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, Relapsed B-cell Acute Lymphoblastic Leukemia, Refractory B-cell Acute Lymphoblastic Leukemia
Sponsor: Novartis Pharmaceuticals

Clinical Development
CTL019
Protocol CCTL019B2205J / NCT02228096
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
Authors
Document type
Amended Protocol Version
EUDRACT number
2015-003736-13
Version number
02 (Clean)
Development phase
II
Document status
Final
Release date
01-Sep-2015
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
 

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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................6
List of figures ......................................................................................................................6
List of tables ........................................................................................................................6
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................13
Amendment 2 ....................................................................................................................14
Amendment 1 ....................................................................................................................21
Protocol summary:.............................................................................................................22
1
Background........................................................................................................................28
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............28
1.2
Introduction to investigational treatment(s) and other study treatment(s).............28
1.2.1
Overview of CTL019............................................................................28
2
Rationale............................................................................................................................33
2.1
Study rationale and purpose...................................................................................33
2.2
Rationale for the study design ...............................................................................34
2.2.1
Rationale for lymphodepletion..............................................................34
2.3
Rationale for dose and regimen selection..............................................................35
2.4
Rationale for choice of combination drugs............................................................36
2.5
Rationale for choice of comparator drugs .............................................................36
3
Objectives and endpoints...................................................................................................36
4
Study design ......................................................................................................................40
4.1
Description of study design ...................................................................................40
4.1.1
Apheresis assessment............................................................................41
4.2
Definition of end of the study................................................................................41
4.3
Early study termination..........................................................................................42
5
Population..........................................................................................................................42
5.1
Patient population..................................................................................................42
5.2
Inclusion criteria ....................................................................................................42
5.3
Exclusion criteria...................................................................................................44
6
Treatment...........................................................................................................................46
6.1
Study treatment......................................................................................................46
6.1.1
Dosing regimen.....................................................................................46
 

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6.1.2
Ancillary treatments..............................................................................50
6.1.3
Rescue medication ................................................................................51
6.1.4
Guidelines for continuation of treatment ..............................................51
6.1.5
Treatment duration................................................................................51
6.2
Dose escalation guidelines.....................................................................................51
6.2.1
Starting dose rationale...........................................................................51
6.2.2
Provisional dose levels..........................................................................51
6.2.3
Guidelines for dose escalation and determination of 
MTD/RP2D/RDE..................................................................................51
6.2.4
Definitions of dose limiting toxicities (DLTs) in a Phase II Study.......52
6.2.5
Criteria for discontinuing a patient’s participation in the study.............63
6.2.6
Concomitant Therapy............................................................................63
6.2.7
Prohibited concomitant therapy ............................................................64
6.3
Patient numbering, treatment assignment or randomization .................................65
6.3.1
Patient numbering .................................................................................65
6.3.2
Treatment assignment ...........................................................................65
6.3.3
Treatment blinding................................................................................65
6.4
Study drug preparation and dispensation...............................................................66
6.4.1
Study drug packaging and labeling.......................................................66
6.4.2
Drug supply and storage........................................................................66
6.4.3
Study drug compliance and accountability ...........................................67
6.4.4
Disposal and destruction .......................................................................67
7
Visit schedule and assessments .........................................................................................68
7.1
Study flow and visit schedule................................................................................68
7.1.1
Screening Phase ....................................................................................84
7.1.2
Pre-Treatment Phase .............................................................................86
7.1.3
Treatment and Primary Follow-Up Phase.............................................87
7.1.4
Secondary Follow-Up Phase.................................................................91
7.1.5
Survival Follow-Up Phase ....................................................................92
7.1.6
Long-Term Follow Up ..........................................................................92
7.2
Assessment types...................................................................................................93
7.2.1
Efficacy assessments.............................................................................93
7.2.2
Safety and tolerability assessments.......................................................95
7.2.3
Pharmacokinetics ..................................................................................99
 

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105
7.2.5
Resource utilization.............................................................................105
7.2.6
Patient reported outcomes...................................................................105
8
Safety monitoring and reporting......................................................................................106
8.1
Adverse events.....................................................................................................106
8.1.1
Definitions...........................................................................................106
8.1.2
Reporting.............................................................................................106
8.1.3
Laboratory test abnormalities..............................................................108
8.1.4
Adverse events of special interest.......................................................109
8.2
Serious adverse events.........................................................................................109
8.2.1
Definitions...........................................................................................109
8.2.2
Reporting.............................................................................................109
8.3
Emergency unblinding of treatment assignment .................................................111
8.4
Pregnancies..........................................................................................................112
8.5
Warnings and precautions....................................................................................113
8.6
Data Monitoring Committee................................................................................113
8.7
Steering Committee .............................................................................................113
8.8
Independent Review Committee (IRC) ...............................................................114
9
Data collection and management.....................................................................................114
9.1
Data confidentiality .............................................................................................114
9.2
Site monitoring ....................................................................................................115
9.3
Data collection.....................................................................................................115
9.4
Database management and quality control..........................................................115
10 Statistical methods and data analysis ..............................................................................116
10.1
Analysis sets ........................................................................................................116
10.1.1
Screened Set........................................................................................116
10.1.2
Enrolled Set.........................................................................................116
10.1.3
Full Analysis Set .................................................................................116
10.1.4
Safety Set ............................................................................................116
10.1.5
Per-Protocol Set ..................................................................................117
10.1.6
Pharmacokinetic analysis set...............................................................117
10.2
Patient demographics/other baseline characteristics ...........................................117
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................118
10.4
Primary objective.................................................................................................118
 

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10.4.1
Variable...............................................................................................118
10.4.2
Statistical hypothesis, model, and method of analysis........................120
10.4.3
Handling of missing values/censoring/discontinuations.....................121
10.4.4
Supportive analyses.............................................................................121
10.5
Secondary objectives ...........................................................................................122
10.5.1
Key secondary objective(s).................................................................122
10.5.2
Other secondary efficacy objectives ...................................................122
10.5.3
Safety objectives .................................................................................126
10.5.4
Pharmacokinetics ................................................................................129
130
130
131
131
10.7
Interim analysis....................................................................................................131
10.8
Sample size calculation........................................................................................133
10.9
Power for analysis of key secondary variables....................................................133
11 Ethical considerations and administrative procedures ....................................................133
11.1
Regulatory and ethical compliance......................................................................133
11.2
Responsibilities of the investigator and IRB/IEC/SRC.......................................133
11.3
Informed consent procedures...............................................................................134
11.4
Discontinuation of the study................................................................................134
11.5
Publication of study protocol and results.............................................................134
11.6
Study documentation, record keeping and retention of documents.....................135
11.7
Confidentiality of study documents and patient records .....................................135
11.8
Audits and inspections.........................................................................................136
11.9
Financial disclosures............................................................................................136
12 Protocol adherence ..........................................................................................................136
12.1
Amendments to the protocol................................................................................136
13 References .......................................................................................................................137
14 Appendices ......................................................................................................................143
14.1
Appendix 1:  Guidelines for efficacy evaluation in Acute Lymphoblastic 
Leukemia (ALL) studies......................................................................................143
Document History ...........................................................................................................143
14.1.1
Introduction.........................................................................................145
14.1.2
Efficacy evaluation..............................................................................145
 

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14.1.3
Data collection ....................................................................................152
14.1.4
Efficacy analysis definitions ...............................................................153
14.1.5
References...........................................................................................158
14.2
Appendix 2: Guidelines for efficacy evaluation in Lymphoblastic Lymphoma 
patients.................................................................................................................160
14.2.1
Introduction.........................................................................................160
14.2.2
Types of efficacy assessments ............................................................160
14.3
Appendix 3: Eligibility based on serologic markers for hepatitis B infection ....164
14.4
Appendix 4: CTL019 Modified Safety Reporting...............................................165
14.4.1
Adverse Event (AE) and Serious Adverse Event (SAE) Reporting ...165
14.4.2
Concomitant Medication.....................................................................166
List of appendices
Appendix 1: Guidelines for efficacy evaluation in Acute Lymphoblastic Leukemia (ALL) 
studies
Appendix 2: Guidelines for efficacy evaluation in Lymphoblastic Lymphoma patients
Appendix 3: Eligibility based on serologic markers for hepatitis B infection
Appendix 4: CTL019 Modified Safety Reporting
List of figures
Figure 1-1
CTL019 chimeric antigen receptor design............................................30
Figure 4-1
Study design..........................................................................................40
Figure 6-1
CRS Management Algorithm:...............................................................54
Figure 7-1
Potential Patient flow scenarios ............................................................68
List of tables
Table 3-1
Objectives and related endpoints ..........................................................37
Table 6-1
CTL019-Therapy-Associated Grading for Cytokine Release 
Syndrome: The Penn Grading Scale for Cytokine Release 
Syndrome (PGS-CRS) ..........................................................................55
Table 6-2
High Dose Vasopressor Use..................................................................57
Table 6-3
Staging & Grading of Acute Graft-Versus-Host Disease .....................58
Table 6-4
Definitions of Chronic Graft-Versus-Host Disease ..............................59
 

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Table 6-5
Concomitant Medication Reporting by Trial Phase..............................64
Table 7-1
Visit evaluation schedule ......................................................................69
Table 7-2
Visit Evaluation Schedule: Treatment and Primary follow-up 
continued (Month 15 through Month 60)..............................................78
Table 7-3
Visit Evaluation Schedule: Secondary Follow-up ................................81
Table 7-4
Imaging or disease assessment collection plan – Primary follow-up 
phase......................................................................................................94
Table 7-5
Karnofsky/Lansky Performance Scales ................................................96
Table 7-6
Local clinical laboratory parameters collection plan ............................98
Table 7-7
Central clinical laboratory parameters collection plan..........................99
Table 7-8
CTL019 pharmacokinetics by q-PCR in peripheral blood collection 
log..........................................................................................................99
Table 7-9
CTL019 pharmacokinetics by flow cytometry in peripheral blood 
collection log.......................................................................................100
Table 7-10
CTL019 pharmacokinetics by q-PCR in bone marrow aspirate 
collection log.......................................................................................100
Table 7-11
CTL019 pharmacokinetics by flow cytometry in bone marrow 
aspirate collection log .........................................................................101
Table 7-12
CTL019 pharmacokinetics by q-PCR in CSF collection log..............101
Table 7-13
Immunogenicity serum sample collection log ....................................101
Table 7-14
Immunogenicity peripheral blood sample collection log....................101
Table 7-15
Tocilizumab, CTL019 Pharmacokinetics (PK), and sIL6R (PD) in 
tocilizumab treated patients during CRS.............................................102
Table 7-16
Anti-cytokine therapy (other than tocilizumab) PK, CTL019 PK 
and sIL6R (PD) in anti-cytokine therapy treated patients during 
CRS .....................................................................................................102
104
Table 10-1
Definition of CR, CRi and relapse at a given evaluation time in 
Acute Lymphoblastic Leukemia patients  (excluding 
Lymphoblastic Lymphoma patients)...................................................119
Table 10-2
Additional definition of remission and relapse at a given evaluation 
time for Lymphoblastic Lymphoma patients ......................................120
Table 10-3
Analyses of duration of response (DOR)............................................123
Table 10-4
Adverse events of special interest (AESI) search criteria...................126
Table 10-5
Noncompartmental pharmacokinetic parameters................................129
Table 10-6
Simulated probabilities to claim success at the interim or final 
analysis................................................................................................132
 

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Table 14-1
Overall disease response classification at a given evaluation time.....150
Table 14-2
Data sources ........................................................................................152
Table 14-3
Options for event dates used in DOR, EFS and RFS...........................157
Table 14-4
Response criteria for mediastinal disease ...........................................162
Table 14-5
Overall disease response classification at a given evaluation time 
for lymphoblastic lymphoma patients.................................................163
 

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List of abbreviations
AE
Adverse Event
4-1 BB
type 2 transmembrane glycoprotein belonging to the TNF superfamily, expressed on activated 
T Lymphocytes
AESI
Adverse Event of Special Interest
ALC
Absolute Lymphocyte Count
ALL
Acute Lymphoblastic Leukemia
ALT
Alanine Aminotransferase/Glutamic Pyruvic Transaminase/SGPT
AML
Acute Myeloid Leukemia
Anti-HBc
Hepatitis B core antibody
Anti-HBs
Hepatitis B surface antibody
AST
Aspartate Aminotransferase/Glutamic Oxaloacetic Transaminase/SGOT
ATC
Anatomical Therapeutic Chemical
ATG
Anti-thymocyte globulin
AUC
Area Under the Curve
AUMC
Area under the first moment curve
B-ALL
B cell lineage acute lymphoblastic leukemia
BCR-ABL
Philadelphia Chromosome
BiPAP
Bilevel Positive Airway Pressure
BM
Bone Marrow
BMT
Bone Marrow Transplantation
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
CHOP
Children’s Hospital of Philadelphia
CI
Confidence Interval
CIF
Cumulative Incidence Function
CLL
Chronic Lymphocytic Leukemia
Cmax
Maximum concentration
CMC
Chemistry/ Manufacturing/ Control 
CMO
Contract Manufacturing Facility Organization
CNS
Central Nervous System
CPAP
Continuous Positive Airway Pressure
CR
Complete remission
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRi
Complete remission with incomplete blood count recovery
CRO
Contract Research Organization
CRp
Complete remission with incomplete platelet recovery
 

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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 T cells)
CVPF
Cell and Vaccine Production Facility
DLI
Donor Lymphocyte Infusion
DLBCL
Diffuse Large B Cell Lymphoma
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
DOR
Duration of Remission
EC
European Commission
ECG
Electrocardiogram
ECHO
Echocardiogram
EDC
Electronic Data Capture
EFS
Event Free Survival
EOS
End of Study
EOT
End of Treatment and Primary Follow-Up
FAB
Fragment Antigen Binding
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
GFR
Glomerular Filtration Rate
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
i.v.
Intravenous(ly)
IB
Investigator Brochure
ICH
International Conference on Harmonization
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
 

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Ig
Immunoglobulin
IL
Interleukin
IL6R
Interleukin 6 receptor
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
ISBT
International Society of Blood Transfusion
IUD
Intrauterine Device
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
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
Polymerase Chain Reaction
 

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PE
Physical examination
PGS-CRS
The Penn Grading Scale for Cytokine Release Syndrome
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
PT
Preferred Term
PT
Prothrombin Time
aPTT
Activated Partial Thromboplastin Time
q-PCR
Quantitative Polymerase Chain Reaction
r/r
Relapsed or refractory
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
REB
Research Ethics Board
RFS
Relapse Free Survival
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
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Event
TCR
T Cell Receptor
TCR-zeta
Signaling domain found in the intracellular region of the TCR zeta, gamma and epsilon chains
TKI
Tyrosine Kinase Inhibitor
TLH
Trilineage Hematopoiesis 
TLS
Tumor Lysis Syndrome
Tmax
Time to peak concentration
TNF
Tumor Necrosis Factor
ULN
Upper Limit of Normal
UPenn
University of Pennsylvania
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
 

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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
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 Novartis Morris Plains 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
A subdivision of the study timeline; divides stages into smaller functional segments 
such as screening, baseline, titration, washout, etc.
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
 

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Amendment 2
Amendment rationale
At the time of this protocol amendment, 9 sites have been initiated, 33 patients have been 
enrolled, and 27 patients have been treated.
The protocol is being amended to:
1. 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, including the expansion of inclusion criteria to enroll 
patients with relapsed or refractory B-cell lymphoblastic lymphoma.
2. Address recommendations from EMA Scientific Advice letter on 25 April 2014
3. Transfer the trial sponsorship from University of Pennsylvania IND to Novartis IND.
Additional PK and cytokine sample time points were added to better define cell expansion and 
CRS, 
 that did not impact total sample 
collection requirements.
Testing for CMV and EBV is not required at screening per current guidelines for autologous 
blood product therapy.
Other changes have been instituted for purposes of clarity and feasibility based on experiences 
from ongoing trials as outlined below.
Key changes include:
1. The trial will be transferred under Novartis IND from UPenn IND. After the IND transfer, 
all CTL019 products will be manufactured according to the Novartis CMC process. An 
interim analysis is planned for patients who were treated with UPenn manufactured 
CTL109 product and have completed 6 months from study day 1 infusion or discontinued
earlier. An α-spending function according to Lan-DeMets (O’Brien-Fleming) will be used 
to construct the efficacy stopping boundaries (Lan and DeMets 1983).
2. Expand the inclusion criteria so that the trial can also enroll patients with relapsed or 
refractory B-cell lymphoblastic lymphoma, and add in the primary objective to assess 
ORR in lymphoblastic lymphoma patients too.
3. The final primary analysis will include at least 50 patients (both acute lymphoblastic 
leukemia and lymphoblastic lymphoma patients) treated using either UPenn CMC or 
Novartis CMC with at least 40 patients < 18 years. Sites will be notified once the cap of 
patients ≥ 18 years is reached.
4. Clarification of primary endpoint to be assessed during the first 6 months after CTL019 
administration.
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, and 
the impact of baseline tumor burden on response.
 

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7. Minimum number of manufactured CTL019 transduced cells for infusion has been 
removed.
8. Updated contraception guidelines for males and  females of childbearing potential.
In addition, other changes have been instituted for purposes of clarity and further efficacy 
follow-up, as outlined below.  Key changes include:
1. Extension of trial follow-up duration from 12 months to 60 months.
2. 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.  
3. Clarifications on adverse event reporting and apheresis collections
Changes to Protocol
1. Table 1-1: Clarity added for patient population on the trials
2. Section 1.2.1.2: Updated clinical experience section with currently available data. 
Clarification on correlation between administration of tocilizumab and CTL019 cell 
expansion. 
3. Table 1-2: Removed and replaced with summary text
4. Table 2-1: Removed and replaced with summary text
5. Section 2.2: Replaced CVPF Penn manufacturing with Novartis manufacturing process 
will be used starting from Amendment 2
6. Section 2.3: Added “viable T” to dose.
7. Table 3-1: Objectives and endpoints updated to clarify primary endpoint to be assessed  6 
months after CTL019 administration, addition of ORR assessment in lymphoblastic 
lymphoma patients, addition of other secondary objectives, 
 
8. Section 4.1: Study design diagram Extension of trial duration from 12 months to 60 
months. Reference added. 
9. Figure 4-1: Study design diagram updated with extension of trial duration from 12 months 
to 60 months. 
10. Section 4.1.1: Clarity on guidelines for optimal apheresis collection
11. Section 4.1.1: Clarity on use of CTL019 manufactured cells if GVHD experienced after 
collection of apheresis product
12. Section 4.1.1: Removed reference to Manual of Procedures.
13. Section 4.2: Updated trial design to reflect extension of trial duration from 12 months to 
60 months. 
14. Section 4.3: Replaced reference to University of Pennsylvania regulatory and safety 
bodies with Novartis.
15. Section 5.1: Addition of lymphoblastic lymphomas to patient population 
16. Section 5.1: Clarification of European PIP required guidelines for primary analysis and 
capping of patients ≥18 years of age. 
 

