A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia
Phase: PHASE2
Conditions: B-cell Acute Lymphoblastic Leukemia
Sponsor: Novartis Pharmaceuticals



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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................6
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................14
Amendment 7 (26-Oct-2020) ............................................................................................15
Amendment 6 (21-Mar-2019) ...........................................................................................18
Amendment 5 (04-Apr-2017)............................................................................................23
Amendment 4 (14-Jun-2016) ............................................................................................24
Amendment 3 (13-Apr-2016)............................................................................................27
Amendment 2 ....................................................................................................................31
Amendment 1 ....................................................................................................................34
Protocol summary..............................................................................................................38
1
Background........................................................................................................................46
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............46
1.2
Introduction to investigational treatment(s) and other study treatment(s).............46
1.2.1
Overview of CTL019............................................................................46
2
Rationale............................................................................................................................50
2.1
Study rationale and purpose...................................................................................50
2.2
Rationale for the study design ...............................................................................52
2.2.1
Rationale for lymphodepletion..............................................................53
2.3
Rationale for dose and regimen selection..............................................................53
2.3.1
Allowable infused cell dose range of CTL019 product ........................54
2.4
Rationale for choice of combination drugs............................................................54
2.5
Rationale for choice of comparators drugs............................................................54
2.6
Risks and benefits..................................................................................................55
3
Objectives and endpoints...................................................................................................55
4
Study design ......................................................................................................................60
4.1
Description of study design ...................................................................................60
4.1.1
Leukapheresis assessment.....................................................................61
4.2
Definition of end of the study................................................................................62
4.3
Early study termination..........................................................................................63
5
Population..........................................................................................................................63
5.1
Patient population..................................................................................................63

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5.2
Inclusion criteria ....................................................................................................64
5.3
Exclusion criteria...................................................................................................65
6
Treatment...........................................................................................................................67
6.1
Study treatment......................................................................................................67
6.1.1
Dosing regimen.....................................................................................68
6.1.2
Ancillary treatments..............................................................................72
6.1.3
Treatment for cytokine release syndrome.............................................72
6.1.4
Guidelines for continuation of treatment ..............................................73
6.1.5
Treatment duration................................................................................73
6.2
Dose escalation guidelines.....................................................................................73
6.2.1
Starting dose rationale...........................................................................73
6.2.2
Provisional dose levels..........................................................................73
6.2.3
Guidelines for dose escalation and determination of 
MTD/RP2D/RDE..................................................................................73
6.2.4
Definitions of dose limiting toxicities (DLTs) in a Phase II Study.......73
6.2.5
Criteria for discontinuing a patient’s participation in the study............85
6.2.6
Concomitant therapy.............................................................................85
6.2.7
Prohibited concomitant therapy ............................................................86
6.3
Dose modifications................................................................................................87
6.3.1
Dose modifications and dose delays .....................................................87
6.3.2
Follow-up for toxicities.........................................................................87
6.4
Patient numbering, treatment assignment or randomization .................................89
6.4.1
Patient numbering .................................................................................89
6.4.2
Treatment assignment ...........................................................................90
6.4.3
Treatment blinding................................................................................90
6.5
Study drug preparation and dispensation...............................................................90
6.5.1
Study drug packaging and labeling.......................................................90
6.5.2
Drug supply and storage........................................................................91
6.5.3
Study drug compliance and accountability ...........................................91
6.5.4
Disposal and destruction .......................................................................92
7
Visit schedule and assessments .........................................................................................92
7.1
Study flow and visit schedule................................................................................92
7.1.1
Screening Phase ..................................................................................108
7.1.2
Pre-Treatment Phase ...........................................................................109
7.1.3
Treatment and Primary Follow-Up Phase...........................................111
7.1.4
Secondary Follow-Up Phase...............................................................116

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7.1.5
Survival Follow-Up Phase ..................................................................119
7.1.6
Long-Term Follow Up ........................................................................119
7.2
Assessment types.................................................................................................120
7.2.1
Efficacy assessments...........................................................................120
7.2.2
Safety and tolerability assessments.....................................................121
7.2.3
Pharmacokinetics ................................................................................125
7.2.4
Biomarkers..........................................................................................131
7.2.5
Optional additional exploratory assessments using remaining 
samples................................................................................................134
7.2.6
Resource utilization.............................................................................134
7.2.7
Patient reported outcomes...................................................................135
8
Safety monitoring and reporting......................................................................................137
8.1
Adverse events.....................................................................................................137
8.1.1
Definitions...........................................................................................137
8.1.2
Reporting.............................................................................................137
8.1.3
Laboratory test abnormalities..............................................................140
8.1.4
Adverse events of special interest.......................................................140
8.2
Serious adverse events.........................................................................................140
8.2.1
Definitions...........................................................................................140
8.2.2
Reporting.............................................................................................141
8.3
Emergency unblinding of treatment assignment .................................................143
8.4
Pregnancies..........................................................................................................143
8.5
Warnings and precautions....................................................................................143
8.6
Data Monitoring Committee................................................................................143
8.7
Steering Committee .............................................................................................144
8.8
Independent Review Committee (IRC) ...............................................................144
9
Data collection and management.....................................................................................144
9.1
Data confidentiality .............................................................................................144
9.2
Site monitoring ....................................................................................................145
9.3
Data collection.....................................................................................................145
9.4
Database management and quality control..........................................................146
10 Statistical methods and data analysis ..............................................................................146
10.1
Analysis sets ........................................................................................................147
10.1.1
Screened Set........................................................................................147
10.1.2
Enrolled Set.........................................................................................147
10.1.3
Full Analysis Set .................................................................................147

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10.1.4
Interim Efficacy Analysis Set .............................................................147
10.1.5
Safety Set ............................................................................................147
10.1.6
Per-Protocol Set ..................................................................................147
10.1.7
Pharmacokinetic analysis set...............................................................148
10.2
Patient demographics/other baseline characteristics ...........................................148
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................148
10.4
Primary objective.................................................................................................149
10.4.1
Variable...............................................................................................149
10.4.2
Statistical hypothesis, model, and method of analysis........................151
10.4.3
Handling of missing values/censoring/discontinuations.....................151
10.4.4
Supportive analyses.............................................................................151
10.5
Secondary objectives ...........................................................................................153
10.5.1
Key secondary objective(s).................................................................153
10.5.2
Other secondary efficacy objectives ...................................................154
10.5.3
Safety objectives .................................................................................159
10.5.4
Pharmacokinetics ................................................................................162
10.6
Exploratory objectives.........................................................................................163
10.6.1
Biomarkers..........................................................................................163
10.6.2
CTL019 product characteristics ..........................................................164
10.6.3
Cytokine release syndrome .................................................................164
10.6.4
Healthcare resource utilization............................................................164
10.7
Interim analysis for Main Cohort ........................................................................165
10.7.1
Interim analysis for the primary endpoint...........................................165
10.7.2
Interim analysis for the key secondary endpoints...............................165
10.8
Sample size calculation........................................................................................166
10.9
Power for analysis of key secondary variables for Main Cohort.........................167
10.9.1
ORR within 3 months in patients infused with CTL019 from US 
manufacturing facility.........................................................................167
10.9.2
Remission with MRD negative bone marrow in patients who 
received CTL019 from all manufacturing facilities............................167
10.9.3
Remission with MRD negative bone marrow in patients who 
received CTL019 from US manufacturing facility.............................168
11 Ethical considerations and administrative procedures ....................................................168
11.1
Regulatory and ethical compliance......................................................................168
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................168
11.3
Informed consent procedures...............................................................................168
11.4
Discontinuation of the study................................................................................169

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11.5
Publication of study protocol and results.............................................................169
11.6
Study documentation, record keeping and retention of documents.....................170
11.7
Confidentiality of study documents and patient records .....................................171
11.8
Audits and inspections.........................................................................................171
11.9
Financial disclosures............................................................................................171
12 Protocol adherence ..........................................................................................................171
12.1
Amendments to the protocol................................................................................171
13 References (available upon request)................................................................................172
14 Appendices ......................................................................................................................179
14.1
Appendix 1: Guidelines for efficacy evaluation in Acute Lymphoblastic 
Leukemia (ALL) studies......................................................................................179
14.1.1
Introduction.........................................................................................182
14.1.2
Efficacy evaluation..............................................................................182
14.1.3
Data collection ....................................................................................190
14.1.4
Efficacy analysis definitions ...............................................................191
14.1.5
References (available upon request) ...................................................196
14.2
Appendix 2: Eligibility based on serologic markers for hepatitis B infection ....197
14.3
Appendix 3: CTL019 modified data reporting – Treatment and Primary 
Follow Up Phase..................................................................................................198
14.3.1
Adverse event (AE) and serious adverse event (SAE) reporting........198
14.3.2
Concomitant medication and laboratory reporting .............................199
14.4
Appendix 4: CTL019 modified data reporting – Secondary Follow Up Phase...201
14.5
Appendix 5: [EU Only: Guidelines for use of fibrinogen concentrate in 
CTL019-associated coagulopathy with hypofibrinogenemia..............................202
14.6
Appendix 6: [Japan Only: Guidelines for use of fibrinogen concentrate in 
CTL019-associated coagulopathy with hypofibrinogenemia].............................204
14.7
Appendix 7: Liver and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................206
14.8
Appendix 8: Specific Renal Alert Critiera and Actions end Event Follow-up....209
List of appendices
Appendix 1 Guidelines for efficacy evaluation in Acute Lymphoblastic Leukemia (ALL) 
studies
Appendix 2 Eligibility based on serologic markers for hepatitis B infection
Appendix 3 CTL019 Modified Data Reporting – Treatment and Primary Follow Up Phase

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Appendix 4 CTL019 Modified Data Reporting – Secondary Follow Up Phase
Appendix 5: [EU Only: Guidelines for use of fibrinogen concentrate in CTL019-associated 
coagulopathy with hypofibrinogenemia]
Appendix 6: [Japan Only: Guidelines for use of fibrinogen concentrate in CTL019-associated 
coagulopathy with hypofibrinogenemia]
Appendix 7: Liver event and Laboratory trigger Definitions and Follow-up Requirements
Appendix 8: Specific Renal Alert Criteria and Actions and Event Follow-up
List of figures
Figure 1-1
CTL019 chimeric antigen receptor design............................................47
Figure 4-1
Study design..........................................................................................61
Figure 7-1
Potential patient flow scenarios ............................................................93
List of tables
Table 3-1
Objectives and related endpoints ..........................................................56
Table 6-1
CRS management algorithm:................................................................76
Table 6-2
CTL019-therapy-associated grading for cytokine release syndrome: ..77
Table 6-3
High dose vasopressor use ....................................................................78
Table 6-4
Staging and grading of acute Graft-Versus-Host Disease.....................79
Table 6-5
Definitions of chronic Graft-Versus-Host Disease ...............................80
Table 6-6
Concomitant medication reporting by trial phase .................................85
Table 7-1
Visit evaluation schedule: treatment and primary follow-up................94
Table 7-2
Visit evaluation schedule: secondary follow-up .................................106
Table 7-3
Imaging or disease assessment collection plan – Primary Follow-up 
Phase ...................................................................................................120
Table 7-4
Karnofsky/Lansky Performance Scales ..............................................122
Table 7-5
Local clinical laboratory parameters collection plan ..........................124
Table 7-6
Central clinical laboratory parameters collection plan........................125
Table 7-7
CTL019 pharmacokinetics by q-PCR in peripheral blood collection 
log........................................................................................................126
Table 7-8
CTL019 pharmacokinetics by flow cytometry in peripheral blood 
collection log.......................................................................................127
Table 7-9
CTL019 pharmacokinetics by q-PCR in bone marrow aspirate 
collection log.......................................................................................127

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Table 7-10
CTL019 pharmacokinetics by flow cytometry in bone marrow 
aspirate collection log .........................................................................128
Table 7-11
CTL019 pharmacokinetics by q-PCR in CSF collection log..............128
Table 7-12
CTL019 transgene persistence in peripheral blood (for patients in 
Secondary Follow-up).........................................................................128
Table 7-13
Immunogenicity serum sample collection log ....................................129
Table 7-14
Immunogenicity peripheral blood sample collection log....................129
Table 7-15
Tocilizumab pharmacokinetics (PK), CTL019 PK and sIL6R (PD) 
in tocilizumab treated patients during CRS ........................................130
Table 7-16
Siltuximab PK, CTL019 PK and sIL6R (PD) in siltuximab treated 
patients during CRS ............................................................................131
Table 7-17
Biomarker sample collection plan.......................................................133
Table 10-1
Definition of CR, CRi and relapse at a given evaluation time............150
Table 10-2
Analyses of duration of response (DOR)............................................156
Table 10-3
Adverse events of special interest (AESI) search criteria...................160
Table 10-4
Noncompartmental pharmacokinetic parameters................................163
Table 10-5
Confidence intervals for ORR in patients infused with CTL019 
manufactured by the Fraunhofer Institute...........................................167
Table 14-1
Overall disease response classification at a given evaluation time.....188
Table 14-2
Data sources ........................................................................................190
Table 14-3
Options for event dates used in DOR, EFS and RFS..........................194
Table 14-4
Eligibility based on serologic markers for hepatitis B infection.........197
Table 14-5
Liver Event and Laboratory Trigger Definitions ................................206
Table 14-6
Follow Up Requirements for Liver Events and Laboratory Triggers.206
Table 14-7
Specific Renal Alert Criteria and Actions...........................................209
Table 14-8
Follow up renal events ........................................................................210

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List of abbreviations
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALC
Absolute Lymphocyte Count
ALL
Acute Lymphoblastic Leukemia
ALP
Alkaline Phosphatase 
ALT
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/SGPT
AML
Acute Myeloid Leukemia
Anti-HBc
Hepatitis B core antibody
Anti-HBs
Hepatitis B surface antibody
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/SGOT
ATG
Anti-thymocyte globulin
ATC
Anatomical Therapeutic Chemical
AUC
Area Under the Curve
AUC28d
Area under the curve from day 0 to 28 days following infusion in the cellular kinetic 
profile
AUC84d
Area under the curve from day 0 to 84 days following infusion in the cellular kinetic 
profile
AUMC
Area under the first moment curve
B-ALL
B cell lineage acute lymphoblastic leukemia
4-1 BB
type 2 transmembrane glycoprotein belonging to the TNF superfamily, expressed on 
activated T Lymphocytes
BCR-ABL
Philadelphia Chromosome
BiPAP
Bilateral Positive Airway Pressure
BM
Bone Marrow
BOR
Best Overall Response
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
CHP
Children’s Hospital of Philadelphia
CI
Confidence Interval
CIF
Cumulative Incidence Function
CLL
Chronic Lymphocytic Leukemia
Cmax
Maximum concentration
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
Central Nervous System
CPAP
Continuous Positive Airway Pressure

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CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CR
Complete remission
CRi
Complete remission with incomplete blood count recovery
CRO
Contract Research Organization
CRp
Complete remission with incomplete platelet recovery
CRP
C-Reactive Protein
CRS
Cytokine Release Syndrome
CSF
Cerebral Spinal Fluid
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Cytotoxic T Lymphocyte
CTL019 cells
CD 19 redirected autologous T cells (also called CART19 cells)
CVPF
DILI
Cell and Vaccine Production Facility
Drug-Induced Liver Injury
DOR
Duration of Remission
DLBCL
Diffuse Large B Cell Lymphoma
DLI
Donor Lymphocyte Infusion
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
EBV
Epstein-Barr Virus
EC
European Commission
ECG
Electrocardiogram
ECHO
Echocardiogram
EDC
Electronic Data Capture
EFS
Event Free Survival
EMA
EOI
European Medicines Agency
End of Induction
EOS
End of Study
EOT
End of Treatment and Primary Follow-Up
EQ-5D
EU
European Quality of Life 5 Dimensions
European Union
FAB
French-American-British
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFP
Fresh Frozen Plasma
FISH
Fluorescent in situ hybridization
FL
Follicular Lymphoma
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony Stimulating Factor

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GFR
GGT
Glomerular Filtration Rate 
Gamma-Glutamyl Transferase
GI
Gastrointestinal
GM-CSF
Granulocyte Macrophage-Colony Stimulating Factor
GMP
Good Manufacturing Practice
GU
Genitourinary
GVHD
Graft versus Host Disease
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HLT
High level term
HSCT
Hematopoietic Stem Cell Transplantation
IA
Interim Analysis 
iAMP21
Intrachromosomal amplification of chromosome 21
IB
Investigator Brochure
ICH
International Conference on Harmonization
ICF
Informed Consent Form
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IL
Interleukin
IL6R
Interleukin 6 receptor
IN
Investigator Notification
INR
International Normalized Ratio
IRC
Independent Review Committee
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISBT
International Society of Blood Transfusion
IUD
Intrauterine Device
i.v.
Intravenous(ly)
IVIG
Intravenous Immunoglobulin
KM
Kaplan Meier
LDH
Lactate Dehydrogenase
LFT
Liver Function Test
LLOQ
Lower Limit of Quantification
LOQ
Limit of Quantification
LP
Lumbar Puncture
LPLV
Last Patient Last Visit
LVEF
Left Ventricular Ejection Fraction
LVSF
Left Ventricular Shortening Fraction
MAP
Master Analysis Plan
MAS
Macrophage Activation Syndrome
MCHC
Mean Corpuscular Hemoglobin Concentration

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MCL
Mantle Cell Lymphoma
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Authorities
MHC
Major Histocompatibility Complex
MLL
Mixed-Lineage Leukemia
MNC
Mononuclear Cells
MRD
Minimal Residual Disease
MRI
Magnetic Resonance Imaging
MRT
Mean Residence Time
MUGA
Multiple Uptake Gated Acquisition
MYC
A regulator gene located on chromosome 8 that is disregulated via translocations in 
Burkitt's lymphoma/leukemia
NCCN
National Comprehensive Cancer Network
NE
Norepinephrine Equivalent
NHL
non-Hodgkin’s lymphomas
NR
No Response
O2
Oxygen
ORR
Overall Remission Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PCR
PCR
Polymerase Chain Reaction
Urine Protein-Creatinine Ratio
PD
Pharmacodynamics
PE
Physical examination
PedsQL
Pediatric Quality of Life questionnaire
pH
Hydrogen ion concentration; a measure of the acidity or basicity of an aqueous 
solution
Ph+
Philadelphia Chromosome Positive
PHI
Personal Health Information
PI
Principal Investigator
PK
Pharmacokinetics
PML
Progressive Multifocal Leukoencephalopathy
PPS
Per-Protocol Set
PR
Partial Remission
PRO
Patient Reported Outcomes
PT
Preferred Term
PT
Prothrombin Time
PT/INR
Prothrombin Time and International Normalized Ratio
qPCR
Quantitative Polymerase Chain Reaction
QoL
Quality of Life
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses
RCL
Replication Competent Lentivirus
RDC
Remote Data Capture

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REB
Research Ethics Board
RFS
Relapse Free Survival
r/r
Relapsed or refractory
SAE
Serious Adverse Event
SC
Steering Committee
scFv
Single chain Fv fragment of an antibody
SCID
Severe Combined Immunodeficiency
SCT
Stem Cell Transplantation
sIg
Surface Immunoglobulin
SmPC
Summary of Product Characteristics 
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Event
TBIL
Total Bilirubin 
Tmax
Time to peak concentration
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
UPCC
University of Pennsylvania Cancer Center
US
United States
VASST
Vasopressin and Septic Shock Trial
VH
Heavy Chain Variable Domain
VL
Light Chain Variable Domain
VSV-G
Vesicular Stomatitis Virus, Glycoprotein
WBC
White Blood Cell
WHO
World Health Organization
WOCBP
Women of child bearing potential

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of patients fulfilling protocol defined criteria 
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; defined as the point at which a patient meets 
all inclusion/exclusion criteria, and after which the patient’s apheresed product is 
received and accepted by the Novartis designated manufacturing facility.
Investigational drug
The study treatment whose properties are being tested in the study; this definition is 
consistent with US Code of Federal Regulations (CFR) 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes approved 
drugs used outside of their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not include other study 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to one 
of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment
Subject Number
A unique identifying number assigned to each patient who enrolls in 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.
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all 
study treatment administration and/or assessments; at this time all study treatment 
administration is discontinued and no further assessments are planned, unless the 
patient will be followed for progression and/or survival
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the tumor, 
whether lymph nodes contain cancer, and whether the cancer has spread from the 
original site to other parts of the body
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient as part of the required study procedures, including active drug run-ins.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Supportive treatment
Refers to any treatment required by the exposure to a study treatment
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points
Withdrawal of study 
consent (WoC)
Withdrawal of consent from the study occurs only when a patient does not 
want to participate in the study any longer and does not allow any further 
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Amendment 7 (26-Oct-2020)
Amendment rationale 
All patients enrolled in the Main Cohort had either received CTL019 infusion or discontinued 
without receiving CTL019 prior to release of amendment 6; enrollment into the Main Cohort 
was completed at the time of protocol amendment 6 release. Amendment 6 was released on 21-
Mar-2019 in the United States (US) only and introduced Cohort 1 (patients who are very high 
risk of first relapse) and Cohort 2 (patients who received CTL019 within 6 months post 
allogeneic hematopoietic stem cell transplantation).  
The current protocol amendment 7 is implemented to:

Terminate the enrollment into cohorts 1 and 2 in the US as of 15-Jun-2020. Patient 
enrollment has been low, in part due to the availability of alternative treatment options.  One 
patient had been treated in Cohort 1 and no patient had been treated in Cohort 2 at the time 
of these cohorts’ termination.  After consulting with the study steering committee, and 
considering the very low recruitment, the decision has been made to terminate the 
enrollment as per the termination letter sent out to Investigators on 15-Jun-2020 and the 
notification sent to FDA on 26-Jun-2020. The decision to terminate Cohort 1 and Cohort 2 
is not due to any new safety concern or safety signal associated with CTL019.  Amendment 
7 documents that the US only cohorts 1 and 2 will not complete enrollment, and the related 
planned analyses will not occur  

Change the required follow-up time of a newborn after live birth from 6 months to 12 
months following pregnancy of a female patient or the partner of any male patient. This 
additional safety monitoring is not due to any new safety concern or emerging data, but is 
taken on a precautionary basis and aligns with current Novartis internal guidelines. Notably, 
this change in follow-up time has already been implemented at US sites with amendment 6, 
however, amendment 7 will be released to all participating sites globally to ensure 
compliance with the 12-month required follow-up of live births

Add the requirement for urine or serum pregnancy testing at all scheduled study visits to 
align with standard CTL019 monitoring requirements

Clarify the requirements for lab testing in the case of secondary malignancies to align with 
program standard language. Notably, this sampling requirement was introduced in 
amendment 6, however it is now being clarified to include RCL testing, and being 
implemented in all participating sites globally with amendment 7

Specify that blood samples for RCL testing are banked beyond month 12, as long as all 
samples through Month 12 were negative
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
1. Protocol Summary: Updated Purpose and Rationale, Primary Objectives, Secondary 
Objectives, Population, Data Analysis as per the changes introduced by the Protocol 
Amendment 7.
2. Section 2.1: Updated to include enrollment termination into Cohort 1 and Cohort 2.

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3. Section 2.2: Updated to include enrollment termination into Cohort 1 and Cohort 2.
Updated to clarify enrollment completion into Main Cohort at time of PA6 release.
4. Section 2.3: Updated to include enrollment termination into Cohort 1 and Cohort 2.
5. Section 2.6: Section revised to include pregnancy risks and contraception requirements as 
per the latest program safety language.
6. Table 3-1: Section updated to include enrollment termination into Cohort 1 and Cohort 2.  
Clarified that endpoints will only be presented as listings for patient in Cohort 1. 
7. Section 4.1: Updated to include enrollment termination into Cohort 1 and Cohort 2.  
Updated to clarify enrollment completion into Main Cohort at time of PA6 release.
8. Section 4.2: Updated definition of end of study and follow-up for patient in Cohort 1.
9. Section 5.1: Updated to include enrollment termination into Cohort 1 and Cohort 2.
Updated number of patients enrolled in study.
10. Section 5.2: Updated to clarify Protocol Amendment 6 inclusion criteria applicable to US 
sites only.
11 Section 6.1.1.2: Updated to include required serum pregnancy testing within 24 hours prior 
to infusion to align with the latest standard program safety language.
12. Section 6.2.4.3: Updated to clarify the requirements for lab testing in case of secondary 
malignancies including Replication-competent lentivirus (RCL) testing and storing of 
blood samples for potential RCL testing in future.
13. Table 7-1: Removed serum pregnancy test at M60 (EOT) visit for only Cohort 1 and 
Cohort 2. Updated to clarify serum pregnancy test will be collected for all WOCBP at 
EOT visit. Serum or urine pregnancy testing added to Visit Evaluation Schedule: 
treatment and primary follow-up phase (Day 28 to Month 54) per standard program safety
language.
14. Table 7-2: Serum or urine pregnancy testing added to Visit Evaluation Schedule: 
secondary follow-up phase per standard program safety language. Updated to clarify 
serum pregnancy test will be collected for all WOCBP at EOT visit.
15. Section 7.1.3: Added serum or urine pregnancy test collection during post-infusion visits 
(Day 28 to Month 54) per standard program safety language.  Also added banking of 
blood samples collected at Months 24 to 54 for potential future RCL testing.  
16. Section 7.1.3.1: Added banking of blood samples for potential future RCL testing. 
Revised language to clarify serum pregnancy test will be performed on all WOCBP at 
M60 (EOT) visit.
17. Section 7.1.4: Added banking of blood samples for potential future RCL testing. Added 
serum or urine pregnancy testing per standard program safety language.
18. Section 7.1.6: Added banking of blood samples for potential future RCL testing.
19. Table 7-5: Updated urine and serum pregnancy testing requirement per standard program 
safety language.
20. Table 7-7: Added banking of blood samples for potential future RCL testing.
21. Table 7-12: Added banking of blood samples for potential future RCL testing.
22. Section 8.4: Added pregnancy testing per standard program safety language and deleted 
duplicate text.

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23. Section 10: Section updated to include enrollment termination into Cohort 1 and Cohort 2 
and to specify that listings will be presented for the single patient enrolled into Cohort 1. 
24. Section 10.2: Section updated to specify analyses will be performed in Main Cohort and 
only listings will be presented in Cohort 1.
25. Section 10.3: Section updated to specify analyses will be performed in Main Cohort and 
only listings will be presented in Cohort 1.
26. Section 10.4: Updated to include enrollment termination into Cohort 1 and Cohort 2.
27. Section 10.4.2: Section updated to remove the primary efficacy analysis for Cohort 1 and 
Cohort 2.  Specified that only listing will be presented in Cohort 1.
28. Section 10.4.4.1: Section revised to specify that subgroup analyses will be performed in 
Main Cohort.
29. Section 10.5.2.12: Section updated to remove Cohort 2 and to specify how the efficacy 
will be summarized in Cohort 1.
30. Section 10.5.3.10: Section updated to remove Cohort 2 and to specify how the safety will 
be reported for Cohort 1.
31. Section 10.5.4: Section revised to specify that analyses will be performed for Main Cohort 
only.  Added that only listings will be presented for Cohort 1.
32. Section 10.6.1: Revised language to clarify additional exploratory assessment may be 
performed in Main Cohort.
33. Section 10.6.1.3: Revised to specify that basic tables, listings and figures will be updated 
for Main Cohort.
34. Section 10.6.2: Revised to specify that CTL019 product characteristics will be 
summarized in Main Cohort.
35. Section 10.6.3: Revised to specify that CRS and response to therapy will be listed for 
Main Cohort.
36. Section 10.6.4: Revised to specify that healthcare resource utilization will be summarized 
in Main Cohort.
37. Section 10.8: Revised to specify one patient enrolled into Cohort 1 and no patients were 
enrolled into Cohort 2.
38. Section 11.3: Added required program standard language for consenting pregnant female
partners of male patients.
39. Editorial changes including minor deletions and additions are also made within this 
protocol amendment.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Amendment 6 (21-Mar-2019) 
Amendment rationale 
At the time of the latest data cut-off (13-Apr-2018), 113 pediatric and young adult patients with 
relapsed or refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) were screened, and 97 
were enrolled in the study and 45 patients are still ongoing in the study overall. At the time of 
data cutoff, enrollment was closed. All enrolled patients have either received CTL019 infusion 
or discontinued without receiving CTL019. All patients who received CTL019, have been 
followed for at least 3 months or have discontinued earlier.
With this clinical protocol amendment 6, approximately 20 additional patients will be screened 
in two additional cohorts to allow at least 15 additional patients to be treated with CTL019 
manufactured from a certified manufacturing facilities participating for this study in each of the 
two cohorts.
At the Amendment 6, three cohort definitions are introduced: 

Main Cohort: all patients screened before protocol Amendment 6 

Cohort 1: patients who are very high risk at first relapse

Cohort 2: patients who received CTL019 within 6 months post allogenic hematopoietic 
stem cell transplantation (allo-HSCT)
Target population (Cohort 1 and Cohort 2): To evaluate if CTL019 is effective in patients with 
very high risk B-ALL at first relapse, the protocol is being amended to add a cohort of at least 
10 infused patients with either very high risk cytogenetic features (extreme hypodiploidy 
defined as fewer than 44 chromosomes and/or Deoxyribonucleic Acid (DNA) index less than 
0.81 or t(17;19) with defined TCF3-HLF fusion) at diagnosis that experience a relapse or any 
patient with B-cell ALL that relapses ≤36 months of initial diagnosis and who has minimal 
residual disease (MRD) ≥0.01% at end of reinduction therapy (Cohort 1). Additionally, to 
investigate the feasibility and safety of administering CTL019 in patients with early relapse post 
HSCT, a second cohort of at least 5 infused patients will be added to this protocol to enroll 
patients that relapsed less than 6 months post allo-HSCT, regardless of the number of relapses 
(Cohort 2). 
This recruitment will be limited only to the United States (US) sites. 
ALL is most common malignancy of childhood (Childhood Blood Cancer Facts and Statistics, 
The Leukemia and Lymphoma Society website, 2018) and relapsed ALL is a leading cause of 
cancer death in children, adolescents and young adults. In patients up to 25 years with refractory 
or in second or greater relapse, CTL019 has shown the potential to be a definitive therapy, 
providing early, deep and durable remissions. Given the unprecedented responses in these 
difficult to treat patients, it has been hypothesized that CTL019 could be effective also in earlier 
lines of therapy in very high risk patients. 
Current treatment protocols for ALL in children emphasize risk-based therapy in order to reduce 
toxicity in low risk patients while ensuring appropriate, more aggressive therapy for those with 
a high risk of relapse (Cooper at al 2015). 

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Very high risk ALL account for app. 8-10% of all B-ALL patients and remains a therapeutic 
challenge. Certain biologic and response factors designate patients to be in the very high risk 
group including those with extreme hypodiploidy (44 or fewer chromosomes and/or DNA index 
less than 0.81), t(9;22) Philadelphia chromosome rearrangement (BCR/ABL1), t(4;11) KMT2A 
(MLL) rearrangement, intrachromosomal amplification of chromosome 21 (iAMP21), those 
over 13 years of age in the United States, and/or failure to achieve complete remission (CR) at 
the end of induction (EOI) therapy (>5 percent lymphoblasts in day 28 bone marrow (BM) or 
the presence of MRD). In the past, this group of patients had overall a poor prognosis, but 
subsets of these patients can be successfully treated with aggressive chemotherapy, often in 
combination with hematopoietic stem cell transplant and / or targeted therapy (such as imatinib 
for Philadelphia Chromosome Positive (Ph+) ALL) with the rate of event-free survival at 5 
years being 40% with standard chemotherapy regimens in this population (Pulsipher et al 2011). 
Augmentation of therapy to include allogeneic stem-cell transplantation in first complete 
remission has been shown to improve disease-free survival for a subset of this patient population, 
but it is associated with higher treatment related morbidity. Several studies have reported that 
transplantation in first complete remission results in a 5-year disease-free survival of 55%-60% 
for patients with very-high risk ALL, including a comparative analysis of transplantation to 
chemotherapy alone which resulted in a 16% survival benefit at 5 years from transplant (Fagioli 
et al 2013, Balduzzi et al 2005, Satwani et al 2007). Despite improvements in survival with 
allogeneic stem-cell transplant, children with very-high risk ALL still have a 24% risk of relapse 
at 10 years compared with a 15% risk observed in standard-risk ALL patients (Fagioli et al 
2013, Malempati et al 2007). Furthermore, the use of allogeneic stem-cell transplantation is less 
effective if patient remains MRD positive after intensive chemotherapy or if patient has certain 
biological features such as extreme hyplodiploidy. Minimal residual disease status in ALL has 
been shown to predict the risk of relapse, event free survival and overall survival (EFS and OS) 
when measured during and after induction therapy in both newly diagnosed and relapsed ALL 
(Borowitz 2015). For example, in a study assessing outcomes after re-induction chemotherapy 
for relapsed pediatric patients, at 5 years, EFS was 15% ± 6% in MRD positive patients while 
EFS was 56% ± 10% in MRD negative patients (Raetz and Bhatla, 2012). 
Early relapse is one of the strongest predictor of survival (time of relapse from initial diagnosis) 
and patients who relapsed less than 18 months after diagnosis had poor outcome, with a 5-yr 
survival rate of approximately 21±1.8% (Nguyen at al, 2008). Leukemia.  Patients with very 
high risk features tend to relapse rapidly after intensive chemotherapy, including post allogeneic 
HSCT. 
The protocol safety language was updated to reflect the current Novartis standard safety 
measures.  Main safety changes include updates to the highly effective contraceptive methods 
for women of childbearing potential (WOCBP) in the respective exclusion criterion, updates to 
the cytokine release syndrome (CRS) algorithm and CRS grading (Lee et al, 2014) based on the 
modified program standard language and Food and Drug Administration (FDA) feedback, 
addition of bio-sampling to follow-up on newly occurring cases of secondary malignancy, and 
management of drug induced liver injury in addition to liver and renal safety monitoring. 
Given that enrollment of the main cohort was completed, no changes to inclusion/exclusion 
criteria were incorporated for the patients already enrolled and treated in the main cohort. 
However, according to Investigator’s Brochure edition 07 (Released date 17 Oct 2018) the 

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contraception requirement changed and for patients to be enrolled in Cohort 1 and Cohort 2 
only exclusion 13 and 18 were retired and criterion 21 added, whereas all other exclusion 
criteria remained unchanged and are applicable.  Collection of serum and peripheral blood for 
immunogenicity at month 24 from patients in Cohort 1 and Cohort 2 was added for longer 
follow up as per the request from Health Authorities.  Leukapheresis assessment was added as 
part of this protocol amendment, as previously leukapheresis for this study was performed under 
the CTL019B2206 study. Lastly, the dosing for the Cohort 1 and Cohort 2 was determined as 
per the label information.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
1. List of abbreviations was updated. 
2. Protocol Summary: Updated Purpose and Rationale, Primary Objectives, Key Secondary
Objectives, Secondary Objectives, Population, Inclusion and Exclusion Criteria, 
Investigational and reference therapy, Data Analysis as per the changes introduced by the 
protocol amendment 6. 
3. Section 1.2.1.2: Updated the clinical experience section with more recent clinical efficacy, 
safety, and cellular kinetics data 
4. Section 2.1: Updated to include rationale and purpose of protocol amendment 6.
5. Section 2.2: Updated to introduce the definitions for the three cohorts, including 
introduction of the two newly added Cohorts 1 and 2. 
6. Section 2.3: Revised text regarding the dose calculation for Cohort 1 and Cohort 2. 
7. Section 3: Updated text stating that hypotheses testing for key secondary objectives are 
applicable for Main cohort only.
8. Table 3-1: Section updated to include primary objectives and endpoints for the newly 
added Cohort 2 and clarified that and the existing primary objectives and endpoints are 
applicable for Main Cohort and Cohort 1 as per Table 3-1.  
9. Section 4.1: Section updated to include the description of the newly added Cohort 1 and 
Cohort 2.
10. Section 4.1.1: Section updated to include criteria to be followed prior to leukapheresis 
collection, requirement for sample sentinel vial collection  as per the latest Investigational 
Leukapheresis, Cryopreservation & Scheduling Manual 
11. Section 5.1: Updated with the patient population information to be included in Cohort 1 
and Cohort 2,
12. Section 5.2: Section  revised to remove the existing inclusion criteria 1 and 6 (which were 
applicable for the screening of patients into Main Cohort only) and to add inclusion 
criteria 11 and 12 which are applicable for the newly added Cohort 1 and Cohort 2
13. Section 5.3: Section revised to remove the existing exclusion criteria 13 and 18 (which 
were applicable for the screening of patients into Main Cohort only) and to add exclusion 
criteria 19, 20, and 21 which are applicable for the newly added Cohort 1 and Cohort 2.   
14. Section 6.1: Study Treatment section was updated with the dosing information for patients 
in Cohort 1 and Cohort 2. 

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15. Section 6.1.3: Treatment for cytokine release section has been updated with the Lee 
grading system and management algorithm based on the latest program standard language 
and FDA feedback.
16. Section 6.2.4.2: General toxicity management considerations section was revised by 
removing the language specific to Japanese patients.  Tables 6-1 and 6-2 have been added 
for the CRS management algorithm and grading as per the Lee. CRS management 
algorithm has been modified at the program level based on FDA feedback.
17. Section 6.2.4.3: New or secondary malignancies toxicity language was updated as per the 
latest program safety language. 
18. Section 6.3.2: Liver safety monitoring language was updated and added sub-sections to 
include renal safety monitoring details as per the latest program safety language. 
19. Section 6.5.3.2 – Disposal information of CTL019 was previously misreported here 
therefore deleted from this section.
20. Section 6.5.4  - Disposal and destruction section was updated
21. Tables 7-1 and 7-2: Primary  follow-up visit evaluation schedule updated with addition of 
leukapheresis/apheresis, leukapheresis/apheresis pre-evaluation and acceptance 
assessments at screening, removal of the serum or urine pregnancy test at pre-infusion, 
addition of the serum pregnancy test at lymphodepleting chemotherapy, pre-infusion 
visits, End of Treatment (EOT) visits,  addition of the EOI local MRD assessment in bone 
marrow aspirate at screening, addition of the menstrual status assessment at screening, 
addition of the (M24) collection of the immunogenicity sample in serum and peripheral 
blood during the treatment and primary follow-up and secondary follow-up visits.
22. Section 7.1.1: Updated to include the EOI MRD local assessment.
23. Section 7.1.3.2: Criteria for premature patient withdrawal form Treatment and Primary 
Follow-up Phase were updated as per latest Novartis standard language. 
24. Section 7.2.3: Updated visit assessments based on Table 7-1 and Table 7-2 with 
Immunogenicity (Serum and Peripheral blood) collection at M24 as per request from 
Health Authority for a longer follow-up.
25. Section 8.1.2: Section updated with the guidelines on reporting the underlying 
malignancies as per the latest program safety language. 
26. Section 8.4: updated to reflect pregnancy reporting as per the latest program safety 
language
27. Section 10: Section updated to include details on newly added Cohort 1 and Cohort 2 and 
to specify which statistical methods and what type of data analysis is applicable for each.
28. Section 10.2: Section updated to remove Chemorefractory definition and to specify that 
this section is applicable for Main Cohort, Cohort1, and Cohort 2.
29. Section 10.3: Updated to specify that this section is applicable for Main Cohort, Cohort1, 
and Cohort 2 
30. Section 10.4: Section updated to clarify which objectives are applicable for Main Cohort, 
Cohort 1, and Cohort 2 
31. Section 10.4.1: Updated to add primary efficacy endpoint for Cohort 1 and primary safety 
endpoints for Cohort 2

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32. Section 10.4.2: Section updated to clarify which method of analysis will be used for Main 
Cohort, Cohort1, and Cohort 2 
33. Section 10.4.4: Section updated to clarify which supportive analyses will be used for Main 
Cohort.
34. Section 10.5: Section updated to include section 10.5.1 to specify that hypothesis testing 
of key secondary end-points will only be performed for patients in Main cohort
35. Section 10.5.2.12: Section added to specify how the efficacy will be summarized in 
Cohort 1 and Cohort 2.
36. Section 10.5.3.10: Section added to specify how the safety will be reported for Cohort 1 
and Cohort 2.
37. Section 10.8: Section updated to include details on the sample size calculations for the 
Cohort 1 and Cohort 2. 
38. Section 10.9: Section header updated to clarify that the key secondary objectives are only 
applicable for Main Cohort. 
39. Section 13: References were updated
40. Section 14.3: Appendix 3 updated with any non-serious Adverse Events (AEs) ≥ Grade 3 
or condition the investigator believes may have a reasonable relationship to CTL019 
therapy and any Serious Adverse Events (SAEs) irrespective of grade in Primary Follow 
up Phase after M12.
41. Section 14.7: Appendix 7 added latest program safety language
42. Section 14.8: Appendix 8 added latest program safety language
43. Editorial changes including minor deletions and additions are also made within this 
protocol amendment. 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.

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Amendment 5 (04-Apr-2017)
Amendment rationale
At the time of this protocol amendment, 26 sites have been initiated and enrollment was closed 
with 92 patients enrolled globally, and 75 patients infused with CTL019. The primary endpoint 
and all three key secondary endpoints were met at the interim analysis conducted with the first 
50 infused patients who had completed at least 3 months of follow-up or discontinued earlier.  
The analyses of these endpoints were updated after all 63 patients who received CTL019 from 
US manufacturing facility had been followed for at least 3 months or discontinued earlier. 
In order to support the development of CTL019 in Japan, at least 5 Japanese patients were to 
be infused with CTL019.  The target number of Japanese patients infused with CTL019 was set 
after consultation with PMDA.  As of enrollment closure on 01-Feb-2017, 2 patients from Japan 
have been infused with CTL019, both from US manufacturing facility.  Therefore the 
enrollment will be re-opened for additional patients in Japan.  Approximately 5 additional 
Japanese patients will be screened to allow at least 3 additional patients to be infused with 
CTL019 manufactured from the US facility (total 5 Japanese patients infused).  Sponsor 
approval will be required to screen more than 5 patients, which is based on target number of 
infused patients.  
While tocilizumab is available in Japan, siltuximab or other alternative anti-IL6 drugs specified 
in the Cytokine Release Syndrome (CRS) management algorithm are not available.  Therefore, 
the CRS management algorithm has been modified to accommodate changes applicable for 
Japan specifically to address the availability of tocilizumab as the only anti-IL-6.  To date the 
experience with siltuximab in patients with sub-optimal responses to tocilizumab is still limited.   
Patients with CRS have been adequately managed utilizing tocilizumab (up to three doses) 
along with steroids and with avoidance of TNF antagonists.  The Japan CRS algorithm now 
establishes 6 lines of management including required 3rd line steroid treatment, three doses of 
tocilizumab and the avoidance of TNF antagonists.  Therefore, the Japan CRS algorithm 
provides adequate management and guidelines for CTL019 related CRS.
Contraception language was changed for clarity. 
Additional safety reporting clarification, is added in patients in secondary follow-up phase 
receiving additional anti-cancer therapies (e.g. stem cell transplant, chemotherapy) after 
CTL019 infusion.  The updated safety reporting requires any severe adverse event or condition 
the investigator believes may have a reasonable relationship to investigational CTL019 therapy 
to be reported in the data base.
Guidelines for use of fibrinogen concentrate in CTL019-associated coagulopathy with 
hypofibrinogenemia for the EU and Japan have been included in the appendices as these 
guidelines were previously distributed to the sites.
Changes to Protocol
1. List of abbreviations: Updated 
2. Amendment 4 Rationale: Corrected reference typo
3. Protocol Summary: Updated population.

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4. Section 1.2.1.2: Added reference to Figure 6-2.
5. Section 2.2: Sample size updated.
6. Section 4.1: Updated with additional enrollment for Japan
7. Section 5.1: Sample size updated to include additional enrollment in Japan
8. Section 5.3: Updated contraception criteria.
9. Section 6.1.3: Updated treatment for cytokine release syndrome for Japan only.
10. Section 6.2.4.2: Updated cytokine release syndrome section to include number of patients 
on CTL019B2202 treated with siltuximab.  Added cytokine release syndrome section for 
Japan only to address absence of siltuximab in Japan and added reference to Japan CRS 
management algorithm. Updated section on B-cell depletion with guidance on vaccines.
11. Figure 6-2: Added Japan CRS management algorithm.
12. Section 7.1.3.3: Updated section.
13. Section 7.1.4.1: Updated section
14. Section 7.2.3: Added statement to clarify CTL019 PK and cellular kinetics.
15. Section 8.4: Updated contraception requirements for male participants and male partners.  
Updated Novartis safety information.  Added instructions for pregnancy outcomes for 
female partners.
16. Section 10.4.4.1: Added Japanese patient sub-group analysis.
17. Section 11.5: Updated section with clinical result reporting and authorship guidelines.
18. Section 14.4: Updated Appendix 4
19. Section 14.5: Added Appendix 5
20. Section 14.6: Added Appendix 6
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, where required.
The changes described in this amended protocol require IRB/EC approval prior to 
implementation only in Japan. In addition, if the changes herein affect the Informed Consent, 
sites are required to update and submit for approval a revised Informed Consent that takes into 
account the changes described in this amended protocol.
Amendment 4 (14-Jun-2016)
Amendment rationale
At the time of this protocol amendment, 26 sites have been initiated, 76 patients have been 
enrolled globally, and 54 patients have been infused with CTL019 manufactured in the US.
In published data (Grupp 2013, Maude 2014) with CTL019 and in current clinical trial 
experience, all complete remissions in pediatric ALL have been achieved no later than Month 
3 post-CTL019 infusion. Discussions with the FDA have indicated that a 3 month follow-up 
may be adequate for initial submission to the FDA to support the marketing authorization of 
CTL019 in the US.

