to participation in the study.
14. Cardiac disorders including 

Unstable angina and/or myocardial infarction within 6 months prior to screening

History of myocardial infarction (MI), unstable angina pectoris, or coronary artery bypass 
graft (CABG) within 6 months prior to screening 

Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and 
third degree AV block)

LVEF <45% as determined by ECHO or MRA or MUGA

NYHA functional class III or IV (Chavey et al 2001)
15. Subjects enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies

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6
Treatment
6.1
Study treatment
A second dose of commercial tisagenlecleucel is not considered study treatment because it is 
released commercially to the treating physician when it is prescribed in the course of medical 
practice. The doses available for reinfusion were previously manufactured for each individual 
patient as commercial product and a physician can request an additional dose for commercial 
release at any time, prior to product expiration and subject to availability. 
Tisagenlecleucel is an autologous cellular immunotherapy product that is comprised of CD3+ 
T-cells that have undergone ex vivo T-cell activation, gene modification, expansion and 
formulation in infusible cryomedia. The transgene to be expressed via lentiviral vector 
transduction is a CAR targeted against the CD19 antigen. The CAR contains a murine scFv that 
targets CD19 linked to a transmembrane region derived from the CD8 receptor, which is linked 
to an intracellular bipartite signaling chain of TCR-ζ (or CD3-ζ) and 4-1BB intracellular 
signaling domains. The extracellular scFv with specificity for CD19 is derived from a mouse
monoclonal antibody. T-cells which are enriched from a 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. 
Tisagenlecleucel will be expanded ex vivo. At the end of the culture, the tisagenlecleucel is 
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 [Kymriah Package Insert] and the current version of the 
[tisagenlecleucel Investigator's Brochure].
Table 6-1
Drug Supply 
Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor 
(global or 
local)
A Commercially 
available second 
dose of 
tisagenlecleucel
prescribed at the 
discretion of the 
treating physician in 
the course of 
medical practice
Cell dispersion 
Intravenous use
Open label, 
Commercial; infusion 
bags
Local 
6.1.1
Investigational and Control Drugs
Not applicable

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6.1.1.1
Decentralized Clinical Trial Model (US sites only)
Not applicable
6.1.1.2
Bio-batch retention samples
Not applicable
6.1.2
Pre-infusion evaluation 
If any of the following criteria is met tisagenlecleucel infusion must be delayed until resolution 
to grade 1. If the period of delay is more than 4 weeks from completing lymphodepletion and 
there is no significant cytopenia (see Section 6.1.6) Lymphodepletion should be repeated, and 
these criteria will need to be re-checked prior to tisagenlecleucel infusion.
1. Rapidly progressing primary disease (e.g. leukemia/lymphoma) 
2. Clinical evidence of CNS involvement by primary disease
3. Laboratory abnormalities that, in the opinion of the investigator, may impact subject safety 
or the subjects’ ability to receive tisagenlecleucel.
4.
Following clinical abnormalities:

Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 
90% or presence of progressive radiographic abnormalities on chest x-ray

Cardiac arrhythmia not controlled with medical management

Hypotension requiring vasopressor support

Clinically significant active infection confirmed by clinical evidence, imaging, or 
positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.). NOTE: All 
viral serology must be repeated, if the interval between testing prior to 
lymphodepletion and tisagenlecleucel infusion exceeds 8 weeks.
5. A significant change in clinical status that would, in the opinion of the investigator, increase 
the risk of adverse events associated with tisagenlecleucel
6. Toxicities from chemotherapy (including lymphodepletion).
7.
Prohibited medications as described in section 6.2.1 
8. 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.

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9. Live vaccines must not be used in tisagenlecleucel recipients for at least 6 weeks prior to 
the start of lymphodepleting chemotherapy, during tisagenlecleucel treatment, and until 
immune recovery following treatment with tisagenlecleucel.
10. Women of child-bearing potential must have a negative serum pregnancy test performed 
within 24 hours prior to tisagenlecleucel infusion. 
6.1.3
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 and uric acid. Subjects with elevated uric acid or high tumor burden will 
receive prophylactic allopurinol, or a non-allopurinol alternative (e.g. febuxostat). 
Infections
Infection prophylaxis with regard to lymphodepletion and other additional treatments should 
follow local guideline. As appropriate, prophylactic antibiotics should be administered and 
surveillance testing should be employed prior to and during treatment with tisagenlecleucel.
Cytokine Release Syndrome
Prior to tisagenlecleucel infusion at least 2 doses of tocilizumab per patient (for the first 3 weeks 
after tisagenlecleucel infusion) must be confirmed as available. Hospitals should have timely 
access to additional doses of tocilizumab for the management of CRS related adverse events
(see Section 6.6.2.1/ Cytokine Release Syndrome (CRS) for details).
Premedication
To minimize potential acute infusion reactions, 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 pre-medication. It is recommended that subjects NOT receive 
systemic corticosteroids other than physiologic replacement, except for serious emergency, 
since this may have an adverse effect on tisagenlecleucel expansion and function.
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 6.2.1

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6.1.4
Additional study treatments
Lymphodepletion
If patients have a White Blood Cell (WBC) count ≤ 1,000 cells/µL within one week prior to 
tisagenlecleucel infusion, lymphodepleting chemotherapy is NOT required.
The availability of tisagenlecleucel must be confirmed prior to starting the lymphodepleting 
regimen. 
Tisagenlecleucel should be infused 2 to 14 days after lymphodepletion depending on the 
lymphodepleting regimen. If there is a delay of more than 4 weeks between completing 
lymphodepleting chemotherapy and the infusion and the WBC count is >1,000cells/μL, the 
patient should be re-treated with lymphodepleting chemotherapy prior to receiving 
tisagenlecleucel. 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 
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). 
Alternative lymphodepletion for pediatric studies:

Cytarabine 500 mg/m2 i.v. daily for 2 days and 

Etoposide 150 mg/m2 i.v. daily for 3 days starting with the first dose of cytarabine
Female patients of childbearing potential must have a negative pregnancy test within 24 hours 
prior to the start of lymphodepleting therapy. If the patient does not require lymphodepleting 
therapy, she should still have a negative pregnancy test at the required visit that takes place 24 
hours prior to tisagenlecleucel infusion.Treatment arms/group
Not applicable
6.1.6
Guidelines for continuation of treatment
Not applicable