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17. Section 5.2: Clarification on the definition of refractory ALL added to criteria # 1
18. Section 5.3: Criteria # 7 retired and replaced with criteria # 15 with extension of window 
for obtaining results within 8 weeks of screening
19. Section 5.3: Criteria # 8 retired and replaced with criteria # 16 with extension of window 
for obtaining results within 8 weeks of screening
20. Section 5.3: Criteria # 10 retired and replaced with criteria # 17 with additional Anti T-cell 
therapy guidance, and clarifications to testing time windows and chemotherapy in 
exclusion criteria.
21. Section 6.1.1.1: Clarification on timing of lymphodepleting chemotherapy before CTL019 
infusion.
22. Section 6.1.1.2: Removed reference to University of Pennsylvania manufacturing facility 
and operational procedures. Anti T-cell Therapy details added. Clarifications on patient 
pre-infusion requirements. The number of tocilizumab doses required on site prior to 
CTL019 infusion changed to two doses. Clarification on which specific manual 
referenced.  Minimum release dose criteria removed. Guidance on monitoring of patient 
temperature added.   
23. Section 6.1.3: Number of tocilizumab doses required on site prior to CTL019 infusion 
changed to two doses.
24. Section 6.2.4.1: University of Pennsylvania Data Safety Monitoring Board (DSMB) 
replaced with Novartis Data Monitoring Committee (DMC).
25. Section 6.2.4.1.1: Replaced reference to University of Pennsylvania regulatory and safety 
bodies with Novartis.
26. Section 6.2.4.2: CRS management algorithm to be followed by investigators.
27. Sections 6.2.4.2 & 6.2.4.3: Safety information added based on most current IB.
28. Figure 6-1: CRF Management Algorithm further clarified
29. Table 6-2: Adjustment of vasopressor doses corrected by weight.
30. Section 6.2.6: Modified concomitant medication reporting better defined; clarification on 
concomitant medication recording prior to screening. Clarification on administration of 
granulocyte colony stimulating factor (G-CSF).
31. Section 6.2.7: Anti T-cell Therapy guidance added. Clarifications added. 
32. Section 6.3.1: Changed “the Sponsor” to “Novartis”.
33. Section 6.4: Clarification on which specific manual referenced, and changed “the person” 
to “personnel” to ensure alignment with manuals. Changed “Regulatory Sponsor” to 
“Novartis”. Clarification on which specific manual referenced.
34. Section 6.4.1: Added “viable T” and “transduced viable T” to dose.
35. Section 6.4.2: Clarification on which specific manual referenced.
36. Section 6.4.3: Clarifications on guidelines of product traceability between patient’s 
autologous apheresis and CTL019 product guidelines added. Clarification on which 
specific manuals referenced.
37. Section 6.4.3.2: Clarification on which specific manual referenced
 

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38. Section 6.4.4: Clarification on which specific manuals referenced. Replaced “the 
Regulatory Sponsor” with “Novartis”
39. Section 7.1: Updated trial design to reflect extension of trial duration from 12 months to 
60 months.
40. Figure 7-1: Added figure to reflect patient flow scenarios.
41. Table 7-1: Day 28 window changed from +/- 7 days to +/- 4 days.
42. Table 7-1: Enrollment window changed from “W-3 to D-8” to “W-8 to D-8”
43. Table 7-1: Pre-infusion window changed from “D-1” to “D-1 +1”
44. Table 7-1: Cytogenetics testing updated for relapsed patients
45. Table 7-1: Added collection timepoints of antineoplastic therapies  treatment post CTL019 
infusion
46. Table 7-1: Separated and added “Labs of Special Interest” from Chemistry panel
47. Table 7-1: Deleted “Viral Serology (CMV/ EBV)” testing
48. Table 7-1: Deleted “Flow Cytometry of bone marrow aspirate (B cell, tumor cell, CD19 
assessment” 
49. Table 7-1: Added MRD assessment by bone marrow aspirate by flow cytometry to 
include normal B and T cell counts amd CD19 status
50. Table 7-1: Tumor cell assessment by flow cytometry of peripheral blood for clarity 
51. Table 7-1: “Aspirate” added to lymph node or other involved tissue assessment
52. Table 7-1: Added Mediastinal disease assessment imaging for lymphoblastic lymphoma 
patients
53. Table 7-1: Added pregnancies and menstrual status
54. Table 7-1: CRS assessment by peripheral blood clarification
55. Table 7-1: Added CTL019 pharmacokinetics by flow cytometry (bone marrow aspirate) 
56.
 
57.
58.
59.
60. Table 7-1: Added apheresis sample for correlative studies
61. Table 7-1: Added CTL019 cell product sample for correlative studies
62. Table 7-2: Added to reflect assessments performed from 12 month to 60 month period of 
Treatment and Primary Follow-Up.
63. Table 7-3: Added to reflect assessments performed during Secondary Follow-Up. 
64. Section 7.1.1: Clarifications made throughout section. “at the time of screening” added to 
performance status assessment; Standard cytogenetics results clarified to be collected “at 
the time of most recent relapse. If not available, test must be performed at screening;
“ within 3 months of screening” added to donor chimerism; “Labs of special interest 
(
 LDH, and fibrinogen)” added;   HIV testing window updated and testing 
methodology updated; Viral serologies deleted; “test within 8 weeks of screening” added 
 

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to Hepatitis B/ C testing; T cell numbers added to bone marrow aspirate and biopsy  and 
peripheral blood flow cytometry. Mononuclear cell isolation for genomic analyses added 
to bone marrow aspirate or biopsy. Mediastinal disease assessment added for relapsed or 
refractory B-cell lymphoblastic lymphoma. 
65. 7.1.1.1: Clarification to operational impact of screening and enrollment requirements from 
transfer of IND from University of Pennsylvania to Novartis IND. Removal of third party 
review for confirmation of clinical eligibility.
66. Section 7.1.2: Section updated with new visit windows and clarifications for pre-infusion 
criteria.
67. Section 7.1.3: Section updated with new visit windows and other clarifications :. T cells 
added for flow cytometry; Day 28 window changed to +- 4 days; “aspirate” added to 
lymph node assessment. Month 12, 15, 18, 21, 24, 30, 36, 42, 48, and 54 visit assessment 
details added. 
68. 7.1.3.1: Updated trial design to reflect extension of trial duration from 12 months to 60 
months.
69. 7.1.3.2: Section updated with criteria for premature patient withdrawal from Treatment 
and Primary Follow-Up 
70.
 
 
71. Section 7.1.4: Section updated and clarified.
72. Section 7.1.4.1: Section added. 
73. Section 7.2.1: Updated with Lymphoblastic Lymphoma efficacy assessment reference. 
74. Table 7-2: Mandated collections added for 60 month extension of trial to peripheral 
blood , extramedullary disease assessment by physical exam, and flow cytometry of 
peripheral blood; Mediastinal disease assessment imagine for lymphoblastic lymphoma 
patients,  T cells added for flow cytometry of peripheral blood; Deleted flow cytometry of 
bone marrow aspirate. 
75. Section 7.2.1.1: Updated with timepoints for extension of trial duration from 12 months to 
60 months. 
76. Section 7.2.1.2: Updated with timepoints for extension of trial duration from 12 months to 
60 months. 
77. Section 7.2.2: Further Tanner staging not required if patient classified as Tanner stage 5
78. Section 7.2.2.4: Added Tanner Staging details.
79. Table 7-4: Table updated for clarification. “B cell and T cell levels” added.  
80.
 
81. Section 7.2.3: Enrollment window changes from “W-3 to D-8” to “W-8 to D-8” and Day 
28 window changed to +/- 4 days for all applicable tables.
82. Table 7-6: Day 11 collection added; Collections added for extension of trial from 12 
months to 60 months; clarification of collection of unscheduled samples. 
 

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83. Table 7-7: Table added for collection of CTL019 PK samples by flow cytometry of 
peripheral blood.
84. Table 7-9: Table added for collection of CTL019 pharmacokinetics by flow cytometry in 
bone marrow aspirate.
85. Table 7-11: Collections added for extension of trial from 12 months to 60 months; 
clarification of collection of unscheduled samples.
86. Table 7-11: Collections added for extension of trial from 12 months to 60 months; 
clarification of collection of unscheduled samples. Clarification added for primary follow 
up only. 
87. Table 7-13: Table added for Tociluzimab CTL019 PK collection 
88. Table 7-14: Table added for Anticytokine therapy (other than Tocilizumab) PK collection 
89. Section 7.2.3.1: Section updated for clarification.
90.
 
91. Section 7.2.4: Section added.
92. Section 8.1.2: Clarification added on adverse event reporting while patient simultaneously 
enrolled on CTL019B2206 and extension of trial from 12 months to 60 months.
93. Section 8.2.2: Clarification added on serious adverse event reporting while patient 
simultaneously enrolled on CTL019B2206 and extension of trial from 12 months to 60 
months; “Regulatory Sponsor” replaced with “Novartis”.
94. Section 8.2.3: Section deleted.
95. Section 8.4: “salpingotomy” corrected to “bilateral salpingectomy”; “the Regulatory 
Sponsor” replaced with “Novartis”.
96. Section 8.6: Section deleted.
97. Section 8.7: Replaced reference to University of Pennsylvania regulatory and safety 
bodies with Novartis and clarifications made
98. Section 8.8: Replaced reference to University of Pennsylvania regulatory and safety 
bodies with Novartis.
99. Section 9: Clarifications added
100.
Section 9.2: Replaced reference to University of Pennsylvania regulatory and safety 
bodies with Novartis.
101.
Section 9.4: Replaced “the Regulatory Sponsor” with “Novartis”.
102.
Section 10: Section updated with new population details and addition of formal 
interim analysis. 
103.
Section 10.1: Section updated based on new population
104.
Section 10.1.6: Clarification added.
105.
Section 10.2: Primary refractory definition clarified
 

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106.
Section 10.4 and subsections: Statistical analysis updates based on changes 
implemented in protocol
107.
Section 10.5.2.2: Section updated
108.
Section 10.5.2.3: Clarification added.
109.
Section 10.5.2.4: Section removed (CR or CRi with MRD negative bone marrow)
110.
Section 10.5.2.7: Section added
111.
Section 10.5.2.8: Section added
112.
Section 10.5.2.9: Section added
113.
Section 10.5.3.7: Section added
114.
Section 10.5.3.9: Section updated
115.
Section 10.5.4: Section update
116.
Table 10-4: Table updated with more details 
117.
Section 10.6.1: Section updated
118.
Section 10.6.1.3: Section updated
119.
Section 10.7: Section updated to include interim analysis. 
120.
Section 10.8: Section updated
121.
Section 10.6.4: Patient reported outcome section removed and moved to Section 
10.5.2.7
122.
Section 10.8: Section updated
123.
Section 11.2: Clarifications made for updated bodied and replaced reference to 
University of Pennsylvania regulatory and safety bodies with Novartis.
124.
Section 11.3: Clarifications made; replaced reference to University of Pennsylvania 
regulatory and safety bodies with Novartis.
125.
Section 11.4 and 11.5: Replaced “the Regulatory Sponsor” with “Novartis”.
126.
Section 11.6: Replaced reference to University of Pennsylvania regulatory and safety 
bodies with Novartis
127.
Section 11.7: Replaced “the Funding Sponsor” with “Novartis”
128.
Section 11.8: Replaced “the Regulatory Sponsor” with “Novartis”.
129.
Section 12: Replaced “the Regulatory Sponsor” with “Novartis”.
130.
Section 12.1: Clarifications made for updated bodied and replaced reference to 
University of Pennsylvania regulatory and safety bodies with Novartis
131.
Section 13: References added
132.
Section 14.1 Appendix 1: Updated 
133.
Section 14.2 Appendix 2: Lymphoblastic lymphoma assessment guidelines added
134.
Section 14.3 Appendix 3: clarifications made
135.
Section 14.4 Appendix 4: CTL019 Modified Safety Reporting guidelines added
 

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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
This protocol amendment was finalized under the UPenn IND and therefore, a rationale was 
not included at the time.  Therefore, at the time of transitioning the trial to Novartis IND, it 
has been retrospectively added. 
At the time of this protocol amendment, no sites had been initiated and first patient first visit 
(FPFV) had not occurred. All sites are to be initiated with the current protocol amendment.
The protocol was being amended in order to include additional safety information and 
includes Health Authority feedback regarding reporting of SAEs including CRS and deaths, 
updating CTL019 dosing, staggered-enrollment design,  follow-up time required after a live 
birth, influenza testing 10 days prior to infusion, general toxicity management, and modified 
Serious Adverse Event (SAE) and Adverse Event (AE) reporting.
 

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Protocol No. CCTL019B2205J
Protocol summary:
Protocol number
CCTL019B2205J
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 second or greater relapse or refractory (r/r) pediatric 
B-cell ALL and Lymphoblastic Lymphoma. Treatment options for r/r B-cell ALL and 
Lymphoblastic Lymphoma include further treatment with salvage chemotherapy, allogeneic 
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 MHC
independent manner. Anti-tumor efficacy has been seen in r/r adult and pediatric ALL and in 
r/r CLL.
Primary 
Objective(s) and 
Key Secondary 
Objective
To evaluate the efficacy of CTL019 therapy in acute lymphoblastic leukemia patients as 
measured by overall remission rate (ORR), 6 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.
ORR in Lymphoblastic Lymphoma patients will be evaluated separately using local 
investigator’s assessment.
Secondary 
Objectives
These objectives will be assessed in the acute lymphoblastic leukemia patients and 
separately in the lymphoblastic lymphoma patients.
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 quality of response by assessing the percentage of patients 
who achieve a best overall response (BOR) of CR or CRi with a minimal residual disease 
(MRD) negative bone marrow 6 months after CTL019 infusion and at D28 by central 
analysis.
Objective 5: To evaluate the relapse-free survival (RFS), event-free survival (EFS) and 
overall survival (OS)
Objective 6: Evaluate the response at Day 28+/-4 days
Objective 7: To evaluate the impact of baseline tumor burden on response
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, and other 
tissues if available)
Objective 10: To describe the prevalence and incidence of immunogenicity to CTL019
Objective 11: To describe the profile of soluble immune factors that may be key to cytokine 
 

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release syndrome
Objective 12: To describe the levels of  B and T cells (peripheral blood and bone marrow) 
prior to and following CTL019 infusion
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 and lymphoblastic lymphoma. 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, quarterly up to 2 years, and semi-annually afterwards up to 5 years, or 
until patient relapse. Safety will be assessed throughout the study. A post-study follow-up for 
lentiviral vector safety will continue under a separate destination protocol for 15 years post 
infusion per health authority guidelines. An interim analysis is planned when all acute 
lymphoblastic leukemia patients who were enrolled and CTL019 manufactured according to 
the UPenn manufacturing process have completed 6 months from study day 1 infusion or 
discontinues earlier.
Population
The target population is comprised of pediatric patients with B-cell ALL and Lymphoblastic 
Lymphoma who are primary refractory, chemo-refractory, relapsed after allogeneic SCT, or 
are otherwise ineligible for allogeneic SCT. Approximately 67 patients will be enrolled to 
allow 50 total patients to be treated which will consist of patients with relapsed or refractory 
acute lypmphoblastic leukemia and/or lymphoblastic lymphoma age 3 at the time of 
screening to age 21 at the time of initial diagnosis. 
In order to satisfy European PIP requirement, at least 40 patients <18 years of age will be 
treated at the time of primary analysis.  Therefore, no more than 10 patients ≥18 years of age 
will be treated. Sites will be notified when this age cap is reached.
The number of acute lymphoblastic leukemia and lymphoblastic lymphoma patients to be 
treated respectively will be based on the actual recruitment of the two populations. It is 
anticipated that the lymphoblastic lymphoma population is small and will represent less than 
10% of the entire population. Therefore with 50 patients treated in the study, it is assumed 
that 45 acute lymphoblastic leukemia patients will be treated.
Inclusion criteria
1. [Retired from UPenn protocol version 2.0]
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:
a. Renal function defined as:
i. Calculated creatinine clearance or radioisotope Glomerular Filtration Rate
(GFR) > 60 mL/min/1.73 m2, OR
ii. 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.Alanine Aminotransferase (ALT) ≤5 times the upper limit of normal (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. Left Ventricular Shortening Fraction (LVSF) ≥ 28% confirmed by echocardiogram, or 
Left Ventricular Ejection Fraction (LVEF) ≥45% confirmed by echocardiogram or MUGA
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening
 

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5. Life expectancy > 12 weeks
6. [Retired from UPenn protocol version 2.0].
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. Once all other eligibility criteria are confirmed, must have an apheresis product of non-
mobilized cells received and accepted by the manufacturing site. 
10. Relapsed or refractory pediatric B-cell Acute Lymphoblastic Leukemia or B-cell 
Lymphoblastic Lymphoma, AND
a. 2nd or greater BM relapse OR
b. Any BM relapse after allogeneic SCT and must be > 6 months from SCT at the time of 
CTL019 infusion OR
c. Primary refractory as defined by not achieving a CR after 2 cycles of a standard 
chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle of 
standard chemotherapy for relapse leukemia OR
d. Patients with Ph+ ALL are eligible if they are intolerant to or have failed two lines of TKI 
therapy, or if TKI therapy is contraindicated OR
e. Ineligible for allogeneic SCT because of:
i. Comorbid disease
ii. Other contraindications to allogeneic SCT conditioning regimen
iii. Lack of suitable donor
iv. Prior SCT
v. Declines allogeneic SCT as a therapeutic option after documented discussion, 
including expected outcomes, about the role of SCT with a BMT physician not part of the 
study team
11. Age 3 at the time of screening to age 21 at the time of initial diagnosis.
Exclusion 
criteria
1. Isolated extra-medullary disease relapse
2. Patients with concomitant genetic syndrome: 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 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. Prior treatment with gene therapy product
6. Treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
7. [Retired from UPenn protocol version 2.0]
8. [Retired from UPenn protocol version 2.0]
9. Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
10. [Retired from UPenn protocol version 2.0]
11. Active 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 participated in an investigational research study using an investigational 
agent within the last 30 days prior to screening
13. Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive 
potential must have a negative serum or urine pregnancy test performed within 48 hours 
before infusion
14. [Retired from UPenn protocol version 2.0]
15. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any 
uncontrolled infection at screening
16. HIV positive test within 8 weeks of screening
17. The following medications are excluded:
a. Steroids: Therapeutic 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 drug used for GVHD must be stopped > 4 weeks prior to 
CTL019 infusion (e.g. calcineurin inhibitors, methotrexate or other chemotherapy drugs, 
mycophenolyate mofetil, rapamycin, thalidomide, or immunosuppressive antibodies such as 
anti-CD20 (rituximab), anti-TNF, anti-IL6 or anti-IL6R)
d. Chemotherapy:
The following drugs must be stopped > 1 week prior to CTL019 infusion and should not be 
administered concomitantly or following lymphodepleting chemotherapy: hydroxyurea, 
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), excluding the required lymphodepleting chemotherapy drugs
Pegylated- aspariginase must be stopped >4 weeks prior to CTL019 infusion  
e. CNS disease prophylaxis:
i. CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 infusion 
(e.g. intrathecal methotrexate)
f. Anti T-cell Therapy: Administration of any T cell lytic or toxic agent (e.g. alemtuzumab) 
prior to CTL019 is strongly discouraged 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 Novartis, consider consultation with an 
pharmacology expert, and consider measuring residual drug levels, if feasible, prior to 
CTL019 infusion.
18. Women regardless of age that may have child-bearing potential (defined as all women 
physiologically capable of becoming pregnant) and all male participants, unless they are 
using highly effective methods of contraception for a period of 1 year after the CTL019 
infusion). Women are to continue contraception until CAR cells are no longer present in the 
blood by PCR. Highly effective contraception methods include:
a. 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)   
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow up hormone level assessment
c. Male sterilization (at least 6 months prior to screening). For female participants on the 
study the vasectomized male partner should be the sole partner for that patient
d. Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception
e. Use of intrauterine devices (IUDs) are excluded due to increased risks of infection and 
bleeding in this population
f. In case of use of oral contraception, women must be stable on the same pill for a 
minimum of 3 months before taking study treatment
Women who are not of reproductive potential (defined as either <11 years of age, Tanner 
Stage 1, post-menopausal for at least 24 consecutive months (i.e. have had no menses) or 
have undergone hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) are 
eligible without requiring the use of contraception. Women who are not yet of reproductive 
potential are to agree to use acceptable forms of contraception when they reach reproductive 
potential if within 1 year of CTL019 or if CAR cells are present in the blood by PCR. 
Acceptable documentation includes written or oral documentation communicated by clinician 
or clinician’s staff of one of the following:
a. Demographics show age <11
b. Physical examination indicates Tanner Stage 1
c. Physician report/letter
d. Operative report or other source documentation in the patient record
 

