Conditions: Diffuse Large B-cell Lymphoma (DLBCL)
Keywords: Diffuse large B-cell lymphoma DLBCL Relapsed/refractory CTL019 CART19 CART CAR T cells Chimeric antigen receptor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 115
Healthy volunteers: no

Brief summary:
This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.

Detailed description:
This was a single arm, open-label, multi-center, Phase II study conducted to determine the efficacy and safety of tisagenlecleucel in adult patients with r/r DLBCL. The study consisted of the following sequential periods: Screening, Pre-Treatment, Treatment and Primary follow-up, Secondary follow-up, Survival follow-up.

Patients were enrolled in 2 cohorts to receive one tisagenlecleucel infusion as follows:

* Main Cohort (patients treated with tisagenlecleucel manufactured at the Novartis manufacturing facility in Morris Plains, US, referred to as "US manufacturing facility") and
* Cohort A (patients treated with tisagenlecleucel manufactured at the Fraunhofer Institut für Zelltherapie, Leipzig, Germany, referred to as "EU manufacturing facility").

The study enrolled adult patients ≥ 18 years with histologically confirmed relapsed or refractory (r/r) DLBCL after ≥ 2 lines of chemotherapy, with a life expectancy of ≥ 12 weeks and not eligible or not consenting to stem cell transplantation (SCT).

Patients had measurable disease at time of enrollment, adequate organ function and zero or one Eastern Cooperative Oncology Group performance status at screening. For each patient, the apheresis product of non-mobilized cells was received and accepted by the manufacturing site.

Arms:
arm 1: Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received tisagenlecleucel.

Interventions: intervention 1: Tisagenlecleucel intervention 2: Lymphodepleting chemotherapy
Intervention descriptions: intervention 1: The target dose of CTL019 transduced cells for adult patients consisted of a single infusion of 5 x 10\^8 viable CTL019 transduced cells, which was administered via intravenous infusion. The acceptable dose range was 1 - 5x10\^8 viable CTL019 transduced cells. intervention 2: Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy cycle was planned. The use of any additional bridging therapy prior to the recommended lymphodepleting chemotherapy was at the discretion of the investigator and dependent on the patient's disease burden. Lymphodepleting chemotherapy was started 14 to 5 days before CTL019 infusion (D1) to allow for at least 48 hours from last dose of lymphodepleting chemotherapy to CTL019 infusion. The lymphodepleting regimen was: Fludarabine (25 mg/m\^2 intravenously \[i.v.\] daily for 3 doses) and cyclophosphamide (250 mg/m\^2 i.v. daily for 3 doses starting with the first dose of fludarabine).

Protocol document:
Prot_000.pdf: 
Clinical Development
CTL019
Oncology Clinical Trial Protocol CCTL019C2201 / NCT02445248
A phase II, single arm, multicenter trial to determine the 
efficacy and safety of CTL019 in adult patients with 
relapsed or refractory diffuse large B-cell lymphoma 
(DLBCL)
Document type
Amended Protocol Version
EUDRACT number
2014-003060-20
Version number
06 (Clean)
Development phase
II
Document status
Final
Release date
15-Apr-2021
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 tables ........................................................................................................................7
List of figures ......................................................................................................................8
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................14
Amendment 6 (15-Apr-2021)............................................................................................15
Summary of previous amendments ...................................................................................18
Protocol summary:.............................................................................................................38
1
Background........................................................................................................................44
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............44
1.1.1
Historical experience with retroviral gene therapies.............................45
1.2
Introduction to investigational treatment(s) and other study treatment(s).............47
1.2.1
Overview of CTL019............................................................................47
2
Rationale............................................................................................................................52
2.1
Study rationale and purpose...................................................................................52
2.2
Rationale for the study design ...............................................................................54
2.2.1
Rationale for lymphodepletion..............................................................56
2.3
Rationale for dose and regimen selection..............................................................56
2.4
Rationale for choice of combination drugs............................................................58
2.5
Rationale for choice of comparators drugs............................................................59
3
Objectives and endpoints...................................................................................................59
4
Study design ......................................................................................................................63
4.1
Description of study design ...................................................................................63
4.1.1
Leukapheresis assessment.....................................................................64
4.2
Definition of end of the study................................................................................65
4.3
Early study termination..........................................................................................65
5
Population..........................................................................................................................66
5.1
Patient population..................................................................................................66
5.2
Inclusion criteria ....................................................................................................66
5.3
Exclusion criteria...................................................................................................68
6
Treatment...........................................................................................................................69
6.1
Study treatment......................................................................................................69
6.1.1
Dosing regimen.....................................................................................70
6.1.2
Ancillary treatments..............................................................................74
6.1.3
Rescue medication ................................................................................74


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6.1.4
Guidelines for continuation of treatment ..............................................74
6.1.5
Treatment duration................................................................................74
6.2
Dose escalation guidelines.....................................................................................74
6.2.1
Starting dose rationale...........................................................................74
6.2.2
Provisional dose levels..........................................................................75
6.2.3
Guidelines for dose escalation and determination of 
MTD/RP2D/RDE..................................................................................75
6.2.4
Definitions of dose limiting toxicities (DLTs) in a phase II study .......75
6.2.5
Criteria for discontinuing a patient’s participation in the study.............85
6.2.6
Concomitant Therapy............................................................................85
6.2.7
Prohibited concomitant therapy ............................................................86
6.3
Dose modifications................................................................................................87
6.3.1
Dose modification and dose delay ........................................................87
6.3.2
Follow-up for toxicities.........................................................................87
6.4
Patient numbering, treatment assignment or randomization .................................89
6.4.1
Patient numbering .................................................................................89
6.4.2
Treatment assignment ...........................................................................90
6.4.3
Treatment blinding................................................................................90
90
91
91
91
92
7
Visit schedule and assessments .........................................................................................92
7.1
Study flow and visit schedule................................................................................92
7.1.1
Screening phase...................................................................................109
7.1.2
Pre-treatment phase.............................................................................111
7.1.3
Treatment and primary follow-up phase.............................................112
7.1.4
Secondary follow-up phase.................................................................117
7.1.5
Survival follow-up phase ....................................................................118
7.1.6
Long-term follow-up...........................................................................118
7.1.7
Discontinuation of study treatment .....................................................118
7.1.8
Withdrawal of consent ........................................................................118
7.1.9
Follow up for safety evaluations.........................................................119
7.1.10
Lost to follow-up.................................................................................119
7.2
Assessment types.................................................................................................119


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7.2.1
Efficacy assessments...........................................................................119
7.2.2
Safety and tolerability assessments.....................................................121
7.2.3
Cellular Kinetics and Pharmacokinetics .............................................125
131
133
134
134
8
Safety monitoring and reporting......................................................................................136
8.1
Adverse events.....................................................................................................136
8.1.1
Definitions...........................................................................................136
8.1.2
Reporting.............................................................................................136
8.1.3
Laboratory test abnormalities..............................................................138
8.1.4
Adverse events of special interest.......................................................139
8.2
Serious adverse events.........................................................................................139
8.2.1
Definitions...........................................................................................139
8.2.2
Reporting.............................................................................................139
8.3
Emergency unblinding of treatment assignment .................................................142
8.4
Contraception.......................................................................................................142
8.5
Pregnancies..........................................................................................................143
8.6
Warnings and precautions....................................................................................143
8.7
Data Monitoring Committee................................................................................143
8.8
Steering Committee .............................................................................................144
8.9
Independent Review Committee (IRC) ...............................................................144
8.10
Follow-up of Secondary Malignancy ..................................................................144
9
Data collection and management.....................................................................................145
9.1
Data confidentiality .............................................................................................145
9.2
Site monitoring ....................................................................................................145
9.3
Data collection.....................................................................................................146
9.4
Database management and quality control..........................................................146
10 Statistical methods and data analysis ..............................................................................146
10.1
Analysis sets ........................................................................................................146
10.1.1
Screened Set........................................................................................147
10.1.2
Enrolled Set.........................................................................................147
10.1.3
Full Analysis Set .................................................................................147
10.1.4
Safety Set ............................................................................................147