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Therefore, the post-infusion follow-up duration for assessing the primary objective of ORR for 
each patient has been changed from 6 months to 3 months. Patients will continue to be follow-
up for efficacy assessments according to Amendment 3 (No change in this regard in 
Amendment 4).  
Novartis plans to use the CTL019 manufacturing process at the Fraunhofer Institut für 
Zelltherapy, Leipzig, Germany, a CMO to establish a second manufacturing site. Therefore, an 
additional cohort of patients (up to 14) will be enrolled from the EU to treat them with CTL019 
manufactured at the facility in Europe (Fraunhofer Institute) has been included to assess the 
efficacy, safety and in vivo cellular pharmacokinetics of patients infused with CTL019 
manufactured by Fraunhofer Institute, and to assess clinical product comparability between the 
US and EU manufacturing facilities. To support the analysis, an additional secondary endpoint 
has been introduced. Therefore, the approximate total number of enrolled patients has been 
revised to 95 patients.
Two additional key secondary endpoints have been incorporated to allow evaluation of ORR 
and MRD-negative ORR only for CTL019 manufactured at the US manufacturing facility.
An interim analysis has been planned to be conducted with the first 50 CTL019 infused patients 
after they have either completed 3 months of follow-up or discontinued earlier.
The schedule of immunogenicity collections has been reduced and limited to 12 months post-
CTL019 infusion. This reduced collection is based upon a single CTL019 infusion schedule 
versus chronic study treatment dosing where in the former an extended sample collection is not 
informative due to the lack of repeated dosing.
A minimum of one year follow-up at the treating investigational site is strongly recommended 
with remote follow-up as a possibility beyond this one year periods for the following reasons:

Relapse patterns and kinetics of relapsed/refractory pediatric ALL patients (majority of 
relapses following CTL019 occur within one year)

Relapse and survival in this population can be adequately collected by the referring 
pediatric oncologist

Treatment schedule is a single dose infusion with limited incentive to return to a treatment 
site

Alignment with FDA
A subgroup analysis has been added for patients with Down Syndrome given their known 
increased treatment related ALL morbidity and mortality rates. Because of increased risk, stem 
cell transplant is often not recommended in this population. Therefore, the experience with 
CTL019 in this rare population may address this unmet medical need. 
The modified data capture for concomitant medications has been clarified to ensure data capture 
of blood products related to a reportable AE or SAE which assists analysis of the overall 
CTL019 safety profile.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.

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The changes described in this amended protocol require IRB/EC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Changes to Protocol
1. Section 2.2: Sample size updated.
2. Table 3-1: Updated primary, key secondary, and other secondary objectives/endpoints
3. Section 4.1: Updated with additional enrollment for manufacturing from Fraunhofer 
Institute
4. Section 5.1: Sample size updated to include patients manufactured from Fraunhofer Institute
5. Section 6.1.1.1: Section updated with clarifications
6. Table 6-1: Penn grading scale for CRS Grade 3 updated to include fibrinogen concentrate
7. Table 7-1: Updated with clarifications and revision to immunogenicity collections
8. Table 7-2: Updated with clarifications and addition of immunogenicity collections
9. Section 7.1.3: Updated visit assessments based on Table 7-1
10. Section 7.1.3.2: Section updated to include importance of return to investigational site 
within first year post-infusion
11. Section 7.1.4: Section updated with clarifications
12. Section 7.1.5: Section updated with clarifications
13. Table 7-5: Correction of errors
14. Section 7.2.3: Tables updated to include unscheduled collection at relapse
15. Table 7-13 and Table 7-14: Updated immunogenicity sample collection schedule per Table 
7-1 and Table 7-2
16. Table 7-15 and Table 7-16: Updated to include collection plan for additional doses of 
tocilizumab and siltuximab
17. Table 7-17: Updated to include unscheduled collection at relapse
18. Section 7.2.5: Section updated.
19. Section 10: Entire section updated to capture analysis plans for updated/new protocol 
objectives at interim and primary analysis, addition of down syndrome subgroup, and better 
define prior response status at baseline
20. Table 10-3: Clarification on AESI group team
21. Appendix 3: Updated to include clarification on blood product reporting in pre-treatment 
and treatment period

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Amendment 3 (13-Apr-2016)
Amendment rationale
At the time of this protocol amendment, 26 sites have been initiated, 69 patients have been 
enrolled, and 41 patients have been infused with CTL019.
The protocol is being amended to institute updates on safety, manufacturing of CTL019 product, 
patient management, and eligibility criteria based on experiences from ongoing trials and 
recommendations from Health Authorities, Study Steering Committee and Data Monitoring 
Committee.
Key changes include:
1. Clinical experience (Section 1.2.1.2) updated to include more recent data and outcome of 
first 3 patient run-in data from this trial.
2. Target CTL019 dose range for patients > 50 kg has been expanded, and allowable infused 
dose ranges have been defined.
The allowable infused cell dose range of CTL019 transduced cells have been defined as 
0.2 to 5.0 x 106 autologous CTL019 transduced viable T cells per kg body weight (for 
patients ≤ 50 kg) and 0.1 to 2.5 x 108 autologous CTL019 transduced viable T cells (for 
patients > 50 kg) based on updated manufacturing cell dose release criteria. CTL019
products below these minimum transduced cell doses will not be released for infusion.
The target cell dose range for purposes of trial analysis remains unchanged for patients ≤ 
50 kg and for patients > 50 kg a range has also now been specified (1 to 2.5 x 108
transduced CTL019 cells
The statistical plan for the per protocol dose analysis for 2 to 5 x 106 CTL019 transduced 
viable T cells per kg body weight is unchanged, and the 1 to 2.5 x 108 CTL019 transduced 
viable T cells is now provided as a range. At the time of this amendment, no patient has 
received a dose < 0.2 x 106 CTL019 transduced viable T cells. This change is considered 
to have a minimal impact on the per protocol dose statistical analysis.
3. Method of bone marrow MRD analysis in the key secondary endpoint was changed from 
qPCR to flow cytometry due to suboptimal sensitivity of the qPCR assay. Analysis by 
qPCR will be an exploratory endpoint.
4. Cellular immunogenicity analysis will be changed to an exploratory endpoint because the 
assay is not fully validated.
5. Cell counts for leukapheresis collection have further been clarified to better inform 
investigators and optimize collection for manufacturing, in addition to the collection of 
sentinel vials to better characterize apheresis product at the manufacturing site.
6. Extended the allowance of more than 10 patients ≥ 18 years old after Sponsor approval
7. ECHO/MUGA screening assessment may be performed within 7 days of screening.
8. IUD in place prior to consent may remain in place.
9. Medication restrictions updated. Use of steroids for non-GVHD and GVHD indications 
has been further clarified. Time windows have been revised to accommodate the 

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respective medication half-lives and dose, and expected time to toxicity resolution (i.e. 
prior radiotherapy).

Clarification that systemic steroids have 72 hour restriction for non-GVHD 
indications

Systemic steroids added to GVHD therapy restrictions

Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to 
CTL019 infusion

Hydroxyurea removed from restriction within 1 week prior to CTL019 infusion as 
this has been changed to 72 hours for this medication

Methotrexate ≥ 25 mg/m2 added to 2 week chemotherapy restriction

Non-CNS and CNS radiotherapy added with time windows

Anti T-cell antibodies prohibited within 8 weeks prior to CTL019 infusion
10. Due to the continued experience with CTL019 in over 100 patients with pediatric r/r ALL, 
the study no longer requires pausing the study for certain life threatening events and 
deaths suspected to be related to CTL019 therapy.
11. CRS algorithm and management updated with additional details to support trial 
investigators on appropriate CRS management.

Included recommended time intervals between subsequent doses of steroids and anti-
cytokine therapies based on cumulative experience in 3 pediatric r/r ALL trials.

Added siltuximab within the CRS algorithm to be given following the 2nd dose of 
tocilizumab due to encouraging experience to date with this anti-cytokine therapy in 
pediatric and adult ALL patients.

Recommended that TNF antagonists not be used for CTL019 associated CRS because 
lack of activity seen to date and the concerns about their immunosuppressive effects.
12. Secondary follow-up phase revised to allow for remote visits and abbreviated 
AE/concomitant medication collection in order to maximize patient data collection post 
CTL019 infusion in non-responding patients and in patients undergoing further anti-tumor 
therapy to meet health authority requirements on cell and gene therapy trials.
13. AESI profile updated based on most current CTL019 safety profile
14. Pediatric ALL efficacy guidelines have been updated to further address certain areas of 
ambiguity for response assessments involving bone marrow biopsy or aspirate, peripheral 
blood, and timing of baseline assessments.

Trilineage Hematopoiesis (TLH) was removed as one of the components of CR 
definition in the bone marrow: ALL NCCN criteria do list this as a recommended 
bone marrow component for response. However, exact criteria for bone marrow TLH 
are not well established and potentially poorly reproducible. This can alternately be 
supported, in a reproducible and quantitative manner, by the use of peripheral blood 
platelet and neutrophil minimum values in the absence of transfusion of these blood 
components.

Changes and rationale of other tumor response elements are listed in Appendix 14.1 
document history.

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15. Exploratory objective is to correlate the relationship between CRS and clinical tumor 
response. Since CRS typically occurs by Day 28 and all tumor responses noted to date 
occurred by Day 28, it is justified to use the same time point for these two correlates.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/EC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Changes to Protocol
1. Section 1.2.1: Correction of typographical error
2. Section 1.2.1.2: Updated with more recent data.
3. Table 1-1: Table removed and reader directed to most current Investigator Brochure
4. Section 2.2: Enrollment numbers corrected.
5. Section 2.3: Target dose updated for patients > 50 kg updated
6. Section 2.3.1: Section added to include allowable infused cell dose range
7. Section 2.6: Added to include short description of risks and benefits
8. Table 3-1: Update to key secondary, other secondary, and exploratory endpoints.
9. Section 4.1.1: Section updated to include ALC and CD3 counts for leukapheresis 
collection and requirement for sample sentinel vials
10. Section 5.1: Updated to include clarity on patients ≥ 18 years of age
11. Section 5.2: Added window within screening for ECHO/MUGA assessments
12. Section 5.3: Updated contraception and concomitant medication criteria.
13. Section 6.1: Updated with new target and allowable infused cell dose ranges
14. Section 6.1.1.1: Clarification regarding use of alternative LD chemo regimen
15. Section 6.1.1.2: Updated to require influenza treatment be administered per label, updated 
concomitant medication restrictions, and added requirement of siltuximab on site within 
24 hours of infusion per new CRS algorithm
16. Section 6.1.3: Title updated and clarifications added regarding CRS management
17. Section 6.2.3.3: Section removed
18. Section 6.2.4.1: Clarifications added
19. Section 6.2.4.2: CRS section updated to include details around cardiac monitoring, 
coagulopathy, and neurotoxicity
20. Figure 6-1: CRS management algorithm updated for more optimal CRS management
21. Figure 6-2: Figure removed
22. Section 6.2.4.3: Hepatitis B reactivation updated and new or secondary malignances 
toxicity added
23. Section 6.2.6: Added reference to Appendix 3: CTL019 Modified Data Reporting

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24. Section 6.2.7: Updated prohibited concomitant medication criteria
25. Section 6.3: Added section and relevant sub-sections to include liver safety monitoring 
details
26. Section 6.4.1: Clarifications added
27. Section 6.5: Clarifications added
28. Section 6.5.1: Updated with new CTL019 dose ranges
29. Section 6.5.2: Minor updates added
30. Section 6.5.3.1: Clarification added
31. Table 7-1: Primary follow-up visit evaluation schedule updated
32. Table 7-2: Secondary follow-up visit evaluation schedule updated
33. Section 7.1.1: Section updated
34. Section 7.1.1.2: Title and section updated
35. Section 7.1.2: Section updated
36. Section 7.1.3: Section updated
37. Section 7.1.4: Section updated to include new secondary follow-up assessment schedule 
and details. AE and concomitant medication reporting details added
38. Section 7.2.2.4: Section updated to clarify tanner staging only for patients < 18 years old
39. Section 7.2.2.5: Section updated
40. Table 7-5: Local laboratory collections updated
41. Table 7-6: Central laboratory collections updated
42. Table 7-12: Table added to account for CTL019 transgene persistence during secondary 
follow-up phase
43. Section 7.2.4: Clarifications added
44. Section 7.2.5: New section added
45. Section 7.2.7.3: Clarifications added regarding translations and completion of 
questionnaires
46. Section 8.1.2: Section updated
47. Section 8.2.2: Section updated
48. Section 8.4: Section updated with new contraception and pregnancy language
49. Section 9.3: Updated to include manufacturing facility data entry
50. Section 9.4: Updated to include manufacturing facility data
51. Section 10.1.5: Section updated
52. Section 10.2: Section updated
53. Table 10-1: Updated according to efficacy guideline revisions
54. Section 10.4.4.1: Section updated
55. Section 10.5.1.1: Section updated
56. Section 10.5.2.3: Section updated
57. Section 10.5.2.10: Section updated
58. Section 10.5.3.2: AESI updates
59. Section 10.5.3.4: Section updated

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60. Table 10-3: AESI terms updated
61. Section 10.5.3.7: Section updated
62. Section 10.5.3.9: Section updated
63. Table 10-4: PK parameters updated
64. Section 11.7: Clarification on confidentiality added
65. Section 13: References updated
66. Section 14.1: Appendix 1 updated with newest efficacy evaluation guidelines
67. Section 14.3: Appendix 3 added
68. Section 14.4: Appendix 4 added
Amendment 2
Amendment rationale
At the time of this protocol amendment, 1 site has been initiated, 3 patients have been enrolled, 
and 1 patient has been treated.
The protocol is being amended to ensure full alignment with the agreed binding measures 
detailed in the Pediatric Investigation Plan (PIP) opinion of the Paediatric Committee of the 
European Medicines Agency, issued on 20 March 2015 and to address recommendations from 
EMA Scientific Advice letter on 25 April 2014.
Key changes include:
1. The full analysis set should include at least 50 patients < 18 years (of which 10 patients 
are < 10 years old). The total number of enrolled patients has been increased accordingly 
to approximately 78 patients to be enrolled.
2. Elevation from secondary to key secondary endpoint for MRD by PCR based on its 
relevance as a surrogate marker correlated with clinical benefit in pediatric ALL. The 
sample size outlined above will provide 85 % to 91 % power to reject null hypothesis that 
percentage of patients with BOR of CR or CRi and MRD negative bone marrow <15% 
depending on the actual total number of patients infused with CTL019.
3. Elevation from exploratory endpoints to secondary endpoints relating to CRS, safety 
monitoring, and PROs
4. Addition of secondary objective: Derivation of a score to predict cytokine release 
syndrome
5. Day 28 tumor assessment window changed from +/- 7 days to +/- 4 days
6. Additional analyses have been included to assess the response at Day 28 +/- 4 days, 
impact of baseline tumor burden on response, etc.
In addition, other changes have been instituted for purposes of safety, clarity and feasibility 
based on experiences from ongoing trials as outlined below. Key changes include:
1. Clarifications to more accurately define the term “refractory ALL” in inclusion criteria #1. 
The two refractory populations now defined have equally poor prognosis at study 
enrollment and are not expected to negatively impact the population homogeneity.
2. Clarifications on influenza testing based on regions and seasonal variations

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3. Extension of healthcare resource utilization collection visits
4. Clarifications on safety reporting and apheresis collections
5. Removal of PedsQL questionnaire collection in children ages 5-7
Changes to Protocol
1. Section 1.1: Correction of typographical errors
2. Section 1.2.1: Reference added
3. Table 1-1: Clarity added for patient population on the trials
4. Section 1.2.1.2: Clarification on correlation between administration of tocilizumab and 
CTL019 cell expansion
5. Section 2.1: References added
6. Section 2.3: Added “viable T” to dose
7. Table 3-1: Objectives and endpoints updated to include key secondary objective, addition 
of other secondary objectives, as well as shifting of exploratory objectives to secondary 
objectives.
8. Section 4.1.1: Clarity on guidelines for optimal apheresis collection
9. Section 4.1.1: Clarity on use of CTL019 manufactured cells if GVHD experienced after 
collection of apheresis product
10. Section 5.1: Patient population increased to approximately 78 patients enrolled, at least 50 
infused patients < 18 years (at least 10 of which < 10 years)
11. Section 5.2: Clarification on the definition of refractory ALL added to criteria # 1
12. Section 5.3: Criteria # 10 retired and replaced with criteria # 15 with additional Anti T-cell 
therapy guidance
13. Section 6.1.1.2: Clarifications on influenza testing based on regions and seasonal 
variations. Anti T-cell Therapy details added. The number of tocilizumab doses required 
on site prior to CTL019 infusion changed to two doses. Clarification on which specific 
manual referenced. Guidance on monitoring of patient temperature added.
14. Section 6.1.3: Number of tocilizumab doses required on site prior to CTL019 infusion 
changed to two doses.
15. Section 6.2.4.2: CRS management algorithm to be followed by investigators
16. Section 6.2.6: Modified concomitant medication reporting better defined; clarification on 
concomitant medication recording prior to screening
17. Section 6.2.7: Anti T-cell Therapy guidance added
18. Section 6.4: Clarification on which specific manual referenced, and changed “the person” 
to “personnel” to ensure alignment with manuals
19. Section 6.4.2: Clarification on which specific manual referenced
20. Section 6.4.3: Clarification on which specific manuals referenced
21. Section 6.4.3.2: Clarification on which specific manual referenced
22. Section 6.4.4: Clarification on which specific manuals referenced
23. Table 7-1: Day 28 window changed from +/- 7 days to +/- 4 days
24. Table 7-1: Hospitalization status collection changed from Day 1 to screening

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25. Table 7-1: MRD assessment by bone marrow aspirate by flow cytometry to include T cell 
counts
26. Table 7-1: MRD assessment in bone marrow aspirate by qPCR added for clarity
27. Table 7-1: “Aspirate” added to lymph node or other involved tissue assessment
28. Table 7-1: If bone marrow unavailable for genomic analysis, peripheral blood can be used 
if tumor cells are present in the peripheral blood at relapse
29. Section 7.1.1: “at the time of screening” added to performance status assessment; T cell 
numbers added to bone marrow aspirate and biopsy and peripheral blood flow cytometry
30. Section 7.1.2: Collection time point of PROs clarified at enrollment; Clarification on 
influenza testing based on regions and seasonal variations
31. Section 7.1.3: T cells added for flow cytometry; Day 28 window changed to +- 4 days; 
“aspirate” added to lymph node assessment
32. Section 7.1.3.3: If bone marrow aspirate is not available, peripheral blood can be used if 
tumor cells are present in the peripheral blood at relapse
33. Section 7.1.4: T cells added for flow cytometry
34. Table 7-3: T cells added for flow cytometry of peripheral blood
35. Section 7.2.2: Further Tanner staging not required if patient classified as Tanner stage 5
36. Section 7.2.2.4.1: Male tanner stage 5 (pubic hair) corrected
37. Table 7-5: CD4 and CD8 added to T cell levels
38. Table 7-6: CD4 and CD8 added to T cell levels
39. Section 7.2.3: Day 28 window changed to +/- 4 days for all applicable tables
40. Table 7-16: Day 28 window changed to +/- 4 days
41. Section 7.2.5: Hospitalization status collection changed from Day 1 to screening
42. Section 7.2.6: Collection time point of PROs clarified at enrollment; instruction that child 
should face away from the parent removed
43. Section 7.2.6.1: Removal of PedsQL Young Child for ages 5-7
44. Section 7.2.6.2: Clarifications and corrections made, and reference to PRO administration 
guidelines added
45. Section 8.1.2: Clarification added on adverse event reporting while patient simultaneously 
enrolled on CTL019B2206
46. Section 8.2.2: Clarification added on serious adverse event reporting while patient 
simultaneously enrolled on CTL019B2206
47. Section 8.4: “salpingotomy” corrected to “bilateral salpingectomy”
48. Section 10: Section updated with new population details
49. Section 10.1: Section updated based on new population
50. Section 10.2: Primary refractory definition clarified
51. Section 10.4 and subsections: Statistical analysis updates based on changes implemented 
in protocol
52. Section 10.5.1.1: Section updated
53. Section 10.5.2.2: Section updated
54. Section 10.5.2.4: Section removed (CR or CRi with MRD negative bone marrow)

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55. Section 10.5.2.7: Section added
56. Section 10.5.2.8: Section added
57. Section 10.5.2.9: Section added
58. Section 10.5.2.10: Section added
59. Section 10.5.3.5: Section added
60. Section 10.5.3.6: Section added
61. Section 10.5.3.7: Section added
62. Section 10.5.3.9: Section updated
63. Section 10.5.4: Section update
64. Table 10-4: Table updated with more details
65. Section 10.6.1: Section updated
66. Section 10.6.1.3: Section updated
67. Section 10.6.4: Patient reported outcome section removed and moved to Section 10.5.2.7
68. Section 10.8: Section updated
69. Section 10.9: Section updated to include key secondary endpoint analysis
70. Section 13: References added
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/EC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.
Amendment 1
Amendment rationale
At the time of this protocol amendment, no sites have been initiated and first patient first visit 
(FPFV) has not occurred. All sites are to be initiated with the current protocol amendment.
The protocol is being amended in order to include additional safety information and includes 
Health Authority feedback regarding reporting of SAEs including CRS and deaths, follow-up 
time required after a live birth, and revision of the inclusion criteria regarding the age at 
screening and local leukapheresis criteria.
Patient Report Outcomes (PROs) have been added to assess the patient’s health related quality 
of life and patient function following cellular therapy.
The window between informed consent and CTL019 infusion has been widened from 8 weeks 
to 16 weeks. From ongoing phase I clinical trial experience in over 40 patients with r/r pediatric 
ALL receiving CTL019 therapy, the interval from ICF to CTL019 infusion has been up to 19 
weeks. Pediatric patients exceeding a 12 week interval from ICF to infusion in this ongoing 
phase I trial have shown similar outcomes with CTL019 with no additional safety concerns 

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compared to those patients with a time window less than 12 weeks. This widened time interval 
from 8 to 16 weeks is necessary to complete all of the following: patient screening, ongoing 
stabilization of r/r leukemic disease with salvage chemotherapy and the management of typical 
complications resulting from salvage chemotherapy and/or the prolonged cytopenias related to 
the disease itself (e.g. infections requiring hospitalization), manufacturing of the cell therapy 
product and administration of the LD chemotherapy. Apheresis could potentially also occur 
during this interval.
Additional PK and cytokine sample time points were added to better define cell expansion and 
CRS, as well as the addition of exploratory endpoints that did not impact total sample collection 
requirements.
Unnecessary testing of CMV and EBV at screening as per current guidelines for autologous 
blood product therapy has been removed.
In addition, other changes have been instituted for purposes of safety, clarity and feasibility 
based on experiences from ongoing trials as outlined below.
Changes to the protocol
1. Section 1.2.1.2: Updated clinical experience section with currently available data.
2. Table 1-2: Removed and replaced with summary text
3. Table 2-1: Removed and replaced with summary text
4. Table 3-1: Updated secondary endpoints and added exploratory endpoints.
5. Figure 4-1: Study design diagram updated with extended windows from ICF to CTL019 
infusion.
6. Section 4.1.1: Clarifications around apheresis product and exploratory endpoint language 
added.
7. Section 5.2: Changed age at screening from age 2 at initial diagnosis to age 3 at screening. 
Added an additional inclusion criteria to confirm patient meets local institutional criteria 
for leukapheresis.
8. Section 5.3: Clarifications to testing time windows and chemotherapy in exclusion criteria.
9. Section 6.1.1.1: Clarification on timing of lymphodepleting chemotherapy before CTL019 
infusion.
10. Section 6.1.1.2: Clarifications on patient safety and requirements prior to CTL019 
infusion. Vital signs follow-up post CTL019 infusion updated in line with data from 
ongoing trials.
11. Section 6.1.3: Clarifications on recording of rescue medications in the clinical database.
12. Figure 6-1: CRF Management Algorithm updated based on experiences from ongoing 
trials.
13. Table 6-2: Adjustment of vasopressor doses corrected by weight
14. Sections 6.2.4.2 & 6.2.4.3: Safety information added based on most current IB.
15. Section 6.2.6: Clarification on administration of granulocyte colony stimulating factor (G-
CSF).
16. Section 6.2.7: Clarifications added.

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17. Section 6.3.1: Re-screening language removed and better delineation of pre-infusion 
requirements have been included
18. Table 7-1: Primary Follow-up VES updated with new time points, clarifications, updated 
windows, addition and removal of assessments, and updates to table references.
19. Table 7-2: Secondary Follow-up VES updated with clarifications and additional 
assessments.
20. Section 7.1.1: Clarifications made throughout section impacting patient safety.
21. Section 7.1.1.1: Removed section due to widened window between ICF and CTL019 
infusion. Screening procedures requiring repeat have been incorporated into other sections 
of the protocol.
22. Section 7.1.1.2: Reference to an enrollment form has been removed. Error in previous 
version.
23. Section 7.1.2: Section updated with new visit windows and clarifications for patient 
safety.
24. Section 7.1.3: Section updated with new visit windows and clarifications for patient 
safety.
25. Section 7.1.3.3: Section updated for clarification.
26. Section 7.1.4: Section updated for clarification.
27. Section 7.1.4.1: Section updated for clarification on research results and biological 
samples.
28. Table 7-3: Table updated for clarification.
29. Section 7.2.2.4: Tanner staging guidelines for male genitalia and public hair stages and 
female breast stages and public hair stages added for clarity.
30. Section 7.2.5: Added resource utilization to capture hospitalizations
31. Section 7.2.6: Added patient reported outcomes
32. Table 7-5: Table updated for clarification.
33. Table 7-6: Table updated for clarification
34. Tables 7-7, 7-8, 7-9, 7-10, 7-11, 7-12, 7-13, 7-14, and 7-15: Tables updated for 
clarification of windows and sample requirements.
35. Section 7.2.3.1: Section updated for clarification.
36. Section 7.2.4: Section updated for clarification.
37. Table 7-16: Table updated for clarification of windows and sample requirements.
38. Section 7.2.6: Section updated to add PRO details.
39. Section 8.2.2: Section updated to address FDA requirements for CRS and deaths.
40. Section 8.4: Section updates to address FDA requirements for follow-up after live birth
41. Section 10.5.4: Section updated for clarification.
42. Section 10.6.1: Section updated for clarification.
43. Section 10.6.1.3: Section updated for clarification.
44. Section 10.6.4: Section added for patient reported outcomes
45. Section 10.6.5: Section added for healthcare resource utilization
46. Section 13: New references added.

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47. Section 14.1.2.3.5: Revision to ALL response guidelines
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/EC approval prior to 
implementation. In addition, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this amended protocol.

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Protocol summary
Protocol number
CCTL019B2202
Title
A Phase II, single arm, multicenter trial to determine the efficacy and safety of CTL019 
in pediatric patients with relapsed or refractory B-cell acute lymphoblastic leukemia
Brief title
Study of efficacy and safety of CTL019 in pediatric ALL patients
Sponsor and Clinical 
Phase
Novartis
Phase II
Multicenter
Investigation type
Biological
Study type
Interventional
Purpose and 
rationale
Outcome remains poor for patients with relapsed or refractory (r/r) pediatric B-cell 
lineage acute lymphoblastic leukemia (B-cell ALL). Treatment options for r/r B-cell ALL 
include further treatment with salvage chemotherapy, second allogeneic stem cell 
transplantation (SCT) or supportive care. Therapy in this population is not curative with 
an overall survival of 3 to 6 months.
CD19 has emerged as an attractive therapeutic target because it is widely expressed 
on normal and malignant B-cells throughout B-cell maturation but not on pluripotent 
stem cells or non–B-cell tissues. The development of chimeric antigen receptor (CAR) 
T cells to target CD19+ cells (CART19 or CTL019) provides an innovative new 
approach to these malignancies. This approach involves autologous patient-derived T 
cells that are genetically modified ex vivo via lentiviral transduction to express a CD19 
antigen recognition domain attached to intracellular signaling domains that mediate T-
cell activation in a Major Histocompatibility Complex (MHC) independent manner. 
Encouraging anti-tumor efficacy has been seen in r/r adult and pediatric ALL and in r/r 
CLL.
Amendment 6 (US only): In patients up to 25 years with refractory or in second or 
greater relapse, CTL019 has shown the potential to be a definitive therapy, providing 
early, deep and durable remissions. Given the unprecedented responses in these 
difficult to treat patients, it has been hypothesized that CTL019 could be effective also 
in earlier lines of therapy in very high risk ALL patients, who have a poor prognosis and 
relapsed after first allo-HSCT, with a median survival of 7.4 months (95% Confidence 
Interval (CI), 6.0-9.6 months) (Crotta et al 2018).
At Amendment 6 (US only), three cohort definitions are introduced (enrollment into 
Cohort 1 and Cohort 2 has been terminated as of 15-Jun-2020):

Main Cohort: all patients screened before protocol amendment 6 (enrollment into 
Main Cohort was completed at the time of the protocol amendment 6 release)

Cohort 1: patients who are very high risk at first relapse

Cohort 2: patients who received CTL019 within 6 months post allo-HSCT
Primary Objective(s)
For Main Cohort and Cohort 1 (enrollment into Cohort 1 has been terminated as of 15-
Jun-2020):  To evaluate the efficacy of CTL019 therapy from all manufacturing facilities 
as measured by overall remission rate (ORR) during the 3 months after CTL019 
administration, which includes Complete Remission (CR) and CR with incomplete blood 
count recovery (CRi) as determined by independent review committee (IRC)
assessment.
Cohort 2: To evaluate the feasibility and safety of CTL019 therapy in patients that 
relapsed < 6 months post allo-HSCT (enrollment into Cohort 2 has been terminated as 
of 15-Jun-2020) 
Key Secondary 
Objectives
Key Secondary Objectives are only applicable for Main Cohort.
Objective 1: Evaluate the efficacy of CTL019 therapy from US manufacturing facility as 
measured by overall remission rate (ORR) during the 3 months after CTL019 
administration, which includes CR and CR with incomplete blood count recovery (CRi) 
as determined by IRC assessment
Objective 2: Evaluate the percentage of patients who achieve a best overall response 
(BOR) of CR or CRi with a MRD negative bone marrow by central analysis using flow 
cytometry among all patients who receive CTL019 from all manufacturing facilities

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Objective 3: Evaluate the percentage of patients who achieve a best overall response 
(BOR) of CR or CRi with a MRD negative bone marrow by central analysis using flow 
cytometry among all patients who receive CTL019 from US manufacturing facility
Secondary 
Objectives
Objective 1: To evaluate the percentage of patients who achieve CR or CRi at Month 6 
without SCT between CTL019 infusion and Month 6 response assessment.
Objective 2: To evaluate the percentage of patients who achieve CR or CRi and then 
proceed to SCT while in remission before Month 6 response assessment.
Objective 3: To evaluate the duration of remission (DOR).
Objective 4: To evaluate the relapse-free survival (RFS), event-free survival (EFS) and 
overall survival (OS).
Objective 5: Evaluate the response at Day 28 +/- 4 days
Objective 6: Evaluate the impact of baseline tumor burden on response
Objective 7: Evaluate the quality of response using MRD disease assessments before 
treatment and at day 28 +/- 4 days after treatment using central assessment by flow 
cytometry and before SCT by local assessment (flow or Polymerase Chain Reaction 
(PCR)).
Objective 8: To evaluate the safety of CTL019 therapy as measured by type, frequency 
and severity of adverse events and laboratory abnormalities.
Objective 9: To characterize the in vivo cellular pharmacokinetic (PK) profile (levels, 
persistence, trafficking) of CTL019 cells in target tissues (blood, bone marrow, Cerebral 
Spinal Fluid (CSF), and other tissues if available).
Objective 10: To describe the prevalence and incidence of immunogenicity to CTL019.
Objective 11: Describe the effect of CTL019 therapy on Patient Reported Outcome 
(PRO)
Objective 12: To derive a score to predict cytokine release syndrome.
Objective 13: To describe the profile of soluble immune factors that may be key to 
cytokine release syndrome.
Objective 14: To describe the levels of B and T cells (peripheral blood and bone 
marrow) prior to and following CTL019 infusion for safety monitoring.
Objective 15: To assess the efficacy, safety and in vivo cellular pharmacokinetics of 
patients infused with CTL019 manufactured by Fraunhofer Institute
With Amendment 6 (US only), all above objectives remain unchanged and applicable 
for Main Cohort and for Cohort 1 and Cohort 2 except objective 15 (the following 
objective is no longer applicable; To assess the efficacy, safety and in vivo cellular 
pharmacokinetics of patients infused with CRL019 manufacture by Fraunhofer 
Institute). Enrollment into Cohort 1 and Cohort 2 has been terminated as of 15-Jun-
2020.
Study design
This is a single arm, open-label, multi-center, phase II study to determine the efficacy 
and safety of CTL019 in pediatric patients with r/r B-cell ALL. The study will have the 
following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & 
Lymphodepleting Chemotherapy), Treatment and Primary Follow-up, Secondary 
Follow-up (if applicable), and Survival Follow-up. The total duration of the study is 5 
years from CTL019 cell infusion. After CTL019 infusion, efficacy will be assessed 
monthly for the first 6 months, then quarterly up to 2 years and semi-annually 
afterwards up to 5 years, or until patient relapse in the Treatment and Primary Follow-
up phase. Safety will be assessed throughout the study. A post-study long term follow-
up for lentiviral vector safety will continue under a separate destination protocol per 
health authority guidelines.
At the beginning of the trial, a safety run-in stage will be conducted to enroll three 
patients for the purpose of assessing the acute safety profile of the Novartis designee 
manufactured CTL019 cell product. For the first three patients enrolled, following 
lymphodepleting chemotherapy and CTL019 infusion, safety profiles from the first 14 
days post-infusion will be reported to the Health Authorities.
Population
At the time of protocol amendment 6, enrollment into the Main Cohort, including 
Japanese patients, has been completed.  Main Cohort: The target population 
comprised of pediatric patients with B-cell ALL who were chemo-refractory, relapsed 
after allogeneic SCT, or were otherwise ineligible for allogeneic SCT. 97 patients were
enrolled between the age of 3 years at the time of screening to the age of 27 years at 
the time of initial diagnosis. This included 65 infused patients less than the age of 18 at 

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the time of screening, 32 of which were under the age of 10. Patients 18 years of age 
or older at screening were limited to 10 total infused patients. When 10 patients ≥ 18 
years of age have been infused, further enrollment in this age category required
Sponsor approvalA total of 14 patients ≥ 18 years of age were infused after approval
from Sponsor. 12 patients were enrolled to ensure at least 10 patients were infused 
with CTL019 manufactured by the Fraunhofer Institut für Zelltherapie und Immunologie, 
Leipzig, Germany (Fraunhofer-Institute), a contract manufacturing organization (CMO).  
5 Japanese patients were screened to allow at least 3 additional patients to be infused 
with CTL019 manufactured by the US facility (total 5 Japanese patients infused).  
Sponsor approval was required to screen more than 5 patients, which was based on 
target number of infused patients.
For amendment 6 (US only), two additional cohorts (Cohort 1 and Cohort 2) were
added to the study for the US participating sites. The target population (Cohort 1) 
comprised either patients with very high risk cytogenetic features at diagnosis - extreme 
hypodiploidy or t(17;19) with defined TCF3-HLF fusion – at the time of first relapse or 
any patient with B-cell ALL that relapses ≤36 months of initial diagnosis and who has 
MRD ≥0.01% at end of reinduction therapy. 
Additionally, to investigate the feasibility and safety of administering CTL019 in patients 
with early relapse post allo-HSCT patients that relapsed less than 6 months post allo-
HSCT, regardless of the number of relapses were also  eligible (Cohort 2). 
Approximately 20 patients were to be screened to ensure 15 infused patients (at least 
10 in Cohort 1 and 5 in Cohort 2).  1 patient was enrolled into Cohort 1 and no patients 
were enrolled into Cohort 2. Enrollment into Cohort 1 and Cohort 2 has been 
terminated as of 15-Jun-2020).
Inclusion criteria
1.
[Retired from Amendment Protocol Version 06]
2.
For relapsed patients, documentation of CD19 tumor expression in bone marrow or 
peripheral blood by flow cytometry within 3 months of study entry
3.
Adequate organ function defined as:

Renal function defined as:

A serum creatinine based on age/gender as follows:
Maximum Serum Creatinine
(mg/dL)
Age
Male
Female
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1.0
1.0
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4

Alanine Aminotransferase (ALT) ≤ 5 times the upper limit of normal (ULN) for 
age

Bilirubin < 2.0 mg/dL

Must have a minimum level of pulmonary reserve defined as ≤Grade 1 
dyspnea and pulse oxygenation > 91% on room air

Left Ventricular Shortening Fraction (LVSF) ≥ 28% confirmed by 
echocardiogram (ECHO), or Left Ventricular Ejection Fraction (LVEF) ≥ 45% 
confirmed by echocardiogram or Multiple Uptake Gated Acquisition (MUGA) 
within 7 days of screening
4.
Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening
5.
Life expectancy > 12 weeks
6.
[Retired from Amendment Protocol Version 06] 
7.
Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at 
screening

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8.
Signed written informed consent and assent forms if applicable must be obtained 
prior to any study procedures
9.
Must meet the institutional criteria to undergo leukapheresis or have an 
acceptable, stored leukapheresis product
10. Once all other eligibility criteria are confirmed, must have a leukapheresis product 
of non-mobilized cells received and accepted by the manufacturing site. Note: 
Leukapheresis product will not be shipped to or assessed for acceptance by the 
manufacturing site until documented confirmation of all other eligibility criteria is 
received.
11. (Protocol Amendment 6 US only) B-cell acute lymphoblastic leukemia and;
Cohort 1:
a.
First relapse AND hypodiploid cytogenetics: fewer than 44 chromosomes and/or 
DNA index < 0.81, or other clear evidence of a hypodiploid clone OR
b.
First relapse AND t(17;19) with defined TCF3-HLF fusion OR 
c.
First relapse with any cytogenetics provided the relapse occurred ≤ 36 months  
of initial diagnosis AND MRD at end of reinduction therapy is ≥0.01% by flow 
cytometry (local assessment)
Cohort 2:
a.
Any BM relapse after allogeneic  stem cell transplantation (HSCT) and must be 
< 6 months from HSCT at the time of CTL019 infusion
12. (Protocol Amendment 6 US only) Age up to 25 years at the time of screening 
Exclusion criteria
1.
Isolated extra-medullary disease relapse
2.
Patients with concomitant genetic syndromes associated with bone marrow failure 
states: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman 
syndrome or any other known bone marrow failure syndrome. Patients with Down 
Syndrome will not be excluded.
3.
Patients with Burkitt’s lymphoma/leukemia (i.e. patients with mature B-cell ALL, 
leukemia with B-cell [surface Immunoglobulin (sIg) positive and kappa or lambda 
restricted positivity] ALL, with French-American-British [FAB] L3 morphology and 
/or a MYC translocation)
4.
Prior malignancy, except carcinoma in situ of the skin or cervix treated with 
curative intent and with no evidence of active disease
5.
Treatment with any prior gene therapy product
6.
Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-
CD19 therapy
7.
Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), 
or any uncontrolled infection at screening
8.
Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening
9.
Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease 
(GVHD)
10. [Retired from Amended Protocol Version 01]
11. Active Central Nervous System (CNS) involvement by malignancy, defined as 
CNS-3 per National Comprehensive Cancer Network (NCCN) guidelines. Note: 
Patients with history of CNS disease that has been effectively treated will be 
eligible
12. Patient has received an investigational medicinal product within the last 30 days 
prior to screening
13. [Retired from Amendment Protocol Version 06] 
14. [Retired from Amended Protocol Version 02]
15. [Retired from Amended Protocol Version 02]
16. [Retired from Amended Protocol Version 04] 
17. The following medications are excluded:
a.
Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours 
prior to CTL019 infusion. However, the following physiological replacement 
doses of steroids are allowed: <12 mg/m2/day hydrocortisone or equivalent

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b.
Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be 
completed > 6 weeks prior to CTL019 infusion
c.
GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 
weeks prior to CTL019 infusion to confirm that GVHD recurrence is not 
observed (e.g. calcineurin inhibitors, methotrexate or other chemotherapy 
drugs, mycophenolyate, rapamycin, thalidomide, or immunosuppressive 
antibodies such as anti-CD20 (rituximab), anti-tumor necrosis factor [anti-
TNF], anti-interleukin 6 [anti-IL6] or anti-interleukin 6 receptor [anti-IL6R], 
systemic steroids)
d.
Chemotherapy:

Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours 
prior to CTL019 infusion

The following drugs must be stopped > 1 week prior to CTL019 infusion 
and should not be administered concomitantly or following 
lymphodepleting chemotherapy: vincristine, 6-mercaptopurine, 6-
thioguanine, methotrexate <25 mg/m2, cytosine arabinoside < 100 
mg/m2/day, asparaginase (non-pegylated)

The following drugs must be stopped > 2 weeks prior to CTL019 infusion: 
salvage chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 
mg/m2, anthracyclines, cyclophosphamide, methotrexate ≥ 25 mg/m2), 
excluding the required lymphodepleting chemotherapy drugs

Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 
infusion
e.
CNS disease prophylaxis:

CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 
infusion (e.g. intrathecal methotrexate)
f.
Radiotherapy

Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 
infusion

CNS directed radiation must be completed > 8 weeks prior to CTL019 
infusion
g.
Anti T-cell Antibodies: Administration of any T cell lytic or toxic antibody (e.g. 
alemtuzumab) within 8 weeks prior to CTL019 is prohibited since residual lytic 
levels may destroy the infused CTL019 cells and/or prevent their in vivo 
expansion. If such an agent has been administered within 8 weeks prior to 
CTL019, contact the Sponsor, consider consultation with an pharmacology 
expert, and consider measuring residual drug levels, if feasible, prior to 
CTL019 infusion.
18. [Retired from Amendment Protocol Version 06] 
19. Pregnant or nursing (lactating) women. 
NOTE: Female study participants of reproductive potential must have a negative serum 
pregnancy test performed within 24 hours before leukapheresis, lymphodepletion and 
prior to CTL019 infusion.
20. 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 signing informed consent and through at least 12 months after 
the CTL019 infusion and until CAR T-cells are no longer present by Quantitative 
Polymerase Chain Reaction (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 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of 
contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks 
before taking study treatment. In case of oophorectomy alone, only when the 

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reproductive status of the woman has been confirmed by follow up hormone 
level assessment

Male sterilization (at least 6 months prior to screening). For female patients on 
the study, the vasectomized male partner should be the sole partner for that 
patient

Use of oral, (estrogen and progesterone), injected or implanted hormonal 
methods of contraception or placement of an intrauterine device (IUD) or 
intrauterine system (IUS), or other forms of hormonal contraception that have 
comparable efficacy (failure rate <1%), for example hormone vaginal ring or 
transdermal hormone contraception. In case of use of oral contraception women 
should have been stable on the same pill for a minimum of 3 months before 
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 Informed Consent Form 
(ICF).
21. Sexually active males must use a condom during intercourse from signing informed 
consent  to at least 12 months after the CTL019 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. In addition, male participants must not donate sperm 
for the time period specified above.
Investigational and 
reference therapy
Main Cohort: 
A target per-protocol dose of CTL019 transduced cells will consist of a single infusion of 
2.0 to 5.0 x 106 CTL019 transduced viable T cells per kg body weight (for patients ≤ 50 
kg) and 1.0 to 2.5 x 108 CTL019 transduced viable T cells (for patients > 50 kg).
The following cell dose ranges may be infused if all other safety release criteria are 
met: 0.2 to 5.0 x 106 CTL019 transduced viable T cells per kg body weight (for patients 
≤ 50 kg) and 0.1 to 2.5 x 108 CTL019 transduced viable T cells (for patients > 50 kg)
Amendment 6 only: Cohort 1 and Cohort 2 (US only):
Based on the patients’ weight  at the time of leukapheresis:

Patients ≤ 50 kg: 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body
weight

Patients > 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells
Efficacy assessments
Primary: ORR, which includes CR and CRi, as determined by assessments of 
peripheral blood, bone marrow, CNS symptoms, physical exam (PE) and CSF. The 
primary endpoint will be based on the IRC assessment. The local investigator’s 
assessed results will be used for sensitivity analysis.
Secondary: Patients with CR or CRi at Month 6 without SCT between CTL019 infusion 
and Month 6 response assessment, patients who achieve CR or CRi and then proceed 
to SCT while in remission prior to Month 6 response assessment, Minimal residual 
disease, duration of remission, relapse-free survival, event-free survival, and overall 
survival
Safety assessments
Adverse events and laboratory abnormalities (type, frequency and severity)
Immunogenicity assessments :
a.
prevalence of immunogenicity against CTL019 (pre-existing), both humoral and 
cellular
b.
incidence of immunogenicity against CTL019, both humoral and cellular
c.
proportion of patients with transient anti-CTL019 antibody assay titers

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Analysis of other secondary or exploratory endpoints will be descriptive and may 
include summary statistics such as means, standard deviations, 95% confidence 
intervals, if applicable. Cumulative Incidence Functions (CIF), Kaplan-Meier curves and 
median time to event will be presented for time-to-event variables (DOR, RFS, EFS and 
OS), if appropriate.
Sample size:
In a previous study of clofarabine in pediatric patients with r/r B-cell ALL who have had 
2 or more prior regimens, the reported ORR was 20%. Based on the null hypothesis of 
ORR ≤ 20% and alternative hypothesis of ORR >20%, up to 76 patients in the FAS will 
provide more than 95% power to demonstrate statistical significance at one-sided 2.5% 
level of significance, if the underlying ORR is 45%. 
Accounting for the patients to assess CTL019 manufactured from the Fraunhofer 
Institute, and assuming 20% to 25% enrolled patients will not be infused due to reasons 
such as CTL019 product manufacturing issues, worsening of patient’s condition, etc., 
approximately 95 patients need to be enrolled.
Cohort 1 and Cohort 2 (US only):
Patients in Cohort 1 and Cohort 2 will be analyzed separately. At the time of enrollment 
termination, only 1 patient was enrolled and infused in Cohort 1. Therefore, only listings 
will be presented for this single patient.
Key words
Relapsed/refractory ALL, relapsed ALL post allogeneic SCT, CTL019

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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
B cell malignancies comprise a heterogeneous group of neoplasms including acute 
lymphoblastic leukemias (ALL), chronic lymphocytic leukemias (CLL), and a vast majority of
non-Hodgkin's lymphomas (NHL). An estimated 91,000 new cases of lymphocytic leukemia 
and NHL were diagnosed in the US in 2012 (National Cancer Institute 2013). There were 
66,371 lymphoid malignancies registered in 2000-2002 by 44 European cancer registries (Sant 
et al 2010). The majority of these malignancies are of B cell origin (Mitchell et al 2012).
ALL is more commonly seen in children although can occur at any age. ALL represent 75% to 
80% of acute leukemias among children, therefore, making it the most common form of 
childhood leukemia (The Leukemia & Lymphoma Society 2009). The median age at diagnosis 
for ALL is 13 years; 60% of patients are diagnosed at younger than 20 years of age, whereas 
23% are diagnosed at 45 years or older. Among children, B-cell lineage ALL constitutes 
approximately 88% of leukemia cases.
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). Despite these treatment modalities, many relapsed patients remain 
incurable. Initial chemotherapy is typically administered over a 2 to 3 year period. With current 
multi-agent treatment regimens, the cure rate among children with ALL is > 80%. Most patients 
(>85%) with relapsed ALL will achieve a second remission (Ko et al 2010); 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 (Tallen et al 2010). Refractory ALL [never achieving a complete remission 
(CR)] in adults or children has a dismal prognosis and these patients do not benefit from SCT. 
Thus relapsed or refractory (r/r) ALL patients, both adult and pediatric, have significant unmet 
medical needs.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of CTL019
Immunotherapy is a treatment that involves activating or enhancing the immune system to help 
fight diseases including cancer. Adoptive immunotherapy with allogeneic donor leukocytes (e.g. 
donor lymphocyte infusion) has potent anti-leukemic effects, however the benefit is confined 
largely to patients with myeloid leukemias, as B-ALL has a durable remission rate of less than 
10% (Kolb et al 1995), and often at the cost of substantial morbidity due to GVHD (Appelbaum 
2001, Sullivan 1989).
Adoptive T-cell therapy is one particular approach that involves engineering T-cell receptors 
(TCRs) to bind to specific antigens present on tumor cells. These modified TCRs, known as 
chimeric antigen receptors (CARs), allow the immune system to specifically target and destroy 
tumor cells in a MHC independent manner (Mellman et al 2011).