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e. Discharge summary
f. Follicle stimulating hormone measurement elevated into the menopausal range
Investigational 
and reference 
therapy
A dose of CTL019 transduced cells will consist of a single infusion of 2 to 5 x 106 CTL019 
transduced viable T cells/kg with a maximum dose of 2.5 x 108 CTL019 transduced viable T 
cells (non-weight adjusted).
Efficacy 
assessments
Primary: Overall Response Rate (ORR),  6 months after CTL019 administration, which 
includes Complete Remission (CR) and Complete Remission with Incomplete Blood Count 
Recovery (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 for acute lymphoblastic leukemia patients, and based on local investigator’s 
assessment for acute lymphoblastic lymphoma patients. The local investigator’s assessed 
results will be used for sensitivity analysis for acute lymphoblastic leukemia patients.
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
d. proportion of patients with sustained anti-CTL019 antibody assay titers
Other 
assessments
Pharmacokinetic assessments planned for this trial include:
●
Detection of CTL019 transgene levels in blood, bone marrow and CSF (if available) by q-
PCR.
●
Expression of CTL019 detected by flow cytometry in blood and bone marrow
●
Maximum Concentration (Cmax), Time of Peak Concentration (Tmax), Area Under the 
Curve (AUCs) and other relevant PK parameters of CTL019 in blood, bone-marrow, CSF (if 
available).
●
Maximum extent of expansion of CTL019 in blood
●
Persistence of CTL019 in blood, bone marrow and CSF (if available)
Data analysis
Primary endpoints:
●
The primary analysis will be carried out after 50 treated patients have completed at least 
6 months of follow-up or have discontinued due to any reason. Updated efficacy and safety 
data will be reported after patients have been followed for a total of 60 months within the 
study protocol.
●
The primary efficacy endpoint, ORR will be assessed by IRC for Acute Lymphoblastic 
Leukemia patients and by local investigator’s assessment for Lymphoblastic Lymphoma 
patients in the full analysis set (FAS). The primary efficacy analysis will be based on 
statistical testing in acute lymphoblastic leukemia patients, descriptive analysis in 
lymphoblastic lymphoma patients, and descriptive analysis in all patients combined.
●
The primary efficacy analysis in acute lymphoblastic leukemia patients will be performed 
 

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by testing the null hypothesis of ORR being less than or equal to 20% against the alternative 
hypothesis that the ORR is greater than 20% at overall one-sided 2.5% level of significance, 
powered for ORR = 45%. 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. 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.
Sensitivity analyses will be performed on the Enrolled Set, the per-protocol set (PPS) and 
with all patients who satisfy all clinical eligibility criteria (defined as all inclusion/exclusion 
criteria except that which pertains to the apheresis product) using the same method as 
described above.
Secondary endpoints:
●
Analysis of 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.
Interim Analysis:
●
An interim analysis is planned when all acute lymphoblastic leukemia patients who were 
enrolled and CTL019 manufactured according to the UPenn manufacturing process have 
completed 6 months from study day 1 infusion or discontinues earlier. Approximately 30 
patients will be included in the interim analysis. An α-spending function according to Lan-
DeMets (O’Brien-Fleming), as implemented in East 6.1, will be used to construct the efficacy 
stopping boundaries (Lan and DeMets 1983). If the interim analysis is performed exactly with 
30 patients, the lower bound of the 2-sided 98.79% exact CI of the ORR will need to be 
greater than 20% to declare statistical significance
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 = 45%, 50 patients in the FAS will provide 95% 
power to demonstrate statistical significance using a 2-look Lan-Demets group sequential 
design with O’Brien-Fleming type boundary at one-sided 2.5% level of significance. 
Assuming 20% to 25% enrolled patients will not be infused due to reasons such as product 
manufacturing issues, worsening of patient’s condition, etc., at least 63 to 67 patients need to 
be enrolled respectively to ensure 50 acute lymphoblastic leukemia or lymphoblastic 
lymphoma patients are treated using either UPenn or Novartis CMC process and hence will 
be used for the primary analysis
Key words
Relapsed/refractory ALL or Lymphoblastic Lymphoma, relapsed ALL, post allogeneic SCT, 
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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 leukemia’s (ALL), chronic lymphocytic leukemia’s (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 are not 
candidates for 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 leukemia’s, 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 et al 1989).
 

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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).
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 et al 2003, 
Brentjens et al 2010, Porter et al 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 et al 1988, Stamenkovic and Seed 1988, Fearon and Carroll 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 et al 
1988, Stamenkovic and Seed 1988, Tedder and Isaacs 1989, Fearon and Carroll 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 et al 2009, Kohn et al 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 et al 1989, Pinthus et al 2003). These 
receptors have the ability to recognize intact membrane proteins independent of antigen
processing. The tumor antigen binding function of CAR is usually accomplished by the 
inclusion of a single chain variable fragment (scFv) antibody, containing the heavy chain 
variable domain (VH) and light chain variable domain (VL) chains joined by a peptide linker 
of about 15 residues in length (Mullaney et al 2001).
 

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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 et al 2011, Grupp et al 2013, Maude 2014).
It is anticipated that CTL019 may offer a therapeutic alternative for patients with r/r B cell 
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 et al 2000, Clay et al 2002, Hombach et al 2002, Pule et al 2003, 
Sadelain 2003). Others have used electroporation or retroviral vectors to create CAR T cells 
and have shown in vivo safety and efficacy of adoptively transferred T cells in 
immunodeficient mouse models (Willemsen et al 2000, Roessig et al 2002, Brentjens et al 
2003, Cooper et al 2003, Serrano et al 2006). The incorporation of costimulatory signaling 
modules such as CD28 and 4-1BB in second generation CARs increases potency of the 
engineered T cells in pre-clinical studies (Finney et al 1998, Krause et al 1998, Eshhar et al 
2001, Maher et al 2002, Finney et al 2004, Friedmann-Morvinski et al 2005, Brentjens et al 
2010). The pre-clinical data supporting CAR T cell persistence, expansion and anti-tumor 
efficacy have been published (Gross and Eshhar 1992, Milone et al 2009).
 

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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 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.
Safety
Pediatric r/r Acute Lymphpblastic Leukemia
Toxicities seen in pediatric r/r ALL patients include expected chemotherapy related adverse 
events (AE) and CTL019 related events of tumor lysis syndrome (TLS) and CRS/macrophage 
activation syndrome (MAS) (Grupp et al 2013, Maude 2014). TLS and CRS/MAS in ALL 
patients typically occurred within days to a week following CTL019 infusion and correlated 
with peak in vivo CTL019 cell expansion. TLS complications were managed as per standard 
of care including prophylactic allopurinol (in patients with elevated uric acid or high tumor 
burden) and fluids, and rasburicase as needed. CRS/MAS has been managed in pediatric ALL 
patients with supportive care and when needed, tocilizumab (anti-IL-6 receptor monoclonal 
antibody) therapy. Since CRS mechanistically is believed to be a required part of the 
antitumor mechanism of in vivo CTL019 cell expansion and tumor killing, tocilizumab was 
administered for CRS only after symptoms became moderate or severe. This included
worsening respiratory distress, pulmonary infiltrates, increasing oxygen requirement (defined 
as high-flow oxygen and/or need for mechanical ventilation), hemodynamic instability despite 
intravenous fluids and moderate/high dose vasopressor support, and/or rapid clinical 
deterioration. Preliminary data supports that management with tocilizumab does not appear to 
diminish CTL019 cell expansion, therefore tocilizumab should be administered for CRS when 
symptoms warrant treatment per the CRS management algorithm (Figure 6-1). Steroids 
following CTL019 infusion were avoided and given only under life threatening situations due 
to their known lympholytic effects. Clinical responses do not appear to correlate prior 
relapsed or refractory status of the patient. CRS severity appears to correlate with pre-infusion 
tumor burden in pediatric ALL but not with CTL019 transduced cell numbers within the range 
of cell doses studied. More severe CRS is associated with earlier clinical onset of CRS related 
symptoms in pediatric r/r ALL patients. Refer to Section 6.2.4.2 for guidance related to CRS 
management and the [Investigator Brochure] for additional safety information.
As of May 2015 51 pediatric r/r ALL patients were treated on the CHP959 Phase I study with 
either one, two, or three doses of CTL019 with split dosing (10%, 30%, 60%). The age range 
of patients was 4 to 22 years. CRS of variable severity was seen in 46 pediatric patients out of 
the 51. Of the 46 patients with CRS, 24 patients had Grade 3 or 4 CRS (47.1%). Median time 
to CRS onset was three days (day 1 to 11) and median time to CRS resolution was 11 days 
(day 6 to 24). CRS that developed into severe Grade 4 (defined as hypotension requiring the 
 

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use of two or more vasopressors or respiratory failure requiring mechanical ventilation) had
an initial onset at median of day 2 after infusion, whereas CRS that did not develop into Grade 
4 (non-severe) had an initial onset at a median of day 5 after infusion. Fifteen patients (33%) 
required tocilizumab (one to three doses) in addition to supportive care for management of 
CRS which resulted in rapid defervescence and stabilization of blood pressure, with 
improvement (weaning from vasopressor support) over a period of 1 to 3 days. Nineteen 
(42%) patients required admission to the intensive care unit (ICU) with 5 patients requiring 
high dose vasopressor support and 6 patients requiring mechanical ventilation. Disseminated 
intravascular coagulation requiring blood product support was seen in 5 patients and
reversible encephalopathy was seen in 16 patients. CRS seen in pediatric patients was 
manageable with supportive care, and, when needed, tocilizumab. All pediatric patients 
recovered fully with complete reversal of symptoms and a normalization of laboratory results. 
Patients achieving a CR also experienced B-cell aplasia and hypogammaglobulinemia, which 
was supported with periodic intravenous immune globulin infusions as per local guidelines. 
GVHD was not seen in the patients who had previously undergone an allogeneic SCT with 
known donor chimerism. No acute fatalities were observed in this phase I study.
Maude et al (2014) reported that 13/30 CTL019 treated patients (25 pediatric and 5 adult) in 
the Phase I trials as of March 2014 had neurologic toxic effects, which ranged from delirium 
during the period of high fevers to global encephalopathy with one or more of the following: 
aphasia, confusion, delirium, and hallucinations. Six patients had delayed encephalopathy that 
occurred after high fevers had resolved and was independent of the severity of the CRS and 
whether the patient had received prior tocilizumab therapy. Symptoms were self-limiting 
(lasting 2 to 3 days and resolving over 2 to 3 days), and they resolved fully without further 
intervention or apparent long-term sequelae. One patient with encephalopathy had two 
seizures that may have been caused by concomitant electrolyte abnormalities. Several patients 
had normal computed tomographic or magnetic resonance imaging of the head and lumbar 
puncture that was negative for infection or leukemia.
Responding CLL and ALL patients demonstrated detectable and prolonged persistence of
CTL019 transduced cells in the setting of CR; over 2 years in one ALL patient, and over 4 
years in two CLL patients (Porter 2011, Grupp 2013, Maude 2014). 
Pediatric r/r Lymphoblastic Lymphoma 
Patients with relapse/refractory B-cell lymphoblastic lymphoma are a very rare patient 
population with no curative therapies other than allogeneic SCT. To date, patients with B cell 
lymphoblastic lymphoma have yet to be treated with CTL019. 
Adult r/r ALL
As of May 2015, 21 adult r/r ALL patients have been treated on a phase I trial (UPCC04409 
protocol, NCT01029366) or phase II trial (UPCC21413 protocol, NCT02030847) under the 
Penn IND. The age range is 20 to 71 years. CRS was seen in 20 of 21 patients. Seventeen 
patients (81%) had Grade 3 or 4 CRS and 17 (85%) of these patients required anti-cytokine 
therapy with tocilizumab.
 

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The phase II adult r/r ALL UPCC21413 trial utilized a single infusion of a higher dose of 
CTL019 cells. Among the first six patients treated, three deaths were attributable to Grade 5 
refractory CRS in the setting of significant concomitant infections. The subsequent six 
patients on this trial were then treated with a reduced cell dose of CTL019. Two early deaths 
out of these six subsequent patients were seen with the lower dose of CTL019 cells, however, 
CRS in these two cases was deemed not to be refractory to intervention. The cause of death 
was cerebral hemorrhage in one patient and sepsis in the other patient. The last three patients 
treated with the same reduced cell dose of CTL019 using a split dosing model. No early 
deaths were observed. 
Other institutions have also reported fatal SAEs in adult patients associated with the use of 
CD19 CARs. In one of these fatal SAEs, death occurred 44 hours post-CD19 CAR T cell 
infusion. The investigators concluded that concomitant sepsis was the most likely cause of 
death and attributed the etiology of the death as “possibly related” to CAR T cell infusion 
(Brentjens 2010). Two other fatal SAEs in adult patients have been reported by other 
institutions outside the University of Pennsylvania. Each of these deaths occurred within the 
first two weeks of CAR infusion.
Efficacy
As of May 2015, of the 51 r/r pediatric ALL patients treated in the CHP959 Phase I study,
46/51 (90%) achieved complete remission (CR or CRi). Similar response rates were seen in 
patients with or without prior allogeneic stem cell transplant. All responding patients 
developed B-cell aplasia. The administered dose range per kg was 1.0 x 106 to 17.3 x 106
transduced CTL019 cells/kg. The total transduced CTL019 cells administered was 0.3 x 108 to 
9.1 x 108 CTL019 cells. 
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 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–
 

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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.
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 and B-cell lymphoblastic 
lymphoma. 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 67 patients to 
allow 50 patients treated. 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.
The initial 30 patients were treated with the University of Pennsylvania manufacturing 
process. The remaining patients to be treated on this trail will utilize product manufactured by
the Novartis manufacturing process.
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 lymphoblastic lymphoma; and 2) the established 
correlation with long-term outcome (Cheson et al 2003, Appelbaum et al 2007, NCCN v1 
2013).
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 and Bevan 1999, Surh and Sprent 2000). Host lymphodepletion 
may enhance the effectiveness of adoptively transferred T cells (Dummer et al 2002). 
Homeostatic T cell proliferation can lead to activation of certain immune cell subsets (King et 
al 2004), providing a clue to improved anti-tumor responses. T cells can undergo up to seven 
rounds of cell division after being deprived of contact with antigen presenting cells (Kaech 
and Ahmed 2001, van Stipdonk et al 2001). Lymphodepletion eliminates regulatory T-cells 
and other competing elements of the immune system that act as “cytokine sinks”, enhancing 
the availability of cytokines such as 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
 

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(Laport et al 2003, Rapoport et al 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, seven 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.
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 one, 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 
 

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than 2 x 106 CTL019 cells/kg may be associated with a lack of response or CR with an early 
relapse.
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, the targeted CTL019 cell dose for pediatric ALL patients is 2 to 5 x 106 CTL019 
transduced viable T cells per kg body weight with a maximum dose of 2.5 x 108 CTL019 
transduced viable T cells (non-weight adjusted).
2.4
Rationale for choice of combination drugs
Not applicable.
2.5
Rationale for choice of comparator drugs
Not applicable.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below. These objectives will be 
assessed in the acute lymphoblastic leukemia patients and separately in the lymphoblastic 
leukemia patients.
If there are no more than 5 lymphoblastic lymphoma patients treated, data for these patients 
will be summarized primarily via listings.
 

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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Evaluate the efficacy of CTL019 therapy as measured by overall 
remission rate (ORR) 6 months after CTL019 administration, which 
includes CR and CR with incomplete blood count recovery (CRi) as 
determined by IRC assessment for acute lymphoblastic leukemia 
patients..
ORR in Lymphoblastic Lymphoma patients will be evaluated separately 
using local investigator’s assessment.
● ORR (= CR + CRi) per IRC assessment in ALL patients; See 
Appendix 1 for response definition
● ORR (= CR + CRi) per local investigator’s assessment in 
lymphoblastic lymphoma  patients; See Appendix 2 for response 
definition
Refer to Section 10.4
Key secondary
Not applicable
Not applicable
Other secondary
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
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 quality of response by assessing the percentage of 
patients who achieve a best overall response (BOR) of CR or CRi with 
a minimal residual disease (MRD) negative bone marrow6 months after 
CTL019 infusion and at D28 by central analysis
● Percentage of patients with BOR of CR or CRi with MRD 
negative bone marrow 6 months after CTL019 infusion, among all 
patients who are infused 
● MRD status before treatment, at day 28 +/- 4 days after 
treatment will also be described
Refer to Section 10.5.2.4
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 10.5.2.5
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 10.5.2.6
 

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Objective
Endpoint
Analysis
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 10.5.2.7
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 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
● Maximum extent of expansion of CTL019 in blood (Cmax/
Cpost-infusion,hr)
● Persistence of CTL019 in blood, bone marrow, andCSF (based 
on Time > Limit of Quantification [LOQ], Time > other threshold 
CTL019 levels, Mean Residence Time [MRT] last)
Refer to Section 10.5.4
Describe the prevalence and  incidence of immunogenicity to CTL019
● Prevalence and incidence of immunogenicity and anti-CTL019 
assay titers 
Refer to Section 10.5.3.4
Describe the profile of soluble immune factors that may be key to 
cytokine release syndrome 
● Frequent monitoring of concentrations of soluble immune factors 
in blood
Refer to Section 10.5.3.6
Describe the levels of B and T cells (peripheral blood and bone 
marrow) prior to and following CTL019 in safety monitoring
● Lymphocyte subsets of B and T cells and description of 
associated  safety events
Refer to Section 10.5.3.7
 

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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 and B-cell lymphoblastic 
lymphoma. 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 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).
For sites with no prior CTL019 experience, a staggered treatment design will be implemented
at each site for the first two patients for logistical and safety purposes. The first patient will be 
treated and a 14 day follow-up period must be completed before the second patient can be 
treated. Then a second patient may be treated and a 14 day follow up period completed. After 
completing this staggered treatment design for the first two patients, subsequent patients may 
proceed with treatment of patients without staggering.
Figure 4-1
Study design
 

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4.1.1
Apheresis assessment
Cryopreserved apheresis 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 apheresis 
product is not available, an apheresis procedure will be scheduled for cell procurement prior 
to study enrollment. It is strongly recommended that apheresis
be scheduled prior to any 
planned chemotherapy or non-physiologic dose of steroid administration as an absolute 
peripheral blood T-cell count. Subjects with an absolute lymphocyte count (ALC) < 500/µL 
during screening, should have a CD3 count of ≥150/ µL to be eligible for leukapheresis 
collection.
For guidelines on optimal patient timing of apheresis collection, please refer to the 
Leukapheresis Key Requirements within the [Leukapheresis, Cryopreservation & Scheduling 
Manual].For patients developing grade 2 to 4 acute GVHD or extensive chronic GVHD 
following the collection of an apheresis product, such an apheresis product cannot be used for 
CTL019 manufacturing or infusion due to concerns of auto-reactive T cells with an increased 
risk for inducing or exacerbating GVHD by the manufactured product.
During the screening phase, informed consent/assent forms will be signed and all clinical 
eligibility criteria (defined as all inclusion/exclusion criteria except that which pertains to the 
apheresis product) will be assessed. Only following informed consent/assent and confirmation 
of all clinical eligibility criteria will the patient’s apheresis product be shipped to the 
manufacturing facility. The manufacturing facility will then evaluate the patient’s apheresis 
product for acceptance. Enrollment is defined as the point at which the patient meets all 
clinical inclusion/exclusion criteria, and the patients’ apheresis product is received and 
accepted by the manufacturing facility.
 