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6.1.7
Treatment durationA single dose of tisagenlecleucel will be given within 30 
minutes of thawing. For more details please refer to [Kymriah Package Insert].
6.1.8
Tisagenlecleucel dosing regimen
The approved dose range for tisagenlecleucel is: 0.2 to 5.0×106 CAR positive viable T cells / 
kg for patients’ ≤ 50 kg body weight or 0.1 to 2.5×108 CAR-positive viable T cells for patients > 
50 kg body weight. For more details please refer to [Kymriah Package Insert].
6.1.8.1
Treatment beyond disease progression
Not applicable
6.2
Other treatment (s)
6.2.1
Concomitant therapy
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 and on the appropriate CRF. During selected 
trial phases, concomitant medication collection will be modified as outlined in Appendix 2: 
Tisagenlecleucel Modified Data Reporting and CRF Completion Guidelines (CCGs). Modified 
collection of concomitant medication information during these periods is designed to capture 
tisagenlecleucel-related toxicity, severity, interventions and response/resolution following 
intervention. Any additions, deletions, or changes of these medications will be documented. 
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject has signed the ICF into the study must be 
recorded on the appropriate Case Report Forms.
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 
including a subject in the study or allowing a new medication to be started. If the subject is 
already included, contact Novartis/sponsor 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 patients 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 (e.g., events such as febrile neutropenia or hematopoietic 
cytopenias). Cytokine release syndrome/MAS 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 patients. Revised inpatient data 

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capture will be utilized for this study to systematically collect subsets of patient data to describe 
the management of safety events associated with tisagenlecleucel therapy for the purpose of:

Adequately informing physicians and patients 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. 
6.2.1.2
Permitted concomitant therapy requiring caution and/or action
Not Applicable
6.2.2
Prohibited medication and non-drug therapies
The patient must be told to notify the investigational site about any medications he/she takes. 
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered during the study must 
be listed on the appropriate CRFs.
Medication restrictions prior to leukapheresis
Not Applicable
Medication restrictions prior to tisagenlecleucel infusion
1. Steroids: Therapeutic doses of steroids must be stopped >72 hours or 5 half-lives, 
whichever is greater, prior to tisagenlecleucel infusion. However, the following 
physiological replacement doses of steroids are allowed: <12 mg/m2/day hydrocortisone 
or equivalent
2. Steroids or other immunosuppressant drugs should NOT be used as pre-medication for 
tisagenlecleucel therapy (refer to Section 6.2.1/ Pre-Infusion Evaluation) or following 
tisagenlecleucel infusion, except as required for physiological glucocorticoid replacement 
therapy, or under life threatening circumstances. Use of steroids with blood product 
administration should be avoided just prior to and following tisagenlecleucel if possible or 
at least minimized.
3. CNS disease prophylaxis or intrathecal therapy must be stopped > 1 week prior to 
tisagenlecleucel infusion (e.g. intrathecal methotrexate) 
4. Radiation therapy must be stopped > 2 weeks prior to tisagenlecleucel infusion 
5. Investigational therapies must not be used at any time while on study until the first 
progression following 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 
7. Granulocyte macrophage-colony stimulating factor has the potential to worsen CRS 
symptoms and is not recommended during the first 3 weeks after tisagenlecleucel infusion 
or until CRS has resolved. Short acting granulocyte colony stimulating factor (G-CSF) 

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should not be given 72 hours prior to tisagenlecleucel infusion and long acting G-CSF 
should not be given 10 days prior to tisagenlecleucel infusion.
8. Antiproliferative therapies, other than lymphodepletion including low dose daily or 
weekly maintenance chemotherapy) should not be used within 2 weeks prior to infusion.
9. Short acting drugs used to treat primary disease (e.g. hydroxyurea) must be stopped > 72 
hours prior to tisagenlecleucel.
6.2.3
Rescue medication
Refer to REMS safety and institutional SOPS for neurotoxicity and CRS management.
6.3
Subject numbering, treatment assignment 
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 
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. Upon signing the informed consent form, the patient is assigned to the 
next sequential Subject No. available to the investigator through the Clinical Data Management
System interface.
Once assigned, the Subject No. must not be reused for any other subject and the Subject No. for 
that individual must not be changed, even if the subject is re-screened. If the subject fails to 
start treatment for any reason, the reason will be entered into the appropriate CRF page
6.3.2
Treatment assignment
Not applicable
6.4
Treatment blinding
Not applicable
6.5
Dose escalation and dose modification
Not applicable
6.5.1
Dose modifications
6.5.1.1
Tisagenlecleucel dose modifications
Prior to administration of subsequent tisagenlecleucel doses, patient should not experience a 
significant change in performance or clinical status or laboratory values compared to initial 
eligibility criteria that would, in the opinion of the treating physician, increase the risk of 
potential side effects of infusion such as cytokine release syndrome. These patients should have 
their infusion delayed until the treating investigator determines it is clinically appropriate to 

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proceed with the tisagenlecleucel infusion. Doses of tisagenlecleucel may be delayed up to 14 
days. The dose changes and the reasons should be captured on the CRF.
6.5.1.2
Dose Modifications for comparator drugs
Not applicable
6.5.1.3
Dose adjustments for QTcF prolongation
Not applicable
6.5.2
Follow-up for toxicities
Not applicable
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 (EC) 1394/2007, the Directive 2004/23/EC as well 
as the rules and principles of the EU “Detailed guidelines on good clinical practice specific to 
advanced therapy medicinal products.” 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 product and the tisagenlecleucel batch, and the link between subject 
identity and unique subject identifier will be confirmed prior to infusion. The [Kymriah Package 
Insert] 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
6.6.2
Recommended treatment of adverse events 
Patients infused with tisagenlecleucel are at risk of developing a number of AE that are related 
either to tisagenlecleucel itself, other therapies (e.g. immunochemotherapy) and conditions 
concurrent with the 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. 

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Drug and non-drug therapies used to treat AEs must be recorded on appropriate CRFs.
Patients treated with tisagenlecleucel should not donate blood, organs, tissues, sperm, oocytes 
and cells.
6.6.2.1
Cytokine Release Syndrome (CRS)
Ensure that at least 2 doses of tocilizumab per patient 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. See full Prescribing 
Information to use tocilizumab safely and effectively [local Actemra Prescribing Information].
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 
patients for signs or symptoms of CRS for at least 4 weeks after treatment with tisagenlecleucel. 
Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur 
at any time. Subjects will be required to remain proximal to the treating site for the first 4 weeks.
At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment 
with supportive care, tocilizumab and/or corticosteroids as indicated.
A recommended treatment algorithm for the management of CRS and the definition of high 
dose vasopressors is presented below in Table 6-1 and Table 6-3, respectively. The CRS 
management algorithm is a guideline and the investigator may use discretion or modify the 
treatment approach as needed for an individual subject. 
Table 6-2
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. 
If neutropenic, 
administer antibiotics 
per local guidelines
Not applicable
Not applicable
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 
High-flow oxygen
Intravenous fluids and 
high-dose 
vasopressor/s
Treat other organ 
toxicities as per local 
guidelines

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CRS severity 
Symptomatic 
treatment
Tocilizumab 
Corticosteroids
vasopressors
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 6-3
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/min*
Vasopressin + NE ≥ 10 
mcg/min*
If on combination 
vasopressors (not 
vasopressin)
NE of ≥ 0.2 mcg/kg/min*
NE of ≥ 20 mcg/min*
§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: NE dose (weight-based 
dosing) = [norepinephrine (mcg/kg/minute)] + [dopamine (mcg/kg/minute) / 2] + [epinephrine (mcg/kg/minute)] + 
[phenylephrine (mcg/kg/minute) / 10] Reference: Per online institutional guideline by MD Anderson Cancer 
Center, Chimeric Antigen Receptor (CAR) Cell Therapy Toxicity Assessment and Management – Pediatric, dated 
30 Jan 2018.
Source: Adapted from Lee et al 2014, Lee et al 2015.
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. Ferritin, CRP and serum cytokine levels should NOT be used for clinical management 
decisions. Cases of transient left ventricular dysfunction, as assessed by ECHO, have been 
reported in some subjects with severe (Grade 4) CRS. Therefore consideration should be given 

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to monitoring cardiac function by ECHO during severe CRS, especially in cases with prolonged 
severe hemodynamic instability, delayed response to high dose vasopressors, and/or severe 
fluid overload.
6.6.2.2
Neurological adverse reactions 
Neurologic events, primarily reflective of encephalopathy and delirium, may occur after 
tisagenlecleucel infusion. These present clinically as signs and symptoms of varying severity 
including: 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. Patients 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 

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 applicable.