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A very promising potential target antigen for B cell malignancies is CD19, a cell-surface protein 
whose expression is restricted to B cells and their precursors (Sadelain 2003, Brentjens 2010, 
Porter 2011). CD19 is not expressed 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 (Ledbetter 
1988, Stamenkovic 1988, Fearon 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 (Ledbetter 1988, Stamenkovic 1988, Tedder 1989, Fearon 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, 4-1BBplus TCRζ (June 2007, June 2009, Kohn 2011).
CTL019 (CART-19) 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 lymphocytes 
transduced with chimeric receptor genes to combine the effector functions of T lymphocytes 
with the ability of antibodies to recognize predefined surface antigens with high specificity in
a non-MHC restricted manner (Gross 1989, Pinthus 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) chains joined by a peptide linker of about 15 residues in length (Mullaney 
et al 2001).
Figure 1-1
CTL019 chimeric antigen receptor design
Early results from ongoing clinical trials of CTL019 in r/r CLL and r/r ALL have shown 
promising and durable anti-tumor efficacy (Porter 2011, Grupp 2013, Maude 2014). It is 
anticipated that CTL019 may offer a therapeutic alternative for patients with r/r B cell 

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malignancies who are either SCT ineligible or who have relapsed after SCT, which may offer 
a greater durability of remission than current salvage therapies. In the future, CTL019 may also 
have the potential to replace SCT as a therapeutic choice, expanding patient eligibility by 
obviating the need for matched donors along with potentially lower rates of upfront mortality 
and morbidity.
1.2.1.1
Non-clinical experience
Extensive literature supports the use of engineered T cells for tumor immunotherapy in rodent 
tumor models (Calogero 2000, Clay 2002, Hombach 2002, Pule 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 2000, Roessig 2002, Brentjens 2003, Cooper 2003, Serrano 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 
1998, Krause 1998, Eshhar 2001, Maher 2002, Finney 2004, Friedmann-Morvinski 2005, 
Brentjens 2010). The pre-clinical data supporting CAR T cell persistence, expansion and anti-
tumor efficacy have been published (Gross 1992, Milone 2009).
1.2.1.2
Clinical experience
For a summary of ongoing human studies with CTL019 (patients treated, disease indication, 
CTL019 dosing), please refer to the most current Investigator Brochure.Initial dosing in adults 
and children, for safety reasons, used a split infusion schedule of escalating doses. However, 
the majority of patients in the two phase I studies received CTL019 as a single one time infusion 
or two sequential infusions due to the onset of fevers and other clinical events precluding further 
infusions. For pediatric patients, cells are dosed per kg body weight where dosing in adults does 
not consider body weight.
Clinical efficacy
CTL019 has been approved by the 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 of adult patients with r/r large 
B-cell lymphoma after two or more lines of systemic therapy including diffuse large B-cell 
lymphoma (DLBCL) not otherwise specified, high grade B-cell lymphoma and DLBCL arising 
from follicular lymphoma [US Prescribing Information (PI) 2018]. European Medicines 
Agency (EMA) has approved CTL019 for the treatment of paediatric 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 
[European Union summary of product characteristics (EU SmPC) 2018]
Efficacy in r/r pediatric and young adult ALL 
Treatment options for patients with r/r ALL include high-dose chemotherapy with subsequent 
HSCT, standard chemo-immunotherapy, targeted treatment with small molecule pathway 
inhibitors, or supportive care with non-curative palliative goals.
Three studies demonstrated the durable anti-tumor efficacy and safety of CTL019 and the 
cellular kinetics of CTL019 in pediatric and young adult patients with r/r B-ALL.

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[CCTL019B2202] (B2202 global pivotal trial) and [CCTL019B2205J] (B2205J US trial) are 
very similar phase II, single arm, multicenter trials to determine the efficacy and safety of 
CTL019 in pediatric and young adult patients with r/r B-ALL. [CCTL019B2101J] (B2101J US 
trial) is a phase I/IIa single center study of CTL019 in pediatric patients with chemotherapy 
resistant or refractory CD19+ leukemia and lymphoma.
Study [B2202] met its primary objective at the interim analysis (IA) performed on the first 50 
patients infused with CTL019 with data cut-off of 17-Aug-2016. The overall remission rate 
(ORR) during three months per Independent Review Committee (IRC) assessment was 82.0% 
(98.9% CI: 64.5, 93.3; p<0.0001). At the IA 2 with data cut-off of 25- Apr-2017 on 75 patients 
infused, 61/75 (81.3%) achieved ORR (Maude NEJM 2018). In addition, study [B2205J] again 
met its primary objective at the second interim analysis (IA) performed on 42 of 58 patients 
infused with CTL019 who completed 6 months of follow-up or discontinued early at the data 
cut-off of 06-Oct-2017.
Results from these two studies are consistent with that observed in B2101J where ORR was 
94.6% (95% CI: 85.1, 98.9). ORR was consistent across all patient subgroups.
In all three studies, responses occurred rapidly (usually within 28 days post-CTL019 infusion) 
and bone marrow MRD data confirmed the depth of remission with all patients with CR or 
complete remission with incomplete blood count recovery (CRi) having MRD negative bone 
marrow (81.3%, 95% CI: 70.7, 89.4; p<0.0001 in study B2202; 64.3%, 95% CI: 48.0, 78.4 in 
study B2205J; and 85.7%, 95% CI: 73.8, 93.6 in study B2101J).
The median duration of remission (DOR) was not reached in studies [B2202] and [B2205J] and 
the estimated probability of remission at Month 6 was 79.5% and 71.4%, respectively. In study 
[B2101J], DOR at Month 6 was 73.9%. 
The median overall survival (OS) in studies [B2202] was 19.1 months and [B2205J] was 23.8 
months. The estimated probability of survival at Month 6 was 90.3% and 79.3%, respectively.
In study [B2101J], OS at Month 6 was 85.7%. The estimated probability of survival at Month 
12 was 76% in study [B2202] and 62.2% in study [B2205J].
Across all three trials in pediatric and young adult r/r B-ALL patients, robust and high response 
rates occurred across the entire range of CTL019 doses and in all patient subgroups. In addition, 
consistently high and durable remissions were observed across these three studies in the 
majority of patients without additional therapies.
Furthermore, two different quality of life (QoL) tools demonstrated improvement in patient 
reported outcomes at 3 and 6 months compared to baseline following CTL019 infusion in study
[B2202] further supporting the clinical benefit.
Clinical Safety in r/r ALL
In patients with refractory or relapsed B cell precursor ALL, the most common adverse 
reactions were cytokine release syndrome (79%), hypogammaglobinemia (43%), infections-
pathogen unspecified (41%), pyrexia (40%), decreased appetite (37%), headache (37%), 
encephalopathy (34%), hypotension (31%), bleeding episodes (31%), tachycardia (26%), 
nausea (26%), diarrhea (26%), vomiting (26%), viral infectious disorders (26%), hypoxia (24%), 
fatigue (22%), acute kidney injury (22%), and delirium (21%). 

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Eleven deaths were reported for patients who received CTL019, of which 2 deaths occurred 
within 30 days of infusion. Seven were disease-related, three were attributed to infections, and 
one to intracerebral hemorrhage [KymriahTM FDA 2017].
Cellular kinetics 
Following infusion of CTL019, CAR-positive T cells in peripheral blood were observed to 
undergo significant expansion and demonstrated measurable persistence in vivo in CR/CRi 
patients. In pooled data from studies [B2202] and [B2205J] the Cmax and area under the curve 
from day 0 to 28 days following infusion in the cellular kinetic profile (AUC28d) as determined 
by qPCR were higher in CR/CRi patients relative to non-responder (NR) patients: 104% higher 
for AUC28d and 73.5% for Cmax (Thudium Mueller et al Clinical Cancer Research 2018). The 
trend was also observed in other indications (adult ALL and adult CLL). In Study [B2202], the 
cellular kinetics measured in bone marrow displayed high levels of transgene at Day 28 in 
CR/CRi patients. The transgene levels declined over time and were measurable at Month 3 and 
Month 6 in responder patients; however, the transgene levels in bone marrow were not 
measurable in bone marrow of NR patients beyond Day 28. Trafficking of CTL019 cells has 
also been demonstrated into the cerebral spinal fluid (CSF) in this patient population (Thudium 
Mueller at al Blood 2017). .
In the combined data pool, tocilizumab (interleukin-6 (IL-6) receptor-inhibitor monoclonal 
antibody) was used for the management of moderate/severe (grade 3 and 4) CRS in 
approximately 42.7% of patients treated with CTL019. Patients who receive tocilizumab for 
CRS often have higher CTL019 exposures (AUC28d, area under the curve from day 0 to 84 days 
following infusion in the cellular kinetic profile (AUC84d), and Cmax) compared to patients 
who did not receive tocilizumab while CTL019 Tmax is comparable. The higher CTL019 
exposures observed in patients treated with tocilizumab is associated with a greater severity of 
CRS, which in turn correlates with higher tumor burden just prior to CTL019 cell infusion. In 
addition, CTL019 cells continued to expand and persist, as measured by transgene levels 
following CTL019 infusion (Thudium Mueller et al Clinical Cancer Research 2018).
For further information refer to the [CTL019 Investigator’s Brochure]. 
2
Rationale
2.1
Study rationale and purpose
Outcome remains poor for patients with r/r pediatric B-cell lineage acute lymphoblastic 
leukemia (B-cell ALL). Treatment options for r/r B-cell ALL include further treatment with 
salvage chemotherapy, second allogeneic stem cell transplantation (SCT) or supportive care. 
Therapy in this population is not curative with an overall survival of 3 to 6 months (Smith 2010, 
Tallen 2010, Martin 2012, Ko 2010, Duval 2010, Oudot 2008). As an example, clofarabine was 
approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 
with r/r ALL after at least 2 prior therapeutic regiments. The overall remission rates were 30% 
for ALL and 38% for Acute Myeloid Leukemia (AML) in Phase I studies (Jeha et al 2004); 
30% (20% CR or complete remission with incomplete platelet recovery [CRp] and 10% Partial 
Remission [PR]) for ALL and 26% for AML in Phase II studies (Jeha et al 2006). The median 

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duration of remission for patients with ALL who achieved at least a partial remission was 9.7 
weeks (range 7 to 335 days) in the Phase II study.
CD19 has emerged as an attractive therapeutic target because it is widely expressed on normal 
and malignant B-cells throughout B-cell maturation but not on pluripotent stem cells or non–
B-cell tissues. The development of CAR T cells to target CD19+ cells (CART19 or CTL019) 
provides an innovative new approach to these malignancies. This approach involves recipient-
derived T cells that are genetically modified ex vivo via lentiviral transduction to express a 
CD19 antigen recognition domain attached to intracellular signaling domains that mediate T-
cell activation in an MHC independent manner. Encouraging anti-tumor efficacy has been seen 
in r/r adult and pediatric ALL and in r/r CLL.
Amendment 6 for US only (enrollment has been terminated as of 15-Jun-2020): In patients up 
to 25 years with refractory or in second or greater relapse, CTL019 has shown the potential to 
be a definitive therapy, providing early, deep and durable remissions. Given the unprecedented 
responses in these difficult to treat patients, it has been hypothesized that CTL019 could be 
effective also in earlier lines of therapy in very high risk ALL patients, who have a poor 
prognosis, with a median survival of 7.4 months (95% CI, 6.0-9.6 months) (Crotta at al, 2018).
Very high risk ALL account for approximately 8-10% of all B-ALL patients and remains a 
therapeutic challenge. Certain biologic and response factors designate patients to be very-high 
risk children in the very high risk group include those with extreme hypodiploidy (44 or fewer 
chromosomes), t(9;22) (Philadelphia chromosome) BCR/ABL1 rearrangement, t(4;11) 
KMT2A (MLL) rearrangement, iAMP21 (intrachromosomal amplification of chromosome 21) 
amplification, those over 13 years of age in the United States, and/or failure to achieve complete 
remission at the end of induction therapy (>5 percent lymphoblasts in day 28 bone marrow or 
the presence of MRD). In the past, this group of patients had overall a poor prognosis, but 
subsets of these patients can be successfully treated with aggressive chemotherapy, often in 
combination with hematopoietic stem cell transplant and / or targeted therapy (such as imatinib 
for Ph+ ALL) with the rate of event free survival at 5 years being 40% with standard
chemotherapy regimens in this population (Pulsipher et al 2011). 
Augmentation of therapy to include allogeneic stem cell transplantation in first complete 
remission has been shown to improve disease free survival for a subset of this patient population, 
but it is associated with higher treatment related morbidity. Several studies have reported that 
transplantation in first complete remission results in a 5-year disease-free survival of 55%-60% 
for patients with very-high risk ALL, including a comparative analysis of transplantation to 
chemotherapy alone which resulted in a 16% survival benefit at 5 years from transplant (Fagioli 
et al 2013, Balduzzi et al 2005, Satwani et al 2007). Despite improvements in survival with 
allogeneic stem cell transplant, children with very-high risk ALL still have a 24% risk of relapse 
at 10 years compared with a 15% risk observed in standard-risk ALL patients (Fagioli et al 
2013, Malempati et al 2007). Furthermore, the use of allogeneic stem cell transplantation is less 
effective if patient remains MRD positive after intensive chemotherapy or if patient has certain 
biological features such as extreme hyplodiploidy. Minimal residual disease status in ALL has 
been shown to predict the risk of relapse, event free survival and overall survival (EFS and OS) 
when measured during and after induction therapy in both newly diagnosed and relapsed ALL 
(Borowitz 2015). For example, in a study assessing outcomes after re-induction chemotherapy 

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for relapsed pediatric patients, at 5 years, EFS was 15% ± 6% in MRD positive patients while 
EFS was 56% ± 10% in MRD negative patients (Raetz et al 2012). 
Early relapse is one of the strongest predictor of survival (time of relapse from initial diagnosis) 
and patients who relapsed less than 18 months after diagnosis had poor outcome, with a 5-yr 
survival rate of approximately 15-21% (Nguyen 2008. Leukemia 2008; 22 (12):2142). Patients 
with very high risk features tend to relapse rapidly after intensive chemotherapy, including post 
allogeneic stem cell transplantation.
2.2
Rationale for the study design
This is a single arm, multi-center, phase II study to determine the efficacy and safety of CTL019 
in pediatric patients with relapsed or refractory B-cell ALL. A single arm study design is 
supported by the absence of effective therapies in this setting, and high unmet medical needs. 
This study will enroll approximately 95 patients to allow at least 50 infused patients less than 
the age of 18 at the time of screening, at least 10 of which will be under the age of 10. Patients 
18 years of age or older at screening will be limited to 10 total infused patients. When 10 patients 
≥ 18 years of age have been infused, further enrollment in this age category will require Sponsor 
approval. Approximately 14 patients will be enrolled to ensure at least 10 patients are infused 
with CTL019 manufactured by the Fraunhofer Institute. Approximately, 5 additional Japanese 
patients will be screened to allow at least 3 additional patients infused with CTL019 
manufactured from the US facility (total 5 Japanese patients infused).  Sponsor approval will 
be required to screen more than 5 patients, based on target number of infused patients.  After 
assessment of eligibility, patients qualifying for the study will be enrolled and start 
lymphodepleting chemotherapy as indicated per protocol, followed by a single dose of CTL019 
transduced cells.
Previous clinical data with CTL019 therapy has been generated using cell product manufactured 
at the Cell and Vaccine Production Facility (CVPF) at the University of Pennsylvania. The 
current trial will utilize product manufactured by Novartis or designee. In vitro studies assessing 
the comparability of these two products will have been completed prior to initiation of this 
protocol. A limited safety run-in stage will be conducted at the beginning of this trial. These 
patients will be included in the total targeted patient population.
The efficacy of CTL019 will be evaluated through the primary endpoint of ORR (ORR = CR + 
CRi) as determined by Independent Review Committee (IRC) assessment, including CR and 
CRi. The choice of ORR as the primary endpoint is based on evidence that ORR: 1) Is a standard 
outcome measurement in ALL; and 2) the established correlation with long-term outcome 
(Cheson 2003, Appelbaum 2007, NCCN v13 2013).
At the Amendment 6 (US only), three cohort definitions are introduced: 
Main Cohort: all patients screened before protocol Amendment 6 (enrollment into Main Cohort 
was completed at the time of the protocol amendment 6 release)
Cohort 1 (US only): patients who are very high risk at first relapse (enrollment has been 
terminated as of 15-Jun-2020)
Cohort 2 (US only): patients who received CTL019 within 6 months post allo-HSCT 
(enrollment has been terminated early as of 15-Jun-2020)

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2.2.1
Rationale for lymphodepletion
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell 
proliferation (Dummer et al 2002), a recent finding that naive T cells begin to proliferate and 
differentiate into memory-like T cells when total numbers of naive T cells are reduced below a 
certain threshold (Goldrath 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). This hypothesis has been tested clinically in patients with metastatic 
melanoma refractory to conventional treatments (Dudley et al 2002). The patients received a 
lymphodepleting conditioning regimen consisting of cyclophosphamide (60 mg/kg x 2 days) 
and fludarabine (25 mg/m2 x 5 days) prior to adoptive transfer of T cells. Patients with myeloma 
have been treated with CARs and lymphopenia after lymphodepleting chemotherapy, and 
observed improved engraftment (Laport 2003, Rapoport 2005). In this protocol, it is proposed 
to infuse CTL019 T cells into patients that are rendered lymphopenic as a result of cytotoxic 
chemotherapy. Recent data indicates that the increased antitumor efficacy of adoptive transfer 
following host conditioning is more than simply “making room” because the quantitative 
recovery of adoptively transferred T cells in mice reveals that in vivo proliferation following 
adoptive transfer is identical in mice with or without previous irradiation (Palmer et al 2004).
In ongoing CTL019 pediatric ALL studies, 13 out of the first 16 patients infused with CTL019 
cells received a lymphodepleting conditioning regimen prior to adoptive transfer of T cells. Six 
patients received a lymphodepleting conditioning regimen consisting of cyclophosphamide and 
fludarabine, five patients received cyclophosphamide and etoposide, one patient received 
etoposide and cytarabine and one patient received cyclophosphamide alone. Of the three 
patients who did not receive a lymphodepleting conditioning regimen, two patients presented 
with Absolute Lymphocyte Count (ALC) < 1000 at the time of infusion.
2.3
Rationale for dose and regimen selection
Animal studies support a threshold dose of CTL019 cells and therefore the initial clinical dose 
selection was within the range of 1 x 107 to 1 x109 CTL019 transduced cells (Milone et al 2009). 
Please see IB for further information on preclinical studies. For safety reasons, initial phase I 
cell dosing was divided among three split infusions (10%, 30% and 60% of the total cell dose). 
Of the 26 pediatric ALL patients that had a complete remission, 13 patients received a single 
infusion due to the onset of fevers, yet CRs were observed with either 1 to 3 infusions.
In phase I CLL studies, patients have shown responses after a single infusion or multiple 
infusions. In the phase II CLL trial, the dose has been given as a single infusion of 1 to 5 x 107
or 1 to 5 x 108 CTL019 transduced cells to study dose optimization. This single infusion was 
clinically well tolerated. No significant differences have been seen in responses or toxicity 
between these two doses. In responding CLL patients with CR or lasting PR, the CTL019 
transduced cell numbers infused have ranged from 1.4 x 107 to 1.1 x 109 cells.

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From the data collected to date in patients with CLL and ALL, there does not appear to be a
discernible dose-response relationship with CTL019 transduced cell numbers infused. This is 
likely the result of CTL019 transduced cells ability to proliferate and expand extensively (e.g. 
1000 to >10,000 fold) in vivo. Thus, the administered dose may underestimate the number of 
CTL019 cells in vivo following engraftment and expansion and will vary from patient to patient. 
Additional considerations in this dose selection take into account the manufacturing feasibility 
of producing adequate numbers of CTL019 transduced cells.
In pediatric ALL patients who were treated in the CHP959 study, patients received once, two 
or three CTL019 infusions. Tumor responses were seen with each of these dosing schedules. 
Nineteen patients within the CHP959 study received only a single infusion of CTL019 due to 
the onset of fever with a cell range of 1.1 x 106 to 6.3 x106 CTL019 cells per kg with an 
acceptable safety profile. At the lower end of this dose range there is concern that doses less 
than 2 x 106 cells/kg may be associated with a lack of response or CR with an early relapse 
however the data at lower doses is limited.
Several patients received total CTL019 cell dose of over 5 x 108 cells (e.g. 6.8, 7.8 and 9.1 x 
108 total CTL019 cells). Since the experience with these higher doses is more limited, a cut off 
of 2.5 x 108 cells as a maximum dose, based upon a weight >50 kg, is proposed. Manufacturing 
consideration and practicality were also considered in the dosing selection.
Therefore, for patients in Main Cohort, the targeted per-protocol CTL019 cell dose range for 
pediatric ALL patients ≤ 50 kg is 2.0 to 5.0 x 106 autologous CTL019 transduced viable T cells 
per kg body weight. For patients > 50 kg, the target dose is 1.0 to 2.5 x 108 autologous CTL019 
transduced viable T cells.
In the Protocol Amendment 6 (US only), the dosing for the Cohort 1 and Cohort 2 was 
determined as per the label information (enrollment has been terminated as of 15-Jun-2020)  
Based on the patients’ weight at the time of leukapheresis: 

Patients ≤ 50 kg: 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight

Patients > 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells
2.3.1
Allowable infused cell dose range of CTL019 product
The allowable cell dose ranges are as follows:

Patients ≤ 50 kg: 0.2 to 5.0 x 106 autologous CTL019 transduced viable T cells per kg 
body weight

Patients > 50 kg: 0.1 to 2.5 x 108 autologous CTL019 transduced viable T cells
Products falling below the minimum values in the above allowable cell dose ranges will not be 
released for infusion.
2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparators drugs
Not applicable.

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2.6
Risks and benefits
The risk to subjects in this trial may be minimized by compliance with the eligibility criteria, 
pre-infusion criteria, CRS treatment algorithm, study procedures, and close clinical monitoring. 
There may be unforeseen risks with CTL019 which could be serious or potentially life 
threatening. Refer to [Investigator Brochure] for further details.
No preclinical reproductive studies have been conducted with CTL019 to assess whether it can 
cause fetal harm when administered to a pregnant woman. It is not known whether CTL019 has 
the potential to be transferred to the fetus via the placenta and could cause fetal toxicity
(including B-cell lymphocytopenia), or transmission of CTL019 via seminal fluid may occur. 
WOCBP 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. No data are currently available to determine the duration of 
contraception after receiving CTL019. There is no information regarding the presence of 
CTL019 in human milk, the effect on the breast-fed child or the effects of CTL019 on milk 
production.
Based on the observed efficacy as assessed by high response rates and lasting remissions of 
CTL019 therapy in pediatric patients with r/r B cell ALL, the potential benefit of CTL019 
therapy in the target patient population treated in study CCTL019B2202 outweighs the potential 
risks of the therapy. CRS is identified as a clinically significant risk of CTL019 treatment. To 
address this risk a CRS treatment algorithm and CRS grading scale has been specifically 
developed and utilized for CTL019. In addition, logistical measures are also recommended to 
further manage this safety risk: patients are required to stay near the treatment site for the first 
21 days, patients are required to stay with a caregiver and record twice daily temperatures during 
first two weeks, and patients/caregivers are required to carry patient identification card with 
investigator contact information. Refer to Section 6.2.4.2 for details on CRS management.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Note that the hypotheses testing for key secondary objectives are applicable to main cohort only.

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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Main Cohort and Cohort 1*
Evaluate the efficacy of CTL019 therapy from all manufacturing 
facilities as measured by overall remission rate (ORR) during the 3 
months after CTL019 administration, which includes CR and CR 
with incomplete blood count recovery (CRi) as determined by IRC 
assessment
Cohort 2*: To evaluate the feasibility and safety of CTL019 therapy 
in patients that relapsed < 6 months post allo-HSCT
ORR (= CR + CRi) assessment; See Appendix 1 for response 
definition
Type, frequency and severity of adverse events and laboratory 
abnormalities
Refer to Section 10.4.
Key secondary (For Main Cohort only)
Evaluate the efficacy of CTL019 therapy from US manufacturing 
facility as measured by overall remission rate (ORR) during the 3 
months after CTL019 administration, which includes CR and CR 
with incomplete blood count recovery (CRi) as determined by IRC 
assessment
ORR (= CR + CRi) assessment; See Appendix 1 for response 
definition
Refer to Section 10.5.1.1
Evaluate the percentage of patients who achieve a best overall 
response (BOR) of CR or CRi with a MRD negative bone marrow 
by central analysis using flow cytometry among all patients who 
receive CTL019 from all manufacturing facilities
Percentage of patients with BOR of CR or CRi with MRD negative 
bone marrow by flow cytometry during the 3 months after CTL019 
infusion among all patients who are infused with CTL019 from all 
manufacturing facilities
Refer to Section 10.5.1.2
Evaluate the percentage of patients who achieve a best overall 
response (BOR) of CR or CRi with a MRD negative bone marrow 
by central analysis using flow cytometry among all patients who 
receive CTL019 from US manufacturing facility
Percentage of patients with BOR of CR or CRi with MRD negative 
bone marrow by flow cytometry during the 3 months after CTL019 
infusion among all patients who are infused with CTL019 from US 
manufacturing facility
Refer to Section 10.5.1.3.
Other secondary (For Main Cohort, Cohort 1* and Cohort 2*)
Evaluate the percentage of patients who achieve CR or CRi at 
Month 6 without SCT between CTL019 infusion and Month 6 
response assessment
Percentage of patients who achieve CR or CRi at Month 6 without 
SCT between CTL019 infusion and Month 6 response 
assessment
Refer to Section 10.5.2.1

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Objective
Endpoint
Analysis
Evaluate the percentage of patients who achieve CR or CRi and 
then proceed to SCT while in remission before Month 6 response 
assessment

Percentage of patients who achieve CR or CRi and then 
proceed to SCT while in remission prior to Month 6 response 
assessment

In addition, all patients that proceed to SCT after CTL019 
infusion will be described
Refer to Section 10.5.2.2.
Evaluate the duration of remission (DOR)

DOR, i.e. the time from achievement of CR or CRi, whichever 
occurs first, to relapse or death due to ALL

Site of involvement of subsequent relapse will be 
summarized
Refer to Section 10.5.2.3.
Evaluate the relapse-free survival (RFS)
RFS, i.e. the time from achievement of CR or CRi whichever 
occurs first to relapse or death due to any cause during CR or CRi
Refer to Section 10.5.2.4.
Evaluate the event-free survival (EFS)
EFS, i.e. the time from date of CTL019 infusion to the earliest of 
death, relapse or treatment failure
Refer to Section 10.5.2.5.
Evaluate the overall survival (OS)
OS, i.e. the time from date of CTL019 infusion to the date of death 
due to any reason
Refer to Section 10.5.2.6.
Evaluate the response at Day 28 +/- 4 days
Proportion of patients attaining CR or CRi at Day 28 +/- 4 days 
post CTL019 infusion
Refer to Section 10.5.2.8.
Evaluate the impact of baseline tumor burden on response
Response as a function of baseline tumor burden (tumor load) 
(MRD, extramedullary disease, etc.)
Refer to Section 10.5.2.9.
Evaluate the quality of response using MRD disease assessments 
before treatment and at day 28 +/- 4 days after treatment using 
central assessment by flow cytometry and before SCT by local 
assessment (flow or PCR)
MRD quantitative result (% leukemic cells) and qualitative result 
(positive/negative)
Refer to Section 10.5.2.10.
Evaluate the safety of CTL019 therapy
Type, frequency and severity of adverse events and laboratory 
abnormalities
Refer to Section 10.5.3.
Characterize the in vivo cellular pharmacokinetic (PK) profile 
(levels, persistence, trafficking) of CTL019 cells in target tissues 
(blood, bone marrow, CSF, and other tissues if available)

CTL019 transgene levels by qPCR in blood, bone marrow 
and CSF if available

Expression of CTL019 detected by flow cytometry in blood 
and bone marrow

Cmax, Tmax, AUCs and other relevant PK parameters of 
CTL019 in blood, bone-marrow, CSF if available

Persistence of CTL019 in blood, bone marrow, and CSF if 
available (eg Mean Residence Time [MRT] last)
Refer to Section 10.5.4.

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4
Study design
4.1
Description of study design
This is a single arm, multi-center, phase II study to determine the efficacy and safety of CTL019 
in pediatric patients with relapsed or refractory B-cell ALL (Main Cohort). Enrollment into the 
Main Cohort was completed at the time of protocol amendment 6). For Amendment 6 (US 
only), the efficacy and safety of patients that are very high risk at first relapse (Cohort 1) OR 
that received CTL019 within 6 months post allo-HSCT will be studied (Cohort 2). Enrollment 
in US only Cohorts 1 and 2 has been terminated early as of 15-Jun-2020)  The study will have 
the following sequential phases for all patients: Screening (Section 7.1.1), Pre-Treatment (Cell 
Product Preparation and Lymphodepleting Chemotherapy; Section 7.1.2), Treatment and 
Primary Follow-up (Section 7.1.3), Secondary Follow-up (if applicable, Section 7.1.4), and 
Survival Follow-up (Section 7.1.5). The total duration of the study is 5 years. After CTL019 
infusion, efficacy will be assessed monthly for the first 6 months, then quarterly up to 2 years 
and semi-annually afterwards up to 5 years, or until patient relapse. Efficacy assessments will 
be based on the Novartis guidelines for response assessment in ALL (Appendix 1), which is 
based on NCCN version 1.2013 guidelines, Cheson et al (2003) and Appelbaum et al (2007). 
Safety will be assessed throughout the study. A post-study long term follow-up (Section 7.1.6) 
for lentiviral vector safety will continue under a separate destination protocol per the following 
health authority guidelines: FDA (2006a), FDA (2006b), European Medicines Agency (EMA) 
(2008) and EMA (2009).
At the beginning of the trial, a safety run-in stage will be conducted to enroll three patients for 
the purpose of assessing the acute safety profile of the Novartis CTL019 cell product. The acute 
and subacute toxicity profile for CTL019 cell product manufactured at the University of 
Pennsylvania has been established in patients with r/r B-cell ALL. This data demonstrates that 
the majority of tumor lysis syndrome (TLS), cytokine release syndrome and chemotherapy 
toxicities have manifested within the first two weeks post-CTL019 infusion in r/r ALL patients.
The first three patients will be enrolled in a staggered manner (waiting 14 days prior to treating 
the next patient) for the purpose of assessing the acute and subacute safety profile. Safety 
profiles during the first 14 days post infusion will be reported to the Health Authorities.
The data to be reported will include demographics, lymphodepleting chemotherapy, total and 
CTL019 transduced viable T cell doses, AE/ Serious Adverse Events (SAEs), standard 
laboratory data (hematology and chemistry) and CTL019 cellular PK.
For the purpose of safety onboarding of new sites, after the above safety run-in stage has been 
completed, a staggered approach will also be utilized at each new respective site (with no prior 
experience administering CTL019) and will occur as follows:

1st patient enrollment, wait 14 days

2nd patient enrollment, wait 14 days

Following completion of this staggered enrollment of the first two patients, the new site 
may then proceed with enrollment of patients without the stagger.

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Initially, manufacturing of CTL019 has been performed at the Novartis Morris Plains 
manufacturing facility and will be expanded to the Fraunhofer Institute to establish a CTL019 
manufacturing site in Europe.  Approximately 14 patients will be enrolled in Region Europe to 
allow at least 10 patients infused with CTL019 manufactured at the Fraunhofer Institute. 
In order to support the development of CTL019 in Japan, at least 5 patients were to be infused.  
2 patients from Japan have been infused with CTL019. At least 5 additional Japanese patients 
will be screened to allow at least 3 additional patients to be infused with CTL019 manufactured 
from the US facility (total 5 Japanese patients infused).  Sponsor approval will be required to 
screen more than 5 patients, which based on target number of infused patients. 
Figure 4-1
Study design
4.1.1
Leukapheresis assessment
Cryopreserved non-mobilized leukapheresis products collected from the patient prior to study 
entry (historical) may be usable for CTL019 manufacturing if collected at an appropriately 
certified apheresis center and the product is accepted by the manufacturing facility. If a 
historical leukapheresis product is not available, leukapheresis will be performed after informed 
consent signature. 
Following informed consent, information on the patients’ leukapheresis material including 
sample sentinel vials collected from leukapheresis (when available) will be sent to Novartis 
manufacturing separately or together with leukapheresis product. 
Please refer to the Leukapheresis Key Requirements within the most recent [Investigational 
Leukapheresis, Cryopreservation & Scheduling Manual] for more detailed instructions on 
optimal timing of leukapheresis collection and the recommended procurement, handling and 
shipment procedures of the leukapheresis samples to the designated manufacturing facility. 

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4.3
Early study termination
The study can be terminated at any time for any reason by the sponsor, Novartis, or if any of 
the stopping criteria described in Section 6.2.4.1.1 are met. The investigator may be informed 
of additional procedures to be followed in order to ensure that adequate consideration is given 
to the protection of the patient’s interests. For patients who have received a CTL019 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 
will be responsible for informing Institutional Review Boards (IRBs) and/or Independent Ethics 
Committees (IECs) of the early termination of the trial.
5
Population
5.1
Patient population
At the time of protocol amendment 6, enrollment into the Main Cohort including Japanese 
patients, has been completed.  The target in Main Cohort population consisted of pediatric 
patients with B-cell ALL who were chemo-refractory, relapsed after allogeneic SCT, or were
otherwise ineligible for allogeneic SCT. 97 patients were enrolled between the age of 3 years 
at the time of screening to the age of 27 years at the time of initial diagnosis. This included 65 
infused patients less than the age of 18 at the time of screening, 32 of which were under the age 
of 10. Patients 18 years of age or older at screening were limited to 10 total infused patients. 
When 10 patients ≥ 18 years of age have been infused, further enrollment in this age category 
required Sponsor approval. A total of 14 patients ≥ 18 years of age were infused after approval 
from Sponsor. 12 patients were enrolled to ensure at least 10 patients were infused with CTL019 
manufactured by the Fraunhofer Institute. The investigator or designee ensured that only 
patients who met all the following inclusion and none of the exclusion criteria were offered 
treatment in the study.
[JAPAN ONLY: In order to support the development of CTL019 in Japan, at least 5 Japanese 
patients were to be infused with CTL019.  2 patients from Japan have been infused with 
CTL019.  5 additional Japanese patients were screened to allow at least 3 additional patients to 
be infused with CTL019 manufactured from the US facility (total 5 Japanese patients infused).]  
Sponsor approval was required to screen more than 5 patients, which was based on target 
number of infused patients.
For amendment 6 (US only), two additional cohorts (Cohort 1 and Cohort 2) were added to the 
study for the US participating sites in the previous main cohort. The target population for Cohort 
1 comprised either patients with very high risk cytogenetic features at diagnosis - extreme 
hypodiploidy defined as fewer than 44 chromosomes and/or DNA index less than 0.81, or 
t(17;19) with defined TCF3-HLF fusion – at the time of first relapse or any patient with B-cell 
ALL that relapses ≤ 36 months of initial diagnosis and who has MRD ≥0.01% at end of 
reinduction therapy. 
Additionally, to investigate the feasibility and safety of administering CTL019 in patients with 
early relapse post allo-HSCT patients that relapsed less than 6 months post allo-HSCT, 
regardless of the number of relapses were also  eligible (Cohort 2). Approximately 20 patients 

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were to be screened to ensure 15 infused patients (at least 10 in Cohort 1 and 5 in Cohort 2).  1 
patient was enrolled into Cohort 1 and no patients were enrolled into Cohort 2. 
Enrollment into Cohorts 1 and 2 has been terminated as of 15-Jun-2020.
5.2
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. [Retired from Protocol Amendment Version 06] 
2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or 
peripheral blood by flow cytometry within 3 months of study entry
3. Adequate organ function defined as:
a. Renal function defined as:

A serum creatinine based on age/gender as follows:
Maximum Serum Creatinine
(mg/dL)
Age
Male
Female
1 to < 2 years
0.6
0.6
2 to < 6 years
0.8
0.8
6 to < 10 years
1.0
1.0
10 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
b. ALT ≤ 5 times the ULN for age
c. Bilirubin < 2.0 mg/dl
d. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and 
pulse oxygenation > 91% on room air
e. LVSF ≥ 28% confirmed by echocardiogram, or LVEF ≥ 45% confirmed by 
echocardiogram or MUGA within 7 days of screening
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening
5. Life expectancy > 12 weeks
6. [Retired from Protocol Amendment Version 06] 
7. Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at 
screening
8. Signed written informed consent and assent forms if applicable must be obtained prior to 
any study procedures
9. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, stored 
leukapheresis product
10. Once all other eligibility criteria are confirmed, must have a leukapheresis product of 
non-mobilized cells received and accepted by the manufacturing site. Note: 
Leukapheresis product will not be shipped to or assessed for acceptance by the 
manufacturing site until documented confirmation of all other eligibility criteria is 
received
11. (Protocol Amendment 6 US only) B-cell acute lymphoblastic leukemia and: 

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Cohort 1: 
a. First relapse AND hypodiploid cytogenetics: fewer than 44 chromosomes and/or 
DNA index < 0.81, or other clear evidence of a hypodiploid clone OR
b. First relapse AND t(17;19) with defined TCF3-HLF fusion OR 
c. First relapse with any cytogenetics provided the relapse occurred ≤ 36 months of 
initial diagnosis AND MRD at end of reinduction therapy is ≥0.01% by flow 
cytometry (local assessment)
Cohort 2 (US only):
a. Any BM relapse after allogeneic stem cell transplantation (allo-HSCT) and must 
be < 6 months from HSCT at the time of CTL019 infusion
12. (Protocol Amendment 6 US only) Age up to 25 years at the time of screening
5.3
Exclusion criteria
Patients meeting any of the following criteria must be excluded from the study:
1. Isolated extra-medullary disease relapse
2. Patients with concomitant genetic syndromes associated with bone marrow failure states: 
such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any 
other known bone marrow failure syndrome. Patients with Down Syndrome will not be 
excluded.
3. Patients with Burkitt’s lymphoma/leukemia (i.e. patients with mature B-cell ALL, 
leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with 
FAB L3 morphology and /or a MYC translocation)
4. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative 
intent and with no evidence of active disease
5. Treatment with any prior gene therapy product
6. Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-
CD19 therapy
7. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any 
uncontrolled infection at screening
8. Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening
9. Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
10. [Retired from Amended Protocol Version 01]
11. Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: 
Patients with history of CNS disease that has been effectively treated will be eligible
12. Patient has an investigational medicinal product within the last 30 days prior to screening
13. [Retired from Amended Protocol Version 06] 
14. [Retired from Amended Protocol Version 02]
15. [Retired from Amended Protocol Version 02]
16. [Retired from Amended Protocol Version 04] 
17.
The following medications are excluded:

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a. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior to 
CTL019 infusion. However, the following physiological replacement doses of 
steroids are allowed: < 12 mg/m2/day hydrocortisone or equivalent
b. Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be 
completed > 6 weeks prior to CTL019 infusion
c. GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 weeks 
prior to CTL019 infusion to confirm that GVHD recurrence is not observed (e.g. 
calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, 
rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20 
(rituximab), anti-TNF, anti-IL6 or anti-IL6R, systemic steroids)
d. Chemotherapy:

Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to 
CTL019 infusion

The following drugs must be stopped > 1 week prior to CTL019 infusion and 
should not be administered concomitantly or following lymphodepleting 
chemotherapy: vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate < 25 
mg/m2, cytosine arabinoside < 100 mg/m2/day, asparaginase (non-pegylated)

The following drugs must be stopped >2 weeks prior to CTL019 infusion: 
salvage chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, 
anthracyclines, cyclophosphamide, methotrexate ≥ 25 mg/m2), excluding the 
required lymphodepleting chemotherapy drugs

Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion
e. CNS disease prophylaxis: CNS prophylaxis treatment must be stopped > 1 week 
prior to CTL019 infusion (e.g. intrathecal methotrexate)
f.
Radiotherapy

Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 
infusion

CNS directed radiation must be completed > 8 weeks prior to CTL019 infusion
g. Anti T-cell Antibodies: Administration of any T cell lytic or toxic antibody (e.g. 
alemtuzumab) within 8 weeks prior to CTL019 is prohibited since residual lytic levels 
may destroy the infused CTL019 cells and/or prevent their in vivo expansion. If such 
an agent has been administered within 8 weeks prior to CTL019, contact the Sponsor, 
consider consultation with an pharmacology expert, and consider measuring residual 
drug levels, if feasible, prior to CTL019 infusion.
18. [Retired from Amended Protocol Version 06]  
19. Pregnant or nursing (lactating) women.  NOTE: Female study participants of reproductive 
potential must have a negative serum pregnancy test performed within 24 hours before 
leukapheresis, lymphodepletion and prior to CTL019 infusion.
20. 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 signing informed consent and through at least 12 months after the CTL019 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:

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
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient

Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before 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.
21. Sexually active males must use a condom during intercourse from signing informed 
consent to at least 12 months after the CTL019 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. In addition, male participants must not donate sperm for the time period 
specified above.
6
Treatment
6.1
Study treatment
CTL019 is an autologous cellular immunotherapy product that is comprised of CD3+ T cells 
that have undergone ex vivo T cell activation, gene modification, expansion and formulation in 
infusible cryomedia. The transgene to be expressed via lentiviral vector transduction is a CAR 
targeted against the CD19 antigen. The CAR contains a murine scFv that targets CD19 linked 
to a transmembrane region derived from the CD8 receptor, which is linked to an intracellular
bipartite signaling chain of TCR-ζ (or CD3-ζ) and 4-1BB intracellular signaling domains. The 
extracellular scFv with specificity for CD19 is derived from a mouse monoclonal antibody. T 
cells which are enriched from a patient leukapheresis unit are expanded ex vivo using 
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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. CTL019 cells 
expand ex vivo for approximately 10 days. At the end of the culture, the CTL019 cells are 
depleted of magnetic beads, washed, concentrated, and cryopreserved. Results from a release 
testing procedure are required prior to release of the product for infusion.
Main Cohort:
A target per-protocol dose of CTL019 transduced cells for pediatric patients will consist of a
single infusion of 2.0 to 5.0 x 106 CTL019 transduced viable T cells per kg body weight (for 
patients ≤ 50 kg) and 1.0 to 2.5 x 108 CTL019 transduced viable T cells (for patients > 50 kg). 
The following cell dose ranges may be infused if all other safety release criteria are met: 0.2 to
5.0 x 106 CTL019 transduced viable T cells per kg body weight (for patient ≤ 50 kg) and 0.1 to 
2.5 x 108 CTL019 transduced viable T cells (for patients > 50 kg).
Amendment 6 only: Cohort 1 and Cohort 2:
Based on the patients’ weight at the time of leukapheresis:

Patients ≤ 50 kg: 0.2 to 5.0 x 106 CAR-positive viable T cells per kg body weight

Patients > 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T cells
6.1.1
Dosing regimen
6.1.1.1
Lymphodepleting chemotherapy
It is anticipated that many patients will have been receiving chemotherapy for relapse or 
resistant disease. Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy 
cycle is planned. The use of any additional chemotherapy prior to the recommended preinfusion, 
lymphodepleting chemotherapy will be at the discretion of the investigator and dependent on 
the patient’s disease burden.
When given, lymphodepleting chemotherapy should be started before CTL019 infusion so that 
CTL019 cells will be given 2 to 14 days after completion of the lymphodepleting chemotherapy. 
The chemotherapy start date will vary based on the selected chemotherapy. The purpose of this 
chemotherapy is to induce lymphopenia in order to facilitate engraftment and homeostatic 
expansion of CTL019 cells. For lymphodepleting chemotherapy, cyclophosphamide-based 
regimens are the agents of choice as there is the most experience with the use of these agents in 
facilitating adoptive immunotherapy. The lymphodepleting regimen is:

Fludarabine (30 mg/m2 intravenously [i.v.] daily for 4 doses) and cyclophosphamide (500 
mg/m2 i.v. daily for 2 doses starting with the first dose of fludarabine)
If there was previous Grade 4 hemorrhagic cystitis with cyclophosphamide, or the patient 
demonstrated a chemorefractory state to a cyclophosphamide-containing regimen administered 
shortly before lymphodepleting chemotherapy, then the following will be used:

Cytarabine (500 mg/m2 i.v. daily for 2 days) and etoposide (150 mg/m2 i.v. daily x 3 days 
starting with the first dose of cytarabine)

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If patients have a White Blood Cell (WBC) count ≤ 1,000 cells/µL within one week prior to 
CTL019 infusion, lymphodepleting chemotherapy is NOT required.
6.1.1.2
CTL019 infusion
The CTL019 cell product will be released to the study site approximately 3 to 4 weeks after 
manufacturing has commenced, provided all required safety and quality release criteria have 
been met.
Prior to CTL019 infusion: the following criteria must be met:
1. Influenza Testing: All patients must undergo a rapid influenza diagnostic test within 10 
days prior to the planned CTL019 infusion. If the patient is positive for influenza, he/she 
should complete a full course of oseltamivir phosphate or zanamivir as described in the 
label (see Tamiflu® or Relenza® package insert for dosing). The patient must complete 
their full course of treatment prior to receiving CTL019. The test does not need to be 
repeated prior to CTL019 infusion however if flu-like or respiratory signs and symptoms 
are present, CTL019 infusion should be delayed until the patient is asymptomatic. For
patients residing in the United States, Canada, Europe, and Japan, influenza testing is 
required during the months of October through May, inclusive. For patients residing in the 
Southern Hemisphere such as Australia, influenza testing is required during the months of 
April through November, inclusive. For patients with significant international travel, both 
calendar intervals may need to be considered.
2. Performance Status: Patient should not experience a significant change in clinical or 
performance status compared to initial eligibility criteria that would, in the opinion of the 
treating physician, increase the risk of adverse events associated with experimental cell 
infusion.
3. Laboratory Abnormalities: Patients experiencing laboratory abnormalities after 
enrollment, that in the opinion of the treating investigator or PI may impact subject safety 
or the subjects’ ability to receive the CTL019 infusion, may have their infusion delayed 
until it is determined to be clinically appropriate to proceed with the CTL019 infusion.
4. Leukemia Disease Status: Prior to CTL019 infusion and following lymphodepleting 
(LD) chemotherapy, patients must not have accelerating disease, as this will put them at 
unacceptable risk for severe CRS. Patients should not receive CTL019 infusion if they 
exhibit significant progression of disease during or following LD chemotherapy as 
evidenced by

Significant and increasing circulating blasts

Significant increases in organomegaly

Clinical evidence of new CNS disease
5. Chemotherapy Toxicity: Patients experiencing toxicities from their preceding 
lymphodepleting chemotherapy will have their infusion schedule delayed until these 
toxicities have been resolved (to grade 1 or baseline). The specific toxicities warranting 
delay of CTL019 cell infusion include:
a. Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 
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b. Cardiac: New cardiac arrhythmia not controlled with medical management. Pre-
infusion ECG also required (Table 7-1).
c. Hypotension: requiring vasopressor support
6. Infection: CTL019 infusion must be delayed if there is an uncontrolled active infection, 
as evidenced by positive blood cultures for bacteria, fungus, or PCR positivity for viral 
DNA within 72 hours of CTL019 cell infusion, or clinical or radiographic evidence of 
active infection. Following the treatment of a recent infection, significant improvement 
must be established either clinically and/or radiographically, prior to CTL019 infusion
7. GVHD Status: Patients should not be infused if they develop grade 2-4 acute or extensive 
chronic GVHD since the time of screening.
8. Concomitant Medications: If patients are taking any of the following medications, their 
infusion must be delayed until the medications have been stopped according to the 
following:
a. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior to 
CTL019 infusion. However, the following physiological replacement doses of 
steroids are allowed: < 12 mg/m2/day hydrocortisone or equivalent
b. Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be 
completed > 6 weeks prior to CTL019 infusion
c. GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 weeks 
prior to CTL019 infusion to confirm that GVHD recurrence is not observed (e.g. 
calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, 
rapamycin, thalidomide, or immunosuppressive antibodies such as rituximab, anti-
TNF, anti-IL6 or anti-IL6R, systemic steroids)
d. Chemotherapy:

Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to 
CTL019 infusion

The following drugs must be stopped > 1 week prior to CTL019 infusion and 
should not be administered concomitantly or following lymphodepleting 
chemotherapy: vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate < 25 
mg/m2, cytosine arabinoside < 100 mg/m2/day, asparaginase (non-pegylated)

The following drugs must be stopped > 2 weeks prior to CTL019 infusion: 
salvage chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, 
anthracyclines, cyclophosphamide, methotrexate ≥ 25 mg/m2), excluding the 
required lymphodepleting chemotherapy drugs

Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion
e. CNS disease prophylaxis:

CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 infusion 
(e.g. intrathecal methotrexate)
f.
Radiotherapy

Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 
infusion

CNS directed radiation must be completed > 8 weeks prior to CTL019 infusion

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g. Anti T-cell Antibodies: Administration of any T cell lytic or toxic antibody (e.g. 
alemtuzumab) within 8 weeks prior to CTL019 is prohibited since residual lytic levels 
may destroy the infused CTL019 cells and/or prevent their in vivo expansion. If such 
an agent has been administered within 8 weeks prior to CTL019, contact the Sponsor, 
consider consultation with a pharmacology expert, and consider measuring residual 
drug levels, if feasible, prior to CTL019 infusion.
9. Stem Cell Transplant: Reconfirm that patient is ≥ 6 months from SCT at the time of 
CTL019 infusion (if applicable)
10. Lymphodepleting Chemotherapy Timing: If a delay is 4 or more weeks from 
completing lymphodepleting chemotherapy and the WBC > 1000/µL, the patient will need 
to be re-treated with lymphodepleting chemotherapy.
11. Cardiac Evaluations: In the event that the time between screening cardiac 
ECHO/MUGA and CTL019 infusion exceeds 6 weeks, cardiac imaging must be repeated 
to confirm a LVSF ≥ 28 % by echocardiogram, or LVEF ≥ 45 % by echocardiogram or 
MUGA.
12. Pregnancy: Patient must undergo a pregnancy test (serum) within 24 hours prior to 
infusion (Table 7-1).
Additional safety procedures prior to administration: The risk of TLS is dependent on 
disease burden. Patients will be closely monitored both before and after lymphodepleting 
chemotherapy and CTL019 infusions including blood tests for potassium and uric acid. Patients 
with elevated uric acid or high tumor burden will receive prophylactic allopurinol, or a non-
allopurinol alternative (e.g. febuxostat). Infection prophylaxis should follow local guidelines 
dictated only by the preceding lymphodepleting chemotherapy. Infection prophylaxis per se for 
CTL019 is not recommended.
The site must confirm that two doses of tocilizumab are on site prior to CTL019 infusion and 
one dose of siltuximab must be accessible within 24 hours of infusion for administration in 
order to manage suspected toxicities.
[JAPAN ONLY: The site must confirm that three doses of tocilizumab are on site prior to 
CTL019 infusion in order to manage suspected toxicities.]
Premedication: Side effects from T cell infusions can include fever, chills and/or nausea. All 
patients should be pre-medicated with acetaminophen or paracetamol and diphenhydramine or 
an H1 antihistamine. These medications can be repeated every 6 hours as needed. Non-steroidal 
anti-inflammatory medication may be prescribed if the patient continues to have fever not 
relieved with acetaminophen or paracetamol. Steroids should NOT be used for premedication. 
It is recommended that patients NOT receive systemic corticosteroids other than physiologic 
replacement of hydrocortisone at any time, except in the case of life threatening emergency, 
since this may have an adverse effect on CTL019 cell expansion and function.
Cell thawing and infusion of CTL019 product: A study physician MUST evaluate the patient 
just prior to infusion to ensure the patient meets CTL019 infusion criteria. Trained study staff 
will administer the CTL019 infusion using precautions for immunosuppressed patients. 
Protective isolation should follow institutional standards and policies. Emergency medical 
equipment should be available during the infusion in case the patient has a significant reaction 
to the infusion such as anaphylaxis or severe hypotension.

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The CTL019 dose will be administered via a single intravenous infusion. Depending on the 
volume of the CTL019 product, it will be given either as an i.v. infusionthrough a latex free i.v. 
tubing WITHOUT a leukocyte filter (approximately 10 – 20 mL per minute adjusted as 
appropriate for smaller children and smaller volumes) or as an i.v. push via a syringe (for 
smaller volumes). It is recommended that the infusion/i.v. push be completed within 30 minutes 
of thawing the cryopreserved product in order to preserve maximum cell viability. Vital signs 
(temperature, respiration rate, pulse, pulse oximetry, and blood pressure) will be taken prior to, 
during and immediately after the infusion and then approximately every 15 minutes for one 
hour and repeated at 2 hours. If vital signs are unsatisfactory and unstable, continue to monitor 
the patient until vital sign stabilization.
All used infusion supplies, including the infusion bag and tubing, must be disposed of according 
to local institutional standard operating procedures. For further details on product storage, 
preparation, thawing and administration, please refer to the specific guidance provided in the 
[Investigational Product Handling Manual].
Following CTL019 infusion: Should emergency treatment be required in the event of life-
threatening hypersensitivity or other acute infusion-related reaction, supportive therapy such as 
oxygen, bronchodilators, epinephrine, antihistamines, and corticosteroids should be given 
according to local institutional guidelines. Patients should be evaluated and carefully monitored 
until complete resolution of signs and symptoms. Patient or patient’s caregiver should monitor 
the patient’s temperature twice a day for the first 14 days. The patient or patient’s caregiver 
should be instructed to call the investigator promptly with any signs of fever for possible 
hospitalization.
Supportive care:
Local guidelines will be followed for the supportive care of 
immunosuppressed and chemotherapy treated patients including infection management. All 
blood products administered should be irradiated. Immunosuppressive medications, including 
steroids, should not be administered unless life threatening circumstances arise.
6.1.2
Ancillary treatments
As side effects from T cell infusions can include fever, chills and/or nausea, all patients should 
be pre-medicated with acetaminophen or paracetamol and diphenhydramine or an H1 
antihistamine, as described above in Section 6.1.1.2. If fever develops please follow your 
institutional guidelines for patients with fever/neutropenia and strongly consider admission for 
close observation.
6.1.3
Treatment for cytokine release syndrome
Management of CRS following CTL019 administration must follow the CRS treatment 
algorithm which has been updated to Lee grading system (Table 6-2) and revised CRS 
management algorithm in Table 6-1. CTL019 administration may require tocilizumab 
(recommended label dose 8 mg/kg for patients weighing ≥ 30 kg and 12 mg/kg for patients 
weighing < 30 kg; IV infusion over 1 hour), steroids, and siltuximab (11 mg/kg IV over 1 hour) 
for the treatment of suspected CRS toxicities as described below in Section 6.2.4.2. The site 
must confirm that two doses of tocilizumab are on site and available for administration prior 
to CTL019 infusion and one dose of siltuximab must be accessible within 24 hours of infusion. 
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given to treat CRS, must be listed on the concomitant medication CRF. Tocilizumab or 
siltuximab should be reported on the “Dosage Administration Record - Tocilizumab” or 
“Dosage Administration Record - Siltuximab” eCRF, respectively.
[JAPAN ONLY: Management of CRS following CTL019 administration must follow the Japan 
CRS treatment algorithm in Figure 6-2. CTL019 administration may require tocilizumab 
(recommended label dose 8 mg/kg for patients weighing ≥ 30 kg and 12 mg/kg for patients 
weighing < 30 kg; IV infusion over 1 hour), and steroids, for the treatment of suspected CRS 
toxicities as described below in Section 6.2.4.2. The site must confirm that three doses of 
tocilizumab are on site and available for administration prior to CTL019 infusion. All other 
medications (except for tocilizumab administration), including steroids given to treat CRS, must 
be listed on the concomitant medication CRF. Tocilizumab should be reported on the “Dosage 
Administration Record - Tocilizumab”eCRF, respectively.]
6.1.4
Guidelines for continuation of treatment
Not applicable.
6.1.5
Treatment duration
A single dose of CTL019 transduced viable T cells will be given.
6.2
Dose escalation guidelines
Not applicable.
6.2.1
Starting dose rationale
Not applicable.
6.2.2
Provisional dose levels
Not applicable.
6.2.3
Guidelines for dose escalation and determination of MTD/RP2D/RDE
Not applicable.
6.2.3.1
Implementation of dose escalation decisions
Not applicable.
6.2.3.2
Intra-patient dose escalation
Not applicable.
6.2.4
Definitions of dose limiting toxicities (DLTs) in a Phase II Study
There are no dose-limiting toxicities in this protocol; however criteria for stopping or pausing 
the trial are detailed below.

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6.2.4.1
Toxicity management, stopping rules and study termination
It is expected that AEs will occur frequently in this population based on the underlying 
advanced hematologic malignancy and that these can be SAEs. Therefore, there is no specific 
occurrence of SAEs that define a stopping rule, but the review of SAEs will form the basis for 
potential early stopping of the study. Only unexpected SAEs that are related to the CTL019 
transduced cells would define a stopping rule. The review of these adverse events, and any 
decision to prematurely stop patient enrollment, will be determined by the Data Monitoring 
Committee (DMC) and reviewed by the IRB at the site level.
Premature termination of the clinical trial may occur because of a regulatory authority decision, 
the DMC, or determination that there are problems in the cell product generation or safety at 
the discretion of the study investigators. Additionally, recruitment may be stopped at the 
sponsor’s discretion and may include reasons such as low recruitment, protocol violations, or 
inadequate data recording.
6.2.4.1.1 Criteria for stopping or pausing the study
During the safety run-in stage the study will be paused, and health authorities notified, if at 
least one of the following events occur:

Life-threatening (grade 4) toxicity attributable to protocol therapy that is unmanageable, 
unexpected and unrelated to chemotherapy and attributable to CTL019 therapy. High 
fevers, hypotension, hypoxia, disseminated intravascular coagulation, encephalopathy 
(e.g. lethargy, confusion, aphasia, seizures), intensive care unit (ICU) admission, dialysis 
and mechanical ventilation are expected. The expected side effects can also result in grade 
4 liver toxicity, nephrotoxicity and other organ involvement

Death suspected to be related to CTL019 therapy
Beyond the safety run-in stage, the overall study will be paused, and health authorities notified 
if:

Any patient develops uncontrolled T cell proliferation beyond 8 weeks from CTL019 cell 
product infusion that does not respond to management

Any patient develops detectable replication competent lentivirus (RCL) during the study

The Sponsor, DMC, or any regulatory body decides for any reason that patient safety may 
be compromised by continuing the study

The Sponsor decides to discontinue the development of the intervention to be used in this 
study
The study may be paused pending notification of the health authorities and the DMC for 
investigation and possible protocol amendment if any patient experiences any of the following 
events within three weeks of the CTL019 cell 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, seizures), ICU admission, dialysis and mechanical 
ventilation are expected. The expected side effects can also result in grade 4 liver toxicity,
nephrotoxicity and other organ involvement

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
Death suspected to be related to CTL019 therapy
6.2.4.2
General toxicity management considerations
Acute infusion reaction
Acetaminophen/paracetamol and diphenhydramine/H1 antihistamine may be repeated every 6 
hours as needed. A course of non-steroidal anti-inflammatory medication may be prescribed if 
the patient continues to have fever not relieved by acetaminophen/paracetamol. It is 
recommended that patients not receive corticosteroids at any time, except those already on 
physiologic replacement therapy, or in the case of a life threatening emergency, since this may 
have an adverse effect on CTL019 cells.
Febrile reaction
In the event of febrile reaction, an evaluation for infection should be initiated, and patients 
managed appropriately with antibiotics, fluids and other supportive care as medically indicated 
and determined by the treating physician. Inpatient treatment is recommended initially. In the 
event that the patient develops sepsis or systemic bacteremia following CTL019 cell infusion, 
appropriate cultures and medical management should be initiated. If a contaminated CTL019 
cell product is suspected, the product can be retested for sterility using archived samples that 
are stored at the manufacturing site. Consideration of a cytokine release syndrome (see below) 
should be given.
Cytokine release syndrome (CRS) / macrophage activation syndrome (MAS)
Data from CTL019 treated patients experiencing CRS show marked elevations in IL6 and IFN-
g. The symptoms generally occur 1-14 days after cell infusion in patients with ALL and may 
include high fevers, rigors, myalgia/arthralgias, nausea/vomiting/anorexia, fatigue, headache, 
encephalopathy, hypotension, dyspnea, tachypnea and hypoxia. Renal failure/renal injury, 
hyperbilirubinemia and increased ALT or AST can also occur. Supportive care and anti-
cytokine therapy have been used for effective management of CRS. Prompt responses to 
tocilizumab have been seen in most patients Several patients with a suboptimal response to the 
first dose of tocilizumab have received a second or third dose of tocilizumab with CRS 
resolution. In patients with incomplete resolution of CRS after several doses of tocilizumab, 
CRS resolution has been observed following siltuximab administration. Five patients with 
Grade 4 CRS have been treated with siltuximab in CTL019B2202 at clinical sites outside of 
Japan.  If the patient experiences ongoing CRS despite administration of repeated anti-cytokine 
directed therapies with tocilizumab, steroids and siltuximab, anti-T-cell therapies such as 
cyclophosphamide, anti-thymocyte globulin (ATG) or alemtuzumab may be considered and 
need to be captured in case report forms. Fatal outcomes associated with CRS have been 
observed in pediatric and adult ALL patients in the context of current significant clinical 
infections. 
A detailed treatment algorithm has been established with clear criteria for CRS management 
and guidance on when to administer tocilizumab and siltuximab as presented below in Table 6-
1 and must be followed by investigators. Tumor necrosis factor (TNF alpha) antagonists have 
been used with CTL019 associated CRS with little evidence for efficacy. Given the apparent 

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lack of activity combined with their immunosuppressive effects, TNF antagonists are not 
recommended. This approach was designed to avoid life-threatening toxicities, while 
attempting to allow the CTL019 transduced cells to establish a proliferative phase which 
appears to correlate with tumor response. Patients will be required to remain proximal to the 
treating site for the first 21 days.
The management of CRS is based solely upon clinical parameters as described in Table 6-1
below. Serum cytokine and inflammatory marker levels should NOT be used for clinical 
management decisions of CRS.
Cases of transient left ventricular dysfunction, as assessed by cardiac ECHO, have been 
reported in some patients with severe CRS (grade 4). Therefore, consideration should be given 
to monitoring cardiac function by cardiac ECHO, during severe CRS, especially in cases with 
prolonged severe hemodynamic instability, delayed response to high dose vasopressors, and/or 
severe fluid overload.
Clinically significant coagulopathy is often seen with moderate to severe CRS (Grade 3 and 4) 
and may continue as CRS is beginning to clinically resolve. Coagulation parameters (PT, aPTT, 
and fibrinogen) should be more frequently monitored in this setting. CTL019 associated 
coagulopathy with or without clinical bleeding and hypofibrinogenemia is strongly 
recommended to be managed with cryoprecipitate or fibrinogen concentrate in addition to 
routine blood product support.
CTL019 related CRS can be associated with neurologic events. Two types of neurologic events 
with respect to timing of onset have been observed. Onset of neurologic events can be 
concurrent with high fevers during the development and maximal grade of CRS. Delayed onset 
of neurologic events can also occur as CRS is resolving or after CRS has completely resolved. 
Consideration should be given to monitoring for neurologic events during and after resolution 
of CRS.
A modification of the Common Terminology Criteria for Adverse Events (CTCAE) CRS 
grading scale has also been established to better reflect CTL019-therapy-associated CRS as 
presented in Table 6-2.
Specific CRFs have been developed for the capture of CRS elements, severity, management 
and response to intervention.
Table 6-1
CRS management algorithm:
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:
Antipyretics, oxygen, 
intravenous fluids 
and/or low dose 
If no improvement after 
symptomatic treatment 
If no improvement within 
12-18 hours of 
tocilizumab, administer 

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CRS severity 
Symptomatic 
treatment
Tocilizumab 
Corticosteroids
- high fever
- hypoxia
- mild hypotension
vasopressors as 
needed.
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)
a daily dose of 2 mg/kg 
i.v. methylprednisolone 
(or equivalent) until 
vasopressor and oxygen 
no longer need, then 
taper.
Symptoms requiring 
aggressive intervention: 
-hypoxia requiring      
high-flow oxygen 
  supplementation or
- hypotension requiring 
  high-dose or multiple 
  vasopressors
High-flow oxygen
Intravenous fluids and 
high-dose 
vasopressor/s
Treat other organ 
toxicities as per local 
guidelines
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 high-
flow oxygen no longer 
need, then taper.
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
As above*
As above*
* If no improvement after tocilizumab and steroids, consider other anti-cytokine and anti-T cell therapies. These 
therapies may include siltuximab (11 mg/kg i.v. over 1 hour), high doses of steroids (e.g. high dose 
methylprednisolone or equivalent steroid dose according to local ICU practice) cyclophosphamide, anti-thymocyte 
globulin (ATG) or alemtuzumab.
Table 6-2
CTL019-therapy-associated grading for cytokine release syndrome:  
(Lee et al 2014) - further Amendment 6
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)

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Grade
Toxicity
Grade 5
Death
*High dose vasopressor doses are shown in Table 6-3
Table 6-3
High dose vasopressor use
Definition of “High-Dose” Vasopressors
Vasopressor
Dose for ≥ 3 hours
Norepinephrine monotherapy
≥ 0.2 mcg/kg/min
Dopamine monotherapy
≥ 10 mcg/kg/min
Phenylephrine monotherapy
≥ 200mcg/min
Epinephrine monotherapy
≥ 0.1 mcg/kg/min
If on vasopressin
High-dose if vaso + Norepinephrine Equivalent (NE) of ≥0.1 mcg/kg/min 
(using VASST formula)
If on combination vasopressors (not 
vasopressin)
Norepinephrine equivalent of ≥ 20 mcg/min (using VASST formula)
VASST Trial Vasopressor Equivalent Equation:
Norepinephrine equivalent dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + [epinephrine 
(mcg/min)] + [phenylephrine (mcg/min) ÷10]
Criteria from Russell et al (2008).
Note: Pediatric weight adjustments should be taken into consideration
Tumor lysis syndrome
Close monitoring for TLS before and after chemotherapy and CTL019 infusions, including 
blood tests (potassium, uric acid, etc.) will be done as follows:

Screening phase:

Prophylactic allopurinol, or a non-allopurinol alternative (e.g. febuxostat), and 
increased oral/ IV hydration prior to lymphodepleting chemotherapy and CTL019
infusion should be given in patients with elevated uric acid or high tumor burden

Early and prompt implementation of supportive care in case of symptoms of acute 
TLS (i.v. hydration and rasburicase as clinically indicated, when uric acid continues 
to rise despite allopurinol/febuxostat and fluids)

Post-infusion Monitoring phase:

Frequent monitoring of the following laboratory tests (2 to 3 times/week for 3 weeks 
from start of lymphodepleting chemotherapy, then weekly): potassium, phosphorus, 
calcium, creatinine, and uric acid

Encourage oral hydration
Laboratory and clinical TLS is defined as follows:

Laboratory TLS is defined as two or more of the following values three days prior to or 
following CTL019 infusion.

Uric acid ≥ 8 mg/dL or 25% increase from baseline

Potassium ≥ 6 mEq/L or 25% increase from baseline

Phosphorus ≥ 6.5 mg/dL (children) or ≥ 4.5 mg/dL (adults) or 25% increase from 
baseline

Calcium ≤ 7 mg/dL or 25% decrease from baseline

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
If zero or one of the laboratory values above are abnormal, continue to manage with 
allopurinol or a non-allopurinol alternative (e.g. febuxostat) and oral hydration. 
Consider IV fluids and rasburicase if uric acid levels remain elevated, and consider in 
hospital monitoring

If Laboratory TLS exists, manage with i.v. fluids, laboratory blood tests every 6 to 8 
hours and inpatient care. Cardiac monitoring should be considered, and rasburicase 
should be considered if uric acid levels remain elevated

Clinical TLS is defined as the presence of laboratory TLS plus ≥ 1 of these criteria in the 
absence of other causes.

Serum creatinine ≥ 1.5 times the upper limit of the age-adjusted normal range

Symptomatic hypocalcemia

Cardiac arrhythmia

If Clinical TLS exists, manage with IV fluids, laboratory blood tests every 6 to 8 
hours, cardiac monitoring, rasburicase/allopurinol/febuxostat and inpatient care 
(consider ICU)
Criteria modified from Cairo and Bishop (2004).
Graft-Versus-Host Disease (GVHD)
The chance of GVHD occurring is low, but it is a potential risk with CTL019 therapy. A prior 
study of activated donor lymphocyte infusions (ex vivo activated cells collected from the donor 
and grown in the same fashion as CTL019 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). 
Ten ALL patients have been treated to date with autologous CTL019 therapy who have had 
prior allogeneic hematopoietic SCT with residual donor chimerism. None of these patients 
developed GVHD after CTL019 infusion.
As part of the exclusion criteria for this protocol regarding GVHD, the grading & staging 
assessment of acute GVHD will follow the criteria described below in Table 6-4, and the 
definition of chronic GVHD will follow the criteria described in Table 6-5.
Table 6-4
Staging and grading of acute Graft-Versus-Host Disease
Extent of organ involvement
Skin
Liver
Gut
Stage
1
Rash on < 25% of skina
Total bilirubin 2-3 mg/dLb
Diarrhea > 500 mL/dayc or 
persistent nausead
2
Rash on 25-50% of skin
Total bilirubin 3-6 mg/dL
Diarrhea > 1,000 mL/day
3
Rash > 50% of skin
Total bilirubin 6-15 mg/dL
Diarrhea > 1,500 mL/day
4
Generalized erythroderma 
with bullous formation
Total bilirubin > 15 mg/dL
Severe abdominal pain with 
or without ileus
Gradee
I
Stage 1-2
None
None
II
Stage 3 or
Stage 1 or
Stage 1
III
Stage 2-3 or
Stage 2-4

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Extent of organ involvement
Skin
Liver
Gut
IVf
Stage 4 or
Stage 4
a.
Use “rule of nines” or burn chart to determine extent of rash.
b.
Range given as total bilirubin. Downgrade by 1 stage if an additional cause of elevated bilirubin has been 
documented.
c.
Volume of diarrhea applies to adults. For pediatric patients, the volume of diarrhea should be based on body 
surface area. Gut staging for pediatric patients was not discussed at the Consensus Conference. Downgrade 
by 1 stage if an additional cause of diarrhea has been documented.
d.
Persistent nausea with histologic evidence of GVHD in the stomach or duodenum.
e.
Criteria for grading given as a minimum degree of organ involvement required to confer that grade.
f.
Grade IV may also include lesser organ involvement but with extreme decrease in performance status.
Chronic GVHD is an immune-mediated disorder that may occur following allogeneic SCT. 
Manifestations include scleroderma, dry eyes, dry mouth, lichenoid oral changes, bronchiolitis 
obliterans, vanishing bile ducts, or weight loss. It is to be diagnosed specifically rather than 
diagnosed when acute GVHD-like syndromes develop late (beyond day +100) after any 
transplant or donor leukocyte infusion.
Table 6-5
Definitions of chronic Graft-Versus-Host Disease
Definite and Possible Manifestations of Chronic GVHD
Organ System
Definite Manifestations of Chronic 
GVHD
Possible Manifestations of Chronic 
GVHD
Skin
Scleroderma (superficial or fasciitis), 
lichen planus, vitiligo, scarring 
alopecia, hyperkeratosis pilaris, 
contractures from skin immobility, nail 
bed dysplasia
Eczematoid rash, dry skin, maculopapular 
rash, hyperpigmentation, hair loss
Mucous membranes
Lichen planus, non-infectious ulcers, 
corneal erosions/non-infectious 
conjunctivitis
Xerostomia, keratoconjunctivitis sicca
Gastrointestinal (GI) tract
Esophageal strictures, steatorrhea
Anorexia, malabsorption, weight loss, 
diarrhea, abdominal pain
Liver
None
Elevation of alkaline phosphatase, 
transaminitis, cholangitis, 
hyperbilirubinemia
Genitourinary (GU)
Vaginal stricture, lichen planus
Non-infectious vaginitis, vaginal atrophy
Musculo-skeletal/ Serosa
Non-specific arthritis, myositis, 
myasthenia, polyserositis, contractures 
from joint immobilization
Arthralgia
Hematologic
None
Thrombocytopenia, eosinophilia, 
autoimmune cytopenias
Lung
Bronchiolitis obliterans
Bronchiolitis obliterans with organizing 
pneumonia, interstitial pneumonitis
1.
At any time point post-transplant, if there are ANY definite symptoms (column 2) then the symptoms should 
be identified as chronic GVHD.
2.
At any time point post-transplant, if there are any possible symptoms (column 3) but no definite symptoms, 
then it is at the physicians’ discretion to identify as either acute or chronic GVHD.
3.
Acute and chronic GVHD cannot be present at the same time. Thus if #1 is fulfilled, then all manifestations of 
GVHD should be identified as chronic GVHD.

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Limited Chronic GVHD

Localized skin involvement and/or liver dysfunction OR

Involvement of only one target organ
Extensive Chronic GVHD

Generalized skin involvement ≥50% of body surface area OR

Localized skin involvement and/or liver dysfunction plus at least one of the following:

Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis

Eye involvement (Schirmer’s test with < 5 mm wetting)

Involvement of minor salivary glands or oral mucosa on lip biopsy

Involvement of any other target organs OR

Involvement of at least two target organs
B cell depletion
Depletion of B cells with resulting hypogammaglobulinemia is expected as a result of CTL019 
on 
target 
effects 
in 
patient 
with 
sustained 
tumor 
response. 
CTL019 
related 
hypogammaglobulinemia is typically managed with immunoglobulin replacement therapy 
dependent upon age specific, disease specific and local institutional guidelines. 
Immunoglobulin replacement during the study period will be recorded. In general B cell aplasia 
and hypogammaglobulinemia, of various causes, can be associated with increased rates of 
infection. Such infections are typically sinopulmonary but other sites and types of infections 
have also been reported.  Institutional guidelines for vaccination (e.g. pneumococcus) should 
be followed before starting CTL019 therapy.
No live vaccines should be used in CTL019 recipients or prospective recipients as the lack of 
effective B cells after infusion makes the likelihood of a systemic infection considerable and 
their value negligible.
Other potential complications of B cell aplasia include progressive multifocal 
leukoencephalopathy (PML) and reactivation of hepatitis B virus. Neither PML nor reactivation 
of hepatitis B virus have been seen yet with CTL019; however, other therapies associated with 
B cell aplasia have seen these complications.
For the first 12 months following CTL019 infusion, data on all significant infections will be 
collected for patients in the primary follow-up. After 12 months following CTL019 infusion or 
if patients move to the secondary follow-up prior to month 12, data on infections will only be 
collected when they are opportunistic or serious and requiring intervention as defined:
1. Requires anti-infective treatment
2. Leads to significant disability or hospitalization
3. Needs surgical or other intervention

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6.2.4.3
Potential toxicities
Replication-competent lentivirus (RCL)
An RCL may be generated during CTL019 manufacturing or subsequently after introduction of 
vector transduced 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 before it can be released to a patient. 
Thus patients will only receive cell products that meet RCL release criteria. Nevertheless, 
generation of an RCL following infusion of the vector product remains a theoretical possibility. 
The development of RCL could pose a risk to both the patient and their close contact(s), and 
therefore, monitoring for RCL will be conducted during the course of the trial (see [Laboratory 
Manual] for a description of the assays). Blood samples for RCL testing will be collected as per 
Table 7-1. If blood samples test are negative through Month 12, all samples taken after Month 
12 will be stored for potential future testing. If a positive RCL assay result is obtained from a 
patient blood specimen, (as detected by Vesicular Stomatitis Virus/Glycoprotein (VSV-G) q-
PCR, for example) the Investigator will be informed and the patient rescheduled for a retest of 
the DNA test. Regulatory agencies and the gene therapy community have previously discussed 
measures to be taken should an RCL be confirmed in a patient. However, because the 
probability and characteristics of an RCL are unknown, no guidelines have been put in place. 
Nevertheless, all agree that the patient must be isolated until an understanding of how to manage 
the patient becomes clear. Some considerations are:

Intensive follow-up of the patient 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
Clonality and insertional oncogenesis
The occurrence of adverse events caused by insertional mutagenesis in three patients in a gene 
therapy trial for X-linked Severe Combined Immunodeficiency (SCID) following stem cell 
therapy emphasizes the potential for problems in translating this approach to the clinic. To date, 
clinically evident insertional mutagenesis has not been reported following adoptive infusion of 
engineered T cells. Lentiviral vectors may have a lower risk than oncoretroviral vectors based 
on several considerations. Monitoring for T cell clonal outgrowth will be performed by q-PCR 
quantitation of the CTL019 transgene, and by complete blood count (CBC). If monoclonality 
is found, further studies including insertion site analysis will be considered.
Uncontrolled T cell proliferation
CTL019 transduced cells could theoretically proliferate without the control of normal 
homeostatic mechanisms. In pre-clinical studies (Milone et al 2009) and clinical experience to 
date (Porter 2011, Grupp 2013), CTL019 transduced cells have only proliferated in response to 
physiologic signals or upon exposure to CD19 antigen. In the context of CTL019 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 beneficial or harmful depending on the 

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Immunogenicity (humoral and cellular) will be measured following CTL019 infusions as 
indicated in the Visit Evaluation Schedule.
Immunoglobulin depletion
Transient or permanent B cell depletion is a risk with CTL019 therapy, since normal B cells 
express CD19. This is expected to resolve if and when the CTL019 cells are cleared. Patients 
may require periodic infusions of immunoglobulin based upon local and age specific guidelines 
for specific patient populations.
Progressive multifocal leukoencephalopathy (PML)
PML is rare but well described with antibodies causing B cell aplasia (Weissert 2011) and is a 
demyelinating disease of the central nervous system, resulting from infection of 
oligodendrocytes and astrocytes, mostly with JC virus. PML classically has a subacute clinical 
presentation with focal neurologic deficits, such as weakness, speech difficulties, unsteady gait 
and hemiparesis. Ophthalmic symptoms are relatively common, occurring as homonymous 
hemianopia which progresses to cortical blindness. Seizure and headache are uncommon. 
Dementia manifesting as mental deficits in cognition, personality changes, and memory 
impairment are also common, but it is almost invariably associated with the focal neurologic 
deficits of PML. By CT or MRI radiographic assessment, lesions are confined to the white 
matter, most commonly of the occipitoparietal lobe and without mass effect.
In general, patients with known B cell aplasia are at increased risk for PML. Therefore patients 
in the study will be monitored at regular intervals for any new or worsening neurological 
symptoms or signs that may be suggestive of PML. The clinician should evaluate the patient to 
determine if the symptoms are indicative of neurological dysfunction, and if so, whether these 
symptoms are possibly suggestive of PML. Consultation with a neurologist should be 
considered as clinically indicated.
Hepatitis B reactivation
Reactivation of hepatitis B refers to the abrupt increase in hepatitis B virus (HBV) replication 
in a patient with inactive or resolved hepatitis B. Reactivation can occur spontaneously, but 
more typically is triggered by immunosuppressive therapy of cancer, autoimmune disease, or 
organ transplantation. Reactivation can be transient and clinically silent, but often causes a flare 
of disease that can be severe resulting in acute hepatic failure. Most instances of reactivation 
resolve spontaneously, but if immune suppression is continued, re-establishment of chronic 
hepatitis occurs which can lead to progressive liver injury and cirrhosis. Reactivation is defined 
as increase of one log in HBV-DNA relative to baseline HBV-DNA or new appearance of 
measurable HBV-DNA (Hoofnagle 2009). Patients with evidence of reactivated hepatitis B 
should initiate either tenofovir or entecavir, and pursue appropriate consultation.
In general, the risk of hepatitis B reactivation is increased in patients with B cell depletion. 
Patients with latent or active hepatitis B are typically excluded from CTL019 treatment 
protocols; however infection could potentially occur following the treatment trial completion 
or early withdrawal. Therefore, patients with a history of hepatitis B should be closely 
monitored for clinical and laboratory signs of active HBV infection. Standard guidelines should 
be followed for the treatment of active/reactivated hepatitis B (Hoofnagle 2009).

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Individuals with evidence of prior unresolved or ongoing HBV infection (See Section 14.2, 
Table 14-4) are at increased risk of reactivation of HBV infection (Patel 2015) and are excluded 
from this study.
New or secondary malignancies
There is a theoretical concern that transduction of a patient’s T-cells with CD19 CAR lentiviral 
vector could result in an oncogenic effect within these T-cells that could result in a T-cell 
leukemia or lymphoma. 
For patients treated with CTL019, treating physician/ healthcare providers should contact 
Novartis if the patient develops a secondary malignancy. 
Upon clinical confirmation of a secondary malignancy, blood samples will be collected for 
CAR-transgene and RCL testing. 
Novartis strongly recommends collection of a portion of a biopsy (e.g. bone marrow, solid 
tumor) from the secondary malignancy (if applicable and previously collected as standard of 
care in diagnosing or treating the secondary malignancy) for exploratory analysis, such as CAR-
transgene and RCL. Additional details for sample handling and shipping are outlined in the 
laboratory manual.
6.2.5
Criteria for discontinuing a patient’s participation in the study
If a patient develops a condition that precludes CTL019 infusion after enrollment but before 
infusion, the patient will be prematurely discontinued. This will be done at the judgment of the 
PI, and could include for example, the occurrence of an intercurrent illness requiring the 
institution of systemic immunosuppression.
6.2.6
Concomitant therapy
Clinically significant prescription and nonprescription medications, excluding vitamins, herbal 
and nutritional supplements, and procedure-related (inpatient or outpatient) medications taken 
by the patient during the 30 days prior to screening will be recorded. At every visit following 
the screening visit up to the month 60 visit, concomitant medications will be recorded in the 
medical record and on the appropriate CRF. During selected trial phases, concomitant 
medication collection will be modified as outlined in Appendix 3: CTL019 Modified Data 
Reporting- Treatment and Primary Follow Up Phase, CRF Completion Guidelines (CCGs), and 
Table 6-6 below. Modified collection of concomitant medications during these trial phases are 
designed to capture CTL019-related toxicity, severity, interventions and response/resolution 
following intervention. Any additions, deletions, or changes of these medications will be 
documented.
Table 6-6
Concomitant medication reporting by trial phase
Trial phase
Inpatient/ICU
Outpatient
Pre-treatment period (ICF to LD chemo/pre-infusion)
Modified
Modified
Treatment period (LD chemo/pre-infusion through M12)
Modified
All concomitant medications
Post-treatment period (after M12 through M60)
Modified
Modified
The following guidelines must be adhered to during the study:

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
Granulocyte macrophage-colony stimulating factor (GM-CSF) should be avoided due to 
the potential to worsen CRS symptoms.

Short acting granulocyte colony stimulating factor (G-CSF) should not be given within 72 
hours of CTL019 infusion and until CRS is resolved. Long acting G-CSF should not be 
given within 10 days of CTL019 infusion and until CRS is resolved. The effects of 
granulocyte colony stimulating factor (G-CSF) are unknown.

Steroids or other immunosuppressant drugs should NOT be used as pre-medication for 
CTL019 therapy (refer to Section 6.1.1.2) or following CTL019 infusion, except as 
required for physiological glucocorticoid replacement therapy, or under life threatening 
circumstances. Use of steroids with blood product administration should be eliminated just 
prior to and following CTL019 if possible or at least minimized.

Patients with moderate to severe signs and symptoms attributable to CRS should be 
managed with supportive care and administration of tocilizumab as defined in Table 6-1
and Section 6.2.4.2.
6.2.7
Prohibited concomitant therapy
Concurrent use of systemic steroids or immunosuppressant medications are prohibited under 
this protocol except as required for physiologic replacement of hydrocortisone, or in the case 
of a life threatening emergency, since this may have an adverse effect of CTL019 cell expansion 
and function.
Specifically, the following medications are excluded:
a. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior to 
CTL019 infusion. However, the following physiological replacement doses of steroids are 
allowed: < 12 mg/m2/day hydrocortisone or equivalent
b. Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be 
completed > 6 weeks prior to CTL019 infusion
c. GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 weeks prior to 
CTL019 infusion to confirm that GVHD recurrence is not observed (e.g. calcineurin 
inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, rapamycin, 
thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-TNF, 
anti-IL6 or anti-IL6R, systemic steroids)
d. Chemotherapy:

Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to 
CTL019 infusion

The following drugs must be stopped > 1 week prior to CTL019 infusion and should 
not be administered concomitantly or following lymphodepleting chemotherapy: 
vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate < 25 mg/m2, cytosine 
arabinoside < 100 mg/m2/day, asparaginase (non-pegylated)

The following drugs must be stopped > 2 weeks prior to CTL019 infusion: salvage 
chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, anthracyclines, 
cyclophosphamide, methotrexate ≥ 25 mg/m2), excluding the required 
lymphodepleting chemotherapy drugs

Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion

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e. CNS disease prophylaxis:

CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 infusion (e.g. 
intrathecal methotrexate)
f.
Radiotherapy:

Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 infusion

CNS directed radiation must be completed > 8 weeks prior to CTL019 infusion
g. Anti T-cell Antibodies: Administration of any T cell lytic or toxic antibody (e.g. 
alemtuzumab) within 8 weeks prior to CTL019 is prohibited since residual lytic levels 
may destroy the infused CTL019 cells and/or prevent their in vivo expansion. If such an 
agent has been administered within 8 weeks prior to CTL019, contact the Sponsor, 
consider consultation with an pharmacology expert, and consider measuring residual drug 
levels, if feasible, prior to CTL019 infusion.
6.3
Dose modifications
6.3.1
Dose modifications and dose delays
Not applicable.
6.3.2
Follow-up for toxicities
6.3.2.1
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of 
CTL019, 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 14-6 in Appendix 7 for complete definitions of liver laboratory triggers 
and liver events.
Every liver event defined in Table 14-5 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 14-6. Repeat liver chemistry tests (alanine transaminase 
(ALT), aspartate transaminase (AST), total bilirubin (TBIL), prothrombin time and 
international normalized ratio (PT/INR), alkaline phosphatase (ALP) and gamma-glutamyl 
transpeptidase (G-GT) to confirm elevation.
These liver chemistry repeats should be performed using the local laboratory used by the site. 
Repeated laboratory test results must be reported as appropriate.
If the initial elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.

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
Discontinuation of the investigational drug, if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event, which can include based on investigator’s 
discretion: 

Serology tests, imaging (e.g., such as abdominal ultrasound (US), computed 
tomography scan (CT) or magnetic resonance imaging scan (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.
6.3.2.2
Follow up on potential drug-induced liver injury (DILI) cases
Patients with significant transaminase increase combined with  TBIL increase may be indicative 
of potential DILI, and should be considered as clinically important events.
The threshold for potential toxicity may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT or AST or TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN, or ALT or AST >5.0 x ULN in isolation.

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], whichever is lower, 
combined with [TBIL > 2 x baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as alkaline phosphatase (ALP) elevation > 2.0 x ULN with R value < 2 in patients without bone 
metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes the relative pattern of ALT and/or ALP elevation is due to cholestatic 
or hepatocellular liver injury).
In the absence of cholestasis, these patients should have repeat LFT testing as soon as possible, 
preferably within 48 hours from the awareness of the abnormal results. The evaluation should 
include laboratory tests, a renewed detailed history, renewed physical assessment and the 
possibility of liver metastasis or new liver lesions, obstructions/compressions, etc should be 
considered.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.