 
4.2
Definition of end of the study
The end of study is defined as the last patient’s last visit (LPLV), which is the last patient’s 
Month 60 evaluation, or the time of premature withdrawal.
Patients who discontinue the “Treatment and Primary Follow-Up Phase” before month 60 will 
continue to be followed in the secondary follow-up phase in order to collect health authority 
requested data (e.g. delayed adverse events) up to 5 years after CTL019 infusion. 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.
In addition, semiannual and annual evaluations will be performed for up to 15 years on all 
patients under a separate destination protocol as recommended by health authority guidance
for patients treated with gene therapies. All patients who either complete the study or 
prematurely discontinue from the study will be enrolled in this destination protocol at the time 
of study completion/discontinuation (separate informed consent/assent forms will be provided 
for this protocol; Section 7.1.6).
 

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Patients may continue to be followed under the current protocol for survival as defined above 
or until they choose to enroll into the 15 year long term follow-up
protocol
([CCTL019A2205B]), whichever occurs first. The survival follow-ups can be conducted in 
the form of telephone contact.
4.3
Early study termination
The study can be terminated at any time for any reason by Novartisor 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 and any other 
regulatory committee as applicable.
5
Population
5.1
Patient population
The primary target population consists of pediatric patients with B-cell 
ALL and 
lymphoblastic lymphoma who are primary refractory, chemo-refractory, relapsed after
allogeneic SCT, or are otherwise ineligible for allogeneic SCT. Approximately 67 patients 
will be enrolled to allow 50 total patients to be treated.
The primary analysis will be comprised of at least 50 acute lymphoblastic leukemia or 
lymphoblastic lymphoma patients treated.
In order to satisfy European PIP requirement, at least 40 patients <18 years of age will be 
treated at the time of primary analysis.  Therefore, no more than 10 patients’ ≥18 years of
age will be treated. Site will be notified when this cap is reaching.
The investigator or designee must ensure that only patients who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. [Retired from UPenn protocol version 2.0]
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:

Calculated creatinine clearance or radioisotope GFR > 60 mL/min/1.73 m2 OR
 

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
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
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening
5. Life expectancy > 12 weeks
6. [Retired from UPenn protocol version 2.0]
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. Once all other eligibility criteria are confirmed, must have an apheresis product of non-
mobilized cells received and accepted by the manufacturing site. Note: Apheresis product 
will not be shipped to or assessed for acceptance by the manufacturing site until 
documented confirmation of all other eligibility criteria is received
10.
Relapsed or refractory pediatric B-cell Acute Lymphoblastic Leukemia and 
Lymphoblastic Lymphoma
a. 2nd or greater BM relapse OR
b. Any BM relapse after allogeneic SCT and must be > 6 months from SCT at the time 
of CTL019 infusion OR
c. Primary refractory as defined by not achieving a CR after 2 cycles of a standard 
chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 
cycle of standard chemotherapy for relapse leukemia OR
d. Patients with Ph+ ALL are eligible if they are intolerant to or have failed two lines of 
TKI therapy, or if TKI therapy is contraindicated OR
e. Ineligible for allogeneic SCT because of:

Comorbid disease

Other contraindications to allogeneic SCT conditioning regimen

Lack of suitable donor

Prior SCT
 

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
Declines allogeneic SCT as a therapeutic option after documented discussion, 
including expected outcomes, about the role of SCT with a BMT physician not 
part of the study team
11. Age 3 at the time of screening to age 21 at the time of initial diagnosis.
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 syndrome: 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. Prior treatment with gene therapy product
6. Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-
CD19 therapy
7. [Retired from UPenn protocol version 2.0]
8. [Retired from UPenn protocol version 2.0]
9. Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
10. [Retired from UPenn protocol version 2.0]
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 participated in an investigational research study using an investigational agent
within the last 30 days prior to screening
13. Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive 
potential must have a negative serum or urine pregnancy test performed within 48 hours 
before infusion
14. [Retired from UPenn protocol version 2.0]
15. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any 
uncontrolled infection at screening
16. HIV positive test within 8 weeks of screening
17. The following medications are excluded:
a. Steroids: Therapeutic 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 drug used for GVHD must be stopped > 4 weeks prior to 
CTL019 infusion (e.g. calcineurin inhibitors, methotrexate or other chemotherapy 
 

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drugs, mycophenolyate, rapamycin, thalidomide, or immunosuppressive antibodies 
such as anti-CD20 (rituximab), anti-TNF, anti-IL6 or anti-IL6R)
d. Chemotherapy:

The following drugs must be stopped > 1 week prior to CTL019 infusion and 
should not be administered concomitantly or following lymphodepleting 
chemotherapy: hydroxyurea, 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), excluding the required lymphodepleting 
chemotherapy drugs

Pegylated- aspariginase 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.
Anti T-cell Therapy: Administration of any T cell lytic or toxic agent (e.g. 
alemtuzumab) prior to CTL019 is strongly discouraged 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 Novartis, 
consider consultation with an pharmacology expert, and consider measuring residual 
drug levels, if feasible, prior to CTL019 infusion.
18. Women of child-bearing potential (defined as all women physiologically capable of 
becoming pregnant) and all male participants, unless they are using highly effective 
methods of contraception for a period of 1 year after the CTL019 infusion).  Women are to 
continue contraception until CAR cells are no longer present in the blood by PCR. Highly 
effective contraception methods include:
a. 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
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment
c. 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.
d. Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception
e. Use of IUDs are excluded due to increased risks of infection and bleeding in this 
population.
f.
In case of use of oral contraception, women must be stable on the same pill for a 
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Women who are not of reproductive potential (defined as either <11 years of age, Tanner 
Stage 1, post-menopausal for at least 24 consecutive months (i.e. have had no menses) or 
have undergone hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) are 
eligible without requiring the use of contraception. Women who are not yet of 
reproductive potential are to agree to use acceptable forms of contraception when they 
reach reproductive potential if within 1 year of CTL019 or if CAR cells are present in the 
blood by PCR. Acceptable documentation includes written or oral documentation 
communicated by clinician or clinician’s staff of one of the following: 
a. Demographics show age <11
b. Physical examination indicates Tanner Stage 1
c. Physician report/letter 
d. Operative report or other source documentation in the patient record 
e. Discharge summary 
f.
Follicle stimulating hormone measurement elevated into the menopausal range
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 murine
monoclonal antibody. T cells are enriched from a patient leukapheresis unit are expanded ex 
vivo using commercially available magnetic beads that are coated with anti-CD3 and anti-
CD28 monoclonal antibodies. The cells are transduced with the CD19 CAR lentiviral vector.
The residual non-integrated vector is washed away during the process. CTL019 cells 
generally are expanded ex vivo for up to 10 days or may be more depending on manufacturing 
conditions. At the end of the culture, the CTL019 cells are depleted of magnetic beads, 
washed, concentrated, and cryopreserved. The product must pass all release criteria prior to 
infusion.
A dose of CTL019 transduced cells for pediatric patients will consist of a single infusion of 2 
to 5 x 106 CTL019 transduced cells per kg body weight with a maximum dose of 2.5 x 108
CTL019 cells (non-weight adjusted).
6.1.1
Dosing regimen
6.1.1.1
Lymphodepleting chemotherapy
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. 
 

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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 required
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 resistance to a previous cyclophosphamide-containing regimen, 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)
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 prepared and released by the manufacturing facility 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 (only 
during the months of October through May) within 10 days prior to the planned CLT019 
infusion. If the patient is positive for influenza, oseltamivir phosphate or zanamivir should 
administered for 10 days as preventative treatment (see Tamiflu® or Relenza® package 
insert for dosing).The patient must complete their 10 day preventative treatment course 
prior to receiving 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 patient is asymptomatic. 
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 
 

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
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
91% or presence of progressive radiographic abnormalities on chest x-ray
b. Cardiac: New cardiac arrhythmia not controlled with medical management. Prior to 
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 new 
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 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 drug used for GVHD must be stopped > 4 weeks prior to 
CTL019 infusion (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)
d. Chemotherapy:

The following drugs must be stopped > 1 week prior to CTL019 infusion and 
should not be administered concomitantly or following lymphodepleting 
chemotherapy: hydroxyurea, 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), excluding the required lymphodepleting 
chemotherapy drugs

Pegylated- aspariginase must be stopped >4 weeks prior to CTL019 infusion 
e. CNS disease prophylaxis:
 

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1. CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 
infusion (e.g. intrathecal methotrexate).
f.
Anti T-cell Therapy: Administration of any T cell lytic or toxic agent (e.g. 
alemtuzumab) prior to CTL019 is strongly discouraged 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 Novartis, 
consider consultation with an pharmacology expert, and consider measuring residual 
drug levels, if feasible, prior to CTL019 infusion.
1. Stem Cell Transplant: Reconfirm that patient is > 6 months from SCT at the time of 
CTL019 infusion (if applicable).
9. Lymphodepleting Chemotherapy Timing: If there is a delay of 4 or more weeks
between completion of lymphodepleting chemotherapy and the scheduled infusion, the 
WBC > 1000/µL, the patient will need to be re-treated with lymphodepleting 
chemotherapy.
10. 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.
11. Pregnancy: Patient must undergo a pregnancy test (urine or serum) within 48 hours prior 
to infusion (Table 7-1)
Additional safety procedures prior to administration: The risk of tumor lysis syndrome 
(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 should 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 on-site 
pharmacy must confirm that two doses of tocilizumab (Section 6.1.3) is on site prior to 
CTL019 infusion and available for administration in order to manage severe 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 
 

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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. A single dose of 2 to 5 x 106 autologous CTL019 transduced viable T cells per 
kg body weight, with a maximum dose of 2.5 x 108 autologous CTL019 transduced viable T 
cells will be administered. For patients with manufactured cell numbers falling below the 
above recommended dose ranges, CTL019 therapy will still be administered if product meets
all other manufacturing release criteria.
Depending on the volume of the CTL019 product, it will be given either as an IV infusion
through a latex free i.v. tubing WITHOUT a leukocyte filter (approximately 10 – 20 mL per 
minute adjusted as appropriate for smaller children and smaller volumes) or as an IV push via 
a syringe (for smaller volumes). It is recommended that the infusion/IV push be completed 
within 30 minutes of thawing the cryopreserved product. The tubing setup should also contain 
a Y-arm with an attached supplemental saline bag to be used after the initial infusion is 
completed.  This will allow any remaining product left behind within the bag and tubing to be 
recovered and infused.  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, 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 temperate twice daily for the first 14 days post CTL019 infusion. 
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 recommend admission 
for close observation.
 

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6.1.3
Rescue medication
Rescue medications are medications given for severe CRS due to CTL019 cells. Please see 
Figure 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) or other 
anti-cytokine therapy for the treatment of suspected CRS toxicities as described below in 
Section 6.2.4.2. The on-site pharmacy must confirm that two doses of tocilizumab are on site 
and available for administration prior to CTL019 infusion. All rescue medications (except 
for tocilizumab or other cytokine therapy administration), including steroids given to treat 
CRS, must be listed on the concomitant medication CRF. Tocilizumab or anti-cytokine 
therapy administration should be reported on the “Tocilizumab Dose Administration” or 
“Concomitant Medication” 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.
6.2.3.3
Use the following text for intra-patient dose escalation for 
combinations
Not applicable.
 

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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.
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.
Premature termination of the clinical trial may also occur because of a regulatory authority 
decision, change in opinion of the IRB, 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 Novartis’ 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
The study will 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

Death suspected to be related to CTL019 therapy
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

Novartis or health authorities decides for any reason that patient safety may be 
compromised by continuing the study

Novartis decides to discontinue the development of the intervention to be used in this 
study
 

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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 occur in patients with ALL 1-14 days after cell infusion and may 
include high fevers, rigors, myalgia/arthralgias, nausea/vomiting/anorexia, fatigue, headache,
encephalopathy, hypotension, dyspnea, tachypnea and hypoxia. Supportive care and 
tocilizumab 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 dose of tocilizumab (within 3-5 days) 
with CRS resolution. One fatal outcome associated with CRS has been observed in an adult 
ALL patient.
Other anti-cytokine therapies may also be considered if the patient does not respond to 
tocilizumab. If the patient experiences ongoing CRS despite administration of anti-cytokine 
directed therapies, anti-T-cell therapies such as cyclophosphamide, anti-thymocyte globulin 
(ATG) or alemtuzumab may be considered and need to be captured in case report forms.
A detailed treatment algorithm has been established with clear criteria for CRS management 
and guidance on when to administer tocilizumab and is presented below in Figure 6-1. 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 near to the treating site for the first 21
days.
The management of CRS is based solely upon clinical parameters as described in Figure 6-1
and must be followed by the investigator. 
 
 

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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 6-1.
Specific CRFs have been developed for the capture of CRS elements, severity, management 
and response to intervention.
Figure 6-1
CRS Management Algorithm:
Pretreatment
Acetaminophen/paracetamol and diphenhydramine /H1 anti-histamine
Prophylaxis for complications of TLS as appropriate
CTL019 infusion
Prodromal syndrome: low grade fevers, fatigue, anorexia (hours to days)
Observation, rule out infection (surveillance cultures)
Antibiotics per local guidelines (febrile neutropenia)
Symptomatic support
Symptom progression: High fevers, hypoxia, mild hypotension
1st Line Management:
Oxygen, fluids, low dose vasopressor support, antipyretics
Monitor/manage complications of TLS
Further symptom progression:

Hemodynamic instability despite intravenous fluids and moderate to “high dose” vasopressor 
support OR

Worsening respiratory distress, including pulmonary infiltrates increasing oxygen requirement 
including high-flow Oxygen (O2) and/or need for mechanical ventilation OR

Rapid clinical deterioration
2nd Line Management:
Tocilizumab:

Patient weight < 30 kg: 12 mg/kg i.v.

Patient weight > 30 kg: 8 mg/kg i.v. (max dose 800 mg)
Hemodynamic and respiratory support
Lack of clinical improvement while awaiting tocilizumab response
3rd Line Management:
Steroids (plan rapid taper)
Starting dose 2 mg/kg methylprednisolone as an initial dose, then 2 mg/kg per day
 

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If no response to steroids, consider 2nd dose of Tocilizumab (dose as above)
Hemodynamic and respiratory support
Lack of clinical improvement while awaiting response to 3rd line management
4th Line Management: 
Consider other diagnosis causing clinical deterioration (i.e. sepsis) 
If no response to steroids and 2nd dose of Tocilizumab, consider other anti-cytokine therapies
Hemodynamic and respiratory support
Lack of clinical improvement while awaiting response to 4th line management
5th Line Management:
Consider other diagnosis causing clinical deterioration (i.e. sepsis) 
If ongoing CRS despite prior therapy, consider anti-T cell therapies such as cyclophosphamide, anti-
thymocyte globulin, or alemtuzumab
Hemodynamic and respiratory support
Table 6-1
CTL019-Therapy-Associated Grading for Cytokine Release Syndrome: 
The Penn Grading Scale for Cytokine Release Syndrome (PGS-CRS)
1
2
3
4
Mild reaction: 
Treated with 
supportive care 
such as anti-
pyretics and anti-
emetics.
Moderate reaction: 
Requiring intravenous 
therapies or parenteral 
nutrition; some signs of 
organ dysfunction (i.e. 
Grade 2 creatinine or 
Grade 3 liver function 
tests [LFTs]) related to 
CRS and not attributable 
to any other condition. 
Hospitalization for 
management of CRS 
related symptoms 
including fevers with 
associated neutropenia.
More severe reaction: Hospitalization 
required for management of symptoms 
related to organ dysfunction including 
Grade 4 LFTs or Grade 3 creatinine
related to CRS and not attributable to any 
other conditions; this excludes 
management of fever or myalgias. 
Includes hypotension treated with 
intravenous fluids* or low dose pressors, 
coagulopathy requiring fresh frozen 
plasma (FFP) or cryoprecipitate, and 
hypoxia requiring supplemental oxygen 
(nasal cannula oxygen, high flow oxygen, 
Continuous Positive Airway Pressure 
[CPAP] or Bilateral Positive Airway 
Pressure [BiPAP]). Patients admitted for 
management of suspected infection due 
to fevers and/or neutropenia may have 
Grade 2 CRS.
Life-threatening 
complications such 
as hypotension 
requiring high dose 
pressors (see Table 
6-2) or hypoxia 
requiring 
mechanical 
ventilation.
*Defined as:  multiple fluid boluses for blood pressure support

Marked elevations in IL-6, interferon gamma and less intensely TNF

Symptoms occur 1 to 14 days after cell infusion in ALL

Symptoms may include: High fevers, rigors, myalgia, arthralgia, nausea, vomiting, 
anorexia, fatigue, headache, hypotension, encephalopathy, dyspnea, tachypnea, and 
hypoxia

The start date of CRS is a retrospective assessment of the date of onset of persistent fevers 
and/or myalgia consistent with CRS and not explained by other events (i.e. sepsis). The 
 

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stop date of CRS is defined as the date when the patient has been afebrile for 24 hours and 
off vasopressors for 24 hours.
 