Chemistry laboratory testing 

EEG
Management 

If the neurological event is concurrent with CRS please refer to Table 6-2. CRS algorithm 
table for treatment recommendation.

Consider anti-seizure medications (e.g. 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 (Teachey, et. al 2018, Neelapu et. al 2018).
6.6.2.3
Infections
Patients with active, uncontrolled infection should not start tisagenlecleucel treatment until the 
infection is resolved. 
Patients should be monitored for signs and symptoms of infection and treated appropriately. As 
appropriate, prophylactic antibiotics should be administered and surveillance testing prior to 
and during treatment with tisagenlecleucel should be employed.
Institutional guidelines for vaccination (e.g., pneumococcus) should be followed before starting 
tisagenlecleucel therapy. As the lack of effective B cells after infusion makes the likelihood of 
a systemic infection considerable, vaccination with live virus vaccines should not be given for 

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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 patients with low immunoglobulin levels preventive measures such as immunoglobulin 
replacement and rapid attention to signs and symptoms of infection should be implemented as 
per age and local specific guidelines. 
6.6.2.4
Tumor Lysis Syndrome (TLS)
Patients should be closely monitored for signs and symptoms of TLS both before and after 
lymphodepleting chemotherapy and tisagenlecleucel infusion including relevant laboratory 
tests. To minimize risk of TLS, patients with elevated uric acid or high tumor burden should 
receive allopurinol, or an alternative prophylaxis, prior to tisagenlecleucel infusion as indicated. 
Subjects diagnosed with TLS should be managed according to local guidelines.
6.6.2.5
Prolonged depletion of normal B cells/ hypo- or agammaglobulinemia 
Monitor immunoglobulin levels after treatment with tisagenlecleucel, use infection precautions 
including antibiotic prophylaxis and immunoglobulin replacement as appropriate and per local 
standard of care.
6.6.2.6
Hematopoietic cytopenias not resolved by day 28
Hematopoietic 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.
Since myeloid growth factors, particularly granulocyte macrophage-colony stimulating factor 
(GM-CSF), have the potential to worsen CRS (if it occurs), these are not recommended during 
the first 3 weeks after tisagenlecleucel infusion or until CRS has resolved.
6.6.2.7
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 4.5.1.3) and CRS (section 6.6.2.1) and 
managed appropriately with fluids, antibiotics, and supportive care, if applicable. 
In the event that the patient develops sepsis or systemic bacteremia following tisagenlecleucel 
cell infusion, appropriate cultures and medical management should be initiated. If a 
contaminated tisagenlecleucel product is suspected, the product can be retested for sterility 
using archived samples that are stored at the manufacturing site. 
6.6.2.8
Hypersensitivity including acute infusion reactions
Patients should be monitored for signs and symptoms of hypersensitivity following initiation of 
tisagenlecleucel infusion and treated appropriately. Tisagenlecleucel is contraindicated in 
patients with known hypersensitivity to tisagenlecleucel or to any component of the product 
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As appropriate, prophylactic medications should be administered to minimize the risk of 
immediate hypersensitivity including acute infusion reactions. It is recommended to pre-
medicate all patients with acetaminophen (paracetamol) and diphenhydramine or another H1 
antihistamine within approximately 30-60 minutes prior to tisagenlecleucel infusion. These 
medications can be repeated every 6 hours as needed. Non-steroidal anti-inflammatory 
medication may be prescribed for fever not responding to acetaminophen. Steroids should not 
be used for premedication. Systemic corticosteroids should only be used for severe conditions.
Should emergency treatment be required in the event of life-threatening hypersensitivity or 
other infusion-related reaction, supportive therapy such as oxygen and drug treatment should 
be given according to local institutional guidelines. Patients should be evaluated and carefully 
monitored until complete resolution of signs and symptoms.
6.6.2.9
Generation of replication competent lentivirus (RCL)
The lentiviral vector has been designed to minimize the probability non-homologous 
recombination, thereby preventing the generation of a RCL, however, this remains a theoretical 
possibility. It will be detected by blood specimen, e.g., using Vesicular Stomatitis 
Virus/Glycoprotein (VSV-G) quantitative PCR. If a positive RCL assay result is obtained from 
a subject, the Investigator will be informed and the subject rescheduled for a retest of the DNA 
test.
Currently, it is not known, how to manage a subject with confirmed RCL and, therefore, should 
be addressed on a case by case basis. 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
6.6.2.10 Secondary malignancies (including vector insertion site 
oligo/monoclonality)
All secondary malignancy should be managed/treated according to current medical practice and 
local standard of care. 
For the follow-up of secondary malignancy, refer to Section 10.2.5
6.6.2.11 Aggravation of graft versus host disease (GVHD)
GVHD can be severe but can be controlled with steroids and other immunosuppressants as per 
local standard of care.
6.6.3
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
For details on the cryopreserved components, and the specific storage and handling 
requirements of the tisagenlecleucel product, see the [Kymriah Package Insert]. 

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6.7.1
Handling of Tisagenlecleucel
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. 
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 patient’s identity with the patient 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.
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.
The investigator must maintain an accurate record of the shipment and infusion of commercial 
tisagenlecleucel for all study participants 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. Please refer to [Kymriah Package Insert] for more information on disposal.
Any used infusion supplies, including the infusion bag(s) and tubing, must be disposed of 
according to local institutional standard operating procedures. For further details, please refer 
to the specific guidance provided in the [Kymriah Package Insert]. 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 
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 [Kymriah Package Insert].
6.7.2
Handling of additional treatment 
Not applicable
7
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.

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If applicable, in cases where the patient'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 (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH/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 tisagenlecleucel can be found in 
the Investigator's Brochure (IB) and [Kymriah Package Insert]. This information will be 
included in the subject informed consent and should be discussed with the patient during the 
study as needed. Any new information regarding the safety profile of the tisagenlecleucel that 
is identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the 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 patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the required assessments and it is indicated 
with an “X” at each visit when they are to be performed. All data obtained from these 
assessments must be supported in the patient’s source documentation. No CRF will be used as 
a source document. The tables indicate which assessments produce data to be entered into the 
clinical database (D) or remain in source documents only (S) (“Category” column). Patients 
should be seen for all visits/assessments as outlined in the assessment schedule (Table 8-1) or 
as close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Patients who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all adverse events and concomitant 
medications should be recorded on the CRF.