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10.1.5
Per-Protocol Set ..................................................................................147
10.1.6
Pharmacokinetic analysis set...............................................................147
10.2
Patient demographics/other baseline characteristics ...........................................148
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................148
10.4
Primary objective.................................................................................................148
10.4.1
Variable...............................................................................................148
10.4.2
Statistical hypothesis, model, and method of analysis........................151
10.4.3
Handling of missing values/censoring/discontinuations.....................151
10.4.4
Supportive analyses.............................................................................151
10.5
Secondary objectives ...........................................................................................152
10.5.1
Key secondary objective(s).................................................................152
10.5.2
Other secondary efficacy objectives ...................................................152
10.5.3
Safety objectives .................................................................................154
10.5.4
Pharmacokinetics ................................................................................157
158
158
160
160
160
160
161
161
161
10.7
Interim analysis....................................................................................................161
10.8
Sample size calculation........................................................................................162
10.9
Power for analysis of key secondary variables....................................................162
11 Ethical considerations and administrative procedures ....................................................163
11.1
Regulatory and ethical compliance......................................................................163
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................163
11.3
Informed consent procedures...............................................................................163
11.4
Discontinuation of the study................................................................................163
11.5
Publication of study protocol and results.............................................................164
11.6
Study documentation, record keeping and retention of documents.....................164
11.7
Confidentiality of study documents and patient records .....................................165
11.8
Audits and inspections.........................................................................................165
11.9
Financial disclosures............................................................................................165


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12 Protocol adherence ..........................................................................................................165
12.1
Amendments to the protocol................................................................................165
13 References (available upon request)................................................................................166
14 Appendices ......................................................................................................................174
 
174
176
177
180
183
187
193
194
195
14.2
Appendix 2: Eligibility based on serologic markers for hepatitis B infection ....196
14.3
Appendix 3: CTL019 modified data reporting – Treatment and Primary 
Follow Up Phase..................................................................................................196
14.3.1
Adverse event (AE) and serious adverse event (SAE) reporting........197
14.3.2
Concomitant medication and laboratory reporting .............................198
14.4
Appendix 4: CTL019 modified data reporting – Secondary Follow Up Phase...200
14.5
Appendix 5: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................200
14.5.1
Liver Event and Laboratory Trigger Definitions ................................200
14.5.2
Follow Up Requirements for Liver Laboratory Triggers - ALT, 
AST, TBL............................................................................................201
14.6
Appendix 6: Specific Renal Alert Criteria and Actions and Event Follow-up....202
14.6.1
Specific Renal Alert Criteria and Actions...........................................202
14.6.2
Follow up of renal events....................................................................203


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List of tables
Table 1-1
Summary of ongoing human studies as of January 2015......................52
Table 3-1
Objectives and related endpoints ..........................................................60
Table 6-1
CTL019 therapy associated grading for cytokine release syndrome: 
The Penn Grading Scale for Cytokine Release Syndrome (PGS-
CRS)......................................................................................................79
Table 6-2
High dose vasopressor use ....................................................................80
Table 6-3
Concomitant medication reporting by study period..............................86
Table 7-1
Primary visit evaluation schedule .........................................................93
Table 7-2
Secondary follow-up visit evaluation schedule (for patients who 
end their primary follow up before M60) ...........................................107
Table 7-3
Imaging or disease assessment collection plan...................................121
Table 7-4
ECOG Performance status grade ........................................................122
Table 7-5
Local clinical laboratory parameters collection plan ..........................123
Table 7-6
Central clinical laboratory parameters collection plan........................123
Table 7-7
CTL019 pharmacokinetics by q-PCR in peripheral blood collection 
log........................................................................................................125
Table 7-8
CTL019 pharmacokinetics by flow cytometry in peripheral blood 
collection log.......................................................................................126
Table 7-9
CTL019 pharmacokinetics by q-PCR in bone marrow aspirate 
collection log.......................................................................................127
Table 7-10
CTL019 pharmacokinetics by flow cytometry in bone marrow 
aspirate collection log .........................................................................127
Table 7-11
CTL019 pharmacokinetics by q-PCR in CSF biopsy or other tissue 
log........................................................................................................128
Table 7-12
Immunogenicity serum sample collection log ....................................128
Table 7-13
Immunogenicity whole blood sample collection log ..........................128
Table 7-14
 CTL019 Pharmacokinetics (PK), 
 in 
treated patients during CRS.............................................129
Table 7-15
 CTL019 PK 
 in 
reated 
patients during CRS ............................................................................130
131
131
133
Table 10-1
Overall response assessment...............................................................149
Table 10-2
Noncompartmental pharmacokinetic parameters................................157
Table 10-3
Simulated scenarios for interim and final analysis .............................162
176


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177
184
191
192
List of figures
Figure 1-1
CTL019 chimeric antigen receptor design............................................48
Figure 2-1
Mechanisms of actions of rituximab, ibrutinib and CTL019 in B 
lymphocytes: .........................................................................................53
Figure 2-2
Expected flow of patients in CTL019C2201 ........................................55
Figure 4-1
CTL019C2201 study design .................................................................64
Figure 6-1
CRS Management Algorithm................................................................78


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List of abbreviations
ABC
Activated B-cell
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE
Adverse Event
AESI
Adverse events of special interest
ALC
Absolute Lymphocyte Count
ALL
Acute Lymphoblastic Leukemia
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/SGPT
aPTT
Activated partial thromboplastin time
ASH
American Society of Hematology
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/SGOT
ATC
Anatomical Therapeutic Chemical
ATG
Anti-Thymocyte Globulin
AUC
Area Under the Curve
BCR
B cell receptor
BiPAP
Bilateral Positive Airway Pressure
BTK
Bruton’s Tyrosine kinase
BUN
Blood Urea Nitrogen
CAR
Chimeric antigen receptor
CBC
Complete Blood Count
CCG
CRF Completion Guidelines
CD19 CART
CD 19 redirected autologous T cells
CFR
Code of Federal Regulations
CGD
Chronic granulomatous disease
CGTU
Cell and Gene Therapies Unit
CI
Confidence Interval
CIF
Cumulative incidence function
Clast
Last observable concentration
CLL
Chronic Lymphocytic Leukemia
cm
Centimeter
Cmax
Maximum concentration
CMR
Complete Metabolic Response
CMV
Cytomegalovirus
CNS
Central Nervous System
CPAP
Continuous Positive Airway Pressure
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CRS
Cytokine Release Syndrome
CSF
Cerebral spinal fluid
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTC
Common toxicity criteria


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CTCAE
Common Terminology Criteria for Adverse Events
CTL
Cytotoxic T-lymphocyte
CVPF
Cell and Vaccine Production Facility
DFS
Disease free survival
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose Limiting Toxicity
DMC
Data monitoring committee
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DS&E
Drug Safety and Epidemiology
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EFS
Event free survival
eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
ESMO
European Society for Medical Oncology
FAS
Full analysis set
FDA
Food & Drug Administration
FDG
Fluorodeoxyglucose
FFP
Fresh frozen plasma
FISH
Fluorescence in situ hybridization
FL
Follicular Lymphoma
FLOW
Flowcytometry
FPFV
First Patient First Visit
GC
Germinal center-like
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
GI
Gastrointestinal
GM-CSF
Granulocyte macrophage-colony stimulating factor
GVHD
Graft versus Host Disease
HA
Health Authority
HBcAb
Hepatitis B core Antibody
HBsAb
Hepatitis B surface Antibody
HBsAg
Hepatitis B surface Antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
HRQoL
Health Relates Quality of Life
HSCT
Hematopoietic stem cell transplantation (refers to both allogenic SCT and autologous SCT)
i.v.
Intravenous(ly)


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IB
Investigator Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
IN
Investigator Notification
INR
International Normalized Ratio
IPI
International Prognostic Index
IRB
Institutional Review Board
IRC
Independent Review Committee
IRT
Interactive Response Technology
IUD
Intrauterine Device
IWRS
Interactive Web Response System
JCV
John Cunningham Virus
kg
Kilogram
KM
Kaplan Meier
LDH
Lactate dehydrogenase
LDi
Longest transverse diameter of a lesion
LFT
Liver function tests
LLOQ
Lower Limit of Quantification
LOQ
Limit of Quantification
LPLV
Last Patient Last Visit
LSS
Lymphoma specific survival
LTFU
Long Term Follow Up
LTR
Long terminal repeat
LVEF
Left Ventricular Ejection 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
mL
milliliter
MNC
Mononuclear cell
MRI
Magnetic Resonance Imaging 
mRNA
Messenger RNA
MTD
Maximum Tolerated Dose
MUGA
Multiple Uptake Gated Acquisition
NCCN
National Comprehensive Cancer Network
NE
Norepinephrine Equivalent