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Table 6-2
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, NEJM 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 within three days 
before or in the days 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

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 
 

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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 6-3, and the 
definition of chronic GVHD will follow the criteria described in Table 6-4.
Table 6-3
Staging & 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
IVf
Stage 4 or
Stage 4
 

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Extent of organ involvement
Skin
Liver
Gut
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 6-4
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.
Limited Chronic GVHD

Localized skin involvement and/or liver dysfunction OR
 

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
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
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.
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. 
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
6.2.4.3
Potential toxicities
Progressive Multifocal Leukoencephalopathy (PML)
PML is rare but well described with antibody therapies causing B cell aplasia (Weissert 
2010). It 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 
 

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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. Please see current guidelines for work up and 
treatment for PML (NINDS Progressive Multifocal Lekoencephalopathy 2015).
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).
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).
Immunogenicity
Immunogenicity of the CAR polypeptide has been described in several studies (Park et al 
2007, Lamers et al 2006, Lamers et al 2007, Lamers et al 2011) Host immune responses may 
result from presentation of CAR transgene expressed immunogenic epitopes including murine 
sequences in the scFV extracellular binding domain (derived from a murine monoclonal 
antibody) or novel epitopes arising at junctions between components of the CAR fusion 
polypeptide. Transgene and vector specific B and T cell immune responses have been 
previously observed in CAR modified autologous T cell therapies even when 
lymphodepleting regimens were used prior to infusion. If an immune response to the CTL019 
cells occurs, it is possible that the cells might be rejected. Such immune responses could also 
have effects such as attenuating the responsiveness of CTL019 cells by causing an immune 
mediated deletion of the CTL019 cells.  Six of 7 evaluable patients had evidence of human 
anti-CAR antibody directed to the murine monoclonal antibody derived scVF in CAIX 
specific CAR T therapy for renal cell carcinoma (Lamers et al 2011). A single patient 
 

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experienced an anaphylactic reaction after multiple, repeated injections of a CAR with a 
murine based scFv (Maus et al 2013). Impaired function of CEA- targeting autologous T cells 
has been observed in vitro following exposure to receptor specific IgG obtained from treated 
patients. (Parkhurst et al 2011).
Immunogenicity (humoral and cellular) will be measured following CTL019 infusions as 
indicated in the Visit Evaluation Schedule.
Replication-competent lentivirus (RCL) testing
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 (as detected by Vesicular Stomatitis Virus/Glycoprotein (VSV-G) qPCR, for 
example). 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 Manual of Procedures for a description of the assays). If a positive 
RCL assay result is obtained from a patient blood specimen, 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
Four of nine treated patients in a gene therapy trial for X-linked Severe Combined 
Immunodeficiency (SCID) developed T cell leukemia 31-68 months post-treatment. The T 
cell leukemias were attributable to clonal expansion conferred by gammaretroviral vector 
integration sites in the CD34+ bone marrow stem cell modification (Hacein-Bey-Abina et al 
2008). This represents the most severe adverse event caused by vector integration. However, 
there is also evidence for retroviral vector integration site dominance in a gene therapy trial of 
-thalassaemia without malignancy (Cavazzana-Calvo et al 2010). The lentiviral vector used 
for CTL019 manufacturing is part of a vector class that may have a lower risk for integration 
in or near oncogenic regions than onco-retroviral vectors (Montini E et al 2009). As of March 
2014, none of the patients treated with CTL019 have developed a new malignancy, T cell or 
otherwise, related to lentiviral vector integration. Subjects will be monitored for evidence of 
unexpected CTL019 expansion by CTL019 transgene quantitation by qPCR and clinical 
 

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monitoring for malignancy by complete blood count (CBC) as part of the study design. If an 
unexpected pattern of CTL019 expansion is observed (i.e. CTL019 expansion in the absence 
of CD19+ target), subjects will be closely monitored clinically for new malignancies, 
particularly T cell, and further studies, including insertion site analysis, will be considered to 
investigate the molecular basis of the expansion. Investigators should consult Novartis if an 
unexpected pattern of CTL019 expansion and/or a new malignancy arises. Subjects will be 
similarly monitored for clonality and insertional oncogenesis when enrolled on the long term 
follow up protocol.
Uncontrolled T cell proliferation
CTL019 transduced cells could theoretically proliferate without t h e  control of normal
homeostatic mechanisms. In pre-clinical studies (Milone et al 2009) and clinical experience to 
date (Porter et al 2011, Grupp et al 2013), 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 extent of proliferation. 
If uncontrolled T cell proliferation occurs (e.g. expansion of T cells in the absence of CD19 
antigen), patients may be treated with corticosteroids such as methylprednisolone (2 mg/kg/d 
i.v.) or chemotherapy, such as high dose cyclophosphamide. Investigators should further 
discuss this with Novartis. Toxicity associated with allogeneic or autologous T cell infusions
has been managed with a course of pharmacologic immunosuppression. T cell associated 
toxicity has been reported to respond to systemic corticosteroids (Lamers et al 2006). This 
theoretical toxicity is distinct from the toxicity associated with a CRS that develops during T 
cell proliferation upon exposure to CD19 expressing cells. CRS associated with T cell 
expansion is managed with anti-cytokine therapy, not immunosuppressants, and is addressed 
in Section 6.2.4.2.
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 Investigator, 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 medication, excluding vitamins, and 
herbal and nutritional supplements, 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 the Modified Data Reporting document and CRF Completion Guidelines (CCGs) (Table 6-
5 and Appendix 4). Modified collection of concomitant medications during these trial phases 
are 
designed 
to 
capture 
CTL019-related 
toxicity, 
severity, 
interventions 
and 
 

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response/resolution following intervention. Any additions, deletions, or changes of these 
medications will be documented. 
Table 6-5
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
See Appendix 4 for further details. 
The following guidelines must be adhered to during the study:

Granulocyte macrophage-colony stimulating factor (GM-CSF) should be avoided due to 
the potential to worsen CRS symptoms. 

Short acting granulocyte colony stimulating factor (G-CSF) should not be given within 72 
hours of 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 Figure 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 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 drug used for GVHD must be stopped > 4 weeks prior to CTL019
infusion (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)
d. Chemotherapy:
 

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
The following drugs must be stopped > 1 week prior to CTL019 infusion and should 
not be administered concomitantly or following lymphodepleting chemotherapy: 
hydroxyurea, 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), excluding the required lymphodepleting chemotherapy drugs

Pegylated- aspariginase 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.
Anti T-cell Therapy: Administration of any T cell lytic or toxic agent (e.g. alemtuzumab) 
prior to CTL019 is strongly discouraged 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 Novartis, consider consultation 
with an pharmacology expert, and consider measuring residual drug levels, if feasible, 
prior to CTL019 infusion.
6.3
Patient numbering, treatment assignment or randomization
6.3.1
Patient numbering
Upon informed consent/assent completion, the patient will initiate screening. Each patient is 
identified in the study database 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 ID number suffixed to it, such that each patient is numbered uniquely 
across the entire database.
Once assigned, the Subject No. must 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
Disposition CRF page.
6.3.2
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.
6.3.3
Treatment blinding
This is an open-label study.
 

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6.4
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, an 
inventory must be performed and a drug receipt log filled out and signed by personnel 
accepting the shipment. It is important that designated study staff counts and 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 Novartis of any damaged or unusable CTL019 cell product that was 
supplied to the investigator’s site.
After logging the CTL019 cells, they will be stored safely and properly (Section 6.4.2). 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 will 
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 returned to the 
manufacturing facility. This issue should be documented properly and the manufacturing 
facility notified on handling of compromised product. For further 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).
6.4.1
Study drug packaging and labeling
Each infusion bag will typically contain 10 – 50 mL of cells containing a cell dose of 2 to 10 x 
106 CTL019 transduced viable T cells per kg body weight with a maximum dose of 2.5 x 108
CTL019 transduced viable T cells (non-weight adjusted). 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 (see Manual of Procedures). The study number and the wording
“FOR AUTOLOGOUS USE ONLY” will be included in the label. In addition the label will 
have at least two unique identifiers such as the patient’s alphanumeric identifier and birth date
according to applicable regulations. Additional label elements required by local regulatory 
guidelines will also be included. Prior to the infusion, two individuals will verify all of this 
information 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.
6.4.2
Drug supply and storage
CTL019 cell product must be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the CTL019 cell product should be 
stored according to the instructions specified on the product labels and in the [Investigational 
Product Handling Manual].
 

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6.4.3
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 CFR 1271.250, 
21 CFR 1271.290, 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.
6.4.3.1
Study drug compliance
As a single administration study, compliance will be assessed by the investigator and/or study 
personnel and captured in the Drug Accountability Form.
6.4.3.2
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 will be reviewed by 
the field monitor during site visits and at the completion of the study.
The investigator will dispose used and unused CTL019 cell product, packaging, and product
labels. A copy of the completed drug accountability log will then be collected by the study
monitor. Please refer to [Investigational Product Handling Manual] for specific details on 
product destruction.
6.4.3.3
Handling of other study treatment
Not applicable.
6.4.4
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. Any unused product and all used infusion supplies, including the infusion bag and 
tubing be disposed of according to local institutional standard operating procedures. 
Additional guidance is provided in the Investigational Product Handling Manual.
In the event that CTL019 study drug manufactured by Novartis or University of Pennsylvania 
was not shipped to the site for infusion, it will be managed per manufacturing facility process. 
The CTL019 product will either be utilized for research purposes or it will be destroyed.
Reconciliation of CTL019 cell product shipped, administered, and remaining, is performed by 
Novartis (or designee). This information is submitted on an annual basis to the health 
 

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authorities in annual reports. All CTL019 cell product disposition will be documented in the 
study files. Refer to [Investigational Product Handling Manual] for details on product 
reconciliation.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 (Screening to Month 12) and Table 7-2 (Month 15 to Month 60) list 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 7-3 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. All data obtained from these assessments must be supported in the patient’s source 
documentation. No CRF will be used as a source document.
Figure 7-1
Potential Patient flow scenarios
 

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Table 7-1
Visit evaluation schedule
Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
Obtain Informed
Consent
D
7.1.1
X
Historical Apheresis
D
4.1.1
X
IWRS/IRT 
S
7.1.1.1
X
X
X
X
X
X
X
X
X
X
X
X
Patient history
Demography
D
7.1.1
X
Inclusion/exclusion 
criteria
D
5.2
5.3
X
Medical History 
(including GVHD 
assessment)
D
7.1.1
6.2.4.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Diagnosis and extent 
of cancer
D
7.1.1
X
Cytogenetics / FISH/ 
D
7.1.1
X
For patients who relapse post infusion, this assessment will be performed on relapsed BM 
evaluation
Donor chimerism
D
7.2.2.5
X
Prior antineoplastic 
therapy
D
7.1.1
X
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
Donor chimerism 
(prior allogeneic SCT 
patients only)
D
7.2.2.5
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
X
Antineoplastic 
therapies after 
CTL019 infusion or 
study discontinuation
D
7.1.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.3
X
X
X
Tanner staging
D
7.1.1
X
X
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pulse oximetry
D
7.2.2.2
X
X
Intervention
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
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
CTL019 infusion 
prerequisite 
assessment
S
6.1.1.2
X
CTL019 transduced 
cell infusion
D
6.1.1.2
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
X
Chemistry
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lab tests of special 
interest  (
 
,  LDH, 
fibrinogen)
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy 
test
D
7.2.2.5
X
Urine pregnancy test
D
7.2.2.5
X
HIV test
D
7.2.2.5
X
Hepatitis B and C
D
7.2.2.5
X
Coagulation factors 
(PT, aPTT, INR, 
fibrinogen, D-dimer) 
D
7.2.2.5
X
X
X
X
X
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
Serum 
immunoglobulin 
levels (IgG,IgA, IgM)
D
7.2.2.5
X
X
X
X
X
X
X
MUGA/ECHO
D
7.2.2.6.2
X
Electrocardiogram 
(ECG)
D
7.2.2.6.1
X
X
Urinalysis
D
7.2.2.5
X
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 time of disease remission at all 
other sites. For patients in CR/CRi, Month 3 
and 6 recommended but not required 
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
Tumor cell 
assessment by flow 
cytometry of 
peripheral blood 
(includes normal B 
cell, count and, CD19 
status)
D
7.2.1
X
X
X
X
X
X
X
X
X
Lymph node or other 
involved tissue 
biopsy or aspirate
D
7.2.1
As clinically indicated
CSF assessment / 
lumbar puncture
D
7.2.1
X
X
If patient is not in CR/CRi at D28, then 
required at time of disease remission at all 
other sites. Otherwise, as clinically 
indicated by the presence of neurologic 
symptoms.
CNS Brain Imaging 
(MRI / CT)
D
7.2.1
As clinically indicated
Mediastinal disease 
assessment (chest 
CT scan or MRI) only 
for lymphoblastic 
lymphoma patients
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.
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
Extramedullary 
Disease assessment 
(physical exam and 
CNS symptom 
assessment)
D
7.2.1
X
X
X
X
X
X
X
X
X
Safety
Adverse events
D
8.1
8.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancies and 
menstrual status
D
7.2.2
X
X
X
X
X
X
X
Immunogenicity 
(serum)
D
7.2.3
X
X
X
X
X
X
Immunogenicity 
(peripheral blood)
D
7.2.3
X
X
X
X
X
X
RCL by VSV-G Q-
PCR (peripheral 
blood)
D
6.2.4.3
X
X
X
X
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
Survival follow-up
D
7.1.7
For all patients who prematurely discontinue from primary follow-up (regardless of remission 
status), follow-up for survival every 3 months until end of study or enrolling into the 15 year long 
term follow-up, whichever comes first
 

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Phase
Category
Protocol Reference 
Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Visit Name
Enrollment/Pre-
chemotherapy 
evaluation
Lymphodepleting 
Chemotherapy
Pre infusion
Infusion
Post Infusion
Study day
W-8 to W-4
W-8to D-8
W-2 to W-1
D-1 +1d
D1
D2
D4 ±1d
D7 ±1d
D11 ±1d
D14 ±3d
D17±3d
D21 ±3d
D28 ±4d
M2 ±14d
M3 ±14d
M4 ±14d
M5 ±14d
M6 ±14d
M9 ±14d
M12 ±14d
End of Phase 
Disposition
D
N/A
X
X
Table 7-2
Visit Evaluation Schedule: Treatment and Primary follow-up continued (Month 15 through Month 60)
Phase
Category
Protocol Reference 
Section
Treatment and Primary Follow-up
Visit Name
Post infusion
End of  
treatment & 
primary 
follow-up
Survival 
follow-up
Study Day
M15
±14d
M18
±14d
M21
±14d
M24
±14d
M30
±14d
M36
±14d
M42
±14d
M48
±14d
M54
±14d
M60
±14d
q3m 
±14d 
Prior/concomitant medications
D
6.2.6
X
X
X
X
X
X
X
X
X
X
Physical examinations (PE)
S
7.2.1.1
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
Height 
D
7.2.2.2
X
X
X
X
X
X
X
X
Tanner Staging
D
7.1.1
X
X
X
X
X
X
X
X
Weight
D
7.2.2.2
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.1
X
X
X
X
X
X
X
X
X
X
Hematology 
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
 

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Phase
Category
Protocol Reference 
Section
Treatment and Primary Follow-up
Visit Name
Post infusion
End of  
treatment & 
primary 
follow-up
Survival 
follow-up
Study Day
M15
±14d
M18
±14d
M21
±14d
M24
±14d
M30
±14d
M36
±14d
M42
±14d
M48
±14d
M54
±14d
M60
±14d
q3m 
±14d 
Chemistry 
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
Antineoplastic therapies after CTL019 infusion or 
study discontinuation 
D
6.2.6
X
X
X
X
X
X
X
X
X
X
Bone marrow biopsy and aspirate
D
7.2.1
As clinically indicated
Tumor cell assessment by flow cytometry of 
peripheral blood (includes normal B cell, count 
and, CD19 status)
D
7.2.1
X
X
X
X
X
Lymph node or other involved tissue biopsy or 
aspirate
D
7.2.1
As clinically indicated
CSF assessment / lumbar puncture
D
7.2.1
As clinically indicated
CNS Brain Imaging (MRI / CT)
D
7.2.1
As clinically indicated
Extramedullary Disease assessment (physical 
exam)
D
7.2.1
X
X
X
X
X
X
X
X
X
X
Safety
Adverse events
D
8.1
X
X
X
X
X
X
X
X
X
X
Pregnancies and menstrual status
D
7.2.2
X
X
X
X
X
X
X
X
X
X
Immunogenicity (serum)
D
7.2.2.4
10.5.3.4
X
X
Immunogenicity (peripheral blood)
D
7.2.2.4
10.5.3.4
X
X
DNA RCL by VSV-G q-PCR (peripheral blood)
D
6.2.4.3
X
X
X
X
 

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Phase
Category
Protocol Reference 
Section
Treatment and Primary Follow-up
Visit Name
Post infusion
End of  
treatment & 
primary 
follow-up
Survival 
follow-up
Study Day
M15
±14d
M18
±14d
M21
±14d
M24
±14d
M30
±14d
M36
±14d
M42
±14d
M48
±14d
M54
±14d
M60
±14d
q3m 
±14d 
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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Table 7-3
Visit Evaluation Schedule: Secondary Follow-up
Phase
Category
Protocol Reference 
Section
Secondary Follow-up
Survival 
Follow-up
Visit Name
Post Infusion
End of 
Secondary 
Follow-up
Study Day
M2
±14d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M21
±14d
M24
±14d
M30
±14d
M36
±14d
M42
±14d
M48
±14d
M54
±14d
M60
±14d
q3m 
±14d 
Patient History
Concomitant 
medications 
(selected)
D
6.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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
X
Height
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
Weight
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
Tanner Staging
D
7.2.2
X
X
X
X
X
X
X
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
Laboratory assessments
Hematology
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy assessments
Relapse 
information (only 
when patient is in 
remission)
D
7.1.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 

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Phase
Category
Protocol Reference 
Section
Secondary Follow-up
Survival 
Follow-up
Visit Name
Post Infusion
End of 
Secondary 
Follow-up
Study Day
M2
±14d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M21
±14d
M24
±14d
M30
±14d
M36
±14d
M42
±14d
M48
±14d
M54
±14d
M60
±14d
q3m 
±14d 
Safety assessments
Protocol defined 
adverse events, 
including new 
malignancies
D
8.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancies and 
menstrual status
D
7.2.2
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
X
X
Performance status
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum 
(immunogenicity,
cytokines) 
D
7.2.4
X
X
X
CTL019 transgene 
persistence 
(peripheral blood)
D
7.2.3
X
X
X
X
X
X
X
X
X
X
X
X
Flow Cytometry of 
peripheral blood (B 
cell, T cell levels –
local assessment)
D
7.2.1
X
X
X
X
X
X
X
X
DNA RCL by VSV-
G q-PCR 
(peripheral blood)
D
6.2.4.3
X
X
X
X
X
X
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
 

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Phase
Category
Protocol Reference 
Section
Secondary Follow-up
Survival 
Follow-up
Visit Name
Post Infusion
End of 
Secondary 
Follow-up
Study Day
M2
±14d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M21
±14d
M24
±14d
M30
±14d
M36
±14d
M42
±14d
M48
±14d
M54
±14d
M60
±14d
q3m 
±14d 
End of phase 
disposition
D
N/A
X
 

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Protocol No. CCTL019B2205J
7.1.1
Screening Phase
After informed consent is obtained, blood tests and assessments to determine eligibility as 
outlined below are performed.
Anti-microbial prophylaxis treatment in these immunosuppressant relapsed/ refractory ALL 
and LBL patients should be considered per local institutional guidelines at study entry or prior 
to lymphodepleting chemotherapy. 
Patients should not be enrolled if they are unable to be followed up long-term i.e. 5 years on 
treatment protocol and  10 additional years follow up as required by the health authorities for 
cell and gene therapy products.
Only following confirmation of all clinical eligibility criteria (defined as all 
inclusion/exclusion criteria except that which pertains to the apheresis product) will the 
patient’s apheresis product be shipped to the manufacturing facility. The manufacturing 
facility will then evaluate the patient’s apheresis product for acceptance.
Patients who have signed an informed consent/assent form will undergo a routine leukemia 
and lymphoma staging workup including:
a. Demography
b. Medical history (including diagnosis and extent of cancer) and prior/concomitant 
medications and antineoplastic therapies
c. Physical Examination (PE) including height, weight, GVHD assessment, Tanner staging 
and 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, 
 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), only if previously received allogeneic 
SCT)
g. Complete Blood Count, Differential
h. Chemistry Panel
i.
Labs of Special Interest (
 LDH, and fibrinogen)
j.
Coagulation panel
k. Urinalysis
l.
Serum pregnancy test (if female of childbearing potential)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 3 for 
interpretation of Hepatitis B results)
n. Serum immunoglobulin levels (IgG, IgA, IgM)
o. MUGA and/or ECHO (performed within 6 weeks of infusion) for LVSF/LVEF
p. ECG
 

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q. Pulse oximetry
r.
 
s.
Peripheral blood collection for flow cytometry (B-cell and T-cell numbers, tumor cell 
numbers, and CD19 assessment)
t.
Lymph node or tissue aspirate or biopsy (if clinically indicated)
u.
 
v. CNS Brain Imaging (MRI/CT) (if clinically indicated)
w. Adverse events
x. Mediastinal disease assessment  (chest CT scan or MRI); only with history of mediastinal 
disease i.e. in patients with r/r lymphoblastic lymphoma 
7.1.1.1
Eligibility Screening & 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 Patient No. assigned at screening by the site investigator or 
designated staff. Once assigned, the Patient No. must not be reused for any other patient and 
the Patient 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, 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 patient not enrolled
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 (if applicable), and screening disposition must be completed for 
patients not enrolled. No other data will be entered into the clinical database for patients who 
are not enrolled.
 