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Table 8-1
Assessment Schedule
Period
Category
Screening
Treatment
End of Study
Visit Name
Screening
Enrollment
Assessment Period
End of Study
Day/Week/Month
-28 to -1
D11
D28±7
M3±14
M6±14
M12±14
Obtain informed consent
D
X
Demography
D
X
Inclusion/exclusion criteria
D
X
Relevant medical history/ current 
medical history
D
X
Physical Exam
S
X
X
X
X
X
X
Height
D
X
Weight
D
X
X
X
X
X
X
Vital Signs
D
X
X
X
X
X
X
Karnofsky/Lansky Performance 
Scales
D
X
X
Serum Pregnancy Test (Table 8-4)
S
X
X
X
Urine Pregnancy Test (Table 8-4)
S
X
X
X
Hematology
D
X
X
X
X
X
X
Chemistry
D
X
X
X
X
X
X
HIV & Hepatitis B & C testing
D
X
Serum immunoglobulin levels (IgG, 
IgA, IgM)
S
X
Rapid influenza test
D
X3
B & T-Cells by Flow Cytometry –
D
X
X
X
X
CTL019 PK by qPCR- NAVIGATE
D
X
X
X
X
Bone Marrow Aspirate or Biopsy
D
X
X
X2
X2
X2
Re-infusion of prescribed, 
commercially available 
tisagenlecleucel
D
X

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Period
Category
Screening
Treatment
End of Study
Visit Name
Screening
Enrollment
Assessment Period
End of Study
Day/Week/Month
-28 to -1
D11
D28±7
M3±14
M6±14
M12±14
Prior/Concomitant Medications
D
X
X
X
X
X
X
Adverse Events (refer to Table 16-1)
D
X
X
X
X
X
X
1 All Day 1 assessments should be performed prior to infusion with the exception of vital signs which will be monitored before and after infusion
2 Optional assessments to be performed if clinically indicated
3 Must be performed within 10 days of infusion during the months of October through May
X = assessment is required 
D = assessment to be recorded in clinical database or received electronically from a vendor 
S = assessment to be recorded in the source documentation only

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8.1
Study Flow
Please refer to Section 3
8.1.1
Screening
Subjects must sign the IRB/IEC approved informed consent form (ICF) before any study 
specific screening procedures. Blood tests and assessments to determine eligibility as outlined 
below will be performed. Screening assessments to determine eligibility should be performed 
as per the assessment schedule detailed in Table 8-1. Bone marrow biopsy or aspirate to be 
performed. 
Subjects who have signed an informed consent/assent will undergo a routine staging workup 
(Table 8-1).
The assessments below do not need to be repeated if performed as part of routine clinical care 
within 4 weeks of the subject signing the ICF:

Serum immunoglobulin levels (IgG, IgA, IgM)

Viral tests (EBV, HIV, HbsAg, HBsAb, HBcAb, HCVAb). If HIV screening test is 
positive then a confirmatory HIV test is required to be performed as per current local 
guidelines (see Appendix 1 for interpretation of Hepatitis B and C results).
8.1.2
Enrollment 
For non-randomized trials: the point at which a patient meets all inclusion/exclusion criteria 
and the patient’s additional tisagenlecleucel product is confirmed available at manufacturing 
facility and prescribed by the treating physician in the course of medical practice.
8.1.3
Leukapheresis
Not applicable 
8.1.4
Information to be collected on screening failures
For subjects that fail screening, the following information will be collected:

Informed Consent Information

Demography

Inclusion/ Exclusion Criteria

Adverse Events (if applicable)

Death (if applicable)

Withdrawal of Consent (if applicable)
8.1.5
Treatment 
Infusion visit (D1)
On the day prior or day of the scheduled infusion, patients will undergo a physical exam 
(including weight and vital signs). A blood sample will be collected pre-infusion for PK 

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assessment, B & T cells by Flow Cytometry 
. In addition, a serum 
pregnancy test will be performed on women of child bearing potential confirming a negative 
pregnancy result. Adverse events and prior/concomitant medications will be reviewed.
All patients must undergo a rapid influenza diagnostic test (only during the months of October 
through May) within 10 days prior to the planned infusion. If the patient is positive for influenza, 
he/she should complete a full course of oseltamivir phosphate or zanamivir as described on the 
label (see Tamiflu® or Relenza® package insert for dosing). The patient must complete their full 
course of treatment prior to infusion. The test does not need to be repeated prior to infusion 
however if influenza sign and symptoms are present, infusion should be delayed until patient is 
asymptomatic.
For patients that require lymphodepleting chemotherapy, tisagenlecleucel infusion will begin 2 
to 14 days after completion. The total window between informed consent and tisagenlecleucel
infusion must not exceed 16 weeks. 
Tisagenlecleucel transduced T-cells will be given as prescribed and in accordance with the
[Kymriah Package Insert]. Vital signs will be monitored before and following infusion. In 
addition, adverse events and prior/concomitant medications will be reviewed.
For details of assessments, refer to Table 8-1. Visit D28 (±7d)
Patients will undergo blood collection for hematology, chemistry, flow cytometry (B cells, T-
cells, and CD19 assessment) 
and CTL019 PK. In addition, patients 
will undergo a physical exam (including vital signs, weight, and extra medullary disease 
assessment) and CNS symptom assessments. A bone marrow biopsy or aspirate will be 
performed. A urine or serum pregnancy test will be performed for females of child bearing 
potential. A lymph node or tissue aspirate or biopsy may be done if clinically indicated. Adverse 
events and prior/concomitant medications will be reviewed. For details of assessments, refer to 
Table 8-1.
Visit M3 (±14d) 
Patients will undergo the following: blood collection for hematology, chemistry, flow 
cytometry (B-cells, T-cells, and CD19 assessment), 
 and CTL019 PK, 
In addition, patients will undergo a physical exam (including vital signs, weight, and 
extramedullary disease assessment) and CNS symptom assessment. Adverse events and 
prior/concomitant medications will be reviewed. A urine or serum pregnancy test will be 
performed for females of child bearing potential. An optional bone marrow biopsy or aspirate 
to be performed if clinically indicated.
For details of assessments at each visit, refer to Table 8-1.
Visit M6 (±14d)
Patients will undergo the following: blood collection for hematology and chemistry, physical 
exam (including vital signs, weight, and extramedullary disease assessment) and CNS symptom 
assessment. Adverse events and prior/concomitant medications will be reviewed. A urine or 
serum pregnancy test will be performed for females of child bearing potential. An optional bone 
marrow biopsy or aspirate to be performed if clinically indicated.