A detailed history, including relevant information, such as review of alcohol consumption, 
illicit drug use, concomitant medications, herbal remedies, supplement consumption, 
history of any pre-existing liver conditions or risk factors, should be collected.

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
Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) such as a right upper quadrant (RUQ) ultrasound with duplex for flow, may be 
warranted.

If bilirubin elevation is an isolated event (no transaminase elevations above baseline is 
seen), then a work-up for hemolysis is appropriate (e.g., reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin).

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.3.2.3
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

Serum creatinine increase ≥ 25% compared to baseline during normal hydration status

Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR new onset dipstick 
proteinuria ≥ 3+ OR new onset dipstick hematuria ≥ 3+ (after excluding menstruation, 
urinary tract infection, extreme exercise, or trauma)
Renal event findings must be confirmed after ≥24 hours but ≤ 5 days at the latest after first 
assessment. 
Every renal laboratory trigger or renal event as defined in Table 14-7 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 14-8 (Appendix 
8)
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Upon informed consent/assent completion, the patient will initiate screening. Each patient is 
identified in the study by a seven digit Subject Number (Subject No.), that is assigned 
sequentially at each site by the site investigator or designated staff when the patient is first 
enrolled for screening and is retained as the primary identifier for the patient throughout his/her 
entire participation in the trial. The Subject No. consists of the four digit Center Number (Center 
No.) (as assigned by Novartis to the investigative site) with a sequential three digit patient 
number suffixed to it, such that each patient is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 

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not be reused for any other patient and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to start treatment for any reason, the reason 
will be documented and entered onto the appropriate CRF page.
6.4.2
Treatment assignment
This is a single-arm open-label study. Patients will be enrolled and assigned to treatment upon 
confirmation of all clinical eligibility, and receipt and acceptance of the apheresed product by 
the manufacturing facility.
6.4.3
Treatment blinding
This is an open-label study.
6.5
Study drug preparation and dispensation
Upon release from the manufacturing facility, the cryopreserved CTL019 cell product is 
shipped to the investigator. Upon receipt of the cryopreserved CTL019 cell product, inventory 
must be performed. The respective drug receipt form is completed and signed by personnel 
accepting the shipment of CTL019. It is important that the designated study staff verifies that 
the shipment contains all the items noted in the shipment inventory. Any damaged or unusable 
CTL019 cell product in a given shipment will be documented in the study files. The investigator 
must notify study sponsor of any damaged or unusable CTL019 cell product that was supplied 
to the investigator’s site.
The CTL019 cell product will remain in storage until the subject is available for infusion and 
ready (Section 6.5.2). Please note the time between product thawing and completion of the 
infusion should not exceed 30 minutes to maintain maximum product viability. Therefore, to 
ensure this timeframe, the product should be thawed in close proximity to the patient’s bedside. 
Additionally, after cell thawing the CTL019 cell product should NOT be washed prior to 
infusion. All contents must be infused. If the CTL019 cell product appears to have a damaged 
or leaking bag, or otherwise appears to be compromised, it should not be infused, and should 
be disposed of according to local institutional standard operating procedures.
For further details on product receipt, storage, preparation, and administration, see Section 
6.1.1.2 and the [Investigational Product Handling Manual] (e.g. option of syringe-based 
administration for pediatric patients with small product volumes).
6.5.1
Study drug packaging and labeling
Each infusion bag will typically contain 10 – 50 mL of cells containing a cell dose of 0.2 to 5.0
x 106 autologous CTL019 transduced viable T cells per kg body weight (for patients ≤ 50 kg) 
and 0.1 to 2.5 x 108 CTL019 transduced viable T cells (for patients > 50 kg). Higher volumes 
may occasionally be necessary depending on transduction efficiency.
Each infusion bag will have affixed to it a label containing the following: A product identifier, 
the proper name of the product, and appropriate product modifiers and attributes according to 
the International Standard for Blood and Transplant (ISBT 128 Standard Terminology for 
Blood, Cellular Therapy, and Tissue Product Description, Version 4.28). The study number and 
the wording “FOR AUTOLOGOUS USE ONLY” will be included in the label. In addition the 

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label will have at least two unique identifiers such as the patient’s alphanumeric identifier and 
birth date according to applicable regulations. Additional label elements required by local 
regulatory guidelines will also be included. Prior to the infusion, two individuals will verify all 
of this information and confirm identity according to local institutional guidelines, to ensure 
that the information is correctly matched to the patient, and that the patient receives only their 
autologous product.
6.5.2
Drug supply and storage
CTL019 cell product must be received, handled and stored safely and properly by designated 
personnel at the study site, CTL019 must be kept in a secured location to which only the 
investigator and designated site personnel have access. Upon receipt, the CTL019 cell product 
should be stored according to the instructions specified on the product labels and in the 
[Investigational Product Handling Manual].
6.5.3
Study drug compliance and accountability
Novartis has established methods to ensure full traceability between the patient’s autologous 
apheresis and the CTL019 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 Novartis Clinical Supplies Quality Assurance (QA) Department. A unique 
patient identifier will be used in order to maintain the chain of identity between the autologous 
apheresis product and the CTL019 batch, and the link between patient identity and unique 
patient identifier will be confirmed prior to infusion. The [Investigational Product Handling 
Manual], [Leukapheresis, Cryopreservation & Scheduling Manual], and [Investigational 
Product Transport Manual] provides an overview of how the company ensures that the cells 
which are procured, processed, stored, and distributed by or on behalf of the Novartis can be 
traced from donor to recipient and vice versa.
6.5.3.1
Study drug compliance
As a single administration study, compliance will be assessed by the investigator and/or study 
personnel and captured on site infusion records and drug accountability records.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of CTL019 cell product in a drug accountability log. Drug accountability records will be 
reviewed by the field monitor during site visits and at the completion of the study.
6.5.3.3
Handling of other study treatment
Not applicable.

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6.5.4
Disposal and destruction
CTL019 cell product may require disposal for a variety of reasons, including but not limited to: 
1) Mislabeled product; 2) Condition of patient prohibits infusion, and/or 3) Patient refuses 
infusion. Disposal of unused CTL019 product must be approved by Novartis study team. Upon 
Novartis’s approval, CTL019 may be disposed of according to local laws/ institutional standard 
operating procedures (SOP).
Any unused product and all used infusion supplies, including the infusion bag 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 [Investigational Product Handling Manual].
Reconciliation of CTL019 cell product shipped, consumed, and remaining, is performed by 
Novartis (or designee). All CTL019 cell product disposition will be documented in the study 
files. 
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments through the end of the Treatment and Primary Follow-up 
phase (Section 7.1.3).
For patients who discontinue early from the Treatment and Primary Follow-Up Phase prior to 
Month 60, the patient will enter a Secondary Follow-Up Phase to collect health authority 
requested data (e.g. delayed adverse events, etc.). The first visit in the Secondary Follow-Up 
Phase is determined according to the time since CTL019 infusion when the patient discontinued 
from the Treatment and Primary Follow-Up Phase. For example, if the patient discontinued 
from the Treatment and Primary Follow-Up phase at Month 10, the first visit in the Secondary 
Follow-Up Phase will be Month 12. Table 7-2 lists all of the assessments through the end of the 
Secondary Follow-up phase (Section 7.1.4). It is anticipated that patients may leave the primary 
follow-up and move to secondary follow-up due to reasons including: treatment failure, relapse 
after remission, pursuing SCT while in remission, or withdrawal from the primary follow-up 
(See Figure 7-1 below).
In each table, required assessments are indicated with an “X”, and the visits when they are 
performed. The letter (D) under the category column indicates the assessments that will have 
data entered into the clinical database and (S) is for assessments that will have data remain as 
source documentation. All data obtained from these assessments must be supported in the 
patient’s source documentation. No CRF will be used as a source document.

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Figure 7-1
Potential patient flow scenarios

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Table 7-1
Visit evaluation schedule: treatment and primary follow-up
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Obtain Informed 
Consent/Assent
D
11.3.
X
IWRS/IRT
S
7.1.1.1.
X
X
X
X
X
X
X
X
X
X
M3 & 
M6 
only
X
Patient history
Demography
D
7.1.1.
X
Inclusion/exclusion criteria D
5.2.
5.3.
X
Medical history
D
7.1.1.
X
Diagnosis and extent of 
cancer
D
7.1.1.
X
Cytogenetics/FISH/Tumor 
Immunophenotyping
D
7.1.1.
X

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Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Prior antineoplastic 
therapy
D
7.1.1.
X
Donor chimerism (prior 
allogeneic SCT patients 
only, or if unknown)
D
6.2.4.2.
7.1.1.
X
Prior/concomitant 
medications
D
6.2.6.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination (PE) S
7.2.1.1.
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status 
assessment
D
7.2.2.3.
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
D
7.2.2.2.
X
X
M6 
only
X
M12 
only
X
M18 
only
X
X
X
Tanner staging (only for 
patients < 18 years old)
D
7.2.2.
X
X
M6 
only
X
M12 
only
X
M18 
only
X
X
X

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Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Weight
D
7.2.2.2.
X
X
X
X
M3 & 
M6 
only
X
X
M18 
only
X
X
X
Vital signs
D
7.2.2.1.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PedsQL and EQ-5D 
Questionnaire
D
7.2.7.
X
X
X
M3 & 
M6 
only
X
X
M18 
only
X
X
Hospitalization status
D
7.2.6.
Hospitalizations from Screening to Month 2
Intervention
Leukapheresis/Apheresis
D
4.1.1
X
Leukapheresis/Apheresis 
pre-evaluation and 
acceptance
D
4.1.1
X
Lymphodepleting 
Chemotherapy
D
6.1.1.1.
X
Other chemotherapy while 
on study
D
6.2.6.
As clinically 
indicated

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Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
CTL019 infusion 
prerequisite assessment
S
6.1.1.2.
X
CTL019 T cell infusion
D
6.1.1.2.
X
Antineoplastic therapies 
after CTL019 infusion or 
study discontinuation
D
6.2.6.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.5.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab tests of special 
interest during CRS only 
(CRP, ferritin, fibrinogen, 
LDH, PT, aPTT, INR, D-
dimer)
D
7.2.2.5.
X
X
X
X
X
X
X
X
X
Serum pregnancy test
D
7.2.2.5.
X
X
X

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Serum or Urine pregnancy 
test
S
7.2.2.5
X
(Serum 
or 
Urine)
X
(Serum 
or 
Urine)
X
Serum 
or 
Urine)
X 
(Serum 
or 
Urine)
X
(Serum 
or 
Urine)
X
(Serum 
or 
Urine)
X (Serum)
HIV Test
D
7.2.2.5.
X
Hepatitis B and C
D
7.2.2.5.
X
Influenza A and B
D
6.1.1.2.
7.1.2.
Within 10 days of 
infusion
Coagulation factors (PT, 
aPTT, INR, fibrinogen, D-
dimer)
D
7.2.2.5.
X
X
X
X
X
X
Serum immunoglobulin 
levels (IgG, IgA, IgM)
D
7.2.2.5.
X
X
X
X
M3 & 
M6 
only
X
MUGA/ECHO
D
7.1.1.
X
Electrocardiogram (ECG)
D
7.1.1.
X
X
Urinalysis
D
7.2.2.5.
X

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Pulse oximetry
D
7.2.2.1.
X
X
Disease Assessments
Bone Marrow biopsy and 
aspirate morphology
D
7.2.1.
X
X
If patient is not in CR/CRi at D28, then 
required at the first time clinical evidence of 
remission is seen by blood and PE.
For patients in CR/CRi, Month 3 and 6 
recommended but not required
EOI local MRD
assessment in bone
marrow aspirate
D
7.2.1
X
MRD assessment in bone 
marrow aspirate by flow 
cytometry (includes 
normal B cell counts and 
CD19 status)
D
7.2.1.
X
X
If patient is not in CR/CRi at D28, then 
required at the first time clinical evidence of 
remission is seen by blood and PE.
For patients in CR/CRi, Month 3 and 6 
recommended but not required
MRD assessment in bone 
marrow aspirate by qPCR
D
7.2.1.
X
X
If patient is not in CR/CRi at D28, then 
required at the first time clinical evidence of 
remission is seen by blood and PE.
For patients in CR/CRi, Month 3 and 6 
recommended but not required

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Tumor cell assessment by 
flow cytometry of 
peripheral blood (includes 
normal B cell counts and 
CD19 status)
D
7.2.1.
X
X
X
X
X
X
M3 & 
M6 
only
X
X
M18 
only
X
X
X
Lymph node or other 
involved tissue aspirate or 
biopsy
D
7.2.1.
As clinically indicated
CSF assessment by 
lumbar puncture
D
7.2.1.
X
X
If patient is not in CR/CRi at D28, then 
required at the first time clinical evidence of 
remission is seen by blood and PE. Otherwise, 
as clinically indicated by the presence of 
neurologic symptoms.
CNS Brain Imaging 
(MRI/CT)
S
7.2.1.
As clinically indicated
Extramedullary disease 
assessment (physical 
exam and CNS symptom 
assessment)
D
7.2.1.1.
7.2.1.2.
X
X
X
X
X
X
X
X

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Safety
Adverse events
D
8.1.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancies and 
menstrual status
S
7.2.2.
7.2.2.5
X
X
X
X
X
X
X
X
Immunogenicity (serum)
D
7.2.2.5.
10.5.3.4.
X
X
X
X
M3 & 
M6
only
X
M12 
only
X M24 only (Cohort 1 and 
Cohort 2)
If patient relapses at any time 
point (before or after Month 
24), then immunogenicity 
sample collection required at 
relapse visit.
Immunogenicity 
(peripheral blood)
D
7.2.2.4.
10.5.3.4.
X
X
X
X
M3 & 
M6 
only
X
M12 
only
X M24 only (Cohort 1 and 
Cohort 2)
If patient relapses at any time 
point (before or after Month 
24), then immunogenicity 
sample collection required at 
relapse visit.

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
RCL by VSV-G q-PCR 
(peripheral blood)
D
6.2.4.3.
X
X
M3 & 
M6 
only
X
M12 
only
X
X
Biomarkers
Cytokines (serum)
D
7.2.4.
X
X
X
X
X
X
X
X
X
M3 & 
M6 
only
X
M12 
only
CRS assessments by 
peripheral blood (anti-
cytokine therapy PK, 
CTL019 PK, cytokines, IL-
6R and inflammatory 
markers)
D
7.1.3.
As clinically indicated dependent upon the presence and time-course of CRS and 
administration of anti-cytokine therapies – refer to Table 7-7, Table 7-8, Table 7-15, Table 7-
16, Table 7-17.
CTL019 pharmacokinetics 
by q-PCR (peripheral 
blood)
D
7.2.3.
X
X
X
X
X
X
X
X
X
M3 & 
M6 
only
X
X
M18 
only
X
X
X

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
CTL019 pharmacokinetics 
and normal T cells by flow 
cytometry (peripheral 
blood)
D
7.2.3.
X
X
X
X
X
X
X
X
M3 & 
M6 
only
X
X
M18 
only
X
X
X
CTL019 pharmacokinetics 
by q-PCR (bone marrow 
aspirate)
D
7.2.3.
X
X
If patient is not in CR/CRi at D28, then 
recommended at the first time clinical 
evidence of remission is seen by blood and 
PE. For patients in CR/CRi, Month 3 and 6 
recommended but not required
CTL019 pharmacokinetics 
by flow cytometry (bone 
marrow aspirate)
D
7.2.3.
X
X
If patient is not in CR/CRi at D28, then 
recommended at the first time clinical 
evidence of remission is seen by blood and 
PE. For patients in CR/CRi, Month 3 and 6 
recommended but not required
CTL019 pharmacokinetics 
by q-PCR (CSF)
D
7.2.3.
X
X
If patient is not in CR/CRi at D28, then 
recommended at the first time clinical 
evidence of remission is seen by blood and 
PE. For patients in CR/CRi, Month 3 and 6 
recommended but not required

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
CTL019 
Immunophenotyping by 
flow cytometry (peripheral 
blood)
D
7.2.4.
X
X
X
X
X
X
M3 & 
M6 
only
X
X
M24 & 
M36 
only

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol Reference Section
Screening
Pre-Treatment Treatment and Primary Follow-up
Survival 
Follow-up
Visit Name
Screening
Enrollment/Pre-
chemotherapy
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post infusion
End of Treatment & 
Primary Follow-up
Survival Follow-up 
After study 
completion
Study Day
W-16 
to
W-12
W-
16 
to
D-1
D-
14 
to
D-2
D-1
+1d D1 D2 D4
±1d
D7
±1d
D11
±1d
D14
±3d
D17
±3d
D21
±3d
D28
±4d
M2 M3 
M4 M5 
M6 
±14d
M9 
M12 
±14d
M15 
M18 
M21 
±14d
M24 
M36 
M48 
±14d
M30 
M42 
M54 
±14d
M60 
±14d
q3m
±14d
Apheresis sample for 
correlative studies
D
7.2.4.
X
CTL019 cell product 
sample for correlative 
studies
D
7.2.4.
X
Survival follow-up
D
7.1.5.
For all patients who receive a CTL019 infusion, follow-up for survival every 3 months until 
end of study or enrolling into the long term follow-up, whichever comes first. If a patient 
misses a quarterly scheduled visit where survival status is required, or if the time-point 
does not align with a scheduled visit, survival status can be obtained via phone contact.
X
End of Phase 
Disposition
D
N/A
X
X
X

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Table 7-2
Visit evaluation schedule: secondary follow-up
For patients who end their primary follow-up before month 60:
Phase
Category
Protocol 
Reference 
Section
Secondary Follow-up
Survival 
Follow-up
Visit Name
Post Infusion
End of 
Secondary 
Follow-up
Survival 
Follow-up 
after study 
completion
Study Day
M2
±14d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M24
±14d
M36
±14d
M48
±14d
M60
±14d
q3m
±14d
Patient History
Concomitant medications 
(selected)
D
7.1.4.1.
X
X
X
X
X
First antineoplastic therapy after 
CTL019 infusion (only for 
patients in remission)
D
7.1.4.
For all patients who are in remission, the first antineoplastic therapy administered (first 
therapy including conditioning for cell therapy (CAR, SCT) plus cell therapy (CAR, SCT) 
should be reported.
Height
D
7.2.2.2.
X
X
X
X
X
Weight
D
7.2.2.2.
X
X
X
X
X
Tanner staging (only for patients 
< 18 years old)
D
7.2.2.
X
X
X
X
X
Efficacy assessments
Relapse information (only for 
patients in remission)
D
7.1.4.
For all patients who are in remission, relapse status should be assessed every 3 months 
until first relapse (if applicable). If a patient misses an annual scheduled visit where 
relapse status is required, or if the time-point does not align with a scheduled visit, relapse 
status can be obtained remotely.
Safety assessments
Protocol defined adverse events, 
including new malignancies and 
significant findings
D
7.1.4.
Protocol defined adverse events should be reported upon investigator knowledge which 
may not align with scheduled visits.
Serum or Urine pregnancy Test
S
7.2.2.5
X
(serum 
or 
urine)
X
(serum 
or 
urine)
X
(serum 
or 
urine)
X
(serum 
or 
urine)
X
(serum 
or 
urine)
X
(serum 
or 
urine)
X
(serum 
or 
urine)
X
(serum 
or 
urine)
X (serum)

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
Phase
Category
Protocol 
Reference 
Section
Secondary Follow-up
Survival 
Follow-up
Visit Name
Post Infusion
End of 
Secondary 
Follow-up
Survival 
Follow-up 
after study 
completion
Study Day
M2
±14d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M24
±14d
M36
±14d
M48
±14d
M60
±14d
q3m
±14d
Pregnancies and menstrual 
status
D
7.2.2.
X
X
X
X
X
Hematology
S
7.2.2.5.
X
X
X
X
X
Physical examination (PE)
S
7.2.1.1.
X
X
X
X
X
CTL019 transgene persistence 
(peripheral blood)
D
7.2.3.
X
X
X
X
X
X
X
X
Flow Cytometry of peripheral 
blood (B cell, T cell levels
D
7.2.1.
X
X
X
X
X
X
X
X
RCL by VSV-G q-PCR 
(peripheral blood)
D
6.2.4.3.
X
X
X
X
X
X
X
Immunogenicity (serum)
D
7.2.2.5.
10.5.3.4.
X
X
X
X 
(Cohort 
1 and 
Cohort 
2)
Immunogenicity (peripheral 
blood)
D
7.2.2.4.
10.5.3.4.
X
X
X
X 
(Cohort 
1 and 
Cohort 
2)
Survival follow-up
D
7.1.5.
For all patients who receive a CTL019 infusion, follow-up for survival every 3 months until 
end of study or enrolling into the long term follow-up, whichever comes first. If a patient 
misses a quarterly scheduled visit where survival status is required, or if the time-point 
does not align with a scheduled visit, survival status can be obtained via phone contact.
X
End of phase disposition
D
N/A
X

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202
7.1.1
Screening Phase
Anti-microbial prophylaxis treatment in these immunosuppressant relapsed/refractory ALL 
patients should be considered per local institutional guidelines at study entry or prior to 
lymphodepleting chemotherapy.
Only following confirmation of all clinical eligibility criteria (defined as all inclusion/exclusion 
criteria except that which pertains to the leukapheresis product) will the patient’s leukapheresis 
product be shipped to the manufacturing facility. The manufacturing facility will then evaluate 
the patient’s leukapheresis product for acceptance.
Patients should not be enrolled if they are unwilling to be followed up long-term i.e. 15 year 
follow up as required by the health authorities for cell and gene therapy products.
CTL019 infusion should occur within 16 weeks of informed consent.
Patients who have signed an informed consent/assent will undergo a routine leukemia staging 
workup including:
a. Demography
b. Medical history (including diagnosis and extent of cancer and any prior history of CNS 
leukemia involvement) and prior/concomitant medications and antineoplastic therapies
c. Physical Examination (PE) including height, weight, GVHD assessment, Tanner staging 
(only for patients < 18 years old), vital signs, extramedullary disease assessment and CNS 
symptom assessment
d. Performance status (Karnofsky [age ≥16 years] or Lansky [age < 16 years]) at the time of 
screening
e. Standard ALL cytogenetics, FISH, and tumor immunophenotyping by flow cytometry 
analysis required (at the time of most recent relapse). If not available, test must be 
performed at screening.
f.
Donor Chimerism (within 3 months of screening, prior allogeneic SCT patients only, or if 
unknown)
g. Complete Blood Count, Differential
h. Chemistry Panel
i.
Coagulation panel
j.
Urinalysis
k. Serum pregnancy test (if WOCBP)
l.
HIV Testing (test within 8 weeks of screening) – If an initial HIV screening test is positive 
then a confirmatory HIV test is required to be performed as per current local guidelines
m. Hepatitis B and Hepatitis C test (test within 8 weeks of screening; see Appendix 2 for 
interpretation of Hepatitis B results)
n. Serum immunoglobulin levels (IgG, IgA, IgM)
o. MUGA or ECHO (performed within 6 weeks of infusion) for LVSF/LVEF
p. ECG
q. Pulse oximetry
r.
Bone marrow aspirate and biopsy for:

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Amended Protocol Version 07 (Clean)
Protocol No. CCTL019B2202

Morphologic blast enumeration

Flow cytometry (B-cell numbers, tumor cell numbers, MRD assessment (including Local 
Assessment with protocol amendment 6 at EOI), CD19 assessment, and CTL019 
immunophenotyping)

CTL019 PK (qPCR and flow cytometry)
s.
Peripheral blood collection for flow cytometry (B and T-cell numbers, tumor cell 
numbers, and CD19 assessment)
t.
Lymph node or tissue aspirate or biopsy (if clinically indicated)
u. Lumbar Puncture (LP) for CSF cytologic assessment and CTL019 PK (by q-PCR)
v. CNS Brain Imaging (MRI/CT) (if clinically indicated)
w. Adverse events
7.1.1.1
Eligibility screening and enrollment
For detailed enrollment procedures, including use of Interactive Response Technology (IRT), 
please refer to the [IRT User Manual].
Once clinical eligibility has been confirmed, only then can the patient’s apheresis product be 
shipped to the manufacturing facility. The manufacturing facility will then evaluate the patient’s 
apheresis product for acceptance and notify the site. Enrollment is defined as the point at which 
a patient meets all clinical inclusion/exclusion criteria and the patient’s apheresis product is 
received and accepted by the manufacturing facility. The patient is then enrolled using the same 
Subject No. assigned at screening by the site investigator or designated staff. Once assigned, 
the Subject No. must not be reused for any other patient and the Subject No. for that individual 
must not be changed. If a screened patient is not enrolled for any reason, the specific reason 
will be entered into the clinical database.
IRT Registration: To document screening and enrollment into the study, the IRT will be 
contacted initially after informed consent/assent is obtained and again after eligibility is 
confirmed.
7.1.1.2
Information to be collected on screening failures
The reason for not being enrolled will be entered in the clinical database. The demographic 
information, informed consent/assent, Inclusion/Exclusion pages, any adverse events leading to 
subject discontinuation, and any adverse events that meet reporting criteria in Appendix 3: 
CTL019 Modified Data Reporting must also be completed for patients not enrolled. No other 
data will be entered into the clinical database for patients who are not enrolled.
7.1.2
Pre-Treatment Phase
For details of assessments, refer to Table 7-1.

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Enrollment/Pre-chemotherapy evaluation visit (W-16 to D-1)
Before the scheduled lymphodepleting chemotherapy regimen is to begin, the patient will 
undergo blood collection for safety and biomarker assessments (including CTL019 PK, 
immunophenotyping 
 humoral & cellular immunogenicity and RCL by 
VSV-G qPCR). These draws can be collected at any time after informed consent is signed up 
until before the lymphodepleting chemotherapy is scheduled. In addition, adverse events and 
prior/concomitant medications will be reviewed. Viably frozen samples from the leukapheresis 
material as well as the CTL019 product will be collected at the manufacturing site for 
correlative studies. In addition, the Patient Reported Outcome questionnaires should be 
completed at the time of enrollment. Under extenuating circumstances where the baseline PRO 
questionnaire(s) was not completed at enrollment, it must be completed before the 
administration of LD chemotherapy or the CTL019 infusion if LD chemotherapy is not 
administered.
Lymphodepleting chemotherapy visit (D-14 to D-2)
It is anticipated that many patients will have been receiving chemotherapy for relapse or 
resistant disease. For inclusion they will have responding or stable disease to the most recent 
therapy. Prior to CTL019 cell infusion and after leukapheresis, an additional chemotherapy 
cycle is planned. Patients referred with stable disease on no recent therapy will be eligible as 
well. The use of additional chemotherapy prior to the recommended preinfusion chemotherapy 
will be at the discretion of the investigator and dependent on the patient’s disease burden. In 
addition for patients in Cohort 1 and Cohort 2, serum pregnancy test will be performed on
WOCBP confirming a negative pregnancy result.
When given, lymphodepleting chemotherapy should be started before CTL019 infusion so that 
these cells will be given 2 to 14 days after completion of the lymphodepleting chemotherapy. 
The timing of chemotherapy initiation therefore depends on the length of the regimen. The 
purpose of the chemotherapy is to induce lymphopenia in order to facilitate engraftment and 
homeostatic expansion of CTL019 cells. Fludarabine (30 mg/m2 i.v. daily for 4 doses) and 
cyclophosphamide (500 mg/m2 i.v. daily for 2 doses starting with the first dose of fludarabine) 
is the regimen of choice, as there is the most experience with the use of this regimen in 
facilitating adoptive immunotherapy. Refer to Section 2.2.1 for additional information 
regarding lymphodepleting chemotherapy.
If patients have a WBC count ≤ 1,000 cells/µL within one week prior to CTL019 infusion, 
lymphodepleting chemotherapy is NOT required. If the time between lymphodepleting 
chemotherapy and CTL019 infusion exceeds 4 weeks, lymphodepleting chemotherapy will be 
repeated only if the patients WBC count is >1,000 cells/µL.
Patients will also undergo blood tests including chemistry, a coagulation panel, and a CBC with 
differential. In addition, adverse events and prior/concomitant medications will be reviewed.
Pre-infusion visit (D-1 +1d)
On the day prior to or day of the scheduled CTL019 infusion, patients will undergo a physical 
exam (including weight and vital signs) and a performance status assessment (Karnofsky (age 
≥16 years) or Lansky (age < 16 years). In addition, serum pregnancy test will be performed on

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WOCBP
confirming a negative pregnancy result. In addition, adverse events and 
prior/concomitant medications will be reviewed.
Note: All patients must undergo a rapid influenza diagnostic test within 10 days prior to the 
planned CTL019 infusion. If the patient is positive for influenza, he/she should complete a full 
course of oseltamivir phosphate or zanamivir as described in the label (see Tamiflu® or 
Relenza® package insert for dosing). The patient must complete their full course of treatment 
prior to receiving CTL019. The test does not need to be repeated prior to CTL019 infusion 
however if flu-like or respiratory signs and symptoms are present, CTL019 infusion should be 
delayed until the patient is asymptomatic. For patients residing in the United States, Canada, 
Europe, and Japan, influenza testing is required during the months of October through May, 
inclusive. For patients residing in the Southern Hemisphere such as Australia, influenza testing 
is required during the months of April through November, inclusive. For patients with 
significant international travel, both calendar intervals may need to be considered.
7.1.3
Treatment and Primary Follow-Up Phase
For details of assessments, refer to Table 7-1.
Infusion visit (D1)
CTL019 infusions will begin 2 to 14 days after lymphodepleting chemotherapy completion and 
within 16 weeks after obtaining informed consent. The time elapsed from informed consent to 
enrollment should not exceed 4 weeks, and enrollment to infusion should not exceed 12 weeks. 
The total window between informed consent and CTL019 infusion must not exceed 16 weeks. 
If this window exceeds 16 weeks, the case must be discussed and approved by the Sponsor in 
order to allow for CTL019 product to be infused.
The day of (but prior to) the CTL019 infusion, patients will undergo blood tests including 
chemistry, a CBC with differential, a coagulation panel and serum cytokines. Final CTL019 
infusion pre-requisites (including an ECG and a rapid influenza test) will be checked prior to 
infusion (per Section 6.1.1.2).
CTL019 transduced T cells will be given as a single dose of 0.2 to 5.0 x 106 CTL019 transduced 
viable T cells per kg body weight (for patients ≤ 50 kg) and 0.1 to 2.5 x 108 CTL019 transduced 
viable T cells (for patients > 50 kg). Vital signs will be monitored before and following CTL019 
infusion (per Section 6.1.1.2). Blood samples will be collected post-infusion for CTL019 PK 
assessment. In addition, adverse events and prior/concomitant medications will be reviewed.
Details on the administration of the CTL019 infusion are found in Section 6.1.1.2.
For all patients who receive a CTL019 infusion, additional follow-up will be made to determine 
survival every 3 months. If a patient misses a quarterly scheduled visit where survival status is 
required, or if the quarterly time-point where survival status is required does not align with a 
scheduled visit, survival status can be obtained via phone contact.
Post-infusion visits: D2, D4±1d, D7±1d, D11±1d, D14±3d, D17±3d, D21±3d
At the intervals following infusion listed above, patients will undergo one or more of the 
following: blood tests including chemistry, lab tests of special interest during CRS only (CRP, 
ferritin, fibrinogen, LDH, PT, aPTT, INR, D-dimer), hematology, coagulation, serum 

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immunoglobulin, humoral & cellular immunogenicity, serum cytokines, CTL019 PK, 
immunophenotyping, flow cytometry (B and T cells, tumor cells and CD19 assessment), a 
physical exam (with vital signs) and performance status assessment. In addition, adverse events 
and prior/concomitant medications will be reviewed. On Day 2, only vital signs, physical 
examination, a performance status assessment, serum cytokines, hematology, and chemistry 
(inclusive of LFTs and creatinine) will be performed.
Sample collections for serum cytokines, CTL019 PK, and inflammatory markers (e.g. ferritin 
and CRP) are mandated during the first 28 days following CTL019 infusion. However, as the 
time-course and rapidity of CRS development varies among patients, additional unscheduled 
samples that might better parallel these individual differences may also be collected as needed, 
if it is clinically feasible. Frequent monitoring of serum CRP, ferritin, and cytokines should be 
considered during the clinical course of CRS of any severity (e.g. every day to several days) 
especially around the following clinical events: initial persistence of fevers, hemodynamic 
instability, initial and worsening of respiratory distress, rapid clinical deterioration, just prior to 
and daily for 2 days following tocilizumab administration, around other clinically significant 
events and upon the clinical resolution of CRS.
Please note that results of cytokine analyses are NOT to be used for clinical management 
decisions of CRS. A detailed treatment algorithm has been established with clear criteria for 
CRS management (see Table 6-1).
For details of assessments at each visit, refer to Table 7-1.
Post-infusion visit (D28 ±4d)
Patients will undergo blood collection for hematology, chemistry, lab tests of special interest 
during CRS only (CRP, ferritin, fibrinogen, LDH, PT, aPTT, INR, D-dimer), coagulation, 
serum immunoglobulins, cytokines, flow cytometry (B and T cells, tumor cells, and CD19 
assessment) humoral and cellular immunogenicity, CTL019 PK, immunophenotyping 
 
Patients will have a lumbar puncture for CSF cytologic assessments and 
CTL019 PK. Patients are required to have a bone marrow biopsy and aspirate for morphology, 
flow cytometry, MRD, CTL019 PK 
. In addition, patients will undergo 
a physical exam (including vital signs, weight, and extramedullary disease assessment), CNS 
symptom assessments and a performance status assessment. Tumor response assessments will 
be conducted (see Appendix 1 for response guidelines). A lymph node or tissue aspirate or 
biopsy may be done if clinically indicated. Adverse events and prior/concomitant medications 
will be reviewed. Serum or urine pregnancy test will be done for WOCBP until contraception 
is no longer required (see exclusion criteria #20).  
For details of assessments, refer to Table 7-1.
Post-infusion visits (M2 ±14d, M3 ±14d, M4 ±14d, M5 ±14d, M6 ±14d)
At the intervals following infusion listed above, patients will undergo one or more of the 
following: blood collection for hematology, chemistry, serum immunoglobulins, flow 
cytometry (B and T cells, tumor cells, and CD19 assessment), cytokines, humoral & cellular 
immunogenicity and CTL019 PK, immunophenotyping, 
, and RCL by 
VSV-G qPCR. In addition, patients will undergo a physical exam (including vital signs, height, 
weight, Tanner staging (only for patients < 18 years old), and extramedullary disease 

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the frequency of integration events in regions with known relationships to human cancers (i.e. 
near oncogenes). If integration site analysis reveals mono- or oligo-clonality pattern and/or 
integration at or near an oncogenic locus, a monitoring plan, including follow-up molecular 
analyses, will be developed in collaboration between the Investigator, Sponsor and Health 
Authorities that is specific for the health care risks that are anticipated given the nature of the 
integration site and vector target cell type.
Post-infusion visit (M15 ±14d, M18 ±14d, M21 ±14d)
Patients will undergo the following: blood collection for hematology, chemistry and CTL019 
PK. Blood will be collected for flow cytometry (B and T cells, tumor cells) at M18 only. In 
addition, patients will undergo a physical exam (including height, weight and Tanner staging at 
M18 only), vital signs, extramedullary disease assessment, CNS symptom assessment and a 
performance status assessment. Adverse events and prior/concomitant medications will be 
reviewed. Any pregnancies will be reported. Serum or urine pregnancy test will be done for
WOCBP until contraception is no longer required (see exclusion criteria #20).  
Post-infusion visit (M24 ±14d, M30 ±14d, M36 ±14d, M42 ±14d, M48 ±14d, M54 ±14d)
Patients will undergo the following: blood collection for hematology, chemistry and CTL019 
PK. Blood will be collected for flow cytometry (B and T cells, tumor cells) and RCL by VSV-
G qPCR annually at M24, M36 and M48 only. If RCL testing was negative through Month 12, 
all samples taken after Month 12 will be stored for potential future testing.
Blood will be 
collected for CTL019 immunophenotyping. In addition, patients will undergo a physical exam 
[including height, weight and Tanner staging (only for patients < 18 years old)], vital signs, 
extramedullary disease assessment, CNS symptom assessment and a performance status 
assessment. Adverse events and prior/concomitant medications will be reviewed. Any 
pregnancies will be reported.
For all patients who receive a CTL019 infusion, follow-up for survival every 3 months until 
end of study or enrolling into the long term follow-up, whichever comes first, is required. If a 
patient misses a quarterly scheduled visit where survival status is required, or if the quarterly 
time-point where survival status is required does not align with a scheduled visit, survival status 
can be obtained via phone contact. Serum or urine pregnancy test will be done for WOCBP
until contraception is no longer required (see exclusion criteria #20).  
7.1.3.1
End of Treatment and Primary Follow-Up (EOT) visit (M60 ± 14d) 
including premature withdrawal
The End of Treatment and Primary Follow-Up (EOT) visit for each patient will be 60 months 
(5 years) from the date of their infusion if they complete all scheduled visits. If a patient 
discontinues early from the primary follow-up, a visit should be scheduled as soon as possible, 
at which time all of the assessments listed for the Month 60 visit will be performed. An End of 
Treatment and Primary Follow-Up Disposition Case Report/ Record Form (CRF) page should 
be completed, giving the date and reason for stopping the study.
During the End of Treatment and Primary Follow-Up visit, patients will undergo the following: 
blood collection for hematology, chemistry, CTL019 PK, flow cytometry (B and T cells, tumor 
cells) and RCL by VSV-G qPCR. If RCL testing was negative through Month 12, all samples 
taken after Month 12 will be stored for potential future testing.
In addition, patients will 

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undergo a physical exam [including height, weight and Tanner staging (only for patients < 18 
years old)], vital signs, extramedullary disease assessment, CNS symptom assessment and a 
performance status assessment. Adverse events and prior/concomitant medications will be 
reviewed.  Serum pregnancy test will be performed on WOCBP confirming a negative 
pregnancy result. Any pregnancies will be reported.
Following completion of the Treatment and Primary Follow-Up, patients will be followed for 
survival until the end of the study as defined in Section 4.2 (Section 7.1.5). Patients who 
discontinue or withdraw from the Treatment and Primary Follow-Up early will be asked to 
continue the study in the Secondary Follow-up Phase through Month 60.
7.1.3.2
Criteria for premature patient withdrawal from Treatment and Primary 
Follow-Up Phase
Patients must be followed according to the visit schedule for the Treatment and Primary Follow-
Up to ensure adequate data are collected for the proper assessment of study primary and 
secondary objectives. It is strongly recommended that patients that remain in remission be 
followed in the Treatment and Primary Follow-Up Phase for at least one year at a minimum at 
the treating investigational site to ensure adequate safety and efficacy data collection. Patients 
may voluntarily withdraw from the Treatment and Primary Follow-Up Phase or be dropped 
from it at the discretion of the investigator at any time. It is anticipated that patients may leave 
the primary follow-up and move to Secondary Follow-Up due to reasons including:

Treatment failure

Relapse after remission

Pursuing HSCT while in remission

Patient voluntary withdrawal from the primary follow-up
For patients who are lost to follow-up, the investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g., dates of telephone 
calls, registered letters, etc.
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:
* Does not want to participate in the study anymore, and 
* Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information. No further assessments conducted, and the data that would have been 
collected at subsequent visits will be considered missing. Further attempts to contact the patient 
are not allowed unless safety findings require communicating or follow-up. All efforts should 
be made to complete the assessments prior to study withdrawal. A final evaluation at the time 
of the patient’s study withdrawal should be made as detailed in the assessment table. Novartis 
will continue to keep and use collected study information (including any data resulting from the 
analysis of a patient’s samples until their time of withdrawal) according to applicable law. 

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During the secondary follow-up phase, patients may be monitored remotely by their health care 
provider or at the investigational site. Patients will undergo one or more of the following at each 
visit according to Table 7-2: Blood collection for hematology, CTL019 transgene persistence, 
flow cytometry (B and T cells) and RCL by VSV-G qPCR. If RCL testing is negative through 
Month 12, all samples taken after Month 12 will be stored for potential future testing.
In 
addition, patients will undergo a physical exam [including height, weight and Tanner staging 
(only for patients < 18 years old)]. If a patient still in remission cannot attend a regularly 
scheduled visit during the secondary follow-up, the investigator should attempt to determine 
relapse status and if the patient receives additional antineoplastic therapies at a minimum.
Adverse events and prior/concomitant medications will be maintained and assessed by the 
investigational site including emergence of new clinical conditions (see Section 7.1.4.1) and 
mutagenic agents (cytotoxic drugs, radiation therapy, antineoplastic therapy, and stem cell 
transplant). If patient is monitored remotely, the investigator will request this information from 
the patient’s health care provider.
Any pregnancies will be reported. Serum or urine pregnancy test will be done for WOCBP until 
contraception is no longer required (see exclusion criteria #20). A serum pregnancy test will be 
done for all WOCBP at M60/EOT (Month 60/End of Trial) visit.Efficacy will be assessed in 
patients who are still in remission until relapse. For these patients, relapse status will be assessed 
at each visit per Table 7-2 and recorded in the clinical database.
For all patients who receive a CTL019 infusion, follow-up for survival every 3 months until 
end of study or enrolling into the long term follow-up, whichever comes first, is required. If a 
patient misses an annual scheduled visit where survival status is required, or if the time-point 
where survival status is required does not align with a scheduled visit, survival status can be 
obtained via phone contact with the patient or correspondence with local health care provider.
For details of assessments, refer to Table 7-2.
7.1.4.1
Adverse event and concomitant medication reporting during 
Secondary Follow-Up Phase
In order to monitor delayed adverse events per Health Authority guidance, selected adverse 
events/serious adverse events and concomitant medications will be recorded in the clinical 
database upon investigator knowledge as follows:
Adverse Events/Serious Adverse Events

New incidence or exacerbation of a pre-existing neurological disorder

New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder

New incidence of other hematologic disorders

Any severe adverse event or condition the investigator believes may have a reasonable 
relationship to CTL019 therapy

Any severe adverse event or condition that is unexpected and the investigator assess a 
reasonable relationship to CTL019 therapy

Positive RCL test result

Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a 
location near a known human oncogene

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
New malignancy, other than primary malignancy

Progressive multifocal leukoencephalopathy (PML)

Hepatitis B reactivation
Concomitant Medications

Intravenous Immunoglobulin

For all patients who are in remission, the first antineoplastic therapy administered (first 
therapy including conditioning for cell therapy (CAR, SCT) plus cell therapy (CAR, SCT) 
should be reported.