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7.1.2
Pre-Treatment Phase
For details of assessments, refer to Table 7-1.
Enrollment/Pre-chemotherapy evaluation visit (W-8 to D-8)
Before the scheduled lymphodepleting chemotherapy regimen is to begin, the patient will 
undergo blood collection for safety and 
 
 humoral & cellular immunogenicity and RCL 
by VSV-G qPCR. These lab draws are preferably drawn at enrollment, however if not 
obtained collection can be done any time prior to lymphodepleting chemotherapy. In addition, 
adverse events and prior/concomitant medications will be reviewed. Samples from the 
apheresis material as well as the CTL019 product will be collected at the manufacturing site 
for correlative studies.
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 apheresis, 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 pre-infusion 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 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, lab tests of special interest (
 
 fibrinogen, and LDH) , and a CBC with differential. Adverse events and 
prior/concomitant medications will be reviewed.
Pre-infusion visit (D-1 +1d)
On the day prior 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, a urine or serum pregnancy test will be 
performed on female patients of childbearing potential confirming a negative pregnancy 
result. In addition, adverse events and prior/concomitant medications will be reviewed.
 

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Note: All patients must undergo a rapid influenza diagnostic test (only during the months of 
October through May) within 10 days prior to the planned CLT019 infusion. If the patient is 
positive for influenza, oseltamivir phosphate or zanamivir should administered for 10 days as 
preventative treatment (see Tamiflu® or Relenza® package insert for dosing). The patient 
must complete their 10 day preventative treatment course prior to receiving CTL019.  The 
test does not need to be repeated prior to CTL019 infusion however if influenza sign and 
symptoms are present, CTL019 infusion should be delayed until patient is asymptomatic.
7.1.3
Treatment and Primary Follow-Up Phase
For details of assessments, refer to Table 7-1.
Infusion visit (D1)
CTL019 infusion will begin 2 to 14 days after completion of lymphodepleting chemotherapy.
The day of (but prior to) the CTL019 infusion, patients will undergo blood tests including 
chemistry, labs of special interest (
 LDH, and fibrinogen), a CBC with 
differential and coagulation panel, and serum cytokine. Final CTL019 infusion pre-requisites 
(including an ECG) will be checked prior to infusion (per Section 6.1.1.2).
CTL019 transduced T cells will be given as a single dose of 2 to 5 x 106 CTL019 transduced
viable T cells per kg body with a maximum dose of 2.5 x 108 CTL019 cells (non-weight 
adjusted). Vital signs will be monitored before and following CTL019 infusion 
(per Section 6.1.1.2). A blood sample 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.
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: physical exam, blood tests including chemistry, labs of special interest (
 
 LDH, and fibrinogen), hematology, coagulation, serum immunoglobulin, humoral & 
cellular immunogenicity, CTL019 PK, 
, 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, performance status, hematology, and 
chemistry (inclusive of LFTs and creatinine) will be performed.
 
 
 
 
 
 
 
 
 
 

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Post-infusion visit (D28 ±4d)
Patients will undergo blood collection for hematology, chemistry, labs of special interest 
(
 LDH, and fibrinogen), coagulation, serum immunoglobulins, 
, flow 
cytometry (B and T cells, tumor cells, and CD19 assessment) humoral and cellular 
immunogenicity, 
. 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.
For details of assessments, refer to Table 7-1.
Post-infusion visits (Monthly from M2 through 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 
, and RCL by 
VSV-G qPCR. In addition, patients will undergo a physical exam (including vital signs, 
height, weight, Tanner staging (month 6 only), and extramedullary disease assessment), CNS 
symptom assessment, and a performance status assessment. Adverse events and 
prior/concomitant medications will be reviewed.
If patients were not in CR or CRi at the D28 visit assessments, a bone marrow biopsy, aspirate 
and CSF assessment/lumbar puncture will be required for tumor response assessments at the 
first visit where clinical evidence remission is observed by peripheral blood and 
extramedullary disease assessment (physical exam and CNS symptom assessments).
Patients may also have a bone marrow biopsy, aspirate, LP/CSF assessment and lymph node 
aspirate or biopsy (if accessible) at month 3 and month 6 for tumor response assessments
(recommended but not required).
For details of assessments at each visit, refer to Table 7-1.
Post-infusion visit (M9 ±14d)
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), and CTL019 PK. In addition, patients will undergo a physical exam (including
vital signs and extramedullary disease assessment), CNS symptom assessment and a 
 

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performance status assessment. Adverse events and prior/concomitant medications will be 
reviewed.
For details of assessments, refer to Table 7-1.
Post-infusion visit (M12 ±14d)
Patients will undergo the following: blood collection for hematology, chemistry, serum 
immunoglobulins, flow cytometry (B and T cells, tumor cells, and CD19 assessment), 
cytokines, humoral and cellular immunogenicity, 
 
 and RCL by VSV-G qPCR. In addition, patients will undergo a physical exam 
(including height, weight, GVHD assessment, Tanner staging, vital signs, and extramedullary 
disease assessment), CNS symptom assessment, and a performance status assessment. 
Adverse events and prior/concomitant medications will be reviewed.
For details of assessments, refer to Table 7-1.
Patients with CD19 CAR transgene levels equal to or greater than 1% of WBC
If ≥ 1% of the WBC in peripheral blood are positive for CD19 CAR vector sequences by 
qPCR at > 12 months from CD19 CART infusion, then the patient will be asked to return for 
a confirmatory blood test prior to the next visit. If ≥1% of the WBC is positive upon the 
receipt of the confirmatory qPCR result, then the genomic vector integration sites will be 
determined. Identified vector integration sites will be evaluated using bioinformatic 
approaches to determine the frequency of integration events in regions with known 
relationships to human cancers (i.e. near oncogenes). If integration site analysis reveals mono-
or oligo-clonality pattern and/or integration at or near an oncogenic locus, a monitoring plan, 
including follow-up molecular analyses, will be developed in collaboration between the 
Investigator, Novartis 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.
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. Blood will be collected for 
 
 humoral & cellular immunogenicity at M24 and M36 only. In addition, 
patients will undergo a physical exam (including height, weight and Tanner staging), vital 
signs, extramedullary disease assessment, CNS symptom assessment and a performance status 
 

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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.
7.1.3.1
End of Treatment and Primary Follow-Up visit (M60 ± 14d) including 
premature discontinuation
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 Treatment and 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 CRF (CRF) page 
should be completed, giving the date and, if applicable, reason for discontinuing from the 
treatment and primary follow up the study.
During the EOT and Primary Follow-Up visit, patients will undergo the following: blood 
collection for hematology, chemistry, serum immunoglobulins, flow cytometry (B and T cells, 
tumor cells, and CD19 assessment), cytokines, humoral and cellular immunogenicity,
 and RCL by VSV-G qPCR. In 
addition, patients will undergo a physical exam (including height, weight, GVHD assessment, 
Tanner staging, vital signs, and 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. 
Following completion of the Treatment and Primary Follow-Up, patients will be followed for 
for survival until end of 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.
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.
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. 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
 

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
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.
7.1.3.3
Relapse Evaluation
If at any time during the Treatment and Primary Follow-Up phase following infusion, a 
patient who was in remission relapses, a full disease evaluation will be completed. As soon as 
possible after awareness of a relapse, the patient will be scheduled for a visit, and will have a 
bone marrow biopsy & aspirate, and peripheral blood collection. The following assessments 
will be performed:
a. Tumor characterization: Can be done on either blood or bone marrow with known tumor 
involvement of these components depending on availability of specimens, but priority is to 
do the majority of testing on bone marrow:
1. Flow cytometry (B and T cells, tumor cells and CD19 assessment)
2. Blood and bone marrow morphology
3. Cytogenetics/ FISH/ 
4.
b. CTL019 cell characterization: Must be done on both peripheral blood and bone marrow,
depending on availability of specimens:
1. PK by q-PCR and flow cytometry
2.
c. Immunogenicity (humoral & cellular)
d.
 
 
In the event of relapse due to extramedullary disease only, the patient may still be followed 
per the treatment and primary follow-up phase visit schedule until the institution of systemic 
antineoplastic therapy.
7.1.4 Secondary Follow-Up Phase
Patients who discontinue the Treatment and Primary Follow-Up Phase before month 60 will 
continue to be followed in the secondary follow-up phase in order to collect health authority 
requested data (e.g. delayed adverse events) up to 5 years after CTL019 infusion.
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 discontinue from the Treatment and Primary Follow-Up 
phase at Month 10, the first visit in the Secondary Follow-Up Phase will be Month 12.
During the secondary follow-up phase, patients will undergo one or more of the following at 
each visit according to Table 7-2: Blood collection for hematology, humoral immunogenicity, 
 

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cytokines, CTL019 transgene persistence, flow cytometry (B and T cells, tumor cells) and 
RCL by VSV-G qPCR. In addition, patients will undergo a physical exam (including height, 
weight and Tanner staging), vital signs, and a performance status assessment. Adverse events 
and prior/concomitant medications will be reviewed. Any pregnancies will be reported. 
Efficacy will be assessed in patients who are still in remission until relapse. For these patients, 
relapse status will be assessed at each visit.
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.
In addition, in the event a patient that is still in remission cannot attend any visit during the 
secondary follow-up, the investigator should attempt to contact the patient by phone to 
determine relapse status.
For details of assessments, refer to Table 7-2.
7.1.4.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study. Patients lost to follow up should be 
recorded as such on the CRF. 
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 Novartis or 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
For all patients who complete or prematurely discontinue from the primary or secondary 
follow-up phase, attempts to follow-up will be made to determine survival every 3 months
post-CTL019 infusion until end of study as defined in Section 4.2 or patient is enrolled in the 
15 year long term follow-up, whichever occurs first.
7.1.6
Long-Term Follow Up
As a single administration study, patients are followed on study for 1 year post-infusion for 
safety and efficacy evaluations. A long term post-study follow-up for lentiviral vector safety 
will continue under a separate protocol for 15 years post infusion per health authority
guidelines (destination protocol).
 

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Under the 15 year 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 enrolled in this 
destination protocol at the time of study completion/discontinuation (a separate informed 
consent/assent forms will be provided for this protocol). One to two times a year patients will 
visit the clinical site for a physical exam and medical history (including concomitant 
medications and adverse events) with careful attention to features possibly related to lentiviral 
associated events such as new malignancies, new incidence or exacerbation of a pre-existing 
neurologic disorder, new incidence or exacerbation of a prior rheumatologic or other 
autoimmune disorder, or new incidence of other hematologic disorders. In addition, labs will 
be drawn to evaluate routine safety endpoints, CTL019 vector persistence and RCL.
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 assessments in ALL patients 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.
Patients with B-cell Lymphoblastic Lymphoma will be assessed for efficacy per local 
investigator assessments only in accordance with Novartis guideline (Appendix 3).
 

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Table 7-4
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 in bone marrow aspirate
by flow cytometry (includes normal B cell 
counts and CD19 status)
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
Mediastinal disease assessment (chest CT 
scan or MRI scan) 
As clinically indicated, 
mandatory only for 
Lymphoblastic Lymphoma 
patients
Mandated: Screening, M1. If at any time point, mediastinal disease is present by CT/MRI 
assessment, then follow-up CT/MRI is required to document the absence of mediastinal 
involvement whenever the patient meets all other criteria for complete remission.
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, 24, 36, 48 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 findings that begin or 
worsen after study treatment (i.e. lymphodepleting chemotherapy) must be recorded on the 
Advert Even page of the patient’s CRF as defined in Section 8.1.1. 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 exam, 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.
7.2.2.1
Vital signs
Vital signs include temperature, blood pressure, pulse measurements, and respiratory rate.
Pulse oximetry will be measured at select visits (see Table 7-1).
7.2.2.2
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured.
 

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7.2.2.3
Performance status
Table 7-5
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
Tanner staging will be updated semiannually. 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 either the primary or secondary follow-up.
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.
 

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Stage 3: Growth of the penis has occurred, at first mainly in length but with some increase in 
breadth. There has been further growth of testes and scrotum.
Stage 4: Penis further enlarged in length and breadth with development of glans. Testes and 
scrotum further enlarged. There is also further darkening of the scrotal skin.
Stage 5: Genitalia adult in size and shape. No further enlargement takes place after Stage 5 is 
reached.
Pubic Hair Stages:
Stage 1: Pre-adolescent. The 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 
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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.
7.2.2.5
Laboratory evaluations
Screening and other laboratory assessments will be performed accordingly to Table 7-1. 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 once, in 
order to rule out laboratory error. "NCS" will be entered on the original laboratory sheet of all 
laboratory values which are outside the reference range, but are judged "not clinically 
significant." The physician making these assessments shall date and initial each form.
Table 7-6
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
Serum Glucose (fasting or non-fasting), Blood Urea Nitrogen (BUN), Creatinine, 
Sodium, Potassium, Calcium, Total Protein, Albumin, Total Bilirubin, Alkaline 
Phosphatase, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), 
Magnesium, Phosphorus, Lactate Dehydrogenase (LDH), 
 
and Uric Acid.
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones,  pH, Protein, 
Specific Gravity, and either leukocyte esterase or nitrites)
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
Serum or urine tests
Viral Serology
Hepatitis C Virus (HCV) 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 with differential (Monocytes, Lymphoctyes, Macrophages, 
Neutrophils, Lyymphoblasts), Red Blood cells, Glucose, Protein 
 

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Test Category
Test Name
B cell and T cell levels
Peripheral blood B cell, CD4 T cell, and CD8 T cell levels (flow cytometry) (all 
patients after 1 year)
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 (flow cytometry), peripheral blood morphologic blast, neutrophil and platelet 
cell counts (flow cytometry)
Table 7-7
Central clinical laboratory parameters collection plan
Test Category
Test Name
MRD
Flow cytometry
MRD flow panel (bone marrow aspirate)
Bcells, CD4 T cells, CD8 T cells, 
, CD19 assessment 
(peripheral blood and bone marrow aspirate)
CTL019 assessments
CTL019 PK by q-PCR and/or flow cytometry (peripheral blood and bone marrow 
aspirate and CSF if available), 
RCL (VSV-G)
VSV-g q-PCR (peripheral blood)
Immunogenicity
Prevalence and Incidence of immunogenicity against CTL019 (peripheral blood and 
serum)
 
 
 
Refer to the [Central Laboratory Manual] for more detailed instructions for the collection, 
handling, and shipment of PK and 
7.2.3
Pharmacokinetics
Table 7-8
CTL019 pharmacokinetics by q-PCR in peripheral blood collection log
Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume** 
1
W-8 to D-8 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
 

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Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume** 
1
M48±14d
3 mL
1
M54±14d
3 mL
1
M60±14d (EOT)
3 mL
1
Unscheduled PK samples related to)***
2 mL/collection
1
Unscheduled (PK samples related to safety events, 
relapse)
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, if clinically feasible. See Section 7.1.3.
 
Table 7-9
CTL019 pharmacokinetics by flow cytometry in peripheral blood 
collection log
Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume 
1
W-8 to D-8 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 (e.g. related to safety events, at
relapse)
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. See section 7.1.3.
Table 7-10
CTL019 pharmacokinetics by q-PCR in bone marrow aspirate 
collection log
Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
W-8 to W-4 Screening
2 mL
1
D28±4d
2 mL
1
M3±14d (recommended but not required)
2 mL
 

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Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
M6±14d (recommended but not required)
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.
**All patient sample volumes subject to adjustment for size and patient condition.
 