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For details of assessments at each visit, refer to Table 8-1.
End of Study (EOS)
Visit M12 (±14d)
Patients will undergo the following: blood collection for hematology, chemistry, flow 
cytometry (B cells, T-cells, and CD19 assessment), 
and CTL019 PK, 
In addition, patients will undergo a physical exam (including height, weight vital signs, and 
extramedullary disease assessment), CNS symptom assessment, and a performance status 
assessment. Adverse events and prior/concomitant medications will be reviewed. A serum 
pregnancy test will be performed for females of child bearing potential. An optional bone 
marrow biopsy or aspirate to be performed if clinically indicated.
For details of assessments, refer to Table 8-1.
Unscheduled Visit
An unscheduled visit may occur at the discretion of the investigator. Assessments will be 
performed as deemed clinically appropriate, an unscheduled central lab kit will be provided. 
Adverse events and prior/concomitant medications should be reviewed.
8.1.6
Survival follow-up
Patients are followed on study for 1 year post-second infusion for safety and efficacy 
evaluations. Investigators are encouraged to report in CIBMTR when appropriate. For a patients 
enrolled on the CIBMTR Registry CTL019B2401, semiannual and annual evaluations will be 
performed on all patients who have received a CTL019 cell product infusion as recommended 
by the FDA and EMA in accordance with the relevant guidelines. All patients who either 
complete the study or prematurely discontinue post-CTL019 infusion will be enrolled in this 
destination protocol at the time of study completion/discontinuation (a separate informed 
consent/assent forms will be provided for this protocol). One to two times a year patients will 
visit the clinical site for a physical exam and medical history (including concomitant 
medications and adverse events) with careful attention to features possibly related to lentiviral 
associated events such as new malignancies, new incidence or exacerbation of a pre-existing 
neurologic disorder, new incidence or exacerbation of a prior rheumatologic or other 
autoimmune disorder, or new incidence of other hematologic disorders.
8.2
Subject demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the CRF.
8.2.1
Demographics
The following demographic data will be collected: 

Age

Gender

Race

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
Ethnicity
8.2.2
Baseline characteristics
The following baseline characteristics will be collected: 

Primary disease

Medical history

Prior medication

Prior antineoplastic therapies

Prognostic factors

MRD Status
8.3
Efficacy
Pharmacodynamic and/or clinical samples will be collected at the time-points defined in the 
Assessment Schedule (Table 8-1).
Efficacy is being measured by 
1. B and T-cells by Flow Cytometry 
2. CTL019 Pharmacokinetics by qPCR
3. MRD in bone marrow 
8.3.1
Efficacy assessments
Efficacy assessments will be performed according to the Novartis guidelines for efficacy 
evaluation in Acute Lymphoblastic Leukemia studies (Appendix 1), which is based on the 
NCCN version 1.2013 guidelines, Cheson et al (2003) and Appelbaum et al (2007).
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.
Table 8-2
Assessments & Specifications 
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 at screening and infusion.
A short physical exam will include the examination of general appearance and vital 
signs (blood pressure [SBP and DBP] and pulse). A short physical exam will be at 
all visits starting from the pre-infusion visit except where a complete physical 
examination is required (see above). 

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Assessment
Specification
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 made after informed consent signed which 
meet the definition of an Adverse Event must be recorded as an adverse event.
Assessment of subject reported symptoms suggestive of leukemic involvement of 
the CNS will be performed and recorded with each physical examination. 
Examples of CNS symptoms suggestive of leukemic involvement may include, but 
are not limited to, severe headache or nausea, meningismus or cognitive 
impairment, without other apparent etiologies.
Vital sign
Vital signs including temperature, BP and pulse measurements. Pulse oximetry will 
be measured at select visits. After the subject has been sitting for five minutes, with 
back supported and both feet placed on the floor, systolic and diastolic blood
pressure will be measured three times using an automated validated device, e.g. 
OMRON, with an appropriately sized cuff. The repeat sitting measurements will be 
made at 1 - 2 minute intervals and the mean of the three measurements will be 
used. In case the cuff sizes available are not large enough for the subject's arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be 
used.
Height and 
weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in 
indoor clothing, but without shoes) will be measured.
Performance 
Status
Performance status scale shown in Table 8-3 will be used to evaluate the 
performance status of the subject at visits as described in theTable 8-1.
Table 8-3
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
90
Able to carry on normal activity; minor 
signs or symptoms of disease
90
Minor restriction in physically strenuous 
play
80
Normal activity with effort; some signs or 
symptoms of disease
80
Restricted in strenuous play, tires more 
easily, otherwise active
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
Ambulatory up to 50% of the time, limited 
active play with assistance/supervision
50
Requires considerable assistance and 
frequent medical care
50
Considerable assistance required for any 
active play, fully able to engage in quiet 
play

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Test Category
Test Name
B&T cells by Flow 
cytometry
CD4, CD3, CD8, CD19, CD16+56, CD3+4+8, CD4/CD8 Ratio, CD3/CD19 
Ratio
Pregnancy Test
Serum pregnancy test performed at Screening, and Pre LD Chemo (Day -
14 to Day -2) if applicable, D1 (Pre Infusion), End of Study (Month 12)
Urine pregnancy test performed at D28, M3, M6. A serum pregnancy test 
can be performed instead of a urine pregnancy test at investigator
discretion.
Assessment will be done locally
Rapid Influenza Test
Assessment will be done locally
8.4.2
Electrocardiogram (ECG)
Not Applicable
8.4.2.1
Cardiac imaging - MRA (magnetic resonance angiography), MUGA 
(multiple gated acquisition) scan or echocardiogram
Not applicable 
8.4.2.2
Cardiac enzymes
Not applicable 
8.4.3
Other safety evaluations
Chest X-ray
Not applicable 
Imaging
Not applicable 
8.4.4
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Clinician Reported Outcomes (ClinRO)
Not applicable
Patient reported outcomes (PRO)
Pediatric Quality of Life inventory – Version 4 (PedsQL™ 4.0)
Not applicable 

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Trial Feedback
Not applicable 
Performance Outcomes (PerfO)
Not applicable 
Observer Reported Outcomes (ObsRO) 
Not applicable 
Proxy Reported Outcomes
Not applicable 
8.5.2
Pharmacokinetics
PK samples will be collected at the visits defined in the Assessment Schedule (Table 8-1).
Follow instructions outlined in the central 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.
Table 8-5
CTL019 pharmacokinetics by q-PCR in peripheral blood collection log
Dose 
Number
Infusion
Day*
Scheduled 
Time Point*
Tisagenlecleucel 
Dose Reference ID
PK 1 
Tisagenlecleucel 
Sample No
Sample 
Volume
2
D1
Pre-dose
201
201
3 mL
2
D28
201
202
3 mL
2
M3
201
203
3 mL
2
M12
201
204
3 mL
2
Unscheduled
201
205
3 mL

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Subjects who discontinue the study or who decide they do not wish to participate in the study 
further should NOT be considered withdrawn from the study UNLESS they withdraw their 
consent (see section 9.1.2/Withdraw of informed consent section). Where possible, they 
should return for the assessments indicated in the assessment schedule. If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should 
be made to contact the subject/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
If the subject is willing, at a minimum, in abbreviated visits, the following data should be 
collected at clinic visits or via telephone/email contact:

new/concomitant treatments

adverse events/Serious Adverse Events
9.1.1.1
Replacement policy
Not applicable 
Expansion part
Not applicable.
9.1.2
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 allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Subject’s participation in the study must be discontinued and no further assessments conducted, 
and the data that would have been collected at subsequent visits will be considered missing.
Further attempts to contact the 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.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.