Data to support adverse events may be requested.
Please refer to Appendix 4: CTL019 Modified Data Reporting – Secondary Follow Up Phase 
for reporting.
7.1.4.1.1 Serious adverse event definition
Serious adverse event (SAE) in the Secondary Follow Up phase is defined as one of the 
following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event

Positive RCL test result

Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a 
location near a known human oncogene

New malignancy (T-cell & non T-cell), other than primary malignancy

Progressive multifocal leukoencephalopathy (PML)

Hepatitis B reactivation

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7.1.4.2
Criteria for premature patient withdrawal from the study
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients lost to follow up should be recorded as such on the CRF. For 
patients who are lost to follow-up, the investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g., dates of telephone 
calls, registered letters, etc.
Patients may be withdrawn from the study if any of the following occur:
a. The patient is lost to follow-up
b. Patient noncompliance with study therapy and/or clinic appointments
c. Voluntary withdrawal; a patient may remove himself/herself from the study at any time 
without prejudice.
d. Termination of the study by the sponsor or the health authorities
Novartis will continue to retain and use all research results that have already been collected for 
the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations).
7.1.5
Survival Follow-Up Phase
The survival phase intent is to collect survival data on patients that have completed the study. 
For all patients who complete the primary follow-up phase through 5 years, or complete the 
secondary follow-up phase through 5 years, additional follow-up will be made to determine 
survival every 3 months until end of study as defined in Section 4.2, or the patient is enrolled 
in the long term follow-up study, whichever occurs first. Survival status can be obtained via 
phone contact with the patient or correspondence with local health care provider.  For all 
patients who are in remission, the first antineoplastic therapy administered (first therapy 
including conditioning for cell therapy (CAR, SCT) plus cell therapy (CAR, SCT) should be 
reported.
7.1.6
Long-Term Follow Up
As a single administration study, patients are followed on study for 5 years post-infusion for 
safety and efficacy evaluations. A long term post-study follow-up for lentiviral vector safety 
will continue under a separate destination protocol. Patients will continue to be followed until 
15 years post-CTL019 infusion per health authority guidelines.
Under the long term follow-up protocol, 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 automatically enrolled in this 
destination protocol at the time of study completion/discontinuation (separate informed 
consent/assent forms will be provided for this protocol). One to two times a year patients will 
visit the clinical site for a physical exam and medical history (including concomitant 
medications and adverse events) with careful attention to features possibly related to lentiviral 
associated events such as new malignancies, new incidence or exacerbation of a pre-existing 
neurologic disorder, new incidence or exacerbation of a prior rheumatologic or other 
autoimmune disorder, or new incidence of other hematologic disorders. In addition, labs will 

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be drawn to evaluate routine safety endpoints, CTL019 vector persistence and RCL. If RCL 
testing was negative through Month 12, all samples taken after Month 12 will be stored for 
potential future testing.
7.2
Assessment types
7.2.1
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).
An Independent Review Committee (IRC) appointed by Novartis will review data related to 
disease response assessment according to the Novartis guideline (Appendix 1). The IRC 
assessment will be used for the primary efficacy analysis. The local investigator assessments 
will be used for sensitivity analysis for select efficacy endpoints.
Table 7-3
Imaging or disease assessment collection plan – Primary Follow-up 
Phase
Procedure
Screening / 
Pre-infusion
Post-infusion Assessments
Bone marrow aspirate and biopsy 
for morphologic blast cell counts
Mandated
Mandated: Month 1 (Day 28). If patient is not in CR/CRi at 
Month 1, then required at the first time clinical evidence of 
remission is seen by peripheral blood and extramedullary 
disease assessment (physical exam and CNS symptoms)
Recommended (but not required) at month 3 and 6 and as 
clinically indicated
Peripheral blood for morphologic 
blast, neutrophil and platelet cell 
counts
Mandated
Mandated: Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24, 30, 
36, 42, 48, 54 and 60 (EOT)
Lymph node or other involved 
tissue aspirate or biopsy
As clinically 
indicated
As clinically indicated
CSF Assessment/Lumbar puncture 
for CNS disease
Mandated
Mandated: Month 1 (Day 28). If patient is not in CR/CRi at 
Month 1, then required at the first time clinical evidence of 
remission is seen by peripheral blood and extramedullary 
disease assessment (physical exam and CNS symptoms)
Additional CSF assessments as clinically indicated
MRD assessments (bone marrow 
aspirate)
Mandated
Mandated: Month 1 (Day 28). If patient is not in CR/CRi at 
Month 1, then required at the first time clinical evidence of 
remission is seen by peripheral blood and extramedullary 
disease assessment (physical exam and CNS symptoms)
Recommended (but not required) at month 3 and 6 and as 
clinically indicated
CNS Brain Imaging (CT/MRI)
As clinically 
indicated
As clinically indicated
Extramedullary disease 
assessment (physical exam and 
CNS symptom assessment)
Mandated
Mandated: Months 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24, 30, 
36, 42, 48, 54 and 60 (EOT)
Flow Cytometry of peripheral blood 
(B and T cell, tumor cell, CD19 
assessment)
Mandated
Mandated: Days 7, 14, and 21, and Months 1, 3, 6, 9, 12, 
18, 24, 30, 36, 42, 48, 54 and 60 (EOT)

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7.2.1.1
Physical examination
A targeted physical examination focusing upon sites of extramedullary disease involvement 
including assessments for hepatomegaly, splenomegaly, skin/gum infiltration, testicular masses 
and other disease manifestations are required. In addition, the physical examination will also 
include the assessments of general appearance, skin, neck, eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, and the neurological system. If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed.
Significant findings that were present prior to the signing of informed consent/assent must be 
included in the Medical History page on the patient’s CRF. Significant new findings that begin 
or worsen after informed consent/assent must be recorded on the Adverse Event page of the 
patient’s CRF. For visits where disease response is assessed (month 1, 2, 3, 4, 5, 6, 9, 12, 15, 
18, 21, 24, 30, 36, 42, 48, 54 and 60), assessment results will be recorded on the physical exam 
disease response CRF page.
7.2.1.2
CNS symptom assessments
Assessment of patient 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. If clinical 
signs of CNS leukemia exist, it must be confirmed by CNS imaging (CT or MRI of brain) or 
other relevant methods (e.g. biopsy, LP, etc.) to define CNS relapse. For visits where disease 
response is assessed (month 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, 21, 24, 30, 36, 42, 48, 54 and 60), 
assessment results will be recorded on the CNS disease response CRF page.
7.2.2
Safety and tolerability assessments
Safety will be monitored by physical examination, assessing immunogenicity against CTL019, 
lab abnormalities as well as collecting adverse events at every visit. For details on AE collection 
and reporting, refer to Section 8.
Tanner staging for patients less than 18 years of age will be updated semiannually in the 
treatment and primary follow-up phase, and annually in the secondary follow-up phase. If a 
patient is classified as Tanner Stage 5 at screening or at any point during the trial, no further 
Tanner staging will be required for the remainder of the trial. Female patient reproductive status 
(menstrual status and pregnancy information) will be updated monthly from month 2 through 
6, then quarterly through two years, then semiannually thereafter during the primary follow-up 
phase. Female patient reproductive status will be updated annually in the secondary follow-up 
phase.
7.2.2.1
Vital signs
Vital signs include temperature, blood pressure, pulse measurements, respiratory rate, and pulse 
oxygen.

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7.2.2.2
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing 
will be measured via a consistent method at each assessment.
7.2.2.3
Performance status
Table 7-4
Karnofsky/Lansky Performance Scales
Karnofsky Scale (age ≥ 16 years)
Lansky Scale (age < 16 years)
Able to carry on normal activity and to work; no special 
care needed.
Able to carry on normal activity; no special care is 
needed
100
Normal no complaints; no evidence of disease
100
Fully active
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
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly.
Moderate to severe restriction
40
Disabled; requires special care and assistance
40
Able to initiate quiet activities
30
Severely disabled; hospital admission is 
indicated although death not imminent
30
Needs considerable assistance for quiet 
activity
20
Very sick; hospital admission necessary; active 
supportive treatment necessary
20
Limited to very passive activity initiated by 
others (e.g. television)
10
Moribund; fatal processes progressing rapidly
10
Completely disabled, not even passive play
0
Dead
0
Unresponsive
7.2.2.4
Tanner staging (only for patients < 18 years old)
7.2.2.4.1 Males
Genitalia stages:
Stage 1: Pre-adolescent. Testes, scrotum, and penis are of about the same size and proportion 
as in early childhood.
Stage 2: The scrotum and testes have enlarged and there is a change in the texture of the scrotal 
skin. There is also some reddening of the scrotal skin.
Stage 3: Growth of the penis has occurred, at first mainly in length but with some increase in 
breadth. There has been further growth of testes and scrotum.
Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and 
scrotum further enlarged. There is also further darkening of the scrotal skin.

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Stage 5: Genitalia adult in size and shape. No further enlargement takes place after Stage 5 is 
reached.
Pubic hair stages:
Stage 1: Pre-adolescent. The velus over the pubesis no further developed than that over the 
abdominal wall, i.e. no pubic hair.
Stage 2: Sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, 
appearing chiefly at the base of the penis.
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the 
junction of the pubes.
Stage 4: Hair is now adult in type, but the area covered by it is still considerably smaller than 
in most adults. There is no spread to the medial surface of the thighs.
Stage 5: Hair distribution is adult in quantity and type and is described in the inverse triangle. 
Hair can be spread to the medial surface of the thighs.
7.2.2.4.2 Females
Breast stages:
Stage 1: Pre-adolescent; elevation of papilla only.
Stage 2: Breast bud stage; elevation of breast and papilla as a small mound, enlargement of 
areola diameter.
Stage 3: Further enlargement of breast and areola, with no separation of their contours.
Stage 4: Projection of areola and papilla to form a secondary mound above the level of the 
breast.
Stage 5: Mature stage; projection of papilla only, due to recession of the areola to the general 
contour of the breast.
Pubic hair stages:
Stage 1: Pre-adolescent; the vellus over the pubes is not further developed than that over the 
anterior abdominal wall, i.e. no pubic hair.
Stage 2. Sparse growth of long, slightly pigmented, downy hair, straight or only slightly curled, 
appearing chiefly along the labia.
Stage 3: Considerably darker, coarser, and more curled. The hair spreads sparsely over the 
junction of the pubes.
Stage 4: Hair is now adult in type, but the area covered by it is still considerably smaller than 
in most adults. There is no spread to the medial surface of the thighs.
Stage 5: Adult in quantity and type, distributed as an inverse triangle of the classically feminine 
pattern. Spread to the medial surface of the thighs, but not up the linea alba or elsewhere above 
the base of the inverse triangle.

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7.2.2.5
Laboratory evaluations
Screening and other laboratory assessments will be performed accordingly to Table 7-1 and 
Table 7-2. Note: Additional assessments should be performed between visits as clinically 
required to follow AEs or CTL019 expected events and for detailed modified data capture for 
inpatient/in hospital events, refer to Section 8.1.1. For all laboratory assessments that occur on 
Day 1, these should be performed prior to CTL019 infusion unless indicated otherwise.
The Investigator will evaluate the clinical significance of each applicable laboratory value 
outside of the reference range. This decision shall be based upon the nature and degree of the 
observed abnormality. Values which are considered clinically significant and/or study related 
to CTL019 will be noted. The Investigator may choose to repeat any abnormal result, in order 
to rule out laboratory error.
With respect to laboratory assessments listed within this protocol, please refer to the 
[Laboratory Manual] for further guidance on prioritizing sample acquisition when patient blood 
volume collection limitations exist.
Table 7-5
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean Corpuscular Hemoglobin Concentration (MCHC), MCV 
(Mean Corpuscular Volume), Platelets, Red blood cells, White blood cells with complete 
differential (Basophils, Eosinophils, Lymphocytes, Atypical Lymphocytes, Monocytes, 
Neutrophils, Lymphoblasts, Plasma cells, Prolymphocytes, Myelocytes, Metamyelocytes, 
and Promyelocytes)
Chemistry
Glucose (fasting or non-fasting), Blood Urea Nitrogen (BUN) or Urea, Creatinine, 
Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alkaline 
Phosphatase, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), 
Magnesium, Phosphorus, Lactate Dehydrogenase (LDH), Ferritin, C-reactive Protein 
(CRP) and Uric Acid.
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, pH, Protein, Specific Gravity)
If macroscopic panel is abnormal then perform microscopic panel (Red Blood Cells, 
White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Coagulation
Prothrombin time (PT) or International normalized ratio (INR), activated Partial 
thromboplastin time (aPTT), fibrinogen, and D-dimer
Pregnancy screen for
WOCBP
Urine or serum pregnancy test is required at all study office visits from Day 28 to the end 
of the study as long as contraception is required.  Serum testing is required at the 
timepoints specified in Table 7-1 and Table 7-2.
Viral Serology
Rapid Influenza A & B, Hepatitis C Virus (HCV) RNA qualitative test or antibody, 
Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (anti-HBc), Hepatitis B 
surface antibody (anti-HBs), HIV (if an initial HIV screening test is positive then a 
confirmatory HIV test is required to be performed as per current local guidelines)
CSF
White Blood Cells, Presence or absence of lymphoblasts, Red Blood cells, Glucose, 
Protein
Additional 
assessments
Serum immunoglobulin levels (IgG, IgA, IgM), peripheral blood, donor chimerism (prior 
allogeneic SCT patients only, or if unknown), bone marrow morphologic blast cell counts, 
peripheral blood morphologic blast, neutrophil and platelet cell counts, EOI MRD 
assessment in bone marrow aspirate.  

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Table 7-7
CTL019 pharmacokinetics by q-PCR in peripheral blood collection log
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
W-16 to D-1 Enrollment/Pre-Chemotherapy
3 mL
1
D1 10 min ± 5 min post-infusion
3 mL
1
D4±1d
3 mL
1
D7±1d
3 mL
1
D11 ±1d
3 mL
1
D14±3d
3 mL
1
D21±3d
3 mL
1
D28±4d
3 mL
1
M3±14d
3 mL
1
M6±14d
3 mL
1
M9±14d
3 mL
1
M12±14d
3 mL
1
M18±14d
3 mL
1
M24±14d
3 mL
1
M30±14d
3 mL
1
M36±14d
3 mL
1
M42±14d
3 mL
1
M48±14d
3 mL
1
M54±14d
3 mL
1
M60±14d (EOT)
3 mL
1
Unscheduled (PK samples related to CRS)***
2 mL/collection
1
Unscheduled (PK samples at relapse)****
3 mL
1
Unscheduled (PK samples related to safety events)
3 mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
**All patient sample volumes subject to adjustment for size and patient condition.
*** Additional unscheduled samples may be collected as needed dependent upon individual patient differences in 
the clinical time-course of CRS and administration of anti-cytokine therapy, if clinically feasible. Unscheduled PK 
sample collections related to CRS will cease once PK sample collections related to anti-cytokine therapy 
commence, if applicable.
**** In the event patient relapses, an unscheduled PK sample should be collected along with corresponding 
immunogenicity sample (refer to Table 7-13)
Note: 
s performed from these same samples 
(refer to Table 7-17). RCL by VSVg qPCR is performed at the relevant time points using DNA extracted from 
these samples. If RCL testing was negative through Month 12, all samples taken after Month 12 will be stored for 
potential future testing.

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Table 7-8
CTL019 pharmacokinetics by flow cytometry in peripheral blood 
collection log
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume
1
W-16 to D-1 Enrollment/Pre-Chemotherapy
2 mL
1
D4±1d
2 mL
1
D7±1d
2 mL
1
D11 ±1d
2 mL
1
D14±3d
2 mL
1
D21±3d
2 mL
1
D28±4d
2 mL
1
M3±14d
2 mL
1
M6±14d
2 mL
1
M9±14d
2 mL
1
M12±14d
2 mL
1
M18±14d
2 mL
1
M24±14d
2 mL
1
M30±14d
2 mL
1
M36±14d
2 mL
1
M42±14d
2 mL
1
M48±14d
2 mL
1
M54±14d
2 mL
1
M60±14d (EOT)
2 mL
1
Unscheduled (PK samples related to CRS)**
2 mL/collection
1
Unscheduled (PK sample at relapse)***
1
Unscheduled (e.g. related to safety events)
2 mL
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
** Additional unscheduled samples may be collected as needed dependent upon individual patient differences in 
the clinical time-course of CRS, if clinically feasible.
***In the event patient relapses, an unscheduled PK sample should be collected along with corresponding 
immunogenicity sample (refer to Table 7-13 and Table 7-14)
Table 7-9
CTL019 pharmacokinetics by q-PCR in bone marrow aspirate 
collection log
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
W-16 to W-12 Screening
2 mL
1
D28±4d
2 mL
1
M3±14d
(recommended but not required)
2 mL
1
M6±14d
(recommended but not required)
2 mL
1
Unscheduled (PK sample at relapse)
2 mL
1
Unscheduled (e.g. related to safety events)
2 mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
**All patient sample volumes subject to adjustment for size and patient condition.
Note: 
 is performed from these same 
samples; refer to Table 7-17.

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Table 7-10
CTL019 pharmacokinetics by flow cytometry in bone marrow aspirate 
collection log
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
W-16 to W-12 Screening
2 mL
1
D28±4d
2 mL
1
M3±14d (recommended but not required)
2 mL
1
M6±14d (recommended but not required)
2 mL
1
Unscheduled (PK sample at relapse)
2 mL
1
Unscheduled (e.g. related to safety events, at relapse)
2 mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
Table 7-11
CTL019 pharmacokinetics by q-PCR in CSF collection log
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume
1
W-16 to W-12 Screening
4-6 mL
1
D28±4d
4-6 mL
1
Unscheduled
4-6 mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
Table 7-12
CTL019 transgene persistence in peripheral blood (for patients in 
Secondary Follow-up)
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume
1
M3±14d
3 mL
1
M6±14d
3 mL
1
M9±14d
3 mL
1
M12±14d
3 mL
1
M24±14d
3 mL
1
M36±14d
3 mL
1
M48±14d
3 mL
1
M60±14d
3 mL
1
Unscheduled (at relapse)**
3 mL
1
Unscheduled (e.g. related to safety events, at relapse)
3 mL
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
Note: RCL by VSVg qPCR is performed at the relevant timepoints using DNA extracted from these samples. If 
RCL testing is negative through Month 12, all samples taken after Month 12 will be stored for potential future 
testing.
**In the event patient relapses, an unscheduled PK sample should be collected along with corresponding 
immunogenicity sample (refer to Table 7-13 and Table 7-14)

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Table 7-13
Immunogenicity serum sample collection log
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
W-16 to D-1 Enrollment/Pre-Chemotherapy
5 mL
1
D14±3d
5 mL
1
D28±4d
5 mL
1
M3±14d
5 mL
1
M6±14d
5 mL
1
M12±14d
5 mL
1
M24±14d****
5 mL
1
Unscheduled (at relapse)***
5 mL
1
Unscheduled (e.g. related to safety events)
5 mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
**Aliquot obtained from serum cytokine collection; refer to Table 7-17.
*** In the event patient relapses, an unscheduled immunogenicity sample should be collected along with 
corresponding PK samples (refer to Table 7-7, Table 7-8, and Table 7-12)
****For patients in Cohort 1 and Cohort 2 as applicable; a corresponding PK sample should be collected at this 
visit
Table 7-14
Immunogenicity peripheral blood sample collection log
Treatment Period 
or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
W-16 to D-1 Enrollment/Pre-Chemotherapy
10 mL
1
D14±3d
10 mL
1
D28±4d
10 mL
1
M3±14d 
10 mL
1
M6±14d 
10 mL
1
M12±14d 
10 mL
1
M24±14d****
10 mL
1
Unscheduled (at relapse)***
10 mL
1
Unscheduled (e.g. related to safety events)
10 mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified
**All patient sample volumes subject to adjustment for size and patient condition.
Note: Immunophenotyping (peripheral blood) is performed from these same samples; refer to Table 7-17.
*** In the event patient relapses, an unscheduled immunogenicity sample should be collected along with 
corresponding PK sample (refer to Table 7-7, Table 7-8, and Table 7-12) 
****For patients in Cohort 1 and Cohort 2 as applicable; a corresponding PK sample should be collected at this 
visit

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Table 7-15
Tocilizumab pharmacokinetics (PK), CTL019 PK and sIL6R (PD) in 
tocilizumab treated patients during CRS
Day/ 
Scheduled 
Time Point*/**
Dose 
Reference 
ID
Tocilizumab 
Sample 
Number
Sample 
Volume 
(serum) 
(PK+PD)
CTL019 
PK by 
qPCR 
Sample 
Number
Sample 
Volume
(whole 
blood)
CTL019 PK 
by flow 
cytometry 
Sample 
Number
Sample 
Volume
(whole 
blood)
D1 (5-15 
minutes post 
infusion)
101
1
5 mL
--
--
--
--
D1 1 hour ± 15 
min post 
infusion
101
2
5 mL
201
2 mL
601
2 mL
D2 ± 2 hours
101
3
5 mL
202
2 mL
602
2 mL
D3 ± 4 hours
101
4
5 mL
203
2 mL
603
2 mL
D7 ± 1d
101
5
5 mL
204
2 mL
604
2 mL
D1 (pre-dose; 
second infusion)
101
6
5 mL
205
2 mL
605
2 mL
D1(5-15 minutes 
post second 
infusion)
102
7
5 mL
--
--
--
--
D2 ± 2 hours 
from second 
infusion
102
8
5 mL
206
2 mL
606
2 mL
D3 ± 4 hours
102
9
5 mL
207
2 mL
607
2 mL
D7 ± 1d
102
10
5 mL
208
2 mL
608
2 mL
D1 (5-15 
minutes pre-
dose; additional 
infusion)
102
11
5 mL
209
2 mL
609
2 mL
D1 (5- 15 
minutes post 
additional 
infusion
103
12
5 mL
--
--
--
--
D2 ± 2 hours
103
13
5 mL
210
2 mL
610
2 mL
D3 ± 4 hours
103
14
5 mL
211
2 mL
611
2 mL
D7 ± 1d
103
15
5 mL
212
2 mL
612
2 mL
Additional ***
104, 105
16, 17, 18, 
19, 20
5 mL
213, 214, 
215, 216
2 mL
613, 614, 
615, 616
2 mL
*All measurement times are relative to tocilizumab infusion unless otherwise specified. A serum sample collected 
at D1 for cytokine analysis (see Table 7-17) would serve as the baseline sample.
**Samples may be collected as needed dependent upon administration of tocilizumab, if clinically feasible.
Unscheduled CTL019 PK sample collections related to CRS as specified in Table 7-7, Table 7-8, and Table 7-17
will cease once PK/PD sample collections related to tocilizumab infusion commence, if applicable.
*** Additional PK samples collected in the event more than 2 tocilizumab doses are administered should follow 
additional PK collection and numbering schedule.

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Table 7-16
Siltuximab PK, CTL019 PK and sIL6R (PD) in siltuximab treated 
patients during CRS
Day/ 
Scheduled 
Time 
Point*/**
Dose 
Reference 
ID
Siltuximab 
Sample 
Number
Sample 
Volume 
(serum) 
(PK+PD)
CTL019 PK 
by qPCR 
Sample 
Number
Sample 
Volume
(whole 
blood)
CTL019 PK 
by flow 
cytometry 
Sample 
Number
Sample 
Volume
(whole 
blood)
D1 (5-15 
minutes post 
infusion)
301
401
5 mL
--
--
--
--
D1 1 hour ± 
15 min post 
infusion
301
402
5 mL
501
2 mL
701
2 mL
D2 ± 2 hours
301
403
5 mL
502
2 mL
702
2 mL
D3 ± 4 hours
301
404
5 mL
503
2 mL
703
2 mL
D7 ± 1d
301
405
5 mL
504
2 mL
704
2 mL
D1 (pre-dose; 
additional 
infusion)
301
406
5 mL
505
2 mL
705
2 mL
D1(5-15 
minutes post 
additional 
infusion)
302
407
5 mL
--
--
--
--
D2 ± 2 hours 
from 
additional 
infusion
302
408
5 mL
506
2 mL
706
2 mL
D3 ± 4 hours
302
409
5 mL
507
2 mL
707
2 mL
D7 ± 1d
302
410
5 mL
508
2 mL
708
2 mL
Additional***
303, 304
411, 412, 
413, 414, 
415
5 mL
509, 510, 
511, 512
2 mL
709,710, 
711, 712
2 mL
*All measurement times are relative to siltuximab administration unless otherwise specified. A serum sample 
collected at D1 for cytokine analysis (see Table 7-17) would serve as the baseline sample.
**Samples may be collected as needed dependent upon administration of siltuximab, if clinically feasible.
Unscheduled CTL019 PK sample collections related to CRS as specified in Table 7-7, Table 7-8, and Table 7-17
will cease once PK/PD sample collections related to siltuximab administration commence, if applicable.
*** Additional PK samples collected in the event more than 1 siltuximab dose is administered should follow 
additional PK collection and numbering schedule.
7.2.3.1
Analytical method
The assays to be utilized for various PK/biomarker assessments 
 
 in peripheral blood and other 
tissues and flow cytometric analysis to detect CTL019 positive cells. Details regarding 
collection and processing of the samples used in these assays will be provided in the Central 
Laboratory Manual.
7.2.4
Biomarkers
The plan for biomarker evaluation focuses on characterization of CTL019 cellular 
pharmacokinetics (see Section 10.5.4), serum cytokines temporally linked to CRS, clonal 
changes in ALL tumor cells and enumeration of normal B cell levels.

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Table 7-17
Biomarker sample collection plan
Day/ Scheduled Time Point*
Sample Volume**
Peripheral blood for serum cytokine analyses
W-16 to D-1 Enrollment/Pre-Chemotherapy
5 mL
D1 (pre-infusion)
10 mL
D2
5 mL
D4±1d
5 mL
D7±1d
5 mL
D14±3d
5 mL
D21±3d
5 mL
D28±4d
5 mL
M3±14d
5 mL
M6±14d
5 mL
M12±14d
5 mL
Unscheduled (PD samples related to CRS)***
5 mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
**All patient sample volumes subject to adjustment for size and patient condition.
*** Additional unscheduled samples may be collected as needed dependent upon individual patient differences in 
the clinical time-course of CRS and should be consistent with timing of unscheduled PK in Table 7-15 and Table 
7-16, if clinically feasible. Please note that results of cytokine analyses are NOT to be used for clinical 
management decisions of CRS. Unscheduled PK/PD sample collections related to CRS will cease once PK/PD 
sample collections related to anti-cytokine therapy as specified in Table 7-15 and Table 7-16 commence, if 
applicable.
W-16 to D-1 Enrollment/Pre-Chemotherapy
3 mL
D28±4d
3 mL
M3±14d
3 mL
M6±14d
3 mL
M12±14d
3 mL
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
*Aliquot obtained from CTL019 peripheral blood q-PCR sample as specified in Table 7-7.
W-16 to W-12 Screening
2 mL
D28±4d
2 mL
M3±14d (recommended but not required)
2 mL
M6±14d (recommended but not required)
2 mL
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
*Aliquot obtained from CTL019 bone marrow q-PCR aspirate as specified in Table 7-9.

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Day/ Scheduled Time Point*
Sample Volume**
CTL019 Immunophenotyping (peripheral blood)
W-16 to D-1 Enrollment/Pre-Chemotherapy
10 mL
D7±1d
10 mL
D14±3d
10 mL
D21±3d
10 mL
D28±4d
10 mL
M3±14d (Primary follow-up only)
10 mL
M6±14d (Primary follow-up only)
10 mL
M9±14d (Primary follow-up only)
10 mL
M12±14d (Primary follow-up only)
10 mL
M24±14d (Primary follow-up only)
10 mL
M36±14d (Primary follow-up only)
10 mL
Unscheduled (related to relapse)
10 mL
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
** Except for collections at M24 and M36, aliquot obtained from peripheral blood immunogenicity assay as 
specified in Table 7-14.
Bone marrow 
W-16 to W-12 Screening
2 mL
Unscheduled (e.g. related to relapse)
2 mL
Bone marrow 
W-16 to W-12 Screening
4 mL
Unscheduled (e.g. related to relapse)
4 mL
7.2.5
Optional additional exploratory assessments using remaining samples
If the patient agrees, the remaining biomarker and/or PK samples as well as any CTL019 
manufactured product that is not infused may be stored for up to 15 years and further analyzed 
to address scientific questions related to CTL019 or cancer, including research related to 
improvements or enhancements in the manufacturing process. A decision to perform such 
additional research studies would be based on outcome data from this study or from new 
scientific findings related to the drug class or disease, as well as reagent and assay availability.
7.2.6
Resource utilization
Hospitalizations will be evaluated in this study as an exploratory endpoint to characterize the 
impact of study treatment on this aspect of healthcare resource utilization. In addition, these 
data may be used to support assessments used to characterize the economic impact of study 
treatment regimens.
Healthcare resource utilization data regarding hospitalizations should be captured from the day 
of screening up to Month 2 for the patient as described in Table 7-1.
Hospitalizations as a result of the following reasons are not to be reported:

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s general 
condition

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
Treatments occurring on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE as described 
in Section 8.2.1 are not required.
Information related to the length of stay (e.g., dates of admission or discharge), hospital ward 
facilities used (e.g., emergency department, intensive care unit, general ward, etc.), reasons for 
hospitalization as associated with the study treatment regimen, disease and/or disease 
progression, or any other reason will be of interest; and hospital discharge information will be 
evaluated.
7.2.7
Patient reported outcomes
Two questionnaires will be used in this study to capture patient reported outcomes (PROs): 
PedsQL and EQ-5D. PedsQL™ will be completed by patients aged 8 and above, and EQ-5D 
will be completed by patients aged 8 and above. Brief description and administration guidelines 
for each questionnaire are given in the sections below.
The patient should be given the questionnaire(s) and completed at the scheduled visit before the 
patient sees the investigator or undergoes other clinical assessments. However, for the 
enrollment visit where the interaction between the physician and the patient cannot be avoided, 
questionnaire(s) can be completed before or after seeing the investigator. Under extenuating 
circumstances where the enrollment (baseline) questionnaire(s) was not completed at the 
enrollment visit, it must be completed before administration of LD chemotherapy or the 
CTL019 infusion if LD chemotherapy is not administered. Questionnaires should be completed 
in the language the respondent is most familiar with. The patient should be given sufficient 
space and time to complete the questionnaire.
The study coordinator should check the questionnaire for completeness and encourage the 
patient to complete any missing responses. The original questionnaire will be kept with the 
patient’s file as the source document. Detailed instructions relating to the administrative 
procedures of the questionnaires will be provided to the sites. Patient’s refusal to complete all 
or any part of a questionnaire should be documented in the study data capture system.
Discourage the parent, child, or other family members from consulting with one another during 
the completion of the questionnaire. Let them know that they can feel free to discuss their 
answers following completion of the questionnaires.
If the child or parent has a question about what an item means or how they should answer it, do 
not interpret the question for them. Repeat the item to them verbatim. Ask them to answer the 
item according to what they think the question means. If they have trouble deciding on an 
answer, ask them to choose the response that comes closest to how they feel. The child has the 
option of not answering a question if they truly do not understand the question.
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs, 
including SAEs, before any clinical study assessments. This assessment should be documented 
in study source records. If AEs or SAEs are confirmed, study investigators should not encourage 
the patient to change responses reported in the completed questionnaires. Study investigators 
must follow reporting instructions outlined in Section 8.

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7.2.7.1
Pediatric Quality of Life Inventory – Version 4 (PedsQL™ 4.0)
The PedsQL is a generic instrument that is commonly used to measure health related quality of 
life (HRQL) in children and youth aged 0-25. The instrument is available for different age 
groups and consist of 23 items covering four dimensions of HRQL: Physical functioning, 
Emotional functioning, Social functioning, and School functioning. The questionnaire requires 
approximately 5 to 10 minutes to complete.
In this study the following versions of PedsQL will be administered to patients ages of 8 and 
above:

PedsQL™ 4.0 (Adult) for patients aged 18 and above at study entry

PedsQL™ 4.0 (Teens) for patients between the ages of 13-17 at study entry

PedsQL™ 4.0 (Children) for patients between the ages of 8-12 at study entry
Children (8-12) and Teens (13-18) may self-administer the PedsQL™ after introductory 
instructions from the administrator. If the administrator determines that the child or teen is 
unable to self-administer the PedsQL(e.g., due to illness, fatigue, reading difficulties), the 
PedsQLshould be read aloud to the child or teen.
If a child has difficulty understanding the age-appropriate PedsQL, the preceding age group 
version may be administered to the child. Since the PedsQL Young Child questionnaire (for 
ages 5-7) will not be utilized in this trial, a patient in the 8-12 year old age group with difficulty 
understanding will therefore not complete a PedsQL questionnaire.
7.2.7.2
EuroQol EQ-5D (EQ-5D)
The EQ-5D is a widely used, self-administered questionnaire designed to assess health status 
in adults, however, later studies have demonstrated acceptable performance in adolescents aged 
12 to 18 years. A child-friendly version, the EQ5DY, has been developed for use in children 
aged 8 years and older (Wille et al 2010).
The measure is divided into two distinct sections. The first section includes one item addressing 
each of five dimensions (mobility, self-care, usual activity, pain/discomfort, and 
anxiety/depression).
Patients rate each of these items from “no problem,” “some problem,” or “extreme problem.” 
A composite health index is then defined by combining the levels for each dimension. The 
second section of the questionnaire measures self-rated (global) health status utilizing a 
vertically oriented visual analogue scale where 100 represents the “best possible health state” 
and 0 represents the “worst possible health state.” Respondents are asked to rate their current 
health by placing a mark along this continuum. The recall period is “today,” and the 
questionnaire requires approximately 5 to 10 minutes to complete.
In this study the following versions of EQ-5D will be used:

EQ-5D for patients aged 13 and above at study entry

EQ-5D-Y for patients between the ages of 8 and 12 at study entry.
7.2.7.3
Questionnaire administration
Completion of the following questionnaire(s) will be required based on age at study entry:

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Age at study entry
PedsQL™ V4 Version
EQ-5D Version
2-4
Not Done
Not Done
5-7
Not Done
Not Done
8-12
PedsQL (Children)
EQ-5D-Y
13-17
PedsQL (Teen)
EQ-5D
18+
PedsQL (Adult)
EQ-5D
Please refer to the Guidelines for administering the PRO questionnaires for further instruction. 
If a child has difficulty understanding the age-appropriate questionnaire version, the preceding 
age group version may be administered to the child, if available. If a translated language is not 
available for the local country language(s) or a patient’s native language, questionnaire 
completion is not required.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed 
consent/assent has been obtained.
Abnormal laboratory values or test results occurring after informed consent/assent constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically 
significant, require therapy (e.g., hematologic abnormality that requires transfusion or 
hematological stem cell support), or require changes in study medication(s).
8.1.2
Reporting
Adverse events that begin or worsen after informed consent/assent will be recorded in the 
patient’s source documents. New or worsening adverse events prior to starting study 
treatment (i.e. lymphodepleting chemotherapy or the pre-infusion visit if the lymphodepleting 
chemotherapy is not given per Section 6.1.1.1) are required to be recorded in the Adverse Events 
CRF if they meet one of the following criteria:

All infections

All clinical AEs grade ≥ 3

All laboratory abnormalities deemed clinically significant by the investigator

All AEs related to a study procedure

All AEs leading to study discontinuation

All SAEs meeting criteria outlined in Section 8.2.2.
Under the circumstance when a patient is simultaneously enrolled in the active phase (up to 
Day 2) of the Novartis CTL019B2206 leukapheresis (apheresis collection) protocol and this 
treatment protocol, collection and reporting of adverse events during this overlapping period 
should follow the CTL019B2206 safety reporting criteria.

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Once the patient begins lymphodepleting chemotherapy or the pre-infusion visit, all new 
or worsening adverse events, including laboratory abnormalities deemed clinically significant 
by the investigator, will be recorded in the Adverse Events CRF up to the Month 12 visit.
Adverse event monitoring should be continued through the Month 60 (EOT) visit. Following 
the Month 12 visit, and through the Month 60 visit, adverse events should only be reported 
to Novartis and recorded in the Adverse Events CRF if it meets one of the following criteria:

Events leading to death

Events related to a study procedure

Infections:

Serious or opportunistic infections. Defined as bacterial, viral, fungal or parasitic 
infections that fulfill one of the following criteria:

Require anti-infective treatment OR

Lead to significant disability or hospitalization OR

Need for surgical or other intervention

New incidence or exacerbation of a pre-existing neurologic disorder

New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder

New incidence of other hematologic disorder

Any severe (≥ Grade 3) adverse event or condition the investigator believes may have a 
reasonable relationship to CD19 CART therapy

Positive RCL test result

Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a 
location near a known human oncogene

New malignancy (T-cell & non T-cell), other than the primary malignancy

Progressive multifocal leucoencephalopathy (PML)

Hepatitis B reactivation
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed according to the Medical Dictionary for Regulatory Authorities
(MedDRA) and the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, 
with the exception of CRS, which will follow Table 6-1. If CTCAE grading does not exist for 
an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to
Grades 1 - 4, will be used. CTCAE Grade 5 (death) will not be used in this study but is collected 
as a seriousness criteria; rather, information about deaths will be collected though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent/assent and at each visit during the 
study. Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:

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1. The severity grade (CTCAE v. 4.03 Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No,
Yes, investigational treatment, Yes, the study treatment (non-investigational), Yes, both 
and/or indistinguishable)
4. Action taken with respect to study or investigational treatment (none, temporarily 
interrupted, permanently discontinued, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
7. Whether it is serious, where a serious adverse event is defined as in Section 8.2.1 and
which seriousness criteria have been met.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression underlying malignancy with fatal outcome should be reported as SAE irrespective 
of causality, if it occurs within 30 days post CTL019 infusion. After 30 days, progression of 
underlying malignancy should be reported as SAE only, if there is at least a possible causal 
relationship to CTL019. Progression of underlying malignancy without fatal outcome should 
not be reported as an AE. 
Modified data capture for inpatient/in hospital events
A significant number of CTL019 treated patients will require multiple days of inpatient and/or 
ICU care. These adverse events are mostly due to CRS and MAS, although there may be some 
contribution from the preceding lymphodepleting chemotherapy (neutropenia fever, 
cytopenias). CRS/MAS toxicity is an ‘on-target’ effect resulting from the expected CTL019 
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. A revised inpatient data 
capture will be utilized for this study to systematically collect subsets of patient data to describe 
the management of safety events associated with CTL019 therapy for the purpose of:
1. Adequately informing physicians and patients of the expected risks of CTL019 and the 
recommended interventions to manage these risks
2. Health authority submission
This is done through a targeted collection of concomitant medications and laboratory data and 
CRS CRFs specifically designed to capture CTL019-related toxicity, severity, interventions and 

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response/resolution following intervention. Details can be found in the CRF Completion 
Guidelines (CCGs).
8.1.3
Laboratory test abnormalities
8.1.3.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities that do not meet the definition of an adverse event should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A medication for the lab abnormality may be required by the protocol 
in which case the lab abnormality would still, by definition, be an adverse event and must be 
reported as such.
8.1.4
Adverse events of special interest
Adverse events of special interest (AESI) are described in Table 10-3. The current search 
criteria of AESI are based on limited experience from ongoing clinical studies without an 
accurate assessment of causality. The search criteria of the AESI may be updated prior to 
database lock for primary analysis reporting. Based on current clinical experience, AESI 
typically occur and resolve within 8 weeks of CTL019 infusion in ALL patients.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
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
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/assent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
Any SAEs experienced during the screening/pre-treatment phase (from the time of patient 
providing informed consent/assent until the patient begins study-related treatment) should 
ONLY be reported to Novartis and be captured if the CRF and safety database if the event meets 
at least one of the following criteria:

All events leading to death.

All pulmonary or cardiac abnormalities

All infections

All events related to a study procedure

Any AE reportable for this study period that also meets criteria for serious

Any substantial change in the status of the patient that precludes the patient from 
proceeding to study treatment (e.g. GVHD, rapid progression of malignancy, marked 
decline in performance status)

Any other substantial change in the clinical status of the patient that the investigator 
deems may have a potential impact on the patients during lymphodepletion and CTL019 
treatment
Under the circumstance when a patient is simultaneously enrolled in the active phase (up to 
Day 2) of the Novartis CTL019B2206 leukapheresis (apheresis collection) protocol and this 
treatment protocol, collection and reporting of serious adverse events during this overlapping 
period should follow the CTL019B2206 safety reporting criteria.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has begun study-related treatment (i.e. lymphodepleting chemotherapy, or pre-CTL019 
infusion visit if no lymphodepleting chemotherapy was given) and through the Month 12 visit 
must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after the Month 12 visit, and through the Month 60 (EOT) visit should 
only be reported to Novartis and recorded in the Adverse Events CRF if it meets one of the 
following criteria:

Events leading to death

Events related to a study procedure

Infections:

Serious or opportunistic infections. Defined as bacterial, viral, fungal or parasitic 
infections that fulfill one of the following criteria:

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
Require anti-infective treatment OR

Lead to significant disability or hospitalization OR

Need for surgical or other intervention

New incidence or exacerbation of a pre-existing neurologic disorder

New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder

New incidence of other hematologic disorder

Any severe (≥ 3 Grade) adverse event or condition the investigator believes may have a 
reasonable relationship to CTL019 therapy

Positive RCL test result

Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a 
location near a known human oncogene

New malignancy (T-cell & non T-cell), other than the primary malignancy

Progressive multifocal leucoencephalopathy (PML)

Hepatitis B reactivation
In addition, at the specific request of a National Health Authority, the following SAEs will be 
reported in an expedited manner:

Any SAE related to a study procedure

All occurrences of CRS grade ≥ 3 (to be reported to National Health Authority on a 
monthly basis)

All deaths regardless of attribution following lymphodepleting chemotherapy and/or 
CTL019 infusion and within 30 days of receiving CTL019 infusion

Deaths attributed to CTL019 occurring 30 days post CTL019 infusion
Any SAEs experienced after the Month 60 (EOT) visit should only be reported to Novartis 
Chief Medical Office and Patient Safety (CMO&PS) if the investigator suspects a causal 
relationship to the study treatment. Recurrent episodes, complications, or progression of the 
initial SAE 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 should be reported 
separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Instructions 
regarding the SAE submission process and requirements for signatures are to be found in the 
investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.

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If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis DS&E 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 drug 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 Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy 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 between CTL019 and any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
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.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between Investigator Brochure (IB) updates 
will be communicated in the form of Investigator Notifications. This information will be 
included in the patient informed consent/assent and should be discussed with the patient during 
the study as needed.
8.6
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be established prior to the enrollment of the first 
patient. The DMC will be responsible for reviewing at regular intervals the safety data of the 
patients treated in the study. The DMC will consist of members who are not involved in patient 
recruitment or trial conduct, with at least two oncologists (at least one pediatric 
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There will be an initial meeting with the DMC to have agreement on their roles and 
responsibilities and the potential data format and procedures that will be reviewed during the 
course of the study. The first DMC safety review meeting will be held when approximately the 
first 5 patients have been treated for at least 1 month or at least 6 months after the first patient 
is enrolled, whichever occurs first. Subsequent safety reviews will occur every six months, 
unless otherwise requested by the Chairman of the DMC. Additional meetings will be held by 
DMC or sponsor’s requests at the time of some safety issues occurrence, especially when 
serious events (e.g., death) occur on the study or safety notifications regarding the study 
treatment outcome.
Detailed recruitment status and interim safety reports will be provided to the DMC on a regular 
basis.
Further details regarding the constitution of the DMC and its specific roles will be provided in 
the DMC charter prior to the enrollment of the first patient.
8.7
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, Novartis representatives from the Clinical Trial team and not members of the DMC. The 
SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter.
8.8
Independent Review Committee (IRC)
An IRC will be established to review data related to disease response assessments during the 
Treatment and Primary Follow-up Phase and determine remission and relapse for the primary 
analysis. An IRC charter will detail the IRC data flow and review process in alignment with the 
response definitions in Appendix 1. Patient management will be based upon local investigator 
assessments. The designation of remission and relapse for the primary analysis and other related 
secondary efficacy endpoints will be based only on the evaluations made by the IRC. Details 
regarding the constitution of the IRC and its specific roles will be documented in the IRC charter 
agreed upon between Novartis and the IRC before initiation of any IRC reviews.
9
Data collection and management
9.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

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
The rights of a research patient to revoke their authorization for use of their PHI
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (patient initials and exact date 
of birth), the system will prompt site to verify that this data is allowed to be collected. If the site 
indicates that country rules or ethics committee standards do not permit collection of these items, 
the system will not solicit patient initials. Year of birth will be solicited (in the place of exact 
date of birth) to establish that the patient satisfies protocol age requirements and to enable 
appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated Contract Research Organization [CRO]) will review the protocol and 
CRFs with the investigators and their staff. During the study, the field monitor will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the CRFs, the 
adherence to the protocol 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.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent/assent form 
(a copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent/assent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the CRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 

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have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRFs are 
complete, accurate, and that entry and updates are performed in a timely manner.
The Novartis designated manufacturing facility is responsible for assuring that the 
manufacturing specific data entered into eCRFs are complete, accurate, and that entry and 
updates are performed in a timely manner.
9.4
Database management and quality control
For studies using eCRFs, 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 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history and adverse events will be coded 
using the MedDRA terminology.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies
of the patient data for archiving at the investigational site.
The Novartis designated manufacturing facility is responsible for assuring that the 
manufacturing specific data entered into eCRFs are complete, accurate, and that entry and 
updates are performed in a timely manner.
10
Statistical methods and data analysis
Data from all participating centers will be combined.
Main Cohort 
An interim analysis  will be performed when the first 50 patients who receive CTL019 have 
completed 3 months follow-up from study day 1 infusion or discontinued earlier. At the time of 
this interim analysis, assessment of all endpoints will be based only on patients who receive 
CTL019 manufactured from US manufacturing facility because there will be no patients treated 
with CTL019 manufactured from other manufacturing facilities.
The final analysis of the primary endpoint will be performed after all patients infused with 
CTL019 have completed 3 months follow-up from study day 1 infusion or discontinued earlier. 
Selected efficacy and safety analysis will be updated annually. 
Cohort 1 and Cohort 2
Patients in Cohort 1  will be analyzed separately. At the time of enrollment termination, only 1 
patient was enrolled and infused in Cohort 1. Therefore, only listings of this single patient will 
be presented.  No patients were enrolled in Cohort 2.

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A final Clinical Study Report (CSR) will be produced once all patients complete the study.
10.1
Analysis sets
The analysis sets to be used are defined as below. The FAS will be used as the primary efficacy 
analysis set. The Safety Set will be used for all the safety analysis. The Pharmacokinetic 
Analysis Set (PAS) will be used for the pharmacokinetics analysis.
All tables and listings will be presented by one treatment arm of CTL019.
10.1.1
Screened Set
The Screened Set comprises all patients who have signed informed consent/assent and screened 
in the study.
10.1.2
Enrolled Set
The Enrolled Set 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’ 
leukapheresis product is received and accepted by the manufacturing facility.
10.1.3
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned, 
and have received infusion of CTL019.
10.1.4
Interim Efficacy Analysis Set
At the time of interim analysis, the Interim Efficacy Analysis Set (IEAS) comprises the first 50 
patients who receive CTL019 infusion.
10.1.5
Safety Set
The Safety Set comprises all patients who received infusion of CTL019.
10.1.6
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the IEAS or FAS (at interim 
and final analysis respectively) who are compliant with major requirements of the clinical study 
protocol (CSP).
Major protocol deviations leading to exclusion from the PPS include:

No diagnosis of ALL at baseline;

Prior therapy does not match with CSP requirements in terms of number and types of 
previous therapy regimens;

Missing or incomplete documentation of disease;
In addition, patients who receive a dose less than the minimum target dose of 2 × 106/kg (for 
patients ≤ 50 kg) or 1 x 108 (for patients > 50 kg) CTL019 transduced viable T cells will also 
be excluded.
The detailed exclusion criteria of PPS will be determined prior to primary analysis.