Table 7-11
CTL019 pharmacokinetics by flow cytometry in bone marrow aspirate 
collection log
Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume**
1
W-8 to W-4 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 (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 7-12
CTL019 pharmacokinetics by q-PCR in CSF collection log
Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume
1
W-8 to W-4 Screening
4-6 mL
1
D28±4d
4-6 mL
1
Unscheduled 
4-6 mL
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
Table 7-13
Immunogenicity serum sample collection log
Treatment Period or Cycle
Day/ Scheduled Time Point*/**
Sample Volume
1
W-8 to D-8 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 (Primary follow-up only)
5 mL
1
M36±14d (Primary follow-up only)
5 mL
1
Unscheduled  (e.g. related to safety events, at relapse)
5mL/collection
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
Table 7-14
Immunogenicity peripheral blood sample collection log
Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume** 
1
W-8 to D-8 Enrollment/Pre-Chemotherapy
10 mL
1
D14±3d
10 mL
1
D28±4d
10 mL
1
M3±14d (Primary follow-up only)
10 mL
1
M6±14d (Primary follow-up only)
10 mL
1
M12±14d (Primary follow-up only)
10 mL
 

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Treatment Period or Cycle
Day/ Scheduled Time Point*
Sample Volume** 
1
M24±14d (Primary follow-up only)
10 mL
1
M36±14d (Primary follow-up only)
10 mL
1
Unscheduled (e.g. related to safety events, at relapse)
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.
Table 7-15
Tocilizumab, CTL019 Pharmacokinetics (PK), and sIL6R (PD) in 
tocilizumab treated patients during CRS
Day/ Scheduled 
Time Point*/**
Dose 
Reference 
ID
Toci 
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
*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 7-8 and Table 7-9 will cease 
once PK/PD sample collections related to tocilizumab infusion commence, if applicable.
Table 7-16
Anti-cytokine therapy (other than tocilizumab) PK, CTL019 PK and 
sIL6R (PD) in anti-cytokine therapy treated patients during CRS
Day/ Scheduled 
Time Point*/**
Dose 
Reference 
ID
Anti-
cytokine 
Rx 
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; second 
infusion)
301
406
5 mL
505
2 mL
705
2 mL
 

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Day/ Scheduled 
Time Point*/**
Dose 
Reference 
ID
Anti-
cytokine 
Rx 
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 
second infusion)
302
407
5 mL
--
--
--
--
D2 ± 2 hours from 
second infusion
302
408
5 mL
506
2 mL
706
2 mL
*All measurement times are relative to anti-cytokine therapy 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 anti-cytokine therapy, if clinically 
feasible. 
Unscheduled CTL019 PK sample collections related to CRS as specified in Table 7-8 and Table 7-9 will cease 
once PK/PD sample collections related to anti-cytokine therapy administration commence, if applicable.
7.2.3.1
Analytical method
The assays to be utilized for various PK/
include q-PCR assay to detect 
CTL019/4-1BB+ cells (transgene copies/microgram DNA) in peripheral blood and other 
tissues and flow cytometric analysis to detect CTL019 positive cells. Details of sample 
collections for these assays will be provided in the [Central Laboratory Manual].
 

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7.2.5
Resource utilization
Not applicable.
7.2.6
Patient reported outcomes
Not applicable.
 

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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 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 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
If a patient is simultaneously enrolled in the active phase (start of apheresis until 24 hours 
thereafter) of the Novartis [CTL019B2206] leukapheresis protocol and this treatment 
protocol, collection and reporting of adverse events during this overlapping period should 
follow the CTL019B2206 safety reporting criteria. Therefore during this overlap period, AEs 
should only be reported to the CTL019B2206 protocol, and not on the CTL019B2205J 
protocol. After completion of the active phase on CCTL019B2206, reporting of SAEs should 
follow the criteria of the respective treatment protocol the patient is participating in.
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.
Adverse event monitoring should be continued through the Month 60 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:
 

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
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 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) version 16.1 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; 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:
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)
 

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6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a serious adverse event is defined as in Section 8.2.1
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 of malignancy (including fatal outcomes), if documented by use of appropriate 
method should not be reported as a serious adverse event.
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 side effects 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 system 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 response/resolution following intervention. Details can be found in the CRF Completion 
Guidelines (CCGs) and the Modified Data Reporting (Appendix 4).
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 
 

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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 (as defined 
above) 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 10-4 below. 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 
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/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 
 

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only be reported Novartis and be captured if the CRF/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
Substantial change in the status of the patient that the investigator deems may have a potential 
impact during lymphodepletion and CTL019 infusion or precludes the patient from 
proceeding to study treatment (e.g. GVHD, rapid progression of malignancy, marked decline 
in clinical status)
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:

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 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)
 

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
Hepatitis B reactivation
In addition, at the specific request of the FDA, the following SAEs will be reported in an
expedited manner to the FDA:

All occurrences of CRS Grade ≥ 3

All deaths regardless of attribution following lymphodepleting chemotherapy and/or 
CTL019 infusion and within 30 days of receiving CTL019 infusion

Death attributed to CTL019 occurring 30 days post CTL019 infusion
Any SAEs experienced after the Month 60 (EOT) visit should only be reported to the Novartis
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, and send the completed, signed form by fax or email within 24 hours to Novartis.
The telephone and telefax number of the contact persons in the local department of DS&E, 
specific to the site, are listed in the investigator folder provided to each site. The original copy 
of the SAE Report Form and the fax confirmation sheet must be kept with the source
documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original 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.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, Novartis may urgently 
require further information from the investigator for Health Authority reporting. Novartismay 
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.
 

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8.4
Pregnancies
No data are currently available to determine the duration of contraception after receiving 
CTL019. CTL019 is within Pregnancy Category C. Animal reproduction studies have not 
been conducted with CTL019. It is also not known whether CTL019 can cause fetal harm 
when administered to a pregnant woman or can affect reproduction capacity.
Women regardless of age that may have child-bearing potential (defined as all women 
physiologically capable of becoming pregnant) are recommended to continue contraception 
until CAR cells are no longer present in blood as measured by PCR and for a minimum of 12 
months from CTL019 infusion. Women who are not yet of reproductive potential are also to 
agree to use acceptable forms of contraception when they reach reproductive potential. Male 
participants must use highly effective methods of contraception for a period of 1 year after 
CLT019 infusion. Highly effective contraception methods include:
a. 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
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of 
oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow up hormone level assessment
c. 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.
d. Use of oral, injected or implanted hormonal methods of contraception or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for example 
hormone vaginal ring or transdermal hormone contraception
e. Use of intrauterine devices are excluded due to increased risks of infection and bleeding.
f.
In case of use of oral contraception, women must be stable on the same pill for a minimum 
of 3 months before taking study treatment.
Women who are not of reproductive potential (defined as either <11 years of age, Tanner 
Stage 1, post-menopausal for at least 24 consecutive months (i.e. have had no menses) or have 
undergone hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) are eligible 
without requiring the use of contraception. Women who are not yet of reproductive potential 
are to agree to use acceptable forms of contraception when they reach reproductive potential if 
within 1 year of CTL019 or if CAR cells are present in the blood by PCR. Acceptable 
documentation includes written or oral documentation communicated by clinician or 
clinician’s staff of one of the following:
a. Demographics show age <11
b. Physical examination indicates Tanner Stage 1
c. Physician report/letter
d. Operative report or other source documentation in the patient record
e. Discharge summary
f.
Follicle stimulating hormone measurement elevated into the menopausal range
 

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To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
must be reported to Novartiswithin 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. Pregnancies will be followed for pregnancy 
outcome. In the case of live birth the newborn will be followed up until 6 months of age to 
detect any developmental issue or abnormality that would not be seen at birth.  Pregnancy 
outcomes must also be collected for the female partners of any males who received CTL019 
in this study. Consent to report information regarding these pregnancy outcomes should be 
obtained from the mother. Pregnancy should be recorded on a Clinical Trial Pregnancy Form 
and reported by the investigator to Novartis. Pregnancy follow-up should be recorded on the 
same form and should include an assessment of the possible relationship to the CTL019 
transduced cells to any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported on the SAE Report Form.
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
Prior to the transfer of the study from UPenn IND to Novartis IND, an independent Data 
Safety Monitoring Board (DSMB) had reviewed safety and efficacy data up until August 
2015. After the transfer of the IND is complete, an independent Novartis Data Monitoring 
Committee with oversee the safety data for the study.
The DMC will be responsible for reviewing 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 hematologist/oncologist) and one 
biostatistician. Safety reviews will occur every six months, unless otherwise requested by the 
Chairman of the DMC. Additional meetings will be held at the request of the DMC or
Novartis’ request, or in the event that significant safety issues arise. 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 outlined in 
the DMC charter.
8.7
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, Novartis representatives from the Clinical Trial team. . The SC will ensure transparent 
management of the study according to the protocol through recommending and approving 
modifications as circumstances require. The SC will review protocol amendments as 
 

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appropriate. Together with the clinical trial team, the SC will also develop recommendations 
for publications of study results including authorship rules. 
The SC will meet regularly, approximately every 3 months.  Documentation of these meetings 
will be maintained in the Master Study File. Actionable outcomes and recommendations will 
be sent to all participating sites for local reporting.
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 assessment and
determine remission and relapse for the primary analysis in acute lymphoblastic leukemia 
patients. 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

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 
 

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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, Novartis personnel or designee 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 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. 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
This study will use a Novartis Electronic Data Capture (EDC) system for data collection.  The 
designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs and, allow modification or verification of 
the entered data by the investigator staff.
The 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.
9.4
Database management and quality control
Novartis or designee 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.
 

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Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the 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.
10
Statistical methods and data analysis
Data from all participating centers will be combined.
The primary analysis will be performed when at least 50 acute lymphoblastic leukemia or 
lymphoblastic lymphoma patients (including 40 patients less than 18 years of age) have 
received CTL019 infusion and completed 6 months from study day 1 infusion or discontinued 
earlier. The additional data for any patients continuing past this time will be further 
summarized in the final Clinical Study Report (CSR) once all patients complete the study.
10.1
Analysis sets
The analysis sets for acute lymphoblastic leukemia patients will be separate from the analysis 
sets for lymphoblastic lymphoma patients. 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.
Tables and listings will be presented by acute lymphoblastic leukemia and lymphoblastic 
lymphoma separately, within the single treatment arm of CTL019. If there are no more than 5 
lymphoblastic lymphoma patients treated, data for these patients will be summarized 
primarily via listings. 
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’ apheresis
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 has received infusion of CTL019.
10.1.4
Safety Set
The Safety Set comprises all patients who received infusion of CTL019.
 

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10.1.5
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with major requirements of the clinical study protocol (CSP).
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 (2 × 106 CTL019 
transduced cells/kg body weight) will also be excluded.
The detailed exclusion criteria of PPS will be determined prior to primary analysis.
10.1.6
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of FAS who have at least one sample 
providing evaluable pharmacokinetic (PK) data. The PAS will be used for summaries (tables 
and figures). FAS will be used for 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
Demographic and other baseline data will be listed by patient and/or summarized 
descriptively for the FAS. Categorical data will be presented as frequencies and percentages. 
For continuous data, summary statistics will be presented (i.e., mean, median, standard 
deviation, minimum, maximum).
Number and percentage of patients failing prior anti-neoplastic medications/therapies will be 
summarized.
Patients will be classified by the allogeneic SCT and residual donor engraftment status into 
one of the following categories:

Relapsed after prior allogeneic SCT with any degree of residual donor engraftment

Relapsed after prior allogeneic SCT with no residual donor engraftment

No prior allogeneic 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

Relapse without SCT: If patient has not had SCT, had a CR from other therapy and 
relapsed prior to the study

Relapse after SCT: If patient has had and relapsed after SCT prior to the study
 

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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The total cells infused (cells/kg) and total CTL019 transduced 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.
10.4
Primary objective
The primary objective of the study is to evaluate the efficacy of CTL019 therapy in acute 
lymphoblastic leukemia patients and separately in lymphoblastic leukemia patients as 
measured by overall remission rate (ORR) during the 6 months after CTL019 administration, 
which includes CR and CR with incomplete blood count recovery (CRi) in the FAS 
population. The primary analysis will be based on the IRC assessment for acute lymphoblastic 
leukemia patients, and based on local investigator’s assessment for lymphoblastic lymphoma 
patients. In addition, sensitivity analysis will be performed using the local investigator 
response assessments instead of the IRC assessment for acute lymphoblastic leukemia 
patients.
10.4.1
Variable
The primary endpoint is the ORR during the 6 months after CTL019 administration, as 
determined by IRC assessment for acute lymphoblastic leukemia patients and as determined 
by local investigator’s assessment for lymphoblastic lymphoma patients.
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

CR or CRi with residual mediastinal disease (for lymphoblastic lymphoma patients only)

No response (NR)

Unknown
The disease response criteria for ALL patients are outline below in Table 10-1. See also
Appendix 1 for details. (Please note: For lymphoblastic lymphoma patients, all criteria below 
plus those listed in Table 10-2, Appendix 2, Table 14-5 must be met.)
 

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Table 10-1
Definition of CR, CRi and relapse at a given evaluation time in Acute 
Lymphoblastic Leukemia patients (excluding Lymphoblastic 
Lymphoma patients)
Response category
Definition
Complete remission (CR)
All the following criteria are met:
Bone marrow
● Trilineage Hematopoiesis (TLH) and < 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
●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, or
●Platelets ≤ 100 x 109/L, 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 is 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 
(physical exam and CNS symptom assessment) at a minimum of 4 weeks (28 days) after the 
 

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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 in the same evaluation for 
disease response evaluation purpose, they will also need to show remission status.
The additional disease response criteria for lymphoblastic lymphoma patients are outline 
below in Table 10-3. See also Appendix 2 for more details.
Table 10-2
Additional definition of remission and relapse at a given evaluation 
time for Lymphoblastic Lymphoma patients
Response category
Definition
Complete remission (CR)
All the criteria for ALL are met, and in addition CR for mediastinal 
disease.
Complete remission with incomplete blood 
count recovery (CRi)
All the criteria for ALL are met, and in addition CR for mediastinal 
disease. 
CR or CRi with residual mediastinal 
disease
All criteria for CR or CRi as defined above are met, except that 
mediastinal disease as defined by CRu or PR is observed.
Relapsed Disease
Same criteria for ALL, and in addition mediastinal relapse will also 
indicate relapse for LBL.
10.4.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be based on statistical testing in acute lymphoblastic 
leukemia patients and descriptive analysis in lymphoblastic lymphoma patients. In addition, it 
will be summarized descriptively in all patients combined.
In acute lymphoblastic leukemia patients, the primary efficacy analysis will be performed by 
testing the null hypothesis of ORR being less than or equal to 20% against the alternative 
hypothesis of ORR being 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 will be analyzed at the interim look and final look of a 
group sequential design based on the data observed in the FAS. The ORR will be summarized 
along with the 2-sided 95% 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 95% 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.
In lymphoblastic lymphoma patients and in all patients combined, the ORR will be 
summarized descriptively together with 95% CIs if appropriate.
Tables and listings will be presented by acute lymphoblastic leukemia and lymphoblastic 
lymphoma separately, as well as one treatment arm of CTL019.
In addition, the percentage of patients who achieve CR or CRi at Day 28 +/- 4 days will also 
be summarized. Response will also be summarized by baseline tumor burden (MRD, 
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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 primary analysis will also be performed on the Enrolled Set and PPS using the same 
methodology. In addition, analysis will also be performed using all patients who satisfy all 
clinical eligibility criteria.
10.4.4.1 Subgroup analysis
Subgroup analyses will be performed on the following based on the patient’s baseline status:

Age: <10 years, ≥10 years to <15 years, ≥15 years to <18 years, ≥18 years

Gender: Male, Female

Race: Asian, Black, Caucasian, Native American, Other, Pacific Islander, Unknown

Ethnicity: Hispanic or Latino, Chinese, Indian, Japanese, Mixed ethnicity, Other

Prior response status: Primary refractory, relapse without SCT, relapse from SCT

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 ≥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
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 can be  
important indicators of overall disease burden, which is a potential predictive factor

BCR-ABL, MLL rearrangement, hypoploidy and 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 et al 2010; van der Veer et al 
2013; NCCN v1 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.
 

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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. 
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)
Not applicable because no formal hypothesis testing is planned other than for the primary 
objective.
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 
proceeding to SCT is defined as the time of commencing the conditioning regimen as required 
for hematopoietic SCT. This definition applies to all analyses.
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.
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 the underlying disease 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
 

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
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 the underlying disease will be considered as a 
competing risk event to other events of interest (relapse or death due to the underlying 
disease).
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 
the underlying disease instead of considering it as the competing risk event to other events of 
interest (relapse or death due to the underlying disease).
The proposed analyses for DOR are summarized in Table 10-3 below. Method 1 will be 
considered as the main analysis for DOR. Additional analyses may be considered.
Table 10-3
Analyses of duration of response (DOR)
Death due to reason other than the underlying disease
SCT after remission
Method 1
Censor at last adequate tumor assessment 
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
Competing risk analysis
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 2, 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.
For Method 3 and Method 4, the CIF is used to estimate the probability of the event of interest 
in the presence of the competing risks (Kim 2007).
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 
 

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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 CR or CRi with MRD negative bone marrow
The percentage of patients who achieved BOR of CR or CRi with MRD negative bone 
marrow (performed by central laboratory with sensitivity of detection of 0.01%) during the 6 
months after CTL019 administration among all patients in the FAS population will be 
summarized along with the 2-sided 95% exact Clopper-Pearson confidence intervals. 
Additional analysis will be done to summarize this percentage among all patients with BOR 
of CR or CRi. See Appendix 1 for details of determination of MRD negativity.
The percentage above will be also summarized among all patients who achieved BOR of CR 
or CRi.
In addition, quality of response using MRD disease assessments before treatment, at day 28 
+/- 4 days after treatment will be described.
10.5.2.5 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
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.
10.5.2.6 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

Relapse

Treatment failure: Defined as no response in the study and discontinuation from the study 
due to any of the following reasons:
 

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
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 (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.
10.5.2.7 Overall survival (OS)
Overall survival (OS) is the time from date of 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. 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 (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.
10.5.2.8 Response at Day 28 +/- 4 days
Proportion of patients attaining CR or CRi at Day 28 +/- 4 days post CTL019 infusion, among 
all patients in the FAS, 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).
 

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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 CTL019 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 CTL019-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) are described in Table 10-4 below. 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 
reporting. AESI that occur within 8 weeks of the CTL019 infusion will be summarized by 
group term and preferred term.
Table 10-4
Adverse events of special interest (AESI) search criteria 
AESI group term
MedDRA term
Type
Syndromes
Cytokine Release Syndrome
PT
Histiocytosis haematophagic
PT
Tumor Lysis Syndrome
PT
Cytokine Release Syndrome Symptoms
Pyrexia
PT
Myalgia
PT
Hypotension
PT
Dyspnea
PT
Tachypnea
PT
Capillary Leak Syndrome
PT
Hypoxia
PT
Organ Failure
PT
Acute Respiratory Distress Syndrome
PT
 

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AESI group term
MedDRA term
Type
Tumor Lysis Syndrome Symptoms
Hyperkalemia
PT
Hyperphosphatemia
PT
Hyperuricemia
PT
Hypocalcemia
PT
Histiocytosis Haematophagic Symptoms
Splenomegaly
PT
Marrow depression and hypoplastic anemias
HLT
Hemolysis
PT
Disseminated intravascular coagulation
PT
Blood triglycerides increased
PT
Organ Dysfunction
Hepatic enzymes and function abnormalities
HLT
Renal Failure and Impairment
HLT
Confusion and disorientation
HLT
Allergic Reaction
Infusion related reaction
PT
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 prevalence of immunogenicity (subjects 
with pre-existing antibodies that bind to CTL019), incidence of immunogenicity (subjects 
with treatment-induced or treatment-boosted antibodies that bind to CTL019), together with 
antibody titers. Data will be further fractionated to determine proportion of subjects 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. 
 