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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.
9.1.3
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, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 

Discontinuation of tisagenlecleucel 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 (provide 
instruction for contacting the subject, when the subject should come for a final visit) 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 a tisagenlecleucel infusion, a long term post-study follow-up 
for lentiviral vector safety will still continue under a separate destination protocol for 15 years 
post infusion per health authority guidelines.
The investigator or sponsor depending on local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial.
9.1.4.1
Criteria for stopping or pausing the study
The study will be paused, and health authorities notified if:

The Sponsor 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 tisagenlecleucel
The study may be paused pending notification of the health authorities for investigation and 
possible protocol amendment if any subject experiences any of the following events within three 
weeks of the tisagenlecleucel infusion:

Life-threatening (grade 4) toxicity attributable to protocol therapy that is unmanageable, 
unexpected and unrelated to chemotherapy and attributable to protocol therapy. High fevers, 
hypotension, hypoxia, disseminated intravascular coagulation, encephalopathy (e.g. 
lethargy, confusion, aphasia, and seizure), ICU admission, dialysis and mechanical 

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ventilation are expected. The expected side effects can also result in grade 4 liver toxicity, 
nephrotoxicity and cardiac dysfunction.

Death suspected to be related to tisagenlecleucel therapy
9.2
Study completion and post-study treatment
The end of the study is defined as the last visit of the last subject.
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 (e.g., 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 use of a 
medicinal (investigational) product.
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 adverse events 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 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. The grade according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03, with the exception of CRS, which will follow Table 4-2. If CTCAE grading 
does not exist for an AE, the severity of mild, moderate, severe or medically significant, 
life-threatening and fatal, corresponding to Grades 1 - 5, will be used
2. Its relationship to tisagenlecleucel if the event is due to lack of efficacy or progression of 
underlying illness (i.e. progression of the study indication) the assessment of causality will 
usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a lack of 
efficacy or progression of underlying illness are not caused by the trial drug, they happen in 
spite of its administration and/or both lack of efficacy and progression of underlying disease 
can only be evaluated meaningfully by an analysis of cohorts, not on a single subject
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported.

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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 tisagenlecleucel.
All adverse events must be treated appropriately. Treatment may include treatment 
interruption or withdrawal.
6. Its outcome, i.e., its recovery status or whether it was fatal
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
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 
eCRF for medical history.
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 Section 10.1.1. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g., continuing at the end of the study), and assessment should be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the study treatment, the interventions required to treat it, and the outcome.
Adverse events separate from the progression of malignancy (e.g., 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 tisagenlecleucel can be found in the 
[tisagenlecleucel Investigator's Brochure] and [Kymriah package insert].
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.

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Detailed AE reporting requirements during the periods of screening, , treatment, follow-up and 
end of study are outlined in Table 16-1.
Detailed information regarding CRS adverse events (e.g. oxygen requirements, vasopressor 
usage) will 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 AE [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 (please refer to the ICH-
E2D Guidelines).
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: 

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
Death within 30 days after tisagenlecleucel infusion, irrespective of causality to 
tisagenlecleucel 

Deaths beyond 30 days after tisagenlecleucel infusion, if there is a least a possible 
causality to tisagenlecleucel 
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 occurring after the subject has provided informed consent
must be reported to Novartis safety within 24 hours of learning of its occurrence as specified 
for each study period, including screening, treatment, follow-up and end of study in Table 16-
1. Detailed instructions regarding the submission process and requirements are to be found in 
the investigator folder provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to tisagenlecleucel, 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 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.
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 2.

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10.1.6
Pregnancy reporting
Pregnancies
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 
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 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 any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
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 Tisagenlecleucel errors including misuse/abuse
While commercial tisagenlecleucel will be prescribed to the patients participating in this trial, 
the procedures for reporting errors in this section will remain applicable and must be followed 
as outlined in this section.
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.
Treatment errors and uses outside of what is foreseen in the protocol will be recorded on the 
appropriate eCRF 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 including 
misuse/abuse
Treatment error type
Document in Dosing 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional 
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.

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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):

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 16-4 in Appendix 3 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 16-3 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 16-4. Repeat liver chemistry tests (ALT, AST, TBL,
PT/INR, ALP and G-GT) to confirm elevation.
These liver chemistry repeats should be performed using the local laboratory used by the site. 
Repeated laboratory test results must be reported as appropriate.
If the initial elevation is confirmed, close observation of the subject will be initiated, including 
consideration of treatment interruption if deemed appropriate.

Discontinuation of tisagenlecleucel, if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event, which can include based on investigator’s 
discretion: 

Serology tests, imaging (e.g., such as abdominal US, CT or MRI, as appropriate) and 
pathology assessments, gastroenterologist’s or hepatologist’s consultancy; obtaining 
more detailed history of symptoms and prior or concurrent diseases, history of 
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:
1. Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

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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.
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 classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) terminology.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis
representative or delegated CRO representative will review the protocol and data capture 
requirements (i.e. eSource DDE or 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 delegated CRO 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. Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the CRFs. 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
The data will be analyzed by Novartis and/or a designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation. 
Data from all participating centers will be combined, so that an adequate number of patients 
will be available for analysis. The primary analysis of the study will be performed after all 
patients have completed the Month 12 visit or prematurely discontinued the study. For this 
analysis, all primary, secondary 
 objectives will be addressed including all 
variables outlined up to Month 12 and all available safety data. A final Clinical Study Report 
(CSR) will be produced for the primary analysis of the study.
As required, interim analyses may be performed every six months annually for publication 
purpose. 
12.1
Analysis sets
The analysis sets to be used are defined as below. The Full Analysis Set (FAS) will be used as 
the primary efficacy analysis set. The Safety Set will be used for all the safety analyses. 
All tables and listings will be presented by one treatment arm of CTL019.
12.1.1
Screened Set
The Screened Set comprises all patients who have signed informed consent/assent and screened 
in the study. 
12.1.2
Enrolled Set
The enrolled set (ENS) comprises all patients who are enrolled in the study. Enrollment is 
defined as the point at which the patient meets all inclusion/exclusion criteria, and the patients’
additional non-expired dose of tisagenlecleucel has been confirmed available. 
12.1.3
Full Analysis Set
The Full Analysis Set FAS comprises all patients whom have received reinfusion of 
tisagenlecleucel.
12.1.4
Safety Set
The Safety Set comprises all patients who received re-infusion of tisagenlecleucel.