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10.1.7
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of IEAS or FAS (at time of interim or final 
analysis respectively) who have at least one sample providing evaluable pharmacokinetic (PK) 
data. The PAS will be used for summaries (tables and figures) and listings of PK data.
Note that patients will be removed from the estimation of certain PK parameters on an 
individual basis depending on the number of available samples. These patients will be identified 
at the time of the analyses.
10.2
Patient demographics/other baseline characteristics
The following analyses will be performed in Main Cohort. Only listings (i.e., demographic and 
other baseline data, prior disease history, etc.) will be presented in Cohort 1.  No patients were 
enrolled in Cohort 2.
Demographic and other baseline data will be listed by patient and/or summarized descriptively 
for the FAS as well as for IEAS. Categorical data will be presented as frequencies and 
percentages. For continuous data, summary statistics will be presented (i.e., mean, median, 
standard deviation, minimum, maximum).
Number and percentage of patients failing prior anti-neoplastic medications/therapies will be 
summarized.
Patients will be classified by the prior allogeneic SCT status (with prior SCT, without prior 
SCT).
Patients will also be classified by their prior response status into:

Primary refractory: If patient never had a morphologic complete remission (CR) prior to 
the study

Relapsed disease: If patient had a CR from other therapy and relapsed prior to the study
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The following analyses will be performed in Main Cohort. Only listings (i.e., total cells infused, 
total CTL019 transduced viable T cells, prior or concomitant medications, etc.) will be 
presented in Cohort 1.
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 infusion will be listed by patient and summarized by the Anatomical Therapeutic Chemical
(ATC) term. Transfusion during the study will be listed. In addition, whether patients have 
received anti-cytokine medications for the management of CRS will be summarized.

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10.4
Primary objective
For the Main cohort and Cohort 1 (enrollment into Cohort 1 has been terminated as of 15-Jun-
2020), the primary objective of the study is to evaluate the efficacy of CTL019 therapy as 
measured by overall remission rate (ORR) during the 3 months after CTL019 administration, 
which includes CR and CR with incomplete blood count recovery (CRi) as determined by IRC 
assessment in the FAS population.
For Cohort 2 (enrollment into Cohort 2 has been terminated as of 15-Jun-2020), the primary 
objective is to assess the safety and feasibility to administering CTL019 within 6 months post 
allo-HSCT. In addition, sensitivity analysis will be performed using the local investigator 
response assessments instead of the IRC assessment.
10.4.1
Variable
The primary efficacy endpoint for Main cohort and Cohort 1 is the ORR as determined by IRC 
assessment during the 3 months after CTL019 administration. The ORR is defined as the 
proportion of patients with a best overall disease response of CR or CRi, where the best overall 
disease response is defined as the best disease response recorded from CTL019 infusion until 
the start of new anticancer therapy. Best response will be assigned according to the following 
order:

CR

CRi

No response (NR)

Unknown

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Table 10-1
Definition of CR, CRi and relapse at a given evaluation time
Response category
Definition
Complete remission 
(CR)
All the following criteria are met:
Bone marrow

< 5% blasts
Peripheral blood

Neutrophils > 1.0 x 109/L, and

Platelets > 100 x 109/L, and

Circulating blasts < 1%
Extramedullary disease

No evidence of extramedullary disease (by physical exam and CNS 
symptom assessment)
Transfusion independency

No platelet and/or neutrophil transfusions ≤ 7 days before peripheral 
blood sample for disease assessment
Complete remission 
with incomplete blood 
count recovery (CRi)
All criteria for CR as defined above are met, except that the following exist:

Neutrophils ≤ 1.0 x 109/L, and/or

Platelets ≤ 100 x 109/L, and/or

Platelet and/or neutrophil transfusions ≤ 7 days before peripheral blood 
sample for disease assessment
Relapsed Disease
Only in patients who obtained a CR or CRi:

Reappearance of blasts in the blood (≥ 1%), or

Reappearance of blasts in bone marrow (≥ 5%), or

(Re-)appearance of any extramedullary disease after CR or CRi
A full response evaluation, including assessments of peripheral blood, bone marrow, CNS 
symptoms, physical exam, and CSF assessment by LP, is required at the first time a CR or CRi 
is demonstrated. Bone marrow biopsy/aspirate and CSF assessment by LP are required 1 month 
(Day 28) after infusion. If the patient is not in CR/CRi at Month 1, then a bone marrow 
biopsy/aspirate and CSF assessment by LP are also required at the first time clinical evidence 
of remission is seen by peripheral blood and extramedullary disease assessment (physical exam 
and CNS symptom assessment) to establish that a patient has achieved CR/CRi for the first time. 
Additional bone marrow biopsies/aspirates and CSF assessments by LP are not required after 
initial establishment of CR or CRi unless clinically indicated (recommended but not required at 
months 3 and 6).
Complete remissions in patients with ALL have been observed to take place within 1 month 
after infusion with CTL019. The onset of complete remissions are rapid and dramatic, and 
patients quickly regain a normal performance status. ALL relapse in the bone marrow is rapidly 
followed by signs or symptoms of disease recurrence as well as abnormalities in the peripheral 
blood.
Therefore, following initial achievement of CR/CRi, patients will be considered to have 
maintained a clinical CR/CRi if the patient has no evidence of extramedullary disease (by 
physical exam and CNS symptom assessment) and circulating blasts in peripheral blood are 
<1%. In order for the best ORR to be categorized as CR or CRi, there must be no clinical 
evidence of relapse as assessed by peripheral blood and extramedullary disease assessment 

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(physical exam and CNS symptom assessment) at a minimum of 4 weeks (28 days) after the 
initial achievement of CR or CRi. Please note, if additional assessments of bone marrow and/or 
CSF are performed in the same evaluation, they will also need to show remission status.
See Appendix 1 for details of disease response criteria.
The primary safety endpoints for Cohort 2 are adverse events and laboratory abnormalities as 
defined in Sections 10.5.3.2 and Section 10.5.3.3.
10.4.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be performed in Main Cohort by testing whether the ORR 
within 3 months is less than or equal to 20% against the alternative hypothesis that ORR within 
3 months is greater than 20% at overall one-sided 2.5% level of significance, i.e.,
H0: p ≤ 0.2 vs. Ha: p >0.2.
The primary efficacy endpoint, ORR within 3 months, will be analyzed at the interim look and 
final look of a group sequential design. The ORR will be summarized along with the 2-sided 
exact Clopper-Pearson confidence intervals with coverage level determined by the O’Brien-
Fleming type α-spending approach according to Lan-DeMets as implemented in East 5.4 (Lan 
and DeMets, 1983). The study will be considered successful if the lower bound of the 2-sided 
exact confidence interval for ORR is greater than 20%, so that the null hypothesis that the ORR 
is less than or equal to 20% can be rejected.
The primary efficacy endpoint, ORR will be analyzed based on the data observed in the IEAS 
and FAS at interim and final analysis, respectively. Hypothesis testing of primary endpoint will 
only be performed for patients in Main cohort.
Only the listing of ORR per IRC and local investigator will be presented in Cohort 1.
10.4.3
Handling of missing values/censoring/discontinuations
Patients in the study who are of unknown clinical response will be treated as non-responders. 
See also the Novartis guideline for efficacy evaluation in ALL (Appendix 1) for more details.
Other missing data are simply noted as missing on appropriate tables/listings.
10.4.4
Supportive analyses
The analysis of the primary efficacy endpoint for Main cohort will be performed among all 
patients in the PPS using the same methodology as outlined at interim and final analysis, 
respectively.
The analysis of primary efficacy endpoint for Main cohort will also be performed among all 
patients in the Enrolled Set who have either discontinued prior to CTL019 infusion or have 
received CTL019 infusion. 
In addition, the analysis of the primary efficacy endpoint for Main cohort will also be performed 
using all patients who satisfy all clinical eligibility criteria and have either discontinued prior 
to CTL019 infusion or have received CTL019 infusion.

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10.4.4.1 Subgroup analysis
Subgroup analyses will be performed in Main Cohort on the following based on the patient’s 
baseline status:

Age: <10 years, ≥10 years to <18 years, ≥18 years

Gender: Male, Female

Race: White, Asian, Other

Ethnicity: Hispanic or Latino, Other

Prior response status: Primary refractory, Chemorefractory, Relapsed disease

Prior SCT therapy: Yes, No

Eligibility for SCT: Eligible for SCT, ineligible for SCT

Baseline bone marrow tumor burden: Low (defined as either morphologic or MRD result 
is <50% and neither is ≥50%), High (defined as either morphologic or MRD result is 
≥50%)

Baseline extramedullary disease presence: Yes, No

Philadelphia chromosome/BCR-ABL: Positive, Negative

Mixed-Lineage Leukemia (MLL) rearrangement: Yes, No

Hypoploidy: Yes, No

BCR-ABL1-like: Yes, No

Complex Karyotypes (≥5 unrelated abnormalities): Yes, No

Down syndrome: Yes, No
The rationale for performing subgroup analyses are as follows:

Age, gender, race and ethnicity are demographic factors that are typically requested by 
health authorities to assess internal consistency of the study results.

Prior response status is a key prognosis factor due to potentially higher rates of treatment 
related morbidity in patients who have relapsed following allogeneic SCT.

Baseline bone marrow tumor burden and extramedullary disease presence are important 
indicators of overall disease burden, which is a potential predictive factor.

BCR-ABL, MLL rearrangement, hypoploidy, BCR-ABL1-like gene signatures and 
complex karyotype (≥ 5 unrelated abnormalities) are high risk factors for ALL. Patients 
with these high risk factors have poorer diagnosis (Harrison 2010; van der Veer 2013). In 
case there are very few patients with these high risk mutations individually, analysis may 
be performed for patients with any of these high risk mutations versus those who do not.

Patients with Down Syndrome is known to have increased ALL treatment related 
morbidity and mortality rates. Because of increased risk, stem cell transplant is often not 
recommended in this population. Therefore, the experience with CTL019 in this rare 
population may offer an unmet medical need.
Subgroup analyses will only be performed if at least 5 patients are present in each subgroup. 
Some grouping of classes will be considered if there are too few patients in some subgroups.
In addition, Japanese patients will be analyzed separately in descriptive manner.

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10.5
Secondary objectives
IRC assessment will be used in the main analysis of secondary endpoints that involve disease 
response.
10.5.1
Key secondary objective(s)
Hypothesis testing of key secondary end-points will only be performed for patients in Main 
cohort.
10.5.1.1 ORR within 3 months in all patients infused with CTL019 from US 
manufacturing facility
The first key secondary objective of the study is to evaluate the efficacy of CTL019 therapy 
from US manufacturing facilities as measured by overall remission rate (ORR) during the 3 
months after CTL019 administration by IRC assessment. 
The hypothesis testing will be performed to test whether the ORR within 3 months is less than 
or equal to 20% against the alternative hypothesis that ORR is greater than 20%.
This hypothesis testing will only be performed when the primary objective is met, so that the 
family-wise type I error rate will be controlled at one-sided 2.5% level under this hierarchical 
testing scheme. The type I error probability will be controlled by using a Lan-DeMets (O’Brien-
Fleming) alpha spending function at 2.5% level of significance.
This key secondary endpoint will be summarized along with the 2-sided exact Clopper-Pearson 
confidence intervals with coverage level according to the above alpha spending function. This 
key secondary objective will be considered successfully met if the lower bound of the 2-sided 
exact confidence interval is greater than 20%, so that the null hypothesis above can be rejected.
10.5.1.2 Remission with MRD negative bone marrow in patients infused with 
CTL019 from all manufacturing facilities
The second key secondary objective of the study is to evaluate the percentage of patients who 
receive CTL019 from all manufacturing facilities and achieve a BOR of CR or CRi with a MRD 
negative bone marrow by central analysis using flow cytometry during the 3 months after 
CTL019 administration. The main analysis of this key secondary objective will be performed 
among all patients in the IEAS or FAS population, at the time of interim and final analysis 
respectively. See Appendix 1 for details of determination of MRD negativity.
This key secondary efficacy analysis will be performed by testing whether the percentage of 
MRD negative responder among all patients who received CTL019 infusion from all 
manufacturing facilities in IEAS or FAS as defined above is less than or equal to 15% against 
the alternative hypothesis that it is greater than 15% at overall one-sided 2.5% level of 
significance, i.e.,
H0: p ≤ 0.15 vs. Ha: p >0.15.
This hypothesis testing will only be performed when both the primary objective and the first 
key secondary endpoint are met, so that the family-wise type I error rate will be controlled at 
one-sided 2.5% level under this hierarchical testing scheme. The type I error probability will be 

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controlled by using a Lan-DeMets (O’Brien-Fleming) alpha spending function at 2.5 % level 
of significance.
This key secondary endpoint will be summarized along with the 2-sided exact Clopper-Pearson 
confidence intervals with coverage level according to the above alpha spending function. This 
key secondary objective will be considered successfully met if the lower bound of the 2-sided 
exact confidence interval is greater than 15%, so that the null hypothesis above can be rejected.
The key secondary endpoint will also be summarized among who achieve a BOR of CR or CRi 
during the 3 months after CTL019 administration.
Additional analysis will be done using the qPCR MRD analysis instead of flow cytometry 
(exploratory only).
10.5.1.3 Remission with MRD negative bone marrow in patients infused with 
CTL019 from US manufacturing facility
The third key secondary objective of the study is to evaluate the percentage of patients who 
achieve a BOR of CR or CRi with a MRD negative bone marrow by central analysis using flow 
cytometry during the 3 months after CTL019 administration among all patients who receive 
CTL019 from US manufacturing facility.
The hypothesis testing will be performed to test whether the above rate is less than or equal to 
15% against the alternative hypothesis that it is greater than 15%.
This hypothesis testing will only be performed when both the primary objective and the first 
two secondary endpoints are met, so that the family-wise type I error rate will be controlled at 
one-sided 2.5% level under this hierarchical testing scheme. The type I error probability will be 
controlled by using a Lan-DeMets (O’Brien-Fleming) alpha spending function at 2.5% level of 
significance.
This key secondary endpoint will be summarized along with the 2-sided exact Clopper-Pearson 
confidence intervals with coverage level according to the above alpha spending function. This 
key secondary objective will be considered successfully met if the lower bound of the 2-sided 
exact confidence interval is greater than 15%, so that the null hypothesis above can be rejected.
10.5.2
Other secondary efficacy objectives
The secondary efficacy objectives are outlined as follows in the order of importance.
Additional analyses will be performed to further assess the efficacy of CTL019 treatment by 
combining data collected in this protocol together with the 15 year long term follow-up protocol, 
if appropriate.
10.5.2.1 Percentage of patients who achieve CR or CRi at Month 6 without SCT 
between CTL019 infusion and Month 6 response assessment
The percentage of patients who achieve CR or CRi at Month 6 without SCT (post CTL019 
infusion) between CTL019 infusion and Month 6 response assessment, among all patients in 
the FAS, will be summarized along with exact 95% Confidence Interval (CI). In addition, the 
percentage among patients who achieved CR or CRi will also be summarized. The time of 

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proceeding to SCT is defined as the time of commencing the conditioning regimen as required 
for hematopoietic SCT. This definition applies to all analyses.
This analysis will be conducted when all patients have completed 6 months post CTL019 
infusion or have discontinued earlier.
10.5.2.2 Percentage of patients who achieve CR or CRi and then proceed to 
SCT while in remission before Month 6 response assessment
The percentage of patients who achieve CR or CRi and then proceed to SCT while in remission 
by the time of Month 6, among all patients in the FAS, will be summarized along with exact 
95% CI. In addition, the percentage will also be summarized among all patients who achieved 
CR or CRi.
This analysis will be conducted when all patients have completed 6 months post CTL019 
infusion or have discontinued earlier.
All patients that proceed to SCT post CTL019 infusion will be listed.
10.5.2.3 Duration of remission (DOR)
Duration of remission (DOR) is defined as the duration from the date when the response criteria 
of CR or CRi is first met to the date of relapse or death due to underlying cancer.
In case a patient does not have relapse or death due to ALL prior to data cutoff, DOR will be 
censored at the date of the last adequate assessment on or prior to the earliest censoring event. 
The censoring reason could be:

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (also see below for handling SCT)

Event after at least two missing scheduled disease assessments
In addition, death due to reason other than ALL will be considered as a competing risk event to 
other events of interest (relapse or death due to ALL).
As SCT is an important treatment option in responding patients, it is appropriate to consider the 
date of SCT as censoring date, instead of censoring at the last tumor assessment date. However, 
censoring due to SCT will overestimate the rate of relapse and therefore may be considered 
inappropriate for the main analysis when a substantial number of patients choose to receive 
SCT (CHMP 2010). If a patient received SCT after a CR or CRi, relapse or survival status after 
SCT will be recorded on the corresponding follow-up eCRFs, although data on individual 
disease response components (e.g. bone marrow) will not be collected. In such cases, the date 
of relapse or death (if due to the underlying cancer) after SCT will be used for the calculation 
of DOR as a sensitivity analysis.
Additional sensitivity analysis will be performed by censoring death due to reason other than 
ALL instead of considering it as the competing risk event to other events of interest (relapse or 
death due to ALL).

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The proposed analyses for DOR are summarized in Table 10-2 below. Method 1 will be 
considered as the main analysis for DOR. Additional analyses may be considered.
Table 10-2
Analyses of duration of response (DOR)
Death due to reason other than ALL
SCT after remission
Method 1
Competing risk analysis
Censor at time of SCT
Method 2
Censor at last adequate tumor assessment
Censor at time of SCT
Method 3
Competing risk analysis
Ignore SCT
Method 4
Censor at last adequate tumor assessment
Ignore SCT
DOR will be assessed only in patients with the best overall response of CR or CRi. The 
estimated percentage of relapsed patients (at 6 months, 12 months, etc.) will be presented with 
95% confidence intervals using the cumulative incidence function (CIF) or the Kaplan-Meier 
(KM) method.
For Method 1 and Method 3, the CIF is used to estimate the probability of the event of interest 
in the presence of the competing risks (Kim 2007).
For Method 2 and Method 4, the distribution function of DOR will be estimated using the KM 
method. The median DOR along with 95% confidence intervals will be presented if appropriate.
Method 1 and Method 3 will be conducted only if there are any patients who respond to CTL019 
but experience the event of death due to reasons other than ALL.
If a considerable number of patients receive SCT while in remission after CTL019 infusion, 
then exploratory analyses may be performed on patients who achieve CR/CRi after CTL019 
infusion to assess the effect of SCT on DOR. Baseline disease characteristics and post-baseline 
factors (e.g. time to CR/CRi, minimal residual disease) that may be correlated with the decision 
to receive SCT and with DOR will be identified. A Cox model with SCT as a time dependent 
covariate and potential confounding factors as additional covariates may then be explored in 
patients who achieve CR/CRi after CTL019 infusion. The hazard ratio (SCT v/s No SCT after 
CR/CRi) estimate along with its 95% confidence interval will be provided. Additional 
exploratory analyses may be considered to account for the confounding factors.
10.5.2.4 Relapse free survival (RFS)
Relapse free survival (RFS) is measured by the time from achievement of CR or CRi whatever 
occurs first to relapse or death due to any cause during CR or CRi.
In case a patient does not have relapse or death due to any cause prior to data cutoff, RFS will 
be censored at the date of the last adequate assessment on or prior to the earliest censoring event.
The censoring reason could be

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (also see below for handling SCT)

Event after at least two missing scheduled disease assessment

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In the main analysis of RFS, patients who proceed to SCT after CTL019 infusion will be 
censored at the time of SCT. In addition, a sensitivity analysis of RFS will be performed without 
censoring SCT.
RFS will be assessed only in patients with the best overall response of CR or CRi. The 
distribution function of RFS will be estimated using the KM method. The median RFS along 
with 95% confidence intervals will be presented if appropriate.
10.5.2.5 Event free survival (EFS)
Event free survival (EFS) is the time from date of first CTL019 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)

Lack of efficacy or progressive disease

New anticancer therapy
In case of treatment failure, the event date will be set to study Day 1 (CHMP 2010).
In case a patient does not have relapse, death due to any cause or treatment failure (e.g. 
discontinuation as a result of withdrawal of consent, lost to follow-up, protocol violation or 
administrative problems) prior to data cutoff, EFS is censored at the last adequate response 
assessment date on or prior to the earliest censoring event (except for SCT). The censoring 
reason could be

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (also see below for handling SCT)

Event after at least two missing scheduled disease assessment
In the main analysis of EFS, patients who proceed to SCT after CTL019 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 IEAS and FAS. The distribution function of EFS will be 
estimated using the KM method. The median EFS along with 95% confidence intervals will be 
presented if appropriate.
10.5.2.6 Overall survival (OS)
Overall survival (OS) is the time from date of first CTL019 infusion to the date of death due to 
any reason.

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In case a patient is alive at the date of last contact on or before data cutoff, 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.
OS will be assessed in all patients in IEAS and FAS. The distribution function of OS will be 
estimated using the Kaplan Meier (KM) method. The median OS along with 95% confidence 
intervals will be presented if appropriate.
10.5.2.7 Patient Reported Outcome
Patient Reported Outcome (PRO), such as scores of health-related quality of life questionnaires 
PedsQL and EQ-5D will be assessed. PedsQL™ will be completed by patients aged 8 and above, 
and EQ-5D will be completed by patients aged 8 and above. Descriptive statistics (e.g. mean, 
median, and frequency) and change from baseline of the summary scores for each post baseline 
time-point/window of assessment will be provided based on all available data at the time of 
final analysis. FAS will be used for all analysis.
10.5.2.8 Response at Day 28 +/- 4 days
Proportion of patients attaining CR or CRi at Day 28 +/- 4 days post CTL019 infusion, in the 
same analysis set as for the primary endpoint, will be summarized along with exact 95 % 
Confidence Interval (CI).
10.5.2.9 Impact of baseline tumor burden on response
Best overall response will be summarized by baseline tumor burden (MRD, extramedullary 
disease, etc).
10.5.2.10Quality of response using MRD disease assessments
The quality of response using MRD disease assessments before treatment, and at day 28 +/- 4 
days after treatment using central assessment by flow cytometry and before SCT by local 
assessment (flow or PCR) will be summarized descriptively.
Both quantitative MRD result and qualitative results (positive/negative) will be summarized if 
available.
10.5.2.11Efficacy, safety and CTL019 PK in patients infused with CTL019 
manufactured by Fraunhofer Institute
The ORR and MRD negative remission rate will be summarized with 95% exact confidence 
intervals for patients infused with CTL019 manufactured by Fraunhofer Institute.  
Key safety summaries for adverse events regardless of relationship to study drug by System 
Organ Class (SOC) and PT, and adverse events of special interest will be performed on the 
Safety Set.
The CTL019 PK parameters for CTL019 transgene levels as measured by q-PCR will also be 
summarized. The CTL019 PK parameters as measured by flow cytometry (exploratory only) 
will also be summarized, as appropriate.

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10.5.2.12 Efficacy in Cohort 1 and Cohort 2
  DOR, EFS and OS will be listed in Cohort 1.  No patients were enrolled in Cohort 2.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
one treatment arm of CTL019.
The overall observation period will be divided into two mutually exclusive segments:

pre-infusion period: from day of patient’s informed consent/assent to the day before 
infusion of CTL019

post-infusion period: starting at day of CTL019 infusion
10.5.3.2 Adverse events (AEs)
Reporting of adverse events will be based on MedDRA and CTCAE version 4.03.
Summary tables for adverse events have to include only AEs that started or worsened during 
the post-infusion period, i.e. the treatment-emergent AEs. However, all safety data (including 
those from the pre-infusion period) will be listed and those collected during the pre-infusion 
period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class, preferred term, severity (based on CTCAE grades), and 
relation to study treatment. 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 serious adverse events will be listed by patient and 
tabulated by type of adverse event.
Adverse events of special interest (AESI) search criteria are updated on a regular basis at the 
CTL019 program level. The most recent version of the AESI search criteria form will be used 
for the reporting activity. The current AESI search criteria are described in Table 10-3 below. 
AESI that occur within 8 weeks of the CTL019 infusion will be summarized by group term and 
preferred term.

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Table 10-3
Adverse events of special interest (AESI) search criteria
AESI group term
MedDRA term or other search criteria
Type
Cytokine Release Syndrome
Cytokine Release Syndrome
PT
Cytokine storm
PT
Shock
PT
Macrophage Activation
PT
Histiocytosis haematophagic
PT
Tumor Lysis Syndrome
Tumor Lysis Syndrome
SMQ
Febrile neutropenia
Neutropenic infection
PT
Neutropenic sepsis
PT
Febrile neutropenia
PT
Infection
Infections and infestations
SOC
Transient neuropsychiatric events
Noninfectious encephalopathy/ delirium
SMQ
Hematopoietic cytopenias not resolved by day 28
Haematopoietic cytopenias
SMQ
Lab abnormalities which do not resolve at least 28 
days post CTL019 infusion
Lab
10.5.3.3 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 be generated separately for hematology, biochemistry and 
urinary laboratory tests:

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)
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time-course of raw or change in laboratory tests over time or box plots might 
be specified in the Master Analysis Plan (MAP) and/or the Report and Analysis Plan (RAP).
10.5.3.4 Immunogenicity
Humoral immunogenicity assessment will include evaluation of pre-existing (pre-treatment) 
and post-treatment anti-CTL019 antibodies and to examine the incidence of immunogenicity 
with treatment, together with antibody titers, as a secondary endpoint. Data may be further 
fractionated to determine proportion of patients who make transient versus sustained antibody 
responses. The assay for humoral immunogenicity will be a cell-based assay, detecting 
antibodies that bind to a Jurkat cell line transfected with the CTL019 construct. This cell line 
stably expresses the complete CTL019 sequence and can be used to detect antibodies that bind 
to any epitope on the extracellular domain of the protein. Cellular immunogenicity assessment 
will include percentage of CD4+ and CD8+ T cells specific for CTL019 as an exploratory 
analysis and reported as appropriate.

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10.5.3.5 Derivation of a score to predict cytokine release syndrome
Clinical and biomarker data will be analyzed to potentially identify an early predictive score 
which reflects the risk of developing severe cytokine release syndrome. Only parameters that 
can be potentially utilized in clinical setting by treating physicians will be considered for the 
score development.
10.5.3.6 Soluble immune factors
Soluble immune and inflammatory cytokines (e.g. IL-10, interferon gamma, IL-6, IL-6 receptor, 
CRP, and ferritin) will be listed and summarized by patient and time point. Baseline and 
absolute and relative change (percent and or fold change) from baseline will be calculated for 
each treatment group and time point and summarized using sample size, mean, standard 
deviation, median, minimum and maximum. If both the baseline and post baseline values are 
below LLOQ, absolute, percent and fold change from baseline will not be imputed and reported 
as missing. Baseline levels may also be summarized by clinical response status and severity of 
CRS and potentially graphed using strip plots. In addition, the maximum change from baseline 
measure for each cytokine may also be graphed against clinical response status and severity of 
CRS response using strip plots. Patient level and averaged cytokine measures and percent 
change from baseline may be displayed using longitudinal plots.
The general principles of analyzing biomarker data as outlined in Section 10.6.1 should also 
apply.
10.5.3.7 B-cell and T-cell level
The levels of B and T cells (peripheral blood and bone marrow) prior to and following CTL019 
infusion will be described.
Malignant and normal B cell populations will be listed and summarized by patient and time 
point. 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.
The general principles of analyzing biomarker data as outlined in Section 10.6.1 should also 
apply.
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

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10.5.3.8 Other safety data
Vital signs will be collected as clinically needed. Findings supportive of GVHD will be listed 
for patients who have received prior allogeneic SCT. All safety data will be listed.
10.5.3.9 Safety subgroup analysis
Key safety summaries for adverse events regardless of relationship to study drug by System, 
Organ, Class (SOC) and PT, and adverse events of special interest will be repeated on the Safety 
Set in the following subgroups:

Age: <10 years, ≥10 years to <18 years, ≥18 years

Gender: Male, Female

Race: White, Asian, Other

Ethnicity: Hispanic or Latino, Other

Prior response status: Primary refractory, Chemorefractory, Relapsed disease

Prior SCT therapy: Yes, No

Down syndrome: Yes, No
The objective of carrying out these subgroup analyses is to identify safety problems that are 
limited to a subgroup of patients or that are more commonly observed in a subgroup of patients.
Summary tables will only be performed if at least 5 patients are present in each subgroup. Some 
grouping of classes will be considered.
10.5.3.10 Safety in Cohort 1 and Cohort 2
All safety data (i.e., adverse events, AESI, key laboratory parameters, immunogenicity data, 
etc.) will be listed for Cohort 1. .
10.5.4
Pharmacokinetics
The following analyses will be performed for Main Cohort only. Only listings (i.e., PK 
parameters, CTL019 transgene level) will be presented for Cohort 1.
CTL019 concentrations in peripheral blood (and bone marrow and CSF if available) will be 
listed, graphed, and summarized by time point as assessed by the following (see Section 10.6.1):

CTL019 transgene levels as measured by q-PCR,

CTL019 transduced cells measured by flow cytometry of CD3-positive, 

CTL019 transduced cells measured by flow cytometry of CD3-positive/ CD4-positive and 
CD3-positive/CD8-positive CTL019 transduced cells. (exploratory only)
The PK parameters listed in Table 10-4 along with other relevant PK parameters will be 
estimated from the individual concentration versus time profiles using a non-compartmental 
approach within the modeling program Phoenix® (Pharsight, Mountain View, CA). The non-
quantifiable concentrations will be imputed to zero for PK concentration summaries, and will 
not be included for estimation of PK parameters. Results reported but deemed unreliable will 
be flagged and excluded from the summaries and PK parameter derivations.

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Table 10-4
Noncompartmental pharmacokinetic parameters
Parameter
Definition
AUC 0 - Tmax
The AUC from time zero to Tmax in peripheral blood (% or copies/µg x days)
AUC Tmax - 28d 
and M3
The AUC from time Tmax to day 28 and M3 or other disease assessment days, in 
peripheral blood (% or copies/µg x days)
AUC 0 - 28d and 
M3
The AUC from time zero to day 28 and M3 or other disease assessment days, in peripheral 
blood (% or copies/µg x days)
Cmax
The maximum (peak) observed in peripheral blood or other body fluid drug concentration 
after single dose administration (% or copies/µg)
Tmax
The time to reach maximum (peak) peripheral blood or other body fluid drug concentration 
after single dose administration (days)
T1/2
The half-life associated with the elimination phase slope of a semi logarithmic 
concentration-time curve (days) in peripheral blood
Clast
The last observed quantifiable concentration in peripheral blood (% or copies/µg)
Tlast
The time of last observed quantifiable concentration in peripheral blood (days)
Descriptive statistics of PK parameters will be summarized by mean, standard deviation, 
coefficient of variation, min and max. When a geometric mean will be presented, it will be 
stated as such. A range of values will be presented for selected variables. Since Tmax is generally 
evaluated by a nonparametric method, median values and ranges will be given for this parameter.
The relationship between anti-cytokine treatment, use of steroids, occurrence of 
immunogenicity or other relevant covariates and PK will be explored. Population or 
mechanistic PK/PD models may also be generated for ALL patients. For patients whose 
tocilizumab PK data were collected during CRS, the tocilizumab concentrations will be 
summarized by time points, relative to time of tocilizumab dose as appropriate and supported 
by data.
10.6
Exploratory objectives
10.6.1
Biomarkers
As a project standard, Novartis Oncology Biostatistics and Data Management will analyze only 
biomarkers collected in the clinical database. For exploratory markers, since the studies are not 
adequately powered to assess specific biomarker–related hypotheses, the goal of these 
exploratory statistical analyses should be considered as the generation of new scientific 
hypotheses or observing new trends. These hypotheses may be compared with results found in 
literature as well as verified with data derived from subsequent clinical trials. No adjustment 
for multiple comparisons is usually planned for exploratory analyses. Furthermore, additional 
post hoc exploratory assessments are expected and may be performed in Main Cohort.
There may be circumstances when a decision is made to stop sample collection, or not perform 
or discontinue the analysis of blood due to either practical or strategic reasons (e.g. issues 
related to the quality of the sample). Under such circumstances, the number of samples may be 
inadequate to perform a rigorous data analysis and the available data will only be listed and 
potentially summarized.

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10.6.1.1 Biomarker Data Analysis Set
The Full Analysis Set will be used for all biomarker analysis. Unless otherwise specified, all 
statistical analyses of biomarker data will be performed on patients with biomarker data.
10.6.1.2 Data handling
Serum cytokine data are generally log normally distributed. A Log2 transformation of the data 
is typically required for normalization prior to performing any statistical assessments. Values 
below the lower limit of quantitation (which may be reported with the label Lower Limit of 
Quantification [LLOQ]) or have a numerical value below the assay’s lower limit of 
quantification) will be imputed / replaced as 0.5×LLOQ, which will be specified by the 
performing lab and is assay and analyte specific. In some cases a value, although below LLOQ, 
is reported, this value should not be used and the data should be imputed as 0.5×LLOQ.
10.6.1.3 Basic tables, listings and figures
For Main Cohort, the ALL 
 as measured by 
 will be 
listed per patient and percent change from baseline will be summarized using sample size, mean, 
standard deviation, median, minimum and maximum. Patient level absolute and relative 
changes may be displayed using longitudinal plots. Additional analyses 
 
 that may be performed after the completion of the end-of-
study CSR will be documented in separate reports. These analyses may include but are not 
limited to the meta-analysis of data from this study combined with data from other studies or 
the analysis of biomarkers generated from samples collected during the study but analyzed after 
the database lock and completion of the CSR. The data analysis will be described in an 
addendum of the RAP or in a stand-alone analysis plan document, as appropriate.
10.6.2
CTL019 product characteristics
Selected clinical outcomes will be summarized descriptively by CTL019 product characteristics 
 for the Main Cohort.
10.6.3
Cytokine release syndrome
To explore the relationship between CRS and other endpoints, the goal of this statistical analysis 
should be considered as the generation of new scientific hypotheses and observing new trends, 
since the studies are not adequately powered to propose a scoring system. For Main Cohort, 
information regarding the severity of cytokine release syndrome, and response to anti-cytokine 
therapy, if any, will be listed and summarized. The summarization is descriptive only to be in 
line with its exploratory nature. Summary by initial tumor burden, clinical tumor response status, 
and PK/PD parameters may be explored.
10.6.4
Healthcare resource utilization
Data relating to resource utilization (described in Section 7.2.6) will be used to support health 
economic evaluations.

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Number of CTL019 inpatients and outpatients infusions will be summarized in Main Cohort. 
Descriptive statistics of hospitalizations, including the total and average number and duration 
of hospitalizations, will be provided in Main Cohort.
Details of data analysis will be specified in the analysis plan as appropriate.
10.7
Interim analysis for Main Cohort
10.7.1
Interim analysis for the primary endpoint
An interim analysis is planned when the first 50 patients infused have completed 3 months from 
study day 1 infusion or discontinued earlier. The interim analysis will be performed by testing 
the null hypothesis of ORR within 3 months being less than or equal to 20% against the 
alternative hypothesis of ORR within 3 months being greater than 20% at overall one-sided 2.5% 
level of significance. 
The study will not be stopped for outstanding efficacy at the interim analysis regardless of the 
interim result.
An α-spending function according to Lan-DeMets (O’Brien-Fleming), as implemented in East 
5.4, will be used to construct the efficacy stopping boundaries (Lan and DeMets 1983). Based 
on the choice of α-spending functions described above, if the interim analysis is performed 
exactly with 50 patients and final analysis will include up to 76 patients (i.e. 50/76=65.8% 
information fraction), the lower bound of the 2-sided 98.9% exact CI of the ORR will need to 
be greater than 20% to declare statistical significance. As a result, an ORR of 19/50 = 38% is 
needed to claim success at interim. If the interim efficacy boundary is not crossed, 2-sided 95.4% 
exact CI will be used at final analysis correspondingly. As a result, an ORR of 23/76 = 30% 
will be needed to claim success at final analysis.
The efficacy boundary at the final analysis will be based on the actual number of patients and 
the alpha already spent at the interim analysis. If the number of patients in the final analysis 
deviates from the expected number of patients, the final analysis criteria will be determined so 
that the overall significance level across all analyses is maintained at one-sided 0.025.
10.7.2
Interim analysis for the key secondary endpoints
If the primary endpoint is met at the interim analysis, the key secondary endpoints will also be 
assessed following hierarchical sequence using an α-spending function according to Lan-
DeMets (O’Brien-Fleming).
10.7.2.1 ORR within 3 months in all patients infused with CTL019 from US 
manufacturing facility
Based on the choice of α-spending functions described above, if the interim analysis is 
performed exactly with 50 patients and final analysis will include up to 66 patients (i.e. 
50/66=75.8% information fraction), the lower bound of the 2-sided 98.0% exact CI of the ORR 
will need to be greater than 20% to declare statistical significance. As a result, an ORR of 18/50 
= 36% is needed to claim success at interim. If the interim efficacy boundary is not crossed, 2-
sided 95.6% exact CI will be used at final analysis correspondingly. As a result, an ORR of 
21/66 = 32% will be needed to claim success at final analysis.

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10.7.2.2 Remission with MRD negative bone marrow in patients infused with 
CTL019 from all manufacturing facilities
Based on the choice of α-spending functions described above, if the interim analysis is 
performed exactly with 50 patients and final analysis will include up to 76 patients (i.e. 
50/76=65.8% information fraction), the lower bound of the 2-sided 98.9% exact CI will need 
to be greater than 15% to declare statistical significance. As a result, a MRD negative rate of 
15/50 = 30% is needed to claim success at interim. If the interim efficacy boundary is not 
crossed, 2-sided 95.4% exact CI will be used at final analysis correspondingly. As a result, an 
ORR of 19/76 = 25% will be needed to claim success at final analysis.
10.7.2.3 Remission with MRD negative bone marrow in patients infused with 
CTL019 from US manufacturing facility
Based on the choice of α-spending functions described above, if the interim analysis is 
performed exactly with 50 patients and final analysis will include up to 66 patients (i.e. 
50/66=75.8% information fraction), the lower bound of the 2-sided 98.0% exact CI of the ORR 
will need to be greater than 20% to declare statistical significance. As a result, an ORR of 15/50 
= 30% is needed to claim success at interim. If the interim efficacy boundary is not crossed, 2-
sided 95.6% exact CI will be used at final analysis correspondingly. As a result, an ORR of 
17/66 = 26% will be needed to claim success at final analysis.
10.8
Sample size calculation
Main Cohort
In a previous study of clofarabine in patients with r/r B-cell ALL who have had 2 or more prior 
regimens, the reported ORR was 20% (95% CI [10%, 34%], Jeha et al (2006)). Hence, an ORR 
of 45% that excludes a 20% ORR at the 0.025 significance level would indicate meaningful 
efficacy in this highly refractory population.
The final analysis of the primary endpoint will be performed after all patients infused with 
CTL019 have completed 3 months follow-up from study day 1 infusion or discontinued earlier. 
The sample size for the final analysis of the primary endpoint will be up to 76 patients.
Based on the null hypothesis of ORR ≤ 20% and alternative hypothesis of ORR > 20%, 76 
patients in the FAS will provide more than 95% power to demonstrate statistical significance at 
one-sided 0.025 level of significance, if the underlying ORR is 45%, taking into account the 
interim analysis as described in Section 10.7. In this setting, an ORR of 30% (=23/76) will be 
needed to claim success.
Within the expected sample size of 76 patients with CTL019, at least 10 patients will be treated 
with CTL019 manufactured by the Fraunhofer Institute.  If there are at least 6 patients among 
them who achieved best overall response of CR or CRi, the lower bound of the 95% confidence 
interval will be higher than 20%. The probability of observing at least 6 CR or CRi among the 
10 patients will be 26% if the true ORR is 45%, and will be 84% if the true ORR is 70%.

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Table 10-5
Confidence intervals for ORR in patients infused with CTL019 
manufactured by the Fraunhofer Institute
Total number of patients
CR + CRi
95% Exact CI
10
5
(18.7%, 81.3%)
6
(26.2%, 87.8%)
7
(34.8%, 93.3%)
8
(44.4%, 97.5%)
9
(55.5%, 99.7%)
10
(69.2%, 100%)
The actual number of patients to be enrolled will depend on the pre-infusion dropout rate. 
Limited data are available so far to provide robust estimate on the pre-infusion dropout rate. 
Assuming 20% to 25% enrolled patients will not be infused due to reasons such as CTL019 
product manufacturing issues, worsening of patient’s condition, etc., approximately 95 patients 
need to be enrolled respectively to reach the number of patients required.
Cohort 1 (US only)
With 10 treated patients in Cohort 1, the confidence intervals for ORR in Cohort 1 will be the 
same as that of patients infused with CTL019 manufactured by the Fraunhofer Institute (Table 
10-5). That is, if there are at least 6 patients in Cohort 1 who achieved best overall response of 
CR or CRi, the lower bound of the 95% confidence interval will be higher than 20%. The 
probability of observing at least 6 CR or CRi among the 10 patients in Cohort 1 will be 26% if 
the true ORR is 45%, and will be 84% if the true ORR is 70%. Only one patient was enrolled 
in Cohort 1 at the time of termination.
Cohort 2 (US only)
The purpose of Cohort 2 is to treat at least 5 patients which received CTL019 within 6 months 
from allo-HSCT to obtain clinical experience (feasibility and safety) in this group of patients. 
The data will be analyzed descriptively only. No patient was enrolled in Cohort 2 at the time of 
enrollment termination.
10.9
Power for analysis of key secondary variables for Main Cohort
10.9.1
ORR within 3 months in patients infused with CTL019 from US 
manufacturing facility
The same efficacy is assumed for patients infused with CTL019 in US manufacturing facility 
vs other manufacturing facilities. Under this assumption and conditional on the statistical 
significance of the primary endpoint, the over power of this endpoint will be greater than 95%, 
taking in account an interim analysis will be performed with first 50 patients, and then a final 
analysis will be performed with up to 66 patients with CTL019 from US manufacturing facility.
10.9.2
Remission with MRD negative bone marrow in patients who received 
CTL019 from all manufacturing facilities
In previous studies in the r/r ALL setting, 67% to 82% patients achieved MRD negative status 
among patients who achieved CR or CRi (Topp et al 2015, O'Brien et al 2012). Considering 

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that an ORR of 45% that excludes 20% at the 0.025 significance level would indicate 
meaningful efficacy for ORR, 34% of patients achieving MRD negative bone marrow that 
excludes 15% at the 0.025 significance level would indicate meaningful efficacy (i.e. 75% 
among complete responders) for the key secondary objective.
Based on the above assumptions, conditional on the statistical significance of the primary and 
the first key secondary endpoint, and taking into account the interim analysis with first 50 
patients as described above, up to 76 patients in the FAS will provide greater than 95 % power 
to demonstrate statistical significance at one-sided 0.025 level of significance, if the underlying 
percentage of patients who achieve BOR or CR or CRi with MRD negative bone marrow is 
34%.
10.9.3
Remission with MRD negative bone marrow in patients who received 
CTL019 from US manufacturing facility
The same efficacy is assumed for patients infused with CTL019 in US manufacturing facility 
vs other manufacturing facilities. Under this assumption and conditional on the statistical 
significance of the primary and first 2 key secondary endpoints, the power of this endpoint will 
be 94%, taking in account an interim analysis will be performed with first 50 patients, and then 
a final analysis will be performed with up to 66 patients with CTL019 from US manufacturing 
facility.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice (GCP), with applicable local regulations (including European Directive 
2001/20/EC and US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent/assent form must be reviewed and approved 
by a properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 

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patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent/assent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol). The process of obtaining informed 
consent/assent should be documented in the patient source documents. The date when a 
patient’s informed consent/assent was actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) and assent form that is considered appropriate for this study and complies with the 
ICH GCP guideline and regulatory requirements. Any changes to this ICF/assent suggested by 
the investigator must be agreed to by Novartis before submission to the IRB/IEC/REB, and a 
copy of the approved version must be provided to the Novartis monitor after IRB/IEC/REB 
approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Male participants 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.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.3.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including timely communication and publication of clinical trial results, 
whatever their outcome.  Novartis assures that the key design elements of this protocol will be 
posted on the publicly accessible database, e.g.www.clintrials.gov before study start. In addition, 
results of interventional clinical trials in adult patients are posted to novartisclinicaltrials.com, 
a publicly accessible database of clinical study results within 1 year of study completion (i.e. 
LPLV); those for interventional clinical trials involving pediatric patients within 6 months of 
study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency.  Author(s) may be requested to 

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present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports full disclosure 
of all funding sources for the study and publications, as well as any actual and potential conflicts 
of interest of financial and non-financial nature by all authors, including medical 
writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study electronic case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. For eCRFs an audit trail will be 
maintained by the system.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless the sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.

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11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis, with the exception of information required to 
manufacture CTL019 product provided to limited personnel at the manufacturing facility. 
Signed informed consent/assent forms and patient enrollment log must be kept strictly 
confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. United Kingdom (UK) requires the notification of urgent 
safety measures within 3 days) but not later than 10 working days.

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Appendices
14.1
Appendix 1: Guidelines for efficacy evaluation in Acute 
Lymphoblastic Leukemia (ALL) studies
Document history
Version
Date
Changes
Draft v1.0
26-Jul-2013
First draft version for SPA
Draft v2.0
2-Dec-2013
Second draft version for SPA

CSF assessment by LP is required to establish CR or CRi for the 
first time

If there is extramedullary disease captured by physical exam, 
results will be classified by suspicion for leukemic involvement

Clarify the population for time to event variable analysis

For the analysis of DOR and other time to event endpoints, 
recommend to perform primary analysis by censoring SCT and 
sensitivity analysis by ignoring SCT

Add recommendation of sensitivity analysis of DOR considering 
death due to ALL as a competing risk

Clarify that for EFS patients who do not achieve complete response 
(CR or CRi) will be considered to have had an event on Day 1. 
Furthermore, patients who withdraw consent or are lost to follow-up 
will be censored in EFS analysis (rather than being considered to 
have had an event)

Other minor editorial changes
Draft v3.0
17-Jan-2014
Third draft version for SPA

Remove wording regarding acute lymphoblastic lymphoma because 
they will be excluded from the population to study

Revise wording regarding “clinical evidence of relapse” which is 
determined by peripheral blood assessment and extramedullary 
assessment (physical exam and CNS symptom assessment)

For the analysis of DOR, “death due to reason other than ALL” will 
be considered as a competing risk event for primary analysis
Draft v4.0
7-Mar-2014
Final version for SPA
Final v1.0
5-Mar-2014
First final version
Final v1.1
23-Dec-2014
Change the calculation of overall response date so that if the overall 
response classified as “No response”, the date of overall response will 
be calculated as the earliest of any component that reveals lack of 
response.
Final v1.2
26-Aug-2015

Clarify that the qualitative assessment of tumor involvement will be 
used to determine response status when no blast count result is 
available from either bone marrow biopsy or aspirate.