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NHL
Non-Hodgkin’s Lymphoma
NK
Natural Killer cell
NMR
No Metabolic Response
NOS 
Not otherwise specified
O2
Oxygen
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic analysis set
PCR
Polymerase Chain Reaction
PD
Progressive disease
PD
Pharmacodynamics
PE
Physical Examination
PET
Positron emission tomography
PFS
Progression Free Survival
PGS-CRS
The Penn Grading Scale for Cytokine Release Syndrome
PHI
Protected Health Information
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetics
PMBCL
Primary mediastinal large cell lymphoma
PMD
Progressive Metabolic Disease
PML
Progressive Multifocal Leukoencephalopathy
PPD
Product of Perpendicular Diameters
PPS
Per Protocol Set
PR
Partial Response
PT
Preferred Term
PT
Prothrombin time
PTLD
Post-transplant lymphoproliferative disorders
qPCR
Quantitative Polymerase Chain Reaction
r/r
Relapsed or refractory
RAP
Report and Analysis Plan
RCL
Replication competent lentivirus
RCR
Replication competent retrovirus
RD
Relapsed Disease
RDE
Recommended dose for expansion
REB
Research Ethics Board
RNA
Ribonucleic acid
RP2D
Recommended phase two dose 
SAE
Serious Adverse Event
SC
Steering Committee
scFv
Single chain variable fragment
SCID-X1
X-linked Severe Combined Immunodeficiency
SCT
Stem cell transplantation
SD
Stable Disease
SDi
Shortest axis perpendicular to LDi


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SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic-pyruvic transaminase
SOC
System Organ Class
SPD
Sum of the product of the diameters
SUSAR
Suspected unexpected serious adverse reactions
SUV
Standard Uptake Value
TCR
T cell receptors
Tlast
Time of last observable concentration
TLS
Tumor lysis syndrome
Tmax
Time to peak concentration
TNC
Total nucleated cells
TNF
Tumor Necrosis Factor
TTF
Time to treatment failure
TTP
Time to progression
TTR
Time to Response
ULN
Upper Limit of Normal
ULOQ
Upper Limit of Quantification
UNK
Unknown
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
WAS
Wiskott-Aldrich syndrome
WBC
White blood cells
WHO
World Health Organization
WOCBP
Women of child bearing potential


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or patient
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.) 
Final Enrollment
Point/time of patient entry into the study when the following have been confirmed:
A. ICF signed
B. Local patient eligibility confirmed
C. Apheresis product reviewed and accepted for manufacturing
Investigational drug
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
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
MAP
Master analysis plan documents project standards in the statistical methods which 
will be used within the individual clinical trial RAP documentation
Subject Number
A unique identifying number assigned to each subject 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
RAP
Report and analysis plan is a regulatory document which provides evidence of 
preplanned analyses
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including
lymphodepleting chemotherapy.
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when a patient permanently stops taking study treatment for any 
reason
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
Withdrawal of Consent
Withdrawal of consent occurs only when a patient does not want to participate in 
the study any longer, and does not want any further visits or assessments, and 
does not want any further study related contact


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Amendment 6 (15-Apr-2021)
Amendment Rationale 
At the time of this amendment, enrollment to the Main Cohort and Cohort A has been completed. 
A total of 167 patients were enrolled in the study and 115 patients were infused with CTL019 
(99 patients infused in the Main Cohort and 16 patients infused in Cohort A). The last patient 
was infused on 20-Feb-2018.
As of April 15th, 2021, there are 24 patients on study in the treatment and primary follow-up 
phase; there are 8 patients on study in the secondary follow-up phase; and there are 3 patients 
in Survival Follow-up. The rest of the patients are off-study. This amendment 6 will apply to 
all countries that still have patients on study and in survival follow-up.
The main purpose of this amendment is to:

Change the required follow-up time of a newborn after live birth from 6 months to 12 
months following pregnancy of a female patient or the partner of any male patient. This 
additional safety monitoring is not due to any new safety concern or emerging data, but is 
taken on a precautionary basis and aligns with current Novartis internal guidelines.

Update the protocol safety language to reflect the current Novartis CTL019 program safety 
language; this includes updates to the Potential Toxicities Section as well as updates to the 
highly effective contraceptive methods in a newly added Contraception Section. Some of 
the changes to the Toxicity Section include deletion of Febrile neutropenia, and addition of 
neurological adverse reactions, viral reactivation, hematological disorders including 
cytopenias and other changes.

Add the requirement for urine or serum pregnancy testing at all study visits to align with 
standard CTL019 monitoring requirements. Changes to the Visit Evaluation Schedule have 
been made starting at Month 30 and after because all remaining patients are past Month 30 
follow-up.

Add language about secondary malignancies and follow up to align with the CTL019 
program standard language.

Specify that blood samples for RCL testing are banked beyond month 12, as long as all 
samples through Month 12 were negative.
Given that enrollment is complete, no changes have been made to the inclusion/exclusion 
criteria, the cytokine release syndrome (CRS) management algorithm and CRS grading scale. 
Changes to the Visit Evaluation Schedule have been made starting at Month 30 and after 
because all remaining patients are past Month 30 follow-up. The only change to the Visit 
Evaluation Schedule is addition of serum or urine pregnancy testing. The contraceptive methods 
included for WOCBP & males in the inclusion criteria are obsolete and are replaced by those 
outlined in the newly added Contraception section.


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Section 6.2.4.2 General toxicity management considerations: The following sentence has been 
added: Patients treated with CTL019 should not donate blood, organs, tissues, sperm, oocytes 
and cells.
Section 6.2.4.2.1 Expected Toxicities: This section has been updated as per the most updated 
standard program safety language. Febrile Reaction has been deleted. Neurological Adverse 
Reactions, Viral Reactivation and Hematological disorders including cytopenias have been 
added.
Section 6.2.4.2.2 Potential Toxicities: This section has been updated as per the most updated 
standard program safety language.
Section 6.3.2.1 Liver safety monitoring: Table 6-4 and 6-5 have been deleted and replaced by 
Appendix 5 which contains updated information based on standard program safety language.
Section 6.3.2.2 Follow up on potential drug-induced liver injury (DILI) cases: This section has 
been added based on standard program safety language.
Section 6.3.2.3 Renal safety monitoring: This section has been added based on standard 
program safety language.
Section 6.3.3 Anticipated risks and safety concerns: This section has been deleted.
Table 7.1 Primary Visit Evaluation Schedule: Serum or urine pregnancy testing has been added 
in the Treatment and Primary Follow-up Phase and in the Secondary Follow-up Phase as per 
standard program safety language. Pregnancies has also been added to the Treatment and 
Primary Follow-up Phase. Changes to the Visit Evaluation Schedule have been made starting 
at Month 30 and after because all remaining patients are past Month 30 follow-up.
Section 7.1.3 Treatment and primary follow-up phase: Section has been updated to reflect the 
addition of urine or serum pregnancy testing added at M30, M36, M42, M48, and M54.
Section 7.1.3.1 End of treatment and primary follow-up (EOT) visit (M60 ±14d) including 
premature withdrawal: Section has been updated to reflect the addition of serum pregnancy 
testing added at M60.
Section 7.1.4 Secondary follow-up phase: Section has been updated to reflect the addition of 
urine or serum pregnancy testing added at M30, M36, M42, M48, and M54. Section has been 
updated to reflect the addition of serum pregnancy testing at M60.
Table 7.5 Local clinical laboratory parameters collection plan: Updated urine and serum 
pregnancy testing requirement per standard program safety language.
Table 7.7 CTL019 pharmacokinetics by q-PCR in peripheral blood collection log: A note has 
been added to clarify that if RCL blood samples test are negative through Month 12, all samples 
taken after Month 12 will be stored for potential future testing.
Section 8.1.2 Reporting: The following statement has been deleted: infections: defined as 
bacterial, viral, fungal, or parasitic.


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Section 8.2.1 Definitions of SAEs: Section updated to add that All malignant neoplasms 
(secondary malignancies, not disease progression of the study indication) will be assessed as 
serious under “medically significant.”
Section 8.2.2.3 Month 12 to Month 60: The following sentence has been deleted: ‘Defined as 
bacterial, viral, fungal, or parasite infections’.
Section 8.4 Contraception: The Contraception Section has been added. The contraceptive 
measures outlined in this section for WOCBP and sexually active males are the effective ones 
and they replace those presented in the Inclusion Criteria section. Since enrollment is complete, 
changes to the inclusion criteria have not been made.
Section 8.5 Pregnancies: Section updated per standard program safety language. In case of live 
birth the newborn will be followed up until 12 months of age (and not 6 months). 
Section 8.10 Follow-up of secondary malignancy language has been added as per program 
standard language. 
Section 11.3 Informed Consent Procedures: Section has been updated as per program standard 
language. 
Section 14.3.1 The following sentence has been deleted: ‘Defined as bacterial, viral, fungal, or 
parasite infections’. 
Appendix 5: Liver event and Laboratory trigger Definitions and Follow-up Requirements: 
Appendix 5 has been added with the most updated Liver event and Laboratory trigger 
Definitions and Follow-up Requirements
Appendix 6: Specific Renal Alert Criteria and Actions and Event Follow-up: Appendix 6 has 
been added with the most updated Specific Renal Alert Criteria and Actions and Event Follow-
up
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, where required.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Summary of previous amendments
Amendment 5 (09-Mar-2017)
Amendment rationale
At the time of this amendment, 144 patients have been enrolled and 95 patients have been 
treated (92 patients treated in the main cohort (US manufacturing) and 3 patients treated in 
cohort A (EU manufacturing)). Screening and enrollment to the main cohort was completed. 
Japanese patients are enrolled only in the main cohort. At the time of enrollment completion in 
the main cohort, there were 3 Japanese patients enrolled, treated and they are in primary follow-
up.
A minimum of 9 Japanese patients must be treated in the study, in order to evaluate the safety 
and efficacy of CTL019 in the Japanese patient population. This number of Japanese patients 
is not based on statistical considerations. It will allow the generation of a reasonable data 
package to support a marketing authorization for CTL019 in Japan. Consequently the protocol 
is amended in order to allow the enrollment of additional Japanese patients.
With this amendment 5, approximately 10 additional Japanese patients will be enrolled in the 
main cohort to allow at least 6 additional patients to be treated to ensure a minimum of 9 and 
maximum of 13 Japanese patients treated with CTL019. The additional Japanese patients will 
be infused with CTL019 manufactured at the Novartis manufacturing facility in Morris Plains, 
USA.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Protocol summary was updated to be consistent with other sections of the document.
Section 2.2 Rationale for the study design: Approximately 10 Japanese patients will be added 
to the previous population, in order to have at least 6 patients treated.
Section 4.1 Description of study design: The description has been updated to include the 
additional Japanese patients.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities, where required.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation only in Japan.


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Amendment 4 (07-Jul-2016)
Amendment rationale
At the time of this amendment, 72 patients have been enrolled and 29 patients have been treated.
The study has been amended to use PET-CT at baseline and month 3 for primary analysis of 
response. PET-CT at these time points had already been part of the protocol. With the wide 
acceptance of metabolic imaging using FDG-PET for staging and response assessment of 
lymphomas and the recommendations by the International Malignant Lymphomas Imaging 
Working Group (Cheson et al 2014) this change is considered to improve the diagnostic quality 
and clinical meaningfulness of the endpoint of ORR in this trial. In the proof of concept study 
performed at the University of Pennsylvania metabolic response at month 1 and month 3 
correlated with duration of response 
. Novartis has revised 
its guideline for efficacy evaluation in DLBCL and FL studies in version 2 to integrate PET, 
accordingly. No new imaging assessments were introduced as PET-CT at baseline and at Month 
3 was already implemented in the original protocol.
Under the protocol version 03, patients with manufactured cell numbers falling below the target 
dose and acceptable dose ranges for this study were eligible to receive CTL019 therapy if the 
product meets all other manufacturing release criteria. Preliminary dose expansion analyses 
suggest that these very low doses show only minimal in vivo expansion and patients are very 
unlikely to derive clinical benefit. Consequently, CTL019 doses lower than the protocol 
specified range will no longer be released.
One additional study cohort was added:

Cohort A aims to assess efficacy and safety and characterize the in vivo cellular PK profile
of CTL019 manufactured at the Fraunhofer Institut für Zelltherapie, Leipzig, Germany.
The CRS treatment algorithm was updated with additional details to support trial investigators 
on appropriate CRS management.
In addition several clarifications have been implemented to ensure protocol adherence.
The changes implemented in this amendment are not impacting the study population of the trial.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Protocol summary was updated to be consistent with other sections of the document.
Section 2.2 Rationale for the study design: One cohort has been added to the previous 
population (main cohort) to assess the clinical profile of CTL019 manufactured at Fraunhofer 
Institut für Zelltherapie.
Table 3-1 Objective and related endpoints: Primary objective was clarified as being applicable 
for the main study cohort only.
Table 3-1 Objectives and related endpoints: PK parameters were updated for the 
characterization of the in vivo cellular PK profile.


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Table 3-1 Objectives and related endpoints: Objectives and endpoints have been added for the 
new cohort.
 
 
 
 
 
Section 4.1 Description of study design: Reference to the response guidance was updated to 
refer to the 
and the section was updated according to the 
.
Section 4.1 Description of study design: Clarification was made that the treatment staggering 
for new sites is to be considered from infusion rather than from enrollment.
Section 4.1 Description of study design: One cohort has been added to the previous population 
(main cohort) to assess the clinical profile of CTL019 manufactured at Fraunhofer Institut für 
Zelltherapie.
Section 4.1.1 Leukapheresis assessment: Wording was updated to remove the cryopreserved 
aspect of the leukapheresis and that the product should be accepted for manufacturing before 
shipment to the manufacturing facility.
Section 5.1 Patient population: Figures regarding the patients to be enrolled and treated have 
been moved to the study design rationale section (section 2.2).
Section 5.2 Inclusion Criteria: Reference to the Cheson Response Criteria was updated to be 
consistent with other sections of the document.
Section 5.2 Inclusion Criteria: Inclusion criterion 10 language was clarified regarding IUDs
Section 5.2 Inclusion Criteria: Inclusion criterion 11 contraception requirement for male patient 
with sterile female partner was clarified
Section 5.3 Exclusion criteria: exclusion criterion 7 was further clarified regarding the 
investigational drug washout period.
Section 5.3 Exclusion criteria: exclusion criterion 8 was further clarified regarding the excluded 
medications.
Section 6.1.1 Dosing regimen: CTL019 product will no longer be released for infusion if the 
dose is lower than the specified dose range.
Section 6.1.1.1 Lymphodepleting chemotherapy: Timeframe for the lymphodepleting
chemotherapy in relation to CTL019 infusion was clarified to be consistent with section 7.1.2.
Section 6.1.1.1 Lymphodepleting chemotherapy: The need for a negative pregnancy test was 
clarified.


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Section 6.1.1.2 CTL019 Infusion: Criteria for prior therapies that have to be met prior to 
CTL019 infusion were clarified and rescue medication that should be available at site was 
further specified.
Section 6.1.3 Rescue medication: Rescue medication that should be available at site was further 
specified.
Section 6.2.4.2.1 Expected toxicities: Wording regarding Cytokine Release Syndrome (CRS) 
and CRS Management Algorithm were updated.
Section 6.2.4.2.2 Potential toxicities: Additional information on prevention of hepatitis B 
reactivation was added
Table 6-1 CTL019 therapy associated grading for cytokine release syndrome: The Penn 
Grading Scale for Cytokine Release Syndrome (PGS-CRS) was updated.
Section 6.2.6 Concomitant Therapy: Data collection for adverse events and concomitant 
medications per study period was clarified.
Section 6.2.7 Prohibited concomitant therapy: Wording on excluded medications was clarified 
to be consistent with other sections of the protocol.
Table 6-5 Liver Event Follow Up Requirements: Wording was clarified to be consistent with 
study treatment.
Section 6.4.2 Treatment assignment: Wording was clarified.
Section 6.5.2 Drug supply and storage: Reference to the Investigation Product Handling Manual 
was added.
Section 6.5.3 Study drug compliance and accountability: Reference to the responsible Quality 
Department was updated.
Section 6.5.4 Study drug disposal and destruction: Wording regarding unused CTL019 product 
was updated.
Table 7-1 Primary visit evaluation schedule: Lymphodepleting Chemotherapy visit column 
changed to reflect time window of -W2 to -D5; IRT Registration was clarified to be required at 
infusion instead of pre-infusion; B-symptoms was changed from infusion to lymphodepleting 
chemotherapy visit to align with baseline imaging; Wording was added to clarify requirements 
for baseline imaging within 4 weeks of infusion; Wording was added to clarify D28 bone 
marrow biopsy only needed if CR and prior bone marrow involvement; Flow cytometry before 
leukapheresis and on leukapheresis product changed to central; Clarification made that 
pregnancy test prior to lymphodepleting therapy can be urine or serum; Serum immunoglobulin 
added at pre-infusion visit and at end of treatment visit;
 
CTL019 pharmacokinetics by flow cytometry was added at Month 18 and Month 60;
 
 
Table 7-2 Secondary follow-up visit evaluation schedule: Removed mentioning of local 
assessment for flow cytometry in peripheral blood; Survival follow-up phase was further 
specified as after study completion.


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Section 7.1.1 Screening phase: Assessments during the screening phase were updated to clarify 
accepted assessments performed during screening for study CTL019B2206 or performed as part 
of clinical routine.
Section 7.1.1.1 Criteria for repeating screening procedures prior to CTL019 infusion: Criteria 
to repeat screening procedures were clarified.
Section 7.1.1.2 Eligibility screening and enrollment: Enrollment process was clarified and 
confirmation of infusion in IRT was added.
Section 7.1.2 Pre-treatment phase: Timing of lymphodepleting chemotherapy visit was clarified 
and assessments to be performed during this visit were further specified. Baseline PET-CT 
assessment was moved to Lymphodepleting chemotherapy visit to further stress the assessment 
should be performed as closely before CTL019 infusion as possible.
Section 7.1.3 Infusion visit (D1): B symptom assessment was removed from the infusion visit 
to align with the baseline imaging assessment. Target dose was clarified to be 5 x 108 CTL019 
transduced cells.
Section 7.1.3 Post-infusion visit (D28 ±7d): Bone marrow biopsy in patients with CR was 
clarified to be only required if the patient had prior bone marrow involvement
Section 7.2.1 Efficacy Assessments: Reference to the response guidance was updated to refer 
to the 
.
Section 7.2.1 Efficacy Assessments: Clarification was made that imaging used to determine 
eligibility must be submitted to the IRC.
Section 7.2.1 Efficacy Assessments: Criteria for use of imaging that was taken prior to ICF was 
updated to refer to 8 weeks before screening instead of treatment
Section 7.2.1 Efficacy Assessments: Clarification was made that imaging used to determine 
eligibility must be submitted to the IRC.
Section 7.2.1 Efficacy Assessments: Wording was added to allow for imaging assessments to 
be completed at any time due to investigator’s discretion. Recommendation was made to assess 
disease status with PET-CT if progression prior to 3 months
Table 7-3 Imaging or disease assessment collection plan: Wording was updated to allow for 
baseline scan within 4 weeks of CTL019 infusion, without regard to lymphodepleting therapy
Section 7.2.2.2 Vital Signs: Requirement for triplicate blood pressure was removed
Table 7-5 Local laboratory parameters collection plan: Flow cytometry of peripheral blood B 
cell and T cell levels (secondary follow-up), and flow cytometry on peripheral blood and 
leukapheresis product was removed to be added as a central assessment
Table 7-6 Central clinical laboratory parameters collection plan: Clarification was made that 
flow cytometry refers to B and T cells. Flow cytometry on peripheral blood and leukapheresis 
product was added. Serum immunoglobulin levels was added for secondary follow-up only
Table 7-7 CTL019 pharmacokinetics by q-PCR in peripheral blood collection log: Clarification 
was made on scheduled time point relative to dosing in order to align with visit evaluation 
schedule. Unscheduled time point at time of relapse added


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Table 7-8 CTL019 pharmacokinetics by flow cytometry in peripheral blood collection log: 
Clarification was made on scheduled time point relative to dosing in order to align with visit 
evaluation schedule. Unscheduled time point at time of relapse added
Table 7-12 Immunogenicity serum sample collection log: Unscheduled time point at time of 
relapse added
Table 7-13 Immunogenicity whole blood sample collection log: Unscheduled time point at time 
of relapse added
Table 7-14 
 CTL019 Pharmacokinetics (PK), 
 
treated patients during CRS: Additional time point added at D3 after second dose. Time points 
added related to 3rd doses and more
Table 7-15 
 CTL019 PK 
 treated patients during 
CRS: New table added
 
 
 
Table 7-17, Table 7-18: Table numbers updated due to new table.
 
Section 8.1.2 Reporting: Wording on modified data capture for inpatient/in hospital events
clarified and reference made to new appendices 3 and 4.
Section 8.2.2.4 Post-treatment protocol: SAE reporting procedure was updated.
Section 8.4 Pregnancies: Requirement for male use of contraception was added to this section 
as per inclusion criteria 11. Language on IUDs was clarified.
Section 10 Statistical methods and data analysis: Primary analysis clarified to be performed on 
patients in the main cohort and changed from 6 months to 3 months.
Section 10.1.2 Enrolled Set: Wording updated to specify apheresis product only has to be 
accepted for manufacturing.
Section 10.1.4 Safety Set: Wording removed stating that the safety set contains the same 
patients as the full analysis set.
Section 10.1.5 Per-Protocol Set: Clarification was made that missing or incomplete 
documentation of disease is referring to baseline assessments. Distinction was made between 
target dose and minimum dose.
Section 10.2 Patient demographics/other baseline characteristics: Updated due to addition of 
new cohort.


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Section 10.3 Treatments (study treatment, concomitant therapies, compliance): Updated due to 
addition of new cohort.
Section 10.4 Primary Objective: Addition of wording to clarify that the primary objective is 
related to the main cohort.
Section 10.4.1 Variable: Changes were made to Table 10-1 and the text to describe how to 
incorporate PET into the overall response assessment as per the 
.
Section 10.4.3 Handling of missing values/censoring/discontinuations: Updated reference to 
Novartis guideline for efficacy evaluation in DLBCL and FL studies based on 
 
.
Section 10.5.2 Other secondary efficacy objectives: Updated due to addition of new cohort.
Section 10.5.2.7 Efficacy in cohort A: Secondary objectives relating to cohort A were added.
Section 10.5.3.4 Immunogenicity updated to be consistent at program level. Section 10.5.3.6 
Safety subgroup analysis: Wording was added to clarify that AEs will also be summarized 
separately for cohort A.
 
Section 10.5.4 Pharmacokinetics: Wording regarding descriptive statistics of key PK 
parameters for cohort A was added.
Table 10-2 Noncompartmental pharmacokinetic parameters updated to be consistent at program 
level.
 
 
Section 10.7 Interim Analysis: Wording was updated to specify that the Interim Analysis will 
be performed on patients in the main cohort when approximately 50 patients have received 
CTL019 infusion and have completed 3 months from study day 1 infusion or discontinued 
earlier.
Section 10.8 Sample size calculation: Wording was updated to specify that sample size 
calculation was performed for the main cohort.
Section 14 Appendix 1: Guidelines for efficacy evaluation in diffuse large B cell lymphoma 
and follicular lymphoma studies (based on Cheson response criteria) were updated to include 
.
Section 14 Appendix 2: Eligibility based on serologic markers for hepatitis B infection: 
Wording below table was updated for consistency and table was re-ordered for clarity
Section 14.3 Appendix 3: CTL019 modified data reporting – Treatment and Primary Follow 
Up Phase was added to provide further guidance.


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Section 14.4 Appendix 4: CTL019 modified data reporting – Secondary Follow Up Phase was 
added to provide further guidance.
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/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 3 (18-Dec-2015)
Amendment rationale
The PET-CT was specified to be performed within 4 weeks of infusion but prior to start of 
lymphodepleting therapy. During the startup of the trial it became evident that the baseline PET-
CT required at screening may often be too far out from the actual CTL019 infusion to serve as 
a valid baseline for subsequent response assessments.
In addition, it was clarified that at least one sentinel vial must be shipped together with the 
leukapheresis product.
Changes to the protocol
Protocol summary was updated to be consistent with other sections of the document.
Section 4.1 Description of study design: Wording was added to clarify the interpretation of the 
Day 28 imaging assessment.
Section 4.1.1 Leukapheresis assessment: The timing of leukapheresis was clarified and wording 
was added regarding shipment of a sample sentinel vial.
Section 5.2 Inclusion criteria: Criterion 8.e. was further specified to define an absolute number 
of CD3+ cells >150/mm3. In addition, a note regarding the apheresis product was removed.
Section 5.3 Exclusion criteria: Therapy mentioned under criterion 8 were further specified or 
removed. Exclusion criterion 18 was removed.
Section 6.1.1.2 CTL019 infusion: Requirements regarding immunosuppressive therapies were 
updated and wording was revised, for consistency.
Figure 6-2 Progressive Multifocal Leukoencephalopathy (PML): diagnosis and treatment: 
Figure was modified to include one box “Infectious disease consultation”.
Section 6.2.4.2.2 Potential toxicities: Wording regarding hepatitis reactivation was updated.
Section 6.2.7 Prohibited concomitant therapy: Allowed dose for steroids was updated for 
consistency.
Table 7-1 Primary visit evaluation schedule: Table was updated to move the PET-CT scan from 
screening to prior to start of lymphodepleting therapy; the allowed interval was added for D4 
and D7 visit; adverse events assessment was updated to be consistent with Section 8.1; HBsAb 
testing was added to viral serology; CTL019 pharmacokinetics by flow cytometry assessment 
was added to D1 visit;
Table 7-1 Primary visit evaluation schedule: Two laboratory assessments were added. “Flow 
cytometry before leukapheresis (peripheral blood)” and “flow cytometry (leukapheresis 
product)”.
Section 7.1.1 Screening phase: HBsAb testing was added to viral serology.
Section 7.1.1 Screening phase: Wording regarding flow cytometry was added.
Section 7.1.1.1 Criteria for repeating screening procedures prior to CTL019 infusion: Criteria 
to repeat screening procedures were clarified.


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Section 7.1.2 Pretreatment phase: Wording added regarding the PET-CT scan to be performed 
within four weeks prior to the scheduled infusion.
Section 7.1.3 Treatment and primary follow-up phase: Wording was added to clarify the 
interpretation of the Day 28 imaging assessment.
Section 7.2.1 Efficacy assessments: Wording was clarified regarding the PET-CT scan to be 
performed within four weeks prior to the scheduled infusion.
Table 7-3 Imaging or disease assessment collection plan: Wording clarified regarding the PET-
CT scan to be performed within four weeks prior to the scheduled infusion.
Section 7.2.2 Safety and tolerability assessments: Wording regarding requirements to repeat 
assessments during screening was removed due to duplication.
Table 7-5 Local clinical laboratory parameters collection plan: HBsAb assessment was added 
to viral serology.
Table 7-5 Local clinical laboratory parameters collection plan: Flow cytometry was added as 
additional assessment.
Table 7-8 CTL019 pharmacokinetics by flow cytometry in peripheral blood collection log: D1 
assessment was added and PK sample numbers were updated accordingly.
Table 7-14
 CTL019 Pharmacokinetics (PK), 
 
treated patients during CRS: Dose reference ID was added.
Section 8.2.2.4 Post-treatment protocol: Wording regarding long-term follow-up protocol was 
added for clarification.
Section 10.6.1.2 Data handling of Serum Cytokine Data: Wording was corrected.
Section 13 References: Two references were added.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Amendment 2 (12-Nov-2015)
Amendment rationale
The protocol was mainly amended to implement clarifications in line with health authority 
feedback and to incorporate recent experience from the University of Pennsylvania (Penn) study 
CTL019A2101J/UPCC13413.
The following modifications were implemented in the protocol:

Histological confirmation of relapse by central pathology review before enrollment was 
added on health authority request to verify that patients entering the study have 
histological relapse

“relapsed/refractory disease after ≥2 lines of chemotherapy …” was defined as “relapsed 
or refractory disease after ≥2 lines of chemotherapy, including rituximab and 
anthracycline,” to ensure patients will have received prior standard treatment regimen.

Data generated from clinical samples from study CTL019A2101J/UPCC13413 identified 
T cell/histiocyte rich large B cell lymphoma (THRBCL) as a subpopulation that is 
unlikely to derive greater benefit from treatment with CTL019. Therefore, patients with 
THRBCL will be excluded from this trial.

Based on one case of encephalitis in study UPCC13413/A2101J the DMC of study 
CTL019 recommended excluding patients with active neurological or inflammatory or 
auto immune disorders (e.g. Guillain-Barre Syndrome, Amyotrophic Lateral Sclerosis) 
from this trial. This exclusion criterion was added accordingly.

It was clarified that patients with primary cutaneous large B-cell lymphoma, primary 
mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Richter’s 
transformation, and Burkitt lymphoma are excluded as they are considered to be separate 
disease entities.
 

Contraception requirements were also clarified to better define the minimal duration of 
contraception after infusion.

Expected toxicities were updated to provide more detailed recommendations for treatment 
of cytokine release syndrome

Language regarding liver safety monitoring was added as per current Novartis standard 
and in order to ensure patients safety and enhance reliability in determining the 
hepatotoxic potential of an investigational treatment.

Pharmacokinetics and correlative objectives and endpoints were updated and clarified to 
better define the specific analysis
 


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
In general, the pharmacokinetics
sections were split for clarification.

Recommendations on vaccination were added
At time of this amendment seven patients had been enrolled. None of the enrolled patients 
would have been excluded from the trial had the amendment been in place prior to enrollment. 
Thus, the current amendment is not expected to influence the study population.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
Glossary of terms: the term “final enrollment” was specified.
Protocol summary was updated to be consistent with other sections of the document.
Section 1.2.1 Overview of CTL019: references to the Investigators Brochure were added.
Section 1.2.1.2 Clinical experience: A summary of Clinical Cellular Kinetics (Pharmaco-
kinetics) was added with current data.
Section 2.3 Rationale for dose and regimen selection: Wording was refined for clarification and 
to differentiate between target dose and allowable dose range.
 
Section 4.1 Description of study design: Study design was clarified with a more detailed figure.
Section 4.1.1 Apheresis assessment: Apheresis procedure and assessment of apheresis product 
by Novartis manufacturing was clarified.
Section 4.2 Definition of end of the study: Revision of the wording to align within the document.
Section 5 Population: The patient population was clarified based on feedback from Health 
Authorities and data generated from study CTL019A2101J/UPCC13413; contraception 
requirements were updated.
Section 6.1.1 Dosing regimen: A definition of the target dose and a description of the 
requirements for infusion of doses below the target dose were added.
Section 6.1.1.1 Lymphodepleting chemotherapy: Wording was clarified.
Section 6.1.1.2 CTL019 infusion: Requirements for influenza testing and other criteria to be 
met before CTL019 infusion were clarified; requirements for infusion of doses below the target 
dose were added to align within the document.
Section 6.1.3 Rescue medication: Rescue medication that should be available at site was further 
specified.


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Section 6.2.4.2.1 Expected toxicities: A recommendation for cardiac monitoring during 
management of Cytokine Release Syndrome (CRS) was added, the CRS Management 
Algorithm was updated to provide additional guidance and a recommendation for vaccination 
was added.
Section 6.2.4.2.2 Potential toxicities: Wording was clarified and recommendations on 
hepatitis B reactivation were added.
Section 6.2.7 Prohibited concomitant therapy: time interval for steroids and anti-proliferative 
therapies prior to infusion was clarified.
Section 6.3.2 Follow-up for toxicities: A section for liver safety monitoring was added.
Section 6.5.1 Study drug packaging and labeling: Wording was clarified.
Section 6.5.3 Study drug compliance and accountability: Wording was clarified.
Section 7.1 Study flow and visit schedule: Columns and assessments in Tables 7-1 and 7-2 were 
clarified.
Table 7-1 Primary visit and evaluation schedule: Wording on Hepatitis B reactivation was 
removed as it was a duplication of Section 6.2.4.2.2. Lines for Leukapheresis pre-evaluation 
and acceptance,
 sample descriptions for PK
samples were clarified; HBcAb testing was added to viral serology.
Section 7.1.1 Screening phase: Assessments to be performed during the screening phase were 
clarified and aligned with other sections of the document and criteria to repeat screening 
procedures prior to CTL019 infusion were aligned with Section 7.2.2.
Section 7.1.2 Pre-treatment phase: Wording regarding lymphodepleting therapy was clarified.
Section 7.1.3 Treatment and primary follow-up phase: Requirements to perform a tumor biopsy 
were clarified.
Section 7.1.5 Survival follow-up phase: Wording was revised for clarification.
Table 7-3 Imaging or disease assessment collection plan: Wording was further specified.
Section 7.2.2.5 Laboratory evaluations: Wording was revised for clarification.
Section 7.2.3 Cellular Kinetics and Pharmacokinetics: Clarifications and updated sample 
numbers were added to sample collection log tables, 
 
 
Section 8.1.4 Adverse events of special interest: Neurotoxicity and hepatic events were added 
to the section.
Section 8.2.2.3 Serious Adverse Event Reporting: Criteria for expedited SAE reporting were 
added.


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Section 8.4 Pregnancies: Contraception requirements were updated.
 
Section 10.4.4.1 Subgroup analysis: Criteria for subgroup analyses were clarified.
Section 10.5.2.1 Duration of overall response (DOR): Optional additional data summary was 
added.
Section 10.5.2.6 Efficacy in histological and molecular subgroups: subgroup of T-cell 
histiocytic-rich large B-cell lymphoma was removed due to exclusion of this subgroup.
Section 10.5.3.4 Immunogenicity: Wording was revised for clarification
Section 10.5.3.6 Safety subgroup analysis: subgroup of T-cell histiocytic-rich large B-cell 
lymphoma was removed due to exclusion of this subgroup.
Section 10.5.4 Pharmacokinetics: Wording was revised for clarification.
Section 10.6.1 Wording was revised for clarification.
Section 10.6.1.3 Basic Tables, Listings and Figures: Wording was revised for clarification.
 
Section 10.6.4 Efficacy in sub-populations: EFS was added as endpoint for the analysis.
Section 14.1 Guidelines for efficacy evaluation in DLBCL and FL studies: Analysis of PET 
results was specified.
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/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 1
Amendment rationale
As of February 2015, this study has not been initiated at any site. The main changes in the 
amendment are as follows:
An interim analysis was added once the first DLBCL 50 patients have been treated and followed 
up for 6 months. Based on the α-spending function according to Lan-DeMets (O’Brien-
Fleming), if the lower bound of 99.08% exact confidence interval for ORR is greater than 20% 
then statistical significance can be declared. If the predicted probability of success (i.e., positive 
result at the end of the study) is less than 10% then the study may be terminated due to futility.
At the beginning of the trial, a safety run-in stage will be conducted to enroll at least three 
patients to assess the acute safety profile and product characteristics of the Novartis 
manufactured CTL019 cell product.
 
The inclusion and exclusion criteria have been modified to ensure a homogenous population.
Language in the protocol has been changed to be consistent with the approved CTL019 standard 
protocol language and protocol language associated with discontinuation from the clinical trial 
has also been updated.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined font for insertions.
Section 1.2.1 Overview of CTL019: 2nd paragraph re-written to be consistent with agreed upon 
CTL019 standard protocol language. Updated reference (Maude et al 2014) added
Section 1.2.1.2 Clinical experience: Updated reference (Maude et al 2014) added. Table 1-1
Summary of ongoing human studies, updated with additional information from July 2014 to 
January 2015.
Section 2.1 Study rationale and purpose: Updated information from the University of 
Pennsylvania phase II lymphoma study added
Section 2.2 Rationale for the study design: Bendamustine added as a lymphodepleting 
chemotherapy option for those patients with cyclophosphamide resistance, language added to 
clarify that patients who either complete or discontinue from the primary follow-up phase will 
have an End of Treatment and Primary Follow-Up Visit. Language added for which section to 
refer to for more information on expected toxicities. Language added to indicate all patients 
will be asked to consent to the LTFU study. Language added for safety run-in stage.
Section 2.2.1 Rationale for lymphodepletion: Updated information from ongoing CTL019 trials 
included in regards to lymphodepleting chemotherapy.
Section 2.3 Rationale for dose regimen and selection: Updated information in regards to 
Cytokine Release Syndrome (CRS) and neurologic disturbances added.


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Section 3 Objectives and endpoints: Changes have been made to further explain and clarify the 
intended study objectives and endpoints in Table 3-1. Evaluate efficacy and safety in 
histological and molecular subgroups added as a secondary objective. The secondary objective 
“characterize the in vivo cellular PK profile” has been updated to indicate as summarized by 
clinical response, corresponding endpoint updated for clarification. 
 
 
 
Specific histological 
subtypes added to secondary objective analysis. 
 
 
 
 
 
Section 4.1 Description of study design: Language added to indicate reason why CT/MRI, PET-
CT have been added to study design. Description of safety run-in stage added.
 
 
 
Section 4.2 Definition of end of the study: New paragraph added to document that patients who 
discontinue from the primary follow-up phase will continue to be followed in the secondary 
follow-up phase to collect health authority requested data. Language added to indicate survival 
follow-up can be conducted via a form or by telephone contact.
Section 4.3 Early study termination: New discontinuation language added to protocol
Section 5.1 Patient population: Clarification to indicate approximately 100 patients enrolled to 
allow for 80 patients to be treated added
Section 5.2 Inclusion criteria: At last relapse removed from inclusion criterion #3 and criterion 
#3 updated to clarify DLBCL to be histologically confirmed by local pathology. Allogeneic 
HSCT removed from inclusion criteria #4. Absolute lymphocyte count (ALC) ≥ 300/mm3 added 
to criterion #8. 8a eGFR criterion modified and without transfusion removed from criterion 8e. 
Criterion #9 clarified to indicate must have an apheresis product accepted for manufacturing.
Section 5.3 Exclusion criteria: Histology other than DLBCL present on biopsy sample, and 
transformed indolent NHL or CLL and allogeneic HSCT removed as exclusion criteria. 
Chemotherapy and radiation therapy exclusion changed from 4 weeks prior to enrollment to 2 
weeks. Language added to clarify that chemotherapy other than lymphodepleting chemotherapy 
within 2 weeks of enrollment is an exclusion criterion. Language added to clarify that HIV 
positive patients are excluded from the study.
Section 6.1.1.2 CTL019 infusion: section modified to be consistent with CTL019 standard 
protocol language, including criteria to be met prior to infusion, infusion time and what to do 
with unused supplies. Criteria #5 updated to be consistent with DLBCL criteria. Language 


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added to indicate a study physician must evaluate the patient prior to infusion. Infusion time 
interval for CTL019 injection removed.
Section 6.1.3 Rescue medication: 
 
 
 Language added to indicate 
steroids given to treat CRS must be listed on the concomitant medication CRF.
Section 6.1.5 Treatment duration: infusion time interval of 2-20 minutes removed
Section 6.2.4.1.1 Criteria for stopping or pausing the study: Section modified to be consistent 
with CTl019 standard protocol language, no new information included and language added 
about stopping or pausing the study during the safety run-in stage added.
Section 6.2.4.2.1 Expected toxicities: Updated information from study UP13413 in regards to 
CRS added. Table 6-2 High dose vasopressor use, dosing information updated
Section 6.4.1 Patient numbering: Clarification provided to indicate center number is four digit 
followed by a three digit patient number
Section 6.5.3 Study drug compliance and accountability: Section updated to be consistent with 
CTL019 standard protocol language
Section 6.5.3.2 Study drug accountability: Verbiage deleted and added to section 6.5.3 to be 
consistent with CTL019 standard protocol language
Section 6.5.4 Study drug disposal and destruction: Section title updated and additional language 
added to refer to product handling manual
Section 7.1 Study flow and visit schedule: Table 7-1 Primary visit evaluation schedule has been 
updated. Antineoplastic therapies after CTL019 infusion indicated after D2 until M60. Imaging 
updated to indicate at M3 if no PET CT and M6. Language added to CRS assessments to 
indicate to refer to additional tables in protocol. Language added to clarify peripheral blood 
assessments. CTL019 pharmacokinetics by flow cytometry (peripheral blood) added as a study 
assessment. 
 CTL019 PK by flow cytometry 
removed from Peripheral blood-central assessment, additional peripheral blood central 
assessment added at day 11. 
 
 Survival follow-up updated 
to start after day 2.
Section 7.1.1 Screening phase: Clarification provided to indicate central pathology assessment 
and central subtype determination not part of the medical history. Language added to clarify 
FDG PET should be a dedicated machine. Language added to viral serology to indicate that if 
the HIV test is positive at screening than a confirmatory HIV test is to be performed as per 
current local guidelines.
Section 7.1.1.1 Rescreening: ECHO/MUGA to be repeated after 6 weeks, and additional 
clarifications per the CTL019 standard protocol language added.
Section 7.1.1.2 Eligibility screening and enrollment: Verbiage has been removed in regards to 
confirming clinical eligibility since this will be done via IRT.


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Section 7.1.2 Pre-treatment phase: Section updated to be consistent with CTL019 standard 
protocol language and also clarifications on timing intervals for lymphodepleting chemotherapy 
updated for DLBCL patients. Language added to indicate that additional frozen samples from 
the apheresis material as well as the CTL019 product will be collected at the manufacturing site 
for correlative studies.
Section 7.1.3 Treatment and primary follow-up phase: 
 
 
Language added to clarify FDG 
PET should be a dedicated machine at the site. Additional language added for clarification on 
survival follow-up every 3 months.
Section 7.1.3.1 End of treatment and primary follow-up (EOT) visit (M60 ±14d) including 
premature withdrawal: Language added to indicate that the patient will be followed for survival 
until the end of this study or the patient enrolled in the long term follow-up (LTFU) study, 
whichever comes first.
Section 7.1.4.1 Criteria for premature patient withdrawal from the study: Language added to 
provide additional information on research results and biological samples.
Section 7.1.5 Survival follow-up phase: Language added to indicate survival status can be 
obtained via phone contact
Section 7.1.7 Discontinuation of study treatment: Section added to be consistent with new 
discontinuation language.
Section 7.1.8 Withdrawal of consent: Section added to be consistent with new discontinuation 
language.
Section 7.1.9 Follow-up for safety evaluations: Section added to be consistent with new 
discontinuation language.
Section 7.1.10 Lost to follow-up: Section added to be consistent with new discontinuation 
language.
Section 7.2.1 Efficacy assessments: Clarification added that efficacy evaluation will be done in 
all lymphomas, not just DLBCL. Language added to describe process to be followed for 
radiological imaging and what will be centrally reviewed by the IRC. Language added to clarify 
central lab is responsible for pathology assessment and molecular subtype determination. 
Randomization changed to enrollment. Language added to indicate acceptable imaging 
modalities for the study.
Section 7.2.2.1 Physical examination: Wrong CRF page originally indicated, updated with 
correct CRF page
Section 7.2.2.5 Laboratory evaluations: Table 7-5 updated to indicate if an initial HIV screening 
test is positive then a confirmatory HIV test is required to be performed as per current local 
guidelines. 
 


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Section 7.2.3 Pharmacokinetics: Table 7-7 updated with additional clarifications. A new table 
inserted for CTL019 pharmacokinetics by flow cytometry in peripheral blood collection log. 
Sample volume updated in Table 7-12 from 6 mL to 10 mL. Table 7-14
 CTL019 
PK 
treated patients updated. 
 
 Language removed to indicate that the D-1 aliquot will be collected pre-infusion.
 
 
 
 
 
 
Section 8.1.2 Reporting: The word “documented” deleted to indicate all infections are to be 
recorded in adverse events CRF. Language added to clarify that regardless of causality all lab 
abnormalities deemed clinically significant, will be recorded in the Adverse Events CRF. 
Language added to indicate within 28 days after CL019 infusion patients will require multiple 
days of ICU care
Section 8.1.4 Adverse events of special interest: Language added to indicate that adverse events 
of special interest may require further investigation. Clarification in regards to current defined 
AESIs for CTL019 and definitions may be updated as new data arises.
Section 8.2.2 Reporting: Section updated to be consistent with approved CTL019 standard 
protocol language, reporting procedures are now clarified by what is required at the different 
study phases, screening/pre-treatment, study-related treatment to Month 12, Month 12 to Month 
60, and post-treatment.
Section 8.4 Pregnancies: Language added to clarify that each pregnancy occurring once patient 
has been infused with CTL019 must be reported within 24 hours. Language updated to be 
consistent with the approved CTL019 standard protocol language. In case of live birth, 
newborns will now be followed for 6 months instead of 3.
Section 8.6 Data Monitoring Committee: language added to section to indicate DMC will 
review data related to interim analysis and safety data at regular intervals.
Section 10.4.1 Variable: change has been made in regards to best overall disease response of 
progressive disease from 12 weeks to 14 weeks after CTL019 infusion as per the Novartis 
modified Cheson criteria.
Section 10.5.2.2 Event free survival (EFS): Adequate assessments no longer available added as 
a censoring reason.
Section 10.5.2.6 Efficacy in histological and molecular subgroups: Section added for 
clarification.
Section 10.5.3.2 Adverse Events (AEs): Section indicated that AESIs will be updated prior to 
reporting and Table 10-2 removed


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Section 10.5.3.6 Safety subgroup analysis: histological and molecular subgroups added to 
analysis
Section 10.5.4 Pharmacokinetics: Updated to include language about what q-PCR generated 
CTL019 concentrations will be displayed graphically. “Mass x time x volume -1” removed from 
Table 10-2 noncompartmental pharmacokinetic parameters. 
 
 
Section 10.6.1.3 Basic Tables, Listings and Figures: Language about CTL019 protein detection 
reagent removed. Language about analysis of leukocyte transcriptome analysis added.
 
 
Section 10.7 Interim analysis: New section to protocol amendment, an interim analysis has been 
added when approximately 50 of the planned 80 patients have received their infusion and 
completed 6 months from study day 1 infusion or discontinued earlier. Table 10-3 included to 
describe the simulated scenarios for interim analysis and final analysis.
Section 10.8 Sample size calculation: Language updated to clarify the rationale for sample size 
calculation
Section 13 References: additional references included in the protocol amendment including; 
(Lan and Demets 1983), (Maude et al 2014)
IRB/IEC/REB Approval
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/ 
Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein affect the informed consent. Sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this protocol amendment.


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Protocol summary:
Protocol number
CCTL019C2201
Title
A Phase II, single arm, multicenter trial to determine the efficacy and safety of 
CTL019 in adult patients with relapsed or refractory DLBCL
Brief title
Study of efficacy and safety of CTL019 in adult DLBCL patients
Sponsor and 
Clinical Phase
Novartis
Phase II Multicenter
Investigation type
Biological
Study type
Interventional
Purpose and rationale
DLBCL is the most frequent lymphoma subtype, representing 30-35% of all non-
Hodgkin lymphomas (NHL). Two-thirds of patients are cured by a combination of 
chemotherapy agents ± radiotherapy in addition to rituximab, but one-third of patients 
have disease that is either refractory to initial therapy or relapses after standard 
therapy. Whether patients refractory to a rituximab-containing regimen should be 
retreated with rituximab is currently unknown based on available data. Relapsed and 
refractory patients have a poor prognosis, particularly those who do not respond to 
2nd line chemotherapy. The median survival of patients non-responding to 2nd line 
chemotherapy is 4 months and only 4% are alive after 1 year. For patients relapsing 
with chemotherapy-sensitive disease, high-dose chemotherapy followed by 
autologous hematopoietic stem cell transplantation (HSCT) provides the best chance 
of cure. However, due to advanced age and comorbidities, only half of all patients 
are eligible for such an intensive approach. Yet, only a modest minority of patients 
undergoing HSCT are cured. In summary, treatment options for patients who do not 
respond to 2nd line chemotherapy or who relapse after autologous HSCT are 
generally considered palliative. Novel therapies are urgently needed for this patient 
population.
The B-cell marker CD19 has emerged as a target for DLBCL treatment in the past 
years. 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 vast majority 
of DLBCL expresses CD19. Autologous T cells have been developed that are 
genetically modified ex-vivo via a lentiviral transduction to express a chimeric antigen 
receptor (CAR) consisting of a CD19 antigen recognition domain attached to 
intracellular signaling domains that mediate T-cell activation. Data from patients with 
B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), 
which