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12.1.5
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with major requirements of the clinical study protocol (CSP).
Detailed criteria and determination of major protocol deviations leading to exclusion from PPS 
will be finalized prior to database lock and primary analysis. 
12.1.6
Cellular kinetic analysis set
The Cellular Kinetic Analysis Set (CKAS) consists of all subjects in the FAS who provide 
evaluable tisagenlecleucel cellular kinetic data. A subject is considered as having evaluable 
cellular kinetic data if at least one cellular kinetic parameter can be derived. The CKAS will be 
used for summaries (tables and figures). The FAS will be used for listings of cellular kinetic 
data.
Note that subjects will be removed from the estimation of certain CK parameters on an 
individual basis depending on the number of available samples. These subjects will be identified 
at the time of the analyses.
12.1.7
Pharmacokinetic analyses set
The Pharmacokinetic Analysis Set (PKAS) consists of subjects in FAS who have taken at least 
one dose of the drug and provided at least one PK concentration.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data will be listed by patient and/or summarized descriptively 
for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, 
summary statistics will be presented (i.e., mean, median, standard deviation (SD), minimum, 
maximum).
The number and percentage of patients with prior anti-neoplastic medications/therapies will be
summarized.
Relevant medical histories and current medical conditions at baseline will be summarized by 
primary system organ class (SOC) and preferred term.
12.3
Treatments
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, SD, median, minimum, and maximum 
will be presented. 
The total cells infused (cells/kg) and total CTL019 transduced viable T cells infused (cells/kg)
will be listed and summarized using descriptive statistics. Patients will be categorized as below, 
within or above the prescribed dose range.
Prior and concomitant medications and significant non-drug therapies prior to and after the start 
of re-infusion will be listed by patient and summarized by the Anatomical Therapeutic

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Chemical (ATC) term. 
12.4
Transfusion during the study will be listed. In addition, whether
patients have received anti-cytokine medications for the 
management of CRS will be summarized.Analysis of the primary 
endpoint(s)
The primary objective of the study is to evaluate the incidence of B cell aplasia after re-infusion 
of tisagenlecleucel.
12.4.1
Definition of primary endpoint(s) 
The primary endpoint for this study is the proportion of patients who restore B-cell aplasia 
within 12 months following re-infusion with tisagenlecleucel.
B-cell aplasia is defined as:

PB absolute B lymphocyte count < 50/µL, AND

presence of CTL019 cells by qPCR in the peripheral blood
12.4.2
Statistical model, hypothesis, and method of analysis
The primary efficacy analysis will be performed on the FAS by testing the following hypothesis: 
H0: p ≤0.10 vs. HA: p > 0.10
The estimated proportion p̂ of patients who restore B-cell aplasia within 12 months following 
re-infusion with the study drug will be presented together with an exact 95% Clopper-Pearson 
confidence interval (CI). 
The null hypothesis (H0) will be rejected if the lower limit of the 95% CI is greater than 0.10, 
demonstrating improvement after re-infusion. 
12.4.3
Handling of missing values/censoring/discontinuations
Patients in the study who are of unknown clinical response will be treated as non-responders. 
Other missing data are simply noted as missing on appropriate tables/listings.
Patients who proceed to HSCT while in remission after tisagenlecleucel re-infusion will be 
censored at the time of HSCT.
The volume of missing data generated due to the COVID-19 pandemic may also be assessed 
and sensitivity analyses will be performed, if deemed appropriate.
12.4.4
Sensitivity and Supportive analyses
In order to assess the robustness of the primary endpoint, sensitivity analyses are planned. These 
may include, but are not limited to:

the analysis of the primary endpoint using the PPS

the analysis of the primary endpoint without censoring for HSCT
As this study is ongoing during the COVID-19 pandemic, the impact of COVID-19 (if any) will 
be explored on topics such as, but are not limited to, the discontinuation rate, the number of 

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protocol deviations, disease status, the use of rescue medications, AEs, laboratory values and 
missing data. As appropriate, a sensitivity analysis of the primary endpoint may be performed 
to assess the impact of COVID-19, if any, in the study.
12.4.4.1 Subgroup analysis
Subgroup analyses will be performed on the primary endpoint based on the patient’s baseline 
status:

Age: <10 years, ≥10 years to <18 years, ≥18 years

Gender: Male, Female

Race: White, Asian, Other

Patients with a loss of B-cell Aplasia within 9 months of first infusion AND are MRD (+) 
at time of enrollment

Patients with a loss of B cell aplasia very early (<3 months), early (>3 to <6 months) and 
late (>6 months) following first infusion
As the sample size is small, data will be only summarized within each subgroup.
12.5
Analysis of secondary endpoints

The secondary efficacy objectives are to evaluate the following: the efficacy of reinfusion 
of tisagenlecleucel for loss of B cell aplasia as measured by overall remission rate (ORR) 
12 months after tisagenlecleucel reinfusion, which includes CR and CR with incomplete 
blood count recovery (CRi) as determined by investigator assessment for pALL 
patientsEvaluate event free survival (EFS)

Evaluate Overall survival (OS)
12.5.1
Overall Remission rate (ORR)
The secondary endpoint is the ORR as determined by investigators assessment during the 12 
months after tisagenlecleucel re-infusion. The ORR is defined as the proportion of patients who 
maintain ORR (= CR + CRi) per Investigator assessment in pALL patients during 12 months 
post-reinfusion.
The secondary efficacy endpoint, ORR within 12 months of re-infusion, will be analyzed using 
the FAS. The ORR will be summarized and exact 95% Clopper-Pearson CIs will be reported.
12.5.2
Event free survival (EFS)
EFS is the time from date of tisagenlecleucel re-infusion to the earliest of the following:

Death from any cause after remission

Relapse

Treatment failure: Defined as no response in the study and discontinuation from the study
due to any of the following reasons:

Death

Adverse event (including abnormal laboratory values or abnormal test procedure

results)

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
Lack of efficacy or progressive disease

New anticancer therapy
In the main analysis of EFS, patients who proceed to SCT after tisagenlecleucel re-infusion will 
be censored at the time of SCT. In addition, a sensitivity analysis of EFS will be performed 
without censoring SCT. EFS will be assessed in all patients in the FAS. The distribution 
function of EFS will be estimated using the Kaplan Meier (KM) method. The median EFS along 
with 95% confidence intervals will be presented, if appropriate.
12.5.3
Overall survival (OS)
OS is the time from date of tisagenlecleucel re-infusion to the date of death due to any reason. 
In case a patient is alive at the date of last contact on or before data cut-off, OS is censored at 
the date of last contact. No censoring will be done in case of SCT. Thus, patients should be 
followed-up for survival also in case of SCT.
12.5.4
Safety endpoints
12.5.4.1 Analysis set and grouping for the analyses
For all safety analyses, the Safety Set will be used. The overall observation period will be 
divided into two mutually exclusive segments:

pre re-infusion period: from day of patient’s informed consent/assent to the day before re-
infusion of tisagenlecleucel.

post re-infusion period: starting at day of tisagenlecleucel re-infusion
12.5.4.2 Adverse events (AEs)
Reporting of adverse events will be based on MedDRA and CTCAE version 4.03. Treatment-
emergent AEs are defined as AEs that started or worsened after tisagenlecleucel re-infusion. 
Summary tables for AEs will include only treatment emergent AEs. However, all safety data
(including those from the pre re-infusion period) will be listed and those collected during the
pre-infusion period are to be flagged. The incidence of treatment-emergent adverse events will 
be summarized by primary SOC, preferred term, severity (based on CTCAE grades), and 
relationship to tisagenlecleucel. Patients who experienced multiple AEs for a preferred term
will be counted once for that preferred term, similarly for patients with multiple AEs per 
primary SOC. A patient with multiple CTC grades for an AE will be summarized under the 
maximum CTC grade recorded for the event. The frequency of Common Toxicity Criteria 
(CTC) grade 3 and 4 AEs will be summarized separately. 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type 
of AE.