Clarify that peripheral blood can be considered to be in remission 
status when bone marrow is in remission status at the same time.

Change the baseline disease assessment definition to indicate that 
the most current assessments within the protocol specified window 
will be used

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Version
Date
Changes
Final v1.3
23-Feb-2016

Remove the wording of Trilineage Hematopoiesis in the response 
assessment because the criteria for assessment, rigorous, and 
reproducible documentation of “trilineage hematopoiesis” in the 
marrow has not been well established. This can alternately be 
supported, in a reproducible and quantitative manner, by the use of 
peripheral blood platelet and neutrophil minimum values in the 
absence of transfusion of these blood components.

Change the baseline disease assessment definition to indicate that 
the most current assessment prior to enrollment/randomization will 
be used. Given the potentially long interval between enrollment and 
infusion of CTL019, more restricted time interval definition of 
baseline disease assessment is now implemented.

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List of abbreviations
ALL
Acute lymphoblastic leukemia
AML
Acute myeloid leukemia
ASH
American Society of Hematology
CHMP
Committee for Medicinal Products for Human Use
CR
Complete remission
Cri
CR with incomplete blood count recovery
(e)CRF
(electronic) case report form
CSF
Cerebral spinal fluid
CT scan
Computed Tomography scan
DOR
Duration of response
EFS
Event-free survival
FDA
United States Food and Drug Administration
IWG
International Working Group
LP
Lumbar puncture
mcL
Micro liter
MNC
Mononuclear cells
MRD
Minimal residual disease
NCI-WG
National Cancer Institute-Working Group
NCCN
National Comprehensive Cancer Network
ORR
Overall remission rate
OS
Overall survival
PR
Partial remission
RAP
Report and Analysis Plan
RBC
Red blood cell
PQ-PCR
Real-time quantitative polymerase chain reaction
RFS
Relapse-free survival
SCT
Stem cell transplant
SPD
Sum of the product of the diameters
TOC
Table of Contents
TTR
Time to remission
WBC
White blood cell

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14.1.1
Introduction
This document provides the working definitions and specifications for a consistent and efficient 
analysis of efficacy for CTL019 clinical studies assessing antineoplastic activity in adult and 
pediatric acute lymphoblastic leukemia (ALL). The current document is written primarily for 
the relapse and refractory disease setting. Modifications may be indicated for earlier disease 
settings.
This document is based on the standardized response criteria defined by National 
Comprehensive Cancer Network (NCCN) Guidelines (NCCN 2013 v1) and further supported 
by the workshop report on acute leukemia from American Society of Hematology (ASH) 
(Appelbaum et al 2007) and the International Working Group (IWG) guideline for acute 
myeloid leukemia (AML) (Cheson et al 2003).
The Cheson IWG guideline and Appelbaum ASH report were used in recent drug approvals 
(e.g. Marqibo) in ALL, prior to the NCCN guideline availability. The NCCN guidance is a more 
recently published United States based guideline for ALL.
The objectives of this document are to:

Ensure that the definitions of responses in a clinical study protocol correctly reflect the 
above mentioned guidelines.

Provide guidance for the response assessment and clinical monitoring to ensure 
consistency in applying the guidelines.
Moreover, this document describes data handling and derivation rules. Respective sections may 
be used in the report and analysis plan (RAP) to provide further details. Relevant sections of 
this document will be copied into individual clinical trial protocols as appendix to the protocol.
14.1.2
Efficacy evaluation
Efficacy assessments are based on bone marrow and blood morphologic criteria, physical 
examination findings, along with laboratory assessments of cerebral spinal fluid (CSF) and bone 
marrow minimal residual disease (MRD) assessment. Radiologic assessments are used only in 
specific settings as defined below. It needs to be clearly specified in the protocol which response 
categories are considered as primary. Selection criteria for choosing efficacy endpoints should 
reflect the study setting accordingly.
14.1.2.1 Types of efficacy assessments
Disease characterization at baseline and evaluation of response rely on the following:

Bone marrow assessment

Peripheral blood assessment

Extramedullary disease assessment, including

CNS disease

Other extramedullary sites

Minimal residual disease (MRD) assessment of bone marrow
For timing and window of the disease assessments for response classification, see Section 
14.1.2.3.1 for details.

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14.1.2.1.1
Assessment of bone marrow blast counts
Bone marrow will be assessed for blast cells. Percentage of blast cells will be determined by 
morphologic or cytologic examination. This assessment can be performed on bone marrow 
biopsy and/or aspirate. If the blast counts are assessed, results from these assessments are 
considered to be interchangeable. Some laboratories do not perform differential counts on bone 
marrow biopsies, but rather provide a qualitative assessment whether there is tumor 
involvement or not: i.e. Yes or No tumor (blast) cells are seen in the bone marrow biopsy section 
or the touch print from the bone marrow biopsy. In this case, it may not be possible to 
definitively determine whether the blast count is <5% or not.
Both bone marrow biopsy and aspirate tests will be considered for response assessment as 
follows:

In the case of only one assessment with non-missing blast count values: Result of the non-
missing assessment will be used.

In the case of both assessments with differing, non-missing blast count values: The highest 
blasts value will be considered. The corresponding assessment date will be used as 
reference for other assessments for the determination of evaluation windows.

In the case of no blast count values available from either aspirate or biopsy, but a 
qualitative assessment of tumor involvement from biopsy is available: The bone marrow 
result will be considered to be in remission if there is no tumor involvement, and will be 
considered to indicate no response or relapsed disease if there is tumor involvement.

In the case of no blast count values available from either aspirate or biopsy, and no 
qualitative assessment of tumor involvement from biopsy is available: The bone marrow 
result will be considered as “unknown”.
14.1.2.1.2
Assessment of peripheral blood
All values must be taken from the same blood sample. Relevant variables are platelet and 
neutrophil counts and percentage of leukemic blasts. Recent transfusion status also has to be 
taken into account (See Section 14.1.2.3.3 for details).
If the peripheral blood count is so low that a differential count cannot be obtained (e.g. typically 
when WBC < 0.5 x 109/L preventing an accurate assessment of differential count), but the bone 
marrow result is showing complete remission status (per definition in Table 14-1). In this case, 
the patient will also be considered to be in remission status in peripheral blood.
14.1.2.1.3
Assessment of extramedullary disease
Extramedullary involvement is to be assessed at baseline and at each visit for response 
assessment. Presence or absence and physical location of extramedullary disease is to be 
captured in the (e)CRF.
Extramedullary disease is to be assessed via physical examination, CSF assessment, and if 
clinically appropriate relevant imaging techniques. In case of extramedullary disease at baseline 
or (re-)appearance during the study, the lesions should be considered for confirmation by 
imaging or biopsy if technically and/or clinically feasible.

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14.1.2.1.3.1 Assessment of CNS disease
Baseline CSF assessment by lumbar puncture (LP) is mandatory. The frequency and timing of 
post-baseline CSF assessment may depend upon the study setting and standard of care for each 
setting (e.g. front line or relapse/refractory, pediatric vs adult, etc.) and should be clearly 
specified in the protocol. At a minimum, lumbar puncture should be performed as clinically 
indicated by the presence of neurologic symptoms.
The classification of CNS status includes the following:

CNS-1 refers to no lymphoblasts in the CSF regardless of WBC count;

CNS-2 is defined as WBC less than 5/mcL in CSF with presence of lymphoblasts;

CNS-3 is defined as WBC of 5/mcL or greater with presence of lymphoblasts.
If the patient has leukemic cells in the peripheral blood and the LP is traumatic and WBC ≥ 
5/mcL in CSF with blasts, then compare the CSF WBC/RBC ratio to the blood WBC/RBC ratio. 
If the CSF ratio is at least two-fold greater than the blood ratio, then the classification is CNS-
3; if not, then it is CNS-2.
CNS remission is defined as achievement of CNS-1 status in a patient with CNS-2 or CNS-3 
at initial assessment.
CNS relapse is defined as development of CNS-3 status or development of clinical signs of 
CNS leukemia (e.g., facial nerve palsy, brain/eye involvement, hypothalamic syndrome, etc.). 
If clinical signs of CNS leukemia exist, it must be confirmed by CNS imaging (CT or MRI of 
brain) or other relevant methods (e.g. biopsy, LP, etc.) to define CNS relapse.
14.1.2.1.3.2 Assessment of mediastinal disease
Radiographic assessments are not standard components for routine disease assessments of acute 
lymphoblastic leukemia (NCCN 2013 v1, Cheson et al 2003).
The classification of mediastinal response in NCCN 2013 v1 based on radiographic assessments 
is hence not applicable for studies where only acute lymphoblastic leukemia patients are studied.
14.1.2.1.3.3 Assessment of other extramedullary disease
The assessment of other extramedullary disease (hepatomegaly, splenomegaly, skin/gum 
infiltration, testicular mass or other masses) will be performed via physical exam.
Hepatomegaly and splenomegaly due to leukemic involvement, disease involvement by lymph 
nodes, infiltration of the skin or gums, unilateral or bilateral testicular mass, or other masses 
will be assessed by physical exam. Results will be coded as “Normal”, “Abnormal with no or 
low suspicion for leukemic involvement”, or “Abnormal with high suspicion for leukemic 
involvement”. The rationale for these three categories is as follows. Other abnormalities that 
are not related to leukemic infiltration can often be observed in these organ sites on physical 
examination in patients with ALL, especially during the first 28 days after lymphodepleting 
chemotherapy followed by CTL019 cell infusion. Definitive proof of leukemic infiltration (e.g. 
liver biopsy) is often not definitive, indicated or ethically justified. Some abnormalities may 
occur (e.g. ecchymosis in skin or gums, acute/transient hepatosplenomegaly associated with 
acute infections or Macrophage Activation Syndrome (MAS)) but are clearly not leukemic 

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involvement. Therefore three categories will more accurately capture these different clinical 
scenarios. In the analysis, “Normal” or “Abnormal with no or low suspicion for leukemic 
involvement” will be considered eligible for overall CR or CRi assessment; “Abnormal with 
high suspicion for leukemic involvement” will not be considered eligible for overall CR or CRi 
assessment, and will be considered to trigger relapsed disease assessment. Serial physical 
examinations for these assessments will be performed (at protocol specified frequency) to 
validate the persistence or resolution of such findings.
Lymph nodes on physical exam are considered to be abnormal if greater than 1.5 cm. Note that 
although the cutoff of 1.5 cm is not defined in the NCCN (NCCN 2013 v1) or the Cheson 
guidelines (Cheson et al 2003), it is used in the international harmonization project revised 
response criteria for lymphoma (Cheson (2007a) and Cheson (2007b)) and the international 
working group guideline for chronic lymphocytic leukemia (Hallek et al 2008).
14.1.2.1.4
Assessment of minimum residual disease (MRD) in bone marrow
MRD in ALL refers to the presence of leukemic cells below the threshold of detection using 
conventional morphologic methods. Patients who experienced a CR according to morphologic 
assessment alone can potentially harbor a large number of leukemic cells in the bone marrow: 
up to 1010 malignant cells which can confer a poor outcome. The most frequently used methods 
for MRD assessment include multicolor flow cytometry to detect abnormal immunophenotypes 
and PCR assays to detect clonal rearrangements in immunoglobulin heavy chain genes and/or 
T-cell receptor genes or fusion transcripts (e.g. BCR-ABL). Current flow cytometry or PCR 
methods can detect leukemic cells at a sensitivity threshold of fewer than 1 × 10-4 (<0.01%) 
 The concordance rate for detecting MRD between 
these methods is high. Numerous studies in childhood and adult ALL have shown the prognostic 
importance of post-induction (and/or post-consolidation) MRD measurements in predicting the 
likelihood of disease relapse. The timing of MRD assessment varies depending on the ALL 
treatment protocol and the disease setting (e.g. initial/up front treatment vs relapse/refractory). 
For MRD evaluation on multicolor flow cytometry, sampling of bone marrow MNCs is 
preferred over peripheral blood samples. At least 1 × 106 MNCs are required for analysis (≈ 2 
mL of bone marrow or 5–10 mL of peripheral blood provides sufficient number of cells for 
multiple analysis). For MRD evaluation with real-time quantitative PCR (RQ-PCR), sampling 
of bone marrow MNC is preferred. At least 1 × 107 MNCs are required for initial marker 
characterization and generation of individual dilution series; 1 × 106 MNCs are sufficient for 
follow-up analysis. The minimal limit of assay sensitivity (to declare MRD negativity) should 
be less than 1 × 10-4 (< 0.01%).
For Ph+ ALL, BCR-ABL quantitative PCR may also be used to assess MRD status.
The timing of MRD assessment is dependent upon the disease setting and should be specified 
in the protocol.
MRD assessment by flow cytometry or RQ-PCR should be performed via a central certified lab 
with 0.01% sensitivity. MRD by 
14.1.2.2 Baseline evaluation
The following baseline assessments are mandatory:

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
Bone marrow biopsy and/or aspirate for blast cell counts (Section 14.1.2.1.1)

Peripheral blood for blast, neutrophil and platelet cell counts (Section 14.1.2.1.2)

CSF cytology via lumbar puncture for WBC, RBC cell and lymphoblast numbers (Section 
14.1.2.1.3.1)

CNS imaging (CT or MRI) or other appropriate assessment if clinical signs of CNS 
leukemia exist (Section 14.1.2.1.3.1)

Physical exam for extramedullary disease (Section 14.1.2.1.3.3)

Blood and bone marrow MRD assessment by flow cytometry (Section 14.1.2.1.4)

Cytogenetics and/or FISH from bone marrow aspirate
For disease characterization at baseline, the most current assessments (bone marrow, blood 
count, CSF, physical exam, etc.) on or prior to the date of enrollment/randomization should be 
used as the baseline assessment.
14.1.2.3 Post-baseline overall disease response evaluation
14.1.2.3.1
Components and timing of overall disease response evaluation
The initial achievement of CR or CRi will require evaluation of remission in bone marrow, 
peripheral blood, and the absence of extramedullary disease. Following initial achievement of 
CR or CRi, if the patients have normal peripheral blood, physical exam and no CNS symptoms, 
they will be considered to remain in clinical CR or CRi, i.e. there is no clinical evidence of 
relapse (Section 14.1.2.3.4).
An overall disease response evaluation must consist all of the following components:

Peripheral blood for morphologic blast, neutrophil and platelet cell counts (Section 
14.1.2.1.2)

CNS symptom assessment (Section 14.1.2.1.3.1)

Physical examination for extramedullary disease (Section 14.1.2.1.3.3)
In addition,

Post-baseline bone marrow biopsies and/or aspirates (Section 14.1.2.1.1) for morphologic 
blast cell counts are required to demonstrate that a patient has achieved CR or CRi for the 
first time. Following initial achievement of CR or CRi, a bone marrow biopsy or aspirate 
will not be required unless it is clinically indicated (e.g. worsening of platelet or 
neutrophils; reappearance of blast in peripheral blood, etc.) or as specified per individual 
protocol.

Post-baseline CSF cytology via lumbar puncture (Section 14.1.2.1.3.1) is required to 
demonstrate that a patient has achieved CR or CRi for the first time. Following initial 
achievement of CR or CRi, a lumbar puncture will not be required unless it is clinically 
indicated by the presence of neurologic symptoms and as specified per individual 
protocol.

MRD assessment (Section 14.1.2.1.4) should be performed per protocol specification.
In order for all components of disease assessments to be qualified as the same response 
evaluation, peripheral blood sample collection, CNS symptom assessment, physical exam, bone 

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marrow biopsy/aspirate (if needed) and lumbar puncture (if needed) need to be performed, in 
general, within 14 days of each other, unless specified otherwise in the protocol.
In case of missing data for the full evaluation required to qualify for a certain response category, 
the overall evaluation “unknown” will be assigned unless at least one observation was made 
which qualifies for relapse. Relapse can be determined by the relapsed component alone.
Also see Section 14.1.2.3.2 and Section 14.1.2.3.4 for the definition and confirmation of disease 
response.
The frequency of response evaluation for each component needs to be clearly specified in the 
protocol. The timing should be coordinated so that a full response evaluation can be made.
14.1.2.3.2
Response criteria
The overall disease response is determined at a given evaluation using the criteria described in 
Table 14-1. Note that:

The NCCN guidance (NCCN 2013 v1) has defined a progressive disease (PD) category. 
In this document, PD is considered the same as “No response”, which is consistent with 
Cheson et al (2003) guideline. The difference between PD and “No response” in ALL is 
not believed to be clinically meaningful.

See Section 14.1.2.1.1 for details regarding assessing bone marrow response status.

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Table 14-1
Overall disease response classification at a given evaluation time
Response category
Definition
Complete remission (CR)
All the following criteria are met:
Bone marrow

< 5% blasts
Peripheral blood

Neutrophils > 1.0 x 109/L, and

Platelets > 100 x 109/L, and

Circulating blasts < 1%
Extramedullary disease

No clinical evidence of extramedullary disease (by physical exam and CNS 
symptom assessment) and

If additional assessments (e.g. CSF assessment by LP, CNS imaging, biopsy, 
etc.) are performed, results must show remission status
Transfusion independency (see Section 14.1.2.3.3).

No platelet and/or neutrophil transfusions less than or equal to 7 days before the 
date of the peripheral blood sample for disease assessment
Complete remission with 
incomplete blood count 
recovery (CRi)
All criteria for CR as defined above are met, except that the following exist:

Neutrophils ≤ 1.0 x 109/L, and/or

Platelets ≤ 100 x 109/L, and/or

Platelet and/or neutrophil transfusions less than or equal to 7 days before the 
date of the peripheral blood sample for disease assessment
No response
Failure to attain the criteria needed for any response categories or relapse
Relapsed Disease
Only in patients who achieved a CR or CRi and who have:

Reappearance of blasts in the blood (≥ 1%), or

Reappearance of blasts in bone marrow (≥ 5%), or

(Re-)appearance of any extramedullary disease after CR or CRi
Unknown
“Unknown” is assigned in case the baseline assessment or the response assessment 
is not done, incomplete, indeterminate, or not performed within the respective time 
frame (Section 14.1.2.2 and Section 14.1.2.3.1).
If there is evidence of relapse, the overall response will assessed as “relapsed 
disease” with the relapsed component alone.
14.1.2.3.3
Evaluation of transfusion dependency
Information on transfusion dependency will be assessed at baseline as well as during the course 
of the trial for all patients. Transfusion of blood products will be recorded in a separate module 
of the (e)CRF. The type of transfusion, start and end date as well as the volume of blood product 
will be captured at each visit with hematologic assessment.
A period of at least one week (7 days) without any transfusion has been taken as a convention 
to define the status of transfusion independence to assess a CR vs CRi response (Cheson et al 
2006). Any sample of peripheral blood sample for disease assessment which was taken less than 
or equal to seven days after a transfusion will be considered as transfusion dependent.
14.1.2.3.4
Establishing CR/CRi and subsequent maintenance of CR/CRi with no 
clinical evidence of relapse
A full response evaluation, including assessments of peripheral blood, bone marrow, CNS 
symptoms, physical exam and CSF assessment by LP, is required at the first time a CR or CRi 

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is demonstrated (Section 14.1.2.3.1). Bone marrow biopsy/aspirate and CSF assessment by LP 
are required 1 month (Day 28) after infusion. If the patient is not in CR/CRi at Month 1, then a 
bone marrow biopsy/aspirate and CSF assessment by LP are also required at the first time 
clinical evidence of remission is seen by peripheral blood and extramedullary disease 
assessment (physical exam and CNS symptom assessment) to establish that a patient has 
achieved CR/CRi for the first time. Additional bone marrow biopsies/aspirates and CSF 
assessments by LP may be recommended in the protocol.
Complete remissions in patients with ALL have been observed to take place within 1 month 
after infusion with CTL019. The onset of complete remissions are rapid and dramatic, and 
patients quickly regain a normal performance status. ALL relapse in the bone marrow is rapidly 
followed by signs or symptoms of disease recurrence as well as abnormalities in the peripheral 
blood.
Therefore, following initial achievement of CR/CRi, patients will be considered to have 
maintained a clinical CR/CRi if the patient has no evidence of extramedullary disease (by 
physical exam and CNS symptom assessment) and circulating blasts in peripheral blood are 
<1%.
In order for the best overall disease response to be categorized as CR or CRi, there must be no 
clinical evidence of relapse as assessed by peripheral blood and extramedullary disease 
assessment (physical exam and CNS symptom assessment) at a minimum of 4 weeks (28 days) 
after the initial achievement of CR or CRi. Please note, if additional assessments (e.g. bone 
marrow, CSF assessment by LP, CNS imaging, biopsy, etc.) are performed (Section 14.1.2.3.1) 
in the same evaluation for disease response evaluation purpose, they will also need to show 
remission status.
The onset date of CR or CRi will then be derived as the evaluation date of the initial CR or CRi 
assessment. If a patient satisfied CRi at one evaluation and later confirmed as a CR in the next 
evaluation, the patient will be considered as having confirmed CR. However, the date of CR 
will be derived as the latter (confirmed) evaluation date.
14.1.2.3.5
Date of overall disease response evaluation
A complete evaluation of response includes at the minimum the assessments of peripheral blood, 
CNS symptoms and physical exam. In addition, bone marrow and CSF assessment may be 
required. All components of disease assessments must be performed within the specified time 
frame (Section 14.1.2.3.1) to be qualified as the same response evaluation.
If the overall disease response is CR, CRi, or Unknown, the evaluation date (i.e. for one 
evaluation number) is defined as the latest of all dates of required measurements at that 
evaluation number. This rule applies also in case of multiple measurements of the same variable.
Relapse or No response can be assessed based on a partial evaluation (e.g. a relapse is assessed 
from blood alone). The assessment date for relapse or no response is calculated as the earliest 
date of all assessments that reveal a relapse or lack of response.

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14.1.3
Data collection
14.1.3.1 Data sources
The summary of data sources refers to disease-specific (e)CRF standard modules. It is not 
appropriate to deviate from these specifications in Table 14-2.
Table 14-2
Data sources
(e)CRF module
Specification
Overall disease response
Overall disease response and assessments of individual components from

bone marrow;

blood;

CNS disease;

other extramedullary disease.
Bone marrow biopsy / aspirate
Aspirate or biopsy; morphologic blast counts and MRD assessment.
Blood response
Response status for platelets, neutrophils, morphologic blast counts; status 
of platelet and/or neutrophils transfusion.
CSF assessment 1
CSF lymphoblast, WBC, RBC
Other CNS disease
CNS symptoms, confirmation of CNS disease via imaging or other methods 
(if applicable)
Extramedullary disease by 
physical exam
Presence/absence, location, method of assessment, confirmation by biopsy 
or imaging or not if feasible
Blood component transfusions
Type and number of units of transfusions, timing with respect to disease 
assessment
Hematopoietic Stem Cell 
Transplant (SCT) – post infusion
Date, type of post-treatment SCT
1 When there is clinical signs of CNS disease and/or at protocol specified time points
14.1.3.2 Recording response evaluation on the (e)CRFs
The components and timing needed to adequately assess overall disease response is outlined in 
Section 14.1.2.3.1. In practice, disease response evaluation (either a complete assessment or 
only some components) may be performed on both scheduled and unscheduled time points. 
Also it is not uncommon in oncology trials that disease responses are sometimes assessed at 
time points not matching the scheduled time points. For example, when a patient’s condition 
prevents certain assessments, the scheduled evaluation will have to be delayed to a later time 
point.
As a result, the recording of response evaluation is aligned using the “Evaluation number” on 
the (e)CRFs. A new evaluation number should be assigned whenever a scheduled or 
unscheduled disease response assessment is performed, and hence is not necessarily aligned 
with the study visits.
When relapse can be judge based on any component. E.g. if a relapse is observed from blood 
sample alone without bone marrow assessment etc. at any time, it will be recorded on the 
(e)CRFs, with all other assessments as “not done” or “unknown”.
See also Section 14.1.2.3.5 regarding assigning date of the overall response.

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14.1.3.3 Capturing overall response evaluation
Data monitoring reports will be prepared to identify investigator’s assessments which differ 
from calculated response based on the rules of this document. This discrepancy may be queried 
for clarification. However, the investigator’s response will not be overruled in any case.
14.1.4
Efficacy analysis definitions
14.1.4.1 Local vs central evaluation of efficacy
The overall disease response at a given assessment may be provided from different sources:

Investigator overall disease response based on local radiological assessments, local 
clinical, pathological (e.g. bone marrow) and laboratory response.

Central review based on review of the totality of the source data by an independent review 
committee (IRC).
The Study Protocol should state which evaluation source will be used for the primary analysis.
14.1.4.2 Best overall disease response
The best overall disease response is the best disease response recorded from 
randomization/first CTL019 infusion until start of new anticancer therapy.
Best response will be assigned according to the following order:
1. CR
2. CRi
3. No response
4. Unknown
The best overall disease response for a patient is always calculated, based on the sequence of 
overall disease responses. For the best overall disease response to be categorized as CR or CRi, 
there must be no clinical evidence of relapse as assessed by peripheral blood and extramedullary 
disease assessment (physical exam and CNS symptom assessment) at a minimum of 4 weeks 
(28 days) after the initial achievement of CR or CRi, as explained in Section 14.1.2.3.4.
The overall remission rate (ORR) is defined as the proportion of patients with a best overall 
disease response of CR or CRi.
14.1.4.3 Time-to-event definitions
General rule for the calculation of the time to event interval is:
Time to event = event date - start date + 1 (in days)
When no post-baseline response assessments are available, the date of randomization/first 
CTL019 infusion will be used as event date when time is to be censored at last post-baseline 
response assessment, i.e. time to event variables will never be negative.
Often censoring time is determined based on date of adequate response assessment. Any 
response assessment is considered to be adequate if the assessment was performed and the 
outcome of the assessment was other than “unknown” or “not done”.

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14.1.4.3.1
Overall survival (OS)
Overall survival (OS) is the time from date of randomization/ first CTL019 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 cutoff, OS is censored at 
the date of last contact. The handling of SCT for the calculation of OS must be clearly specified 
in the protocol. See also Section 14.1.4.4 for more discussion.
OS will be assessed in all patients (FAS).
14.1.4.3.2
Duration of remission (DOR)
Duration of remission (DOR) is defined as the duration from the first documented onset of CRi 
or CR to the date of relapse or death due to ALL.
In case a patient does not have relapse or death due to ALL prior to data cutoff, DOR will be 
censored at the date of the last adequate assessment on or prior to the earliest censoring event. 
The censoring reason could be

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy

Event after at least two missing scheduled disease assessment
In addition, death due to reason other than ALL can be considered as either a competing risk 
event to other events of interest (relapse or death due to ALL), or a censoring event. The 
protocol should clearly specify which analysis is used as the primary analysis for DOR.
Since patients in remission might choose to receive SCT, censoring due to SCT will 
overestimate the risk of relapse and therefore may be considered inappropriate for the main 
analysis, when there is a substantial number of patients choose to receive SCT (CHMP 2010). 
The handling of SCT for the calculation of DOR must be clearly specified in the protocol.
See also Section 14.1.4.4 for more discussion.
DOR will be assessed only in patients with the best overall response of CR or CRi.
14.1.4.3.3
Relapse-free survival (RFS)
Relapse-free survival (RFS) is measured by the time from achievement of CR or CRi whatever 
occurs first to relapse or death due to any cause during CR or CRi.
In case a patient does not have relapse or death due to any cause prior to data cutoff, RFS will 
be censored at the date of the last adequate assessment on or prior to the earliest censoring event.
The censoring reason could be

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy

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
Event after at least two missing scheduled disease assessment
The handling of SCT for the calculation of RFS must be clearly specified in the protocol.
See also Section 14.1.4.4 for more discussion.
RFS will be assessed only in patients with the best overall response of CR or CRi.
14.1.4.3.4
Event-free survival (EFS)
Event-free survival (EFS) is the time from date of randomization/first CTL019 infusion to 
the earliest of the following:

Death from any cause

Relapse

Treatment failure: Defined as no response in the study and discontinuation from the study 
due to any of the following reasons:

Adverse event (including abnormal laboratory values or abnormal test procedure 
results)

Lack of efficacy

New anticancer therapy
In case of treatment failure, the event date will be set to study Day 1 (CHMP 2010).
In case a patient does not experience an event (e.g. discontinuation as a result of withdrawal of 
consent, lost to follow-up, protocol violation or administrative problems) prior to data cutoff, 
EFS is censored at the last adequate response assessment date on or prior to the earliest 
censoring event. The censoring reason could be

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy

Event after at least two missing scheduled disease assessment
The handling of SCT for the calculation of EFS must be clearly specified in the protocol.
See also Section 14.1.4.4 for more discussion.
EFS will be assessed in all patients (FAS).
14.1.4.4 Event and censoring date, sensitivity analyses
This section outlines the possible event and censoring dates for relapse (Table 14-3), addresses 
the issues of missing response assessments during the study, and the options for handling new 
anticancer therapy. It is important that the protocol and RAP specify the primary analysis in 
detail with respect to the definition of event and censoring dates and also include a description 
of sensitivity analyses to be performed.
SCT is a standard treatment option for ALL patients. For time-to-event endpoints it needs to be 
specified in the protocol how patients who choose to undergo SCT following study protocol 
treatment will be handled for analysis.

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Using the draft FDA guideline (2007) on endpoints (Clinical Trial Endpoints for the Approval 
of Cancer Drugs and Biologics) and the EMA guideline on the evaluation of Anticancer 
Medicinal Products in Man on Confirmatory studies in Haematological Malignancies (CHMP 
2010) as references, the following analyses can be considered:
Table 14-3
Options for event dates used in DOR, EFS and RFS
Situation
Options for event date
(1) = default unless specified differently in the 
protocol or analysis plan
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment
Censor
B
Relapse at scheduled assessment 
date or before next scheduled 
assessment
(1) Date of relapse
(2) Date of next scheduled assessment
Event
Event
C1
Relapse after exactly one missing 
assessment
(1) Date of relapse
(2) Date of next scheduled assessment
Event
Event
C2
Relapse after two or more missing 
assessments
(1) Date of last adequate assessment
(2) Date of next scheduled assessment
(3) Date of relapse
Censor
Event
Event
D
New anticancer therapy given 
(excluding SCT)
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censor
Censor
Event
Ignored
E
SCT
(1) Date of SCT
(2) N/A
(3) Date of SCT
(4) Date of last adequate assessment prior to SCT
Censor
Ignored
Competing 
Risk Event
Censor
F
Death due to reasons other than 
ALL (for DOR only)
(1) Date of death
(2) Date of last adequate assessment
Competing 
Risk Event
Censor
The primary analysis and the sensitivity analyses must be specified in the study protocol. 
Clearly define if and why options (1) are not used for situations, D and (if applicable) E.
Situations C (C1 and C2): Relapse or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual relapse or death date in the case of one missing assessment

(C2) censoring at the date of the last adequate assessment in the case of two or more 
consecutive missing assessments
In the case of two or more missing assessments (situation C2), option (3) may be considered 
jointly with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the event to the next scheduled assessment as proposed with option (2) 
in situations C1 and C2.
Situation D: New anticancer therapy (excluding SCT) given: the handling of this situation must 
be specified in detail in the protocol. However, option (1), i.e. censoring at last adequate 
assessment prior to new anticancer therapy may be used as a default in this case.

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Situation E: As SCT is an important treatment option in responding patients, it is appropriate 
to consider the date of SCT as censoring date, instead of censoring at the last tumor assessment 
date. However, censoring due to SCT will overestimate the rate of relapse and therefore may 
be considered inappropriate for the default analysis when a substantial number of patients 
choose to receive SCT. Analysis ignoring SCT should be considered (CHMP 2010).
Since SCT during remission after the experimental treatment may affect the risk of relapse, a 
sensitivity analysis may be considered in which SCT is regarded as a competing risk to the 
event of interest (e.g., relapse after the experimental treatment). In this analysis, the cumulative 
incidence function (CIF), instead of the usual KM, is used to estimate the probability of 
remaining free of the event of interest in the presence of the competing risk (Kim 2007).
Situation F: Note that the KM method used to analyze DOR in the presence of censoring can 
be biased if the censoring event is not independent to the event of interest (i.e. relapse and death 
due to ALL). Therefore, analysis can also be performed considering death due to reason other 
than ALL as a competing risk event. In this case, the cumulative incidence function (CIF) 
instead of KM is used to estimate the probability of relapse in the presence of the competing 
risk (Kim 2007).
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for response assessments, e.g. by assigning the dates for censoring 
and events only at scheduled visit dates. The latter could be handled by replacing in Table 14-
3 the “Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:
Date of previous scheduled assessment (from baseline) is the date when a response 
assessment would have taken place, if the protocol assessment scheme was strictly followed 
from baseline, immediately before or on the date of the last adequate assessment.
The need for these types of sensitivity analyses will depend on the individual requirements for 
the specific study and have to be specified in the study protocol or RAP documentation.

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14.1.5
References (available upon request)
Appelbaum FR, et al. (2007) End points to establish the efficacy of new agents in the 
treatment of acute leukemia. Blood 109: 1810-1816
Cheson B, Bennet JM, Kopecky K, et al. (2003) Revised Recommendations of the 
International Working Group for Diagnosis, Standardization of Response Criteria, Treatment 
Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. 
Journal of Clinical Oncology; 21(24):4642-9
Cheson BD (2007a) The international harmonization project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin N Am 21:841-854
Cheson BD, Greenberg P, Bennett J, et al. (2006) Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108: 419-425
Cheson BD, Pfistner B, Juweid ME, et al. (2007b) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586
CHMP (2010) Appendix 2 to the Guidance on the evaluation of anticancer medicinal products 
in man (CPMP/EWP/205/95 Rev. 3) on confirmatory studies in haematological malignancies
FDA Guideline (2007) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Hallek M, et al. (2008) Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia 
updating the National Cancer Institute–Working Group 1996 guidelines. Blood 111.12: 5446-
5456
Kim H (2007) Cumulative Incidence in Competing Risks Data and Competing Risks 
Regression Analysis. Clinical Cancer Research 2007;13:559-565
National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2013 v1), Acute 
Lymphoblastic Leukemia

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14.2
Appendix 2: Eligibility based on serologic markers for hepatitis B 
infection
Table 14-4
Eligibility based on serologic markers for hepatitis B infection
Test
Results
HBsAg
+
-
-
-
-
Anti-HBc
Any
+
-
+
-
Anti-HBs
Any
-
+
+
-
Eligibility
Not Eligible
Not Eligible
Eligible
Eligible
Eligible
If indeterminate results are obtained, viral DNA levels should be measured to confirm 
negative viral status.
HBsAg positive: Indicates active infection and/or chronic active and potential for reactivation 
with fulminant hepatitis. These patients are not eligible for this trial.
Anti-HBs positive: Protective – Indicates vaccination or previous infection that has been 
successfully resolved. These patients are eligible for this trial.
HBsAg negative, Anti-HBc positive, Anti-HBs negative: Indicates latent infection. These 
patients are also at risk for viral reactivation. These patients are not eligible for this trial.

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Appendix 3: CTL019 modified data reporting – Treatment and Primary Follow Up Phase
14.3.1
Adverse event (AE) and serious adverse event (SAE) reporting
Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment Period
(Starting from LD 
chemo/pre-infusion visit)
Post-treatment Period
Through Month 12 Visit
After Month 12 Visit, through Month 60
Non-serious Adverse 
Events (AE)

Modified:

All infections

All laboratory abnormalities deemed 
clinically significant by the investigator

All clinical AEs grade ≥ 3

All AEs related to a study procedure

All AEs leading to study discontinuation
All events, including all 
laboratory abnormalities 
deemed clinically 
significant by the 
investigator

Modified –Whether serious or non-serious, report following:

Any SAE irrespective of grade

Events leading to death

Related to a study procedure

Infections

Serious or opportunistic infections. Defined as bacterial,
viral, fungal or parasitic infections that fulfill one of the 
following criteria: Require anti-infective treatment OR Lead 
to significant disability or hospitalization OR Need surgical or 
other intervention

New incidence or exacerbation of a pre-existing neurologic 
disorder

New incidence or exacerbation of a prior rheumatologic or 
other autoimmune disorder

New incidence of other hematologic disorder

Any severe (≥ Grade 3) adverse event or condition the 
investigator believes may have a reasonable relationship to 
CD19 CART therapy

Positive RCL test result

Vector insertion site sequencing result with a mono-or 
oligoclonality pattern or in a location near a known human 
oncogene

New malignancy (T-cell & non T-cell), other than the primary 
malignancy

Progressive multifocal leucoencephalopathy (PML)

Hepatitis B reactivation
Serious Adverse 
Events (SAE)
Modified:

All events leading to death

All events related to a study procedure

Any AE reportable for this study period 
that also meets criteria for serious

All pulmonary or cardiac abnormalities

All infections

Any substantial change in the status of 
the patient that precludes the patient 
from proceeding to study treatment 
(e.g. GVHD, rapid progression of 
malignancy, marked decline in 
performance status)

Any other substantial change in the 
status of the patient that the 
investigator deems may have a 
potential impact on the patients during 
lymphodepletion and CTL019 
treatment
All

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14.3.2
Concomitant medication and laboratory reporting
Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment Period
(Starting from LD chemo/pre-infusion visit, through Month 12 )
Post-treatment Period
(After Month 12, through Month 60 )
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient
Concomitant 
medications
Modified:
Drugs:
Record all of the following medications:

Anticytokine therapies (e.g. tocilizumab, or other)

Corticosteroids (including prophylactically for blood product administrations, 
physiologic replacement doses, high or stress doses, etc.)

Anti-seizure medications

Allopurinol, or non-allopurinol alternatives

Rasburicase

Immunoglobulin therapy

Any medication given therapeutically for an SAE

Vasopressors and cardiac inotropic agents (see below)

Narcotics and sedatives (see below)

Antineoplastic therapies (e.g. lymphodepeleting 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. ug/kg/hr, mg/hr, etc.)
Narcotics and sedatives:

For dose, record only total daily dose
Blood products (e.g. red cells, platelets, FFP, cryoprecipitate):

If administered ≤7 days of a tumor response assessment:
o
Record ALL blood products, including prophylaxis (to distinguish CR vs 
CRi)

If NOT administered ≤7 days of a tumor response assessment:
o
Only record blood products if given for bleeding (excludes prophylactic 
use)

Related to an AE or SAE defined as reportable for this period
Electrolyte & vitamin replacement:
All
Modified:

Related to an AE or SAE defined as 
reportable for this period

Mutagenic agents (including cytotoxic 
drugs)

Radiation & antineoplastic therapy 
(including SCT)

Immunoglobulin therapy

Immunosuppressive agents (including 
dose of steroids higher than physiologic 
replacement therapy doses of steroids (< 
12 mg/m2/day hydrocortisone or 
equivalent)

Investigational therapy

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Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment Period
(Starting from LD chemo/pre-infusion visit, through Month 12 )
Post-treatment Period
(After Month 12, through Month 60 )
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient

Record all electrolyte replacement if given for a ≥ Grade 3 electrolyte disturbance 
and list these as an adverse event (AE).

Do not record ≤ Grade 2 or 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
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 treated prophylactically are NOT to be 
recorded (e.g. maintenance electrolyte replacement, platelets given without 
clinical bleeding)
All
Modified:

Record all scheduled labs (per Visit 
Evaluation Schedule)

Record all results (scheduled or 
unscheduled) for: LDH, Uric acid, CRP, 
Ferritin, and fibrinogen (related to 
CRS/TLS/MAS)

Record all other laboratory values if they 
are ≥ Grade 3

For laboratory abnormalities reportable as 
AE/SAE, record laboratory results that 
support the event (scheduled or 
unscheduled)

For any AE/SAE that may be caused 
by a laboratory abnormality, the 
laboratory value(s) (any grade) must 
also be recorded (e.g. “muscle 
cramps” potentially caused by 
hypokalemia)

Laboratory abnormalities that are 
treated prophylactically are NOT to 
be recorded (e.g. maintenance 
electrolyte replacement, platelets 
given without clinical bleeding)

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Appendix 4: CTL019 modified data reporting – Secondary Follow Up Phase
Adverse Events/ Serious Adverse Events
Concomitant Medications

New incidence or exacerbation of a pre-existing neurological disorder

New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder

New incidence of other hematologic disorders

Any severe adverse event or condition the investigator believes may have a reasonable 
relationship to CTL019 therapy

Any severe adverse event or condition that is unexpected and the investigator assess a 
reasonable relationship to CTL019 therapy

Positive RCL test result

Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a location near a 
known human oncogene

New malignancy (T-cell & non T-cell), other than primary malignancy

Progressive multifocal leukoencephalopathy (PML)

Hepatitis B reactivation

Intravenous Immunoglobulin

For all patients who are in remission, the first 
antineoplastic therapy administered (first 
therapy including conditioning for cell therapy 
(CAR, SCT) plus cell therapy (CAR, SCT) 
should be reported.

Data to support adverse events may be 
requested

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14.5
Appendix 5: [EU Only: Guidelines for use of fibrinogen 
concentrate in CTL019-associated coagulopathy with 
hypofibrinogenemia
If cryoprecipitate is not readily available guidance is being provided below on the use of 
fibrinogen concentrate for the management of CTL019 associated coagulopathy with 
hypofibrinogenemia.  Note this guidance is for Norway, Spain, Austria and Italy only.

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Appendix 6: [Japan Only: Guidelines for use of fibrinogen 
concentrate in CTL019-associated coagulopathy with 
hypofibrinogenemia]
If cryoprecipitate is not readily available guidance is being provided below on the use of 
fibrinogen concentrate for the management of CTL019 associated coagulopathy with 
hypofibrinogenemia.  Note this guidance is for Japan only.

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14.7
Appendix 7: Liver and Laboratory trigger Definitions and Follow-
up Requirements
Table 14-5
Liver Event and Laboratory Trigger Definitions 
Definition/ threshold
LIVER LABORATORY TRIGGERS
3 x ULN < ALT / AST ≤ 5 x ULN
1.5 x ULN < TBL ≤ 2 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone 
pathology)
TBL > 2 × ULN (in the absence of known Gilbert 
syndrome)
ALT or AST > 3 × ULN and INR > 1.5
Potential Hy’s Law cases (defined as ALT or AST > 3 
× ULN and TBL > 2 × ULN [mainly conjugated 
fraction] without notable increase in ALP to > 2 × 
ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or 
vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver 
toxicity*
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver 
neoplasms TBL: total bilirubin; ULN: upper limit of normal
Table 14-6
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
Discontinue the study treatment 
immediately (if applicable)
Hospitalize, if clinically appropriate
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
ALT, AST, TBL, indirect and direct
bilirubin, albumin, Alb, PT/INR,  ALP 
and GGT, until resolution (frequency 
at investigator discretion)
ALT or AST
> 8 × ULN
Discontinue the study treatment 
immediately (if applicable)
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
ALT, AST, TBL, indirect and direct 
bilirubin, albumin, Alb, PT/INR,  ALP 
and GGT until resolutionc (frequency 
at investigator discretion)

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

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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
> 1.5 to ≤ 2 × ULN 
(patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate 
close observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks or at 
next visit
Jaundice
Discontinue the study treatment 
immediately (if applicable)
Hospitalize the patient
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
ALT, AST, TBL, indirect and direct 
bilirubin, albumin, Alb, PT/INR,  ALP 
and GGT until resolutionc (frequency 
at investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*
Consider study treatment 
interruption or discontinuation (if 
applicable) 
Hospitalization if clinically 
appropriate
Establish causality
Record the AE and contributing 
factors (e.g., concomitant 
medication, medical history, lab) in 
the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
cResolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable 
values at three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level 
after a maximum of 6 months, (4) liver transplantation, and (5) death.
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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Appendix 8: Specific Renal Alert Critiera and Actions end Event 
Follow-up
Table 14-7
Specific Renal Alert Criteria and Actions 
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%
Consider causes and possible interventions
Follow up within 2-5 days
Serum creatinine increase ≥50 % +
OR if <18 years old, eGFR ≤35 mL/min/1.73 m2
Consider causes and possible interventions 
Repeat assessment within 24-48 hours if 
possible 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
Consider patient hospitalization and specialized 
treatment
New onset dipstick proteinuria ≥ 3+ OR
(Spot) urinary protein-creatinine ratio (PCR) ≥ 
1g/g (or mg/ mmoL equivalent as converted by 
the measuring laboratory)
Consider causes and possible interventions 
Assess serum albumin & serum total protein
Repeat assessment to confirm 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and 
corrected
New onset hematuria ≥3+ on urine dipstick
Assess & document 

Repeat assessment to confirm 

Distinguish hemoglobinuria from hematuria 

Urine sediment microscopy 

Assess serum creatinine

Exclude infection, trauma, bleeding from 
the distal urinary tract/bladder, 
menstruation 

Consider bleeding disorder
+Corresponds to KDIGO criteria for Acute Kidney Injury

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Table 14-8
Follow up 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