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10.5.3.5 Derivation of a score to predict cytokine release syndrome 
Clinical 
 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 
 
 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.
 
10.5.3.7 B-cell and T-cell levels
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. 
It is anticipated that all patients who achieve complete remission will exhibit B-cell aplasia. 
Timing of B-cell recovery (i.e. when normal B-cell becomes detectable again after patients 
achieving complete response) will be summarized.
CD8 and CD4 positive T cells will be listed and summarized by time point. Data may also be 
summarized by response status and potentially graphed using strip plots. Patient level and 
average longitudinal plots of the cell counts and percent changes from baseline may be 
generated.
 
For abnormal T cell or B cell results, associated safety events such as infections and use of 
associated therapies (i.e. antibiotics, immunoglobulin replacement) will be investigated using 
patient listings.
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.
 

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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 <15 years, ≥15 years to <18 years,  ≥18 years

Gender: Male, Female

Race: Asian, Black, Caucasian, Native American, Other, Pacific Islander, Unknown

Ethnicity: Hispanic or Latino, Chinese, Indian, Japanese, Mixed ethnicity, Other

Prior response status: Primary refractory, relapse without SCT, relapse from SCT

Prior SCT therapy and residual donor engraftment status: Prior SCT with any degree of 
residual donor engraftment, SCT without residual donor engraftment, or no prior SCT.
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.
10.5.4
Pharmacokinetics
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 

 
The PK parameters listed in Table 10-5 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). All 
concentrations below the limit of quantitation or missing data will be labeled as such in the 
concentration data listings. Concentrations below the limit of quantitation will be treated as 
zero in summary statistics. For the calculation of the PK parameters, a zero value will be 
imputed for the values below the limit of quantification after the administration and during the 
expansion phase. The values below the limit of quantification during the elimination phase 
will not be imputed and will be considered as missing.
Table 10-5
Noncompartmental pharmacokinetic parameters
AUC 0 - Tmax
The AUC from time zero to Tmax in peripheral blood (% or copies/µg x days x volume-1)
AUC Tmax - 28d or 
M3 
The AUC from time Tmax to day 28 and M3 or other disease assessment days, in 
peripheral blood ((% or copies/µg x days x volume-1)
AUC 0 - 28d or M3 
The AUC from time zero to day 28 and M3 or other disease assessment days, in peripheral 
blood (% or copies/µg x volume-1)
Cmax
The maximum (peak) observed in peripheral blood or other body fluid drug concentration 
after single dose administration (% or copies/µg x volume-1)
 

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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
Ci
Initial concentration in peripheral blood following infusion (µg x volume-1) (only applicable 
for qPCR)
(Cmax / Ci)
In vivo CTL019 T-cell expansion in peripheral blood (using ratio of Cmax to Ci (only 
applicable for qPCR)
TLOG
Duration of time patient concentration levels are at or above the limit of quantitation (LOQ) 
for a given assay (days)
MRTlast
Mean residence time from the time of dosing to the time of the last measurable 
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 might be expored. Population or 
mechanistic PK/PD 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.
 

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10.7
Interim analysis
The trial will be transferred under Novartis IND from UPenn IND. After the IND transfer, all 
CTL019 products will be manufactured according to the Novartis CMC process. The trial was 
initially conducted under the UPenn IND  with CTL019 product manufactured according to 
the UPenn CMC process. From protocol amendment 2 going forward, the trial is transferred 
under Novartis IND. After the IND transfer, all CTL019 products will be manufactured 
according to the Novartis CMC process. 
 

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An interim analysis is planned when all patients who were treated with UPenn manufactured 
CTL019 product and have completed 6 months from study day 1 infusion or discontinued
earlier. Only acute lymphoblastic leukemia patients will be treated with UPenn manufactured 
CTL019 products. The interim analysis will be performed in the acute lymphoblastic 
leukemia patients by testing the null hypothesis of ORR being less than or equal to 20% 
against the alternative hypothesis of ORR being greater than 20% at overall one-sided 2.5% 
level of significance. 
Approximately 30 patients will be included in the interim analysis and approximately 45 
patients will be included in the final analysis in acute lymphoblastic leukemia patients. 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 30 patients, the lower bound of the 2-sided 98.79% exact CI of the 
ORR will need to be greater than 20% to declare statistical significance. As a result, an ORR 
of 13/30 = 43% is needed to claim success at interim. At the final analysis, 2-sided 95.37% 
exact CI will be used correspondingly. As a result, an ORR of 16/45 = 35% will be needed to 
claim success at final analysis.
In case the actual number of patients at the interim analysis cut-off date is not exactly equal to 
30 patients, the efficacy boundaries will need to be re-calculated based on the actual number 
of patients using the pre-specified α-spending functions. 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 n, 
the final analysis criteria will be determined so that the overall significance level across all 
analyses is maintained at one-sided 0.025.
Statistical properties of the group sequential design are summarized in Table 10-6 below.
Table 10-6
Simulated probabilities to claim success at the interim or final 
analysis
Scenario
Look
# of 
patients
Simulated cumulative 
probabilities (%) to claim 
success
Simulated incremental 
probabilities (%) to claim 
success
p=0.4
Interim
30
42%
Final
45
78%
36%
p=0.45 (H1)
Interim
30
64%
Final
45
93%
29%
p=0.5
Interim
30
83%
Final
45
99%
16%
Note: Simulation is performed in R 3.0.0 with number of simulations = 10,000.
In addition, the DMC will review safety data periodically.
 

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10.8
Sample size calculation
The final primary analysis will be performed when at least 50 acute lymphoblastic leukemia 
or lymphoblastic lymphoma patients (with at least 40 patients <18 years of age) have received 
CTL019 infusion and completed 6 months from study day 1 infusion or discontinued earlier. 
The sample size calculation is primarily based on the hypothesis testing for acute 
lymphoblastic leukemia patients.
The number of acute lymphoblastic leukemia and lymphoblastic lymphoma patients to be 
treated respectively will be based on the actual recruitment of the two populations. It is 
anticipated that the lymphoblastic lymphoma population is small and will represent less than 
10% of the entire population. Therefore with 50 patients treated in the study, it is assumed that 
45 acute lymphoblastic leukemia patients will be treated.
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.
Based on the null hypothesis of ORR ≤ 20% and alternative hypothesis of ORR > 20%, 45
acute lymphoblastic leukemia patients in the FAS will provide 93% power to demonstrate 
statistical significance using a 2-look Lan-Demets group sequential design with O’Brien-
Fleming type boundary at one-sided 0.025 level of significance, if the underlying ORR is 
45%. 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 
product manufacturing issues, worsening of patient’s condition, etc., at least 63 to 67 patients 
need to be enrolled respectively to ensure at least 50 infused patients (including 40 patients
less than age of 18) are treated and hence will be used for the primary analysis.
10.9
Power for analysis of key secondary variables
Not applicable because no formal hypothesis testing is planned other than for the primary 
objective.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the
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/SRC
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Institutional Biosafety Committee/Scientific 
 

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Review Committee (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 the Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IBCs/ 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 
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 form
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.
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 assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report, the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
 

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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 Novartis 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 Novartisprovides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines
11.7
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. Signed informed consent/assent forms and 
patient enrollment log must be kept strictly confidential to enable patient identification at the 
site.
 

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11.8
Audits and inspections
Source data/documents must be available to inspections by Novartisor 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 the 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 Clinical Study Report (CSR) 
developed by Novartis.
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/REB at the 
study site should be informed according to local regulations but not later than 10 working 
days.
 

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13
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14
Appendices
14.1
Appendix 1: 
Guidelines for efficacy evaluation in Acute Lymphoblastic 
Leukemia (ALL) studies
Author(s)
Document type:
CTL019 Project Specific Guideline
Document status:
Version 1.2: 26-Aug-l--2015
Document History
Version
Date
Changes
Final 1.0
5-Mar-2014
First version
Final 1.1
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 1.2 
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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List of abbreviations
ALL
Acute lymphoblastic leukemia
(e)CRF
(electronic) case report form
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
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
NCCN
National Comprehensive Cancer Network
NCI-WG
National Cancer Institute-Working Group
ORR
Overall remission rate
OS
Overall survival
PQ-PCR
Real-time quantitative polymerase chain reaction
PR
Partial remission
RAP
Report and Analysis Plan
RBC
Red blood cell
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
 

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For timing of the disease assessments for response classification, see Section 14.1.2.3.1 for 
details. The timing of each assessment for disease response should coincide with the other 
response assessment timing.
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).
In some rare cases the blood results are not available (e.g. typically when WBC < 500
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.
 

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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.
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 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 
 

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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 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 et al 2007a and Cheson et al 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%) bone marrow mononuclear cells (MNCs). 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.
 

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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.
 
14.1.2.2 Baseline evaluation
The following baseline assessments are mandatory:

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 of brain) 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)

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 bone marrow assessment within the 
protocol specified window should be used as the baseline bone marrow assessment. The blood 
count and extramedullary disease (physical exam, CSF, etc) assessments that are most 
proximal to the above defined baseline bone marrow assessment should then be used as the 
baseline blood count and baseline extramedullary disease assessments, respectively.
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 
 

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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 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.
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
● Trilineage Hematopeisis (TLH) and < 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 
 

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Response category
Definition
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, or 
● Platelets ≤ 100 x 109/L, 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
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 
 

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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 a response.
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
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(e)CRF module
Specification
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 
(s)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.
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 
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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”.
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.
 

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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

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
 

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
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.
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:
 

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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.
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 
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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.
14.1.5
References
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, 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 
 

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updating the National Cancer Institute–Working Group 1996 guidelines. Blood 111.12: 5446-
5456.
National Comprehensive Cancer Network (NCCN) Guidelines (NCCN, 2013 v1), Acute 
Lymphoblastic Leukemia
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.
Kim H (2007) Cumulative Incidence in Competing Risks Data and Competing Risks 
Regression Analysis. Clinical Cancer Research 2007;13:559-565.
 

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14.2
Appendix 2: Guidelines for efficacy evaluation in Lymphoblastic 
Lymphoma patients
14.2.1
Introduction
The efficacy evaluation in lymphoblastic lymphoma patients follows the same guidelines for 
acute lymphoblastic leukemia (ALL) patients as outlined in Appendix 1. In addition, based on 
the standardized response criteria defined by National Comprehensive Cancer Network 
(NCCN) Guidelines (NCCN 2013 v1) and further supported by other literatures, 
considerations outlined below should be followed.
14.2.2
Types of efficacy assessments
In addition to all the efficacy assessments for ALL patients, mediastinal disease must be 
assessed for extramedullary disease.
14.2.2.1 Assessment of mediastinal disease
A baseline CT or MRI (CT/MRI) scan of the mediastinum is only required to confirm whether 
mediastinal disease is present for patients with a history of lymphoblastic lymphoma. If a 
patient does not have a history of lymphoblastic lymphoma, no CT/MRI scan is required 
throughout the study.
For patients with history of lymphoblastic lymphoma, the frequency and timing of post-
baseline chest CT/MRI assessment may depend upon the study setting (e.g. front line or 
relapse/refractory, pediatric vs adult, etc.) and should be clearly specified in the protocol. 
Post-baseline chest CT/MRI assessment is required at Month 1 only for patients with proven 
mediastinal disease at baseline. Additional chest CT/MRI assessments may be performed per 
protocol specification. 
If at any time point, mediastinal disease is present by CT/MRI assessment, then follow-up 
CT/MRI is required to document the absence of mediastinal involvement whenever the patient 
meets all other criteria for complete remission. The timing of the CT/MRI must be within the 
required time window of the other disease response components.
For optimal evaluation of patients, the same imaging method of assessment (i.e. CT or MRI) 
and technique (i.e. with or without contrast) should be used to characterize each identified and 
reported lesion at baseline and during follow-up. A change in methodology can be defined as 
either a change in contrast use (e.g. keeping the same technique, like CT, but switching from 
with to without intravenous contrast use or vice-versa, regardless of the justification for the 
change) or a change in technique (e.g. from CT to MRI, or vice-versa). 
The investigator or the central blinded reviewer should decide if a definitive overall 
radiological response can be provided and justified to be based on the available information. 
Otherwise, overall lesion response should be “Unknown”, unless there is evidence of relapse.
Although the NCCN guideline has provided some guidance on the classification of 
mediastinal response, the exact definition of lymph node normalization requires further 
clarification. Following the NCCN guideline (NCCN 2013 v1) and also referencing the 
 

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international harmonization project revised response criteria for lymphoma (Cheson et al 
2007a and Cheson et al 2007b), the following guidelines are adopted:
Radiological classification of mediastinal lymph nodes 
Lymph nodes in the mediastinum are classified according to their size and/or relationship to 
the disease:

A lymph node that can be measured accurately in 2 perpendicular dimensions and if the 
long axis is > 15 mm, regardless of the length of the short axis above will constitute a 
measurable nodal lesion.

A lymph node not meeting the measurability requirement (above) but with long axis > 15 
mm (e.g. short axis cannot be measured accurately) will constitute a non-measurable 
nodal lesion

A lymph node not meeting the measurability criteria but with a size of 11 mm to 15 mm in 
the long axis and > 10 mm in the short axis will be checked for relationship to disease:

If it is thought to be disease related, it will constitute a non-measurable nodal lesion

If it is not thought to be disease related, it will constitute an abnormal lymph node but 
not a lesion.

All other lymph nodes will be considered normal and will not constitute nodal lesions.
Normalization of mediastinal lymph nodes after baseline
Mediastinal lymph nodes will be considered to have normalized if:

A measurable nodal lesion hast become ≤ 15 mm in long axis.

A non-measurable nodal lesion has decreased to ≤ 10 mm in the short axis and be ≤ 15 
mm in long axis.
New mediastinal lymph nodes
A new mediastinal lymph node is defined as:

Either a previously normal mediastinal lymph node becoming > 15 mm in any axis, or,

A previously identified abnormal mediastinal lymph node showing an increase of at least 
50% in the long axis.
Response criteria for mediastinal disease
The response for measurable mediastinal lymph nodes is evaluated by calculating the Sum of 
the Products of the greatest perpendicular Diameters (SPD) of all measurable lesions (see 
Table 14-4), except when there is complete normalization of all measurable mediastinal 
lymph nodes.
 

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Table 14-4
Response criteria for mediastinal disease
Response Status 1
Criteria
Complete Response (CR)
Complete normalization of all mediastinal lymph nodes 
CR Unconfirmed (CRu)
Residual mediastinal lymph nodes that have regressed by >75% in the 
SPD from baseline & without unequivocal worsening of non-measurable 
lymph nodes
Partial Response (PR)
At least 50% decrease from baseline in the SPD of all measurable 
mediastinal lymph nodes & without unequivocal worsening of non-
measurable lymph nodes
No Response (NR)
Failure to attain the criteria needed for CR, CRu or PR
Relapse
Recurrence of mediastinal lymph nodes after achieving mediastinal CR 
or CRu
1 At each assessment (if the measurable mediastinal lymph nodes are not in CR status), the response status 
based on SPD calculation will be first assessed for meeting NR status criteria, then PR status.
Note that NCCN guidance has defined a mediastinal progressive disease (PD) category. In 
this document, mediastinal PD is considered the same as “No response”. The difference 
between mediastinal progressive disease and no response in lymphoblastic lymphoma within 
the mediastinum is not believed to be clinical meaningful.
14.2.2.2 Baseline Evaluation
CT or MRI scan is required for patients with a history of lymphoblastic lymphoma. 
For disease characterization at baseline, the most current bone marrow assessment within the 
protocol specified window should be used as the baseline bone marrow assessment. The blood 
count and extramedullary disease (physical exam, CSF, imaging if indicated) assessments that 
are most proximal to the above defined baseline bone marrow assessment should then be used 
as the baseline mediastinal disease assessments.
14.2.2.3 Post-baseline overall disease response evaluation
Post-baseline CT/MRI for mediastinal disease assessment is required to demonstrate that a 
patient has achieved CR or CRi for the first time.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 marrow biopsy/ aspirate (if 
needed), CT/MRI scan (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.
The overall disease response is determined at a given evaluation using the criteria described in 
Table 14-5 below. 
 

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Table 14-5
Overall disease response classification at a given evaluation time for 
lymphoblastic lymphoma patients
Response category
Definition
Complete remission (CR)
All the criteria for ALL are met, and in addition CR for mediastinal 
disease.
Complete remission with incomplete blood 
count recovery (CRi)
All the criteria for ALL are met, and in addition CR for mediastinal 
disease. 
CR or CRi with residual mediastinal disease
All criteria for CR or CRi as defined above are met, except that 
mediastinal disease as defined by CRu or PR is observed.
No response
Failure to attain the criteria needed for any response categories or 
relapse
Relapsed Disease
Same criteria for ALL, and in addition mediastinal relapse will also 
indicate relapse for lymphoblastic lymphoma.
Unknown
Same criteria for ALL.
Note that the NCCN guideline (NCCN 2013 v1) has defined mediastinal response criteria 
including CRu and PR, however has not incorporated these categories into the overall disease 
response. Residual nodal disease in the presence of clearance of all other sites of disease may 
represent a unique biologic setting. Therefore, in the case a patient achieves CR or CRi at all 
other non-mediastinal disease sites, and has residual mediastinal disease (mediastinal CRu or 
PR), a category for overall disease response of “CR or CRi with residual mediastinal disease” 
has been included in this document, which is not part of the NCCN guideline. The clinical 
significance of such a category, however, has not been demonstrated.
14.2.2.3.1
Establishing and subsequent maintenance of response with no clinical 
evidence of relapse
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, CT/MRI scans, etc.) are performed in 
the same evaluation for disease response evaluation purpose, they will also need to show 
remission status.
14.2.2.3.2
Date of overall disease response evaluation
Dates of CT/MRI scans are also considered in the same fashion as other components to 
determine the date of overall response for lymphoblastic lymphoma patients.
 

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14.3
Appendix 3: 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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14.4
Appendix 4: CTL019 Modified Safety Reporting
14.4.1
Adverse Event (AE) and Serious Adverse Event (SAE) Reporting
Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Post-treatment Period
(Starting from LD chemo/pre-infusion visit )
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, including all 
laboratory 
abnormalities 
deemed clinically 
significant by the 
investigator
Modified –Whether serious or non-serious, report following:
● Events leading to death
● Related to a study procedure
● 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 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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14.4.2
Concomitant Medication
Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Post-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:
● Record ALL blood products, including prophylaxis (to distinguish CR vs CRi)
● If NOT administered ≤7 days of a tumor response assessment:
● Only record blood products if given for bleeding (excludes prophylactic use)
Electrolyte & vitamin replacement:
● 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 
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
● Immunosuppresive agents (including 
dose of steroids higher than physiologic 
replacement therapy doses of steroids  
(6-12 mg/m2/day hydrocortisone or 
equivalent)
● Investigational therapy
 

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Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Post-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
Laboratory 
data
Modified:
● Record all scheduled labs (per Visit Evaluation Schedule)
● Record all results (scheduled or unscheduled) for:  LDH, Uric acid, 
, 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, 
 
 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)