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12.5.4.3 Adverse events of special interest (AESI) are defined by the important 
identified risk and important potential risk as presented in the 
effective Risk Management Plan (RMP). MedDRA search criteria to 
retrieve AEs indicative of these risks are updated on a regular basis at
the tisagenlecleucel program level. The most recent version of the 
AESI search criteria form will be used for the reporting activity.
Laboratory abnormalities

For laboratory tests covered by the CTCAE, the study’s biostatistics and reporting team 
will grade laboratory data accordingly. 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 also be generated separately for hematology and biochemistry: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)
 
 
12.5.4.4 B-cell and T-cell level
The levels of B and T cells (peripheral blood prior to and following tisagenlecleucel infusion)
will be described. Baseline and absolute and relative change (percent change) from baseline 
will be calculated and summarized using sample size, mean, standard deviation, median, 
minimum and maximum. Baseline and change from baseline to minimum cell number may also 
be summarized by response status and potentially graphed using strip plots. Patient level and 
averaged cell counts and percent change from baseline may be displayed using longitudinal 
plots. 
It is anticipated that all patients who achieve complete remission will exhibit B-cell aplasia.
Timing of B-cell recovery will be summarized. CD8 and CD4 positive T cells will be listed and 
summarized by time point. Data may also be summarized by response status and potentially 
graphed using strip plots. Patient level and average longitudinal plots of the cell counts and 
percent changes from baseline may be generated. For abnormal T cell or B cell results, 
associated safety events such as infections and use of associated therapies (i.e. antibiotics, 
immunoglobulin replacement) will be investigated using patient listings. CKAS set will be used 
for the analysis of 
 and biomarkers.
12.5.5
Pharmacokinetics
Plasma concentration data will be listed by treatment, subject, and visit/sampling time point. 
Descriptive summary statistics will be provided by treatment and visit/sampling time point, 
including the frequency (n, %) of concentrations below the LLOQ and reported as zero for the 
Pharmacokinetic Analysis Set.

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Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations. 
12.5.6
Biomarkers
Not applicable
12.5.7
PK/PD relationships
Not applicable
12.5.8
Patient reported outcomes
Not applicable
12.7
Interim analyses
No formal interim analysis will be performed for this study. As required, interim analyses may 
be performed every six months annually for publication purpose. 
12.8
Sample size calculation
This study is an exploratory study to determine the safety and efficacy of tisagenlecleucel re-
infusion with an early loss of B-cell aplasia.
Sample size was based on an exact test for single proportion to test the null hypothesis H0:
p<=0.10. Where p is the proportion of patients who establish B cell aplasia during 12 months.
If the true rate p>= 0.25, then with an one sided alpha level of 2.5% and at least 80% power, a 
minimum of 49 evaluable patients will be required for the study. Considering drop-out rate of 
10%, a total of approximately 54 patients will be enrolled into the study.
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 (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 

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start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
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 (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) .
This study only involves healthy volunteers and as such Novartis/sponsor will register the 
protocol as required to databases specified by local regulations (e.g. EudraCT during CTA filing 
for studies in EU/EEA). After study completion (defined as last patient last visit) and 
finalization of the study report, results of this trial may be submitted for publication (e.g. peer-
reviewed journal) or registered to databases where required by local regulations.
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 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 

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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.
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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15
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16
Appendices
16.1
Appendix 1: 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 (2014-2017).

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16.2
Appendix 2: Tisagenlecleucel modified data reporting –
Treatment and Follow Up Phase
This guidance is used to determine whether or not an AE, SAE, concomitant medication, or 
laboratory result has to be recorded in the eCRF during the relevant study period. Before using 
this guidance, the investigator should determine whether or not an AE is serious using the 
criteria found in the protocol section 10, and then use the applicable row of this guidance to 
determine whether or not that event is to be recorded in the eCRF.

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Table 16-1
Adverse event reporting
Table 16-2
Concomitant Medication and Laboratory Reporting
Screening and Pre-treatment Period
(ICF to LD chemo/ re-infusion )
Treatment and Follow-up Period 
(Starting from LD chemo / infusion , through Month 12 or 
discontinuation)
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Concomitant 
medications
Modified:
Drugs:
All
Signed ICF through start of lymphodepleting 
chemotherapy or re-infusion
Start of lymphodepleting chemotherapy or re-infusion
through Month 12 or discontinuation
AEs
(non-serious and 
serious)
All AEs grade ≥ 3
All SAEs and deaths
All laboratory abnormalities deemed clinically significant by the 
investigator
All infections
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

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

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Appendix 3: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements
Table 16-3
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 16-4
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
Discontinue the study treatment 
immediately (if applicable)
Hospitalize, if clinically appropriate
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
ALT, AST, TBIL, indirect and direct 
bilirubin, albumin, Alb, PT/INR, ALP 
and GGT, until resolution (frequency
at investigator discretion)
ALT or AST
> 8 × ULN
Discontinue the study treatment 
immediately (if applicable)
Hospitalize if clinically appropriate
Establish causality
ALT, AST, TBIL, indirect and direct 
bilirubin, albumin, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)

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

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Criteria
Actions required
Follow-up monitoring
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice
Discontinue the study treatment 
immediately (if applicable)
Hospitalize the patient
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
ALT, AST, TBIL, indirect and direct 
bilirubin, albumin, Alb, PT/INR, ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*
Consider study treatment 
interruption or discontinuation (if 
applicable) 
Hospitalization if clinically 
appropriate
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and 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 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
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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Table 16-6
Follow up of renal events
Assess, document and record in the appropriate CRF

Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells

Blood pressure and body weight

Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and 
uric acid

Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the CRF. 
Monitor patient regularly (frequency at investigator’s discretion) until: 

Event resolution: serum creatinine within 10% of baseline or PCR <1 g/g or albumin-creatinine 
ratio <300 mg/g)
or

Event stabilization: serum creatinine level with ± 10% variability over last 6 months or PCR 
stabilization at a new level with ± 50% variability over last 6 months

Analysis of urine markers in samples collected over the course of the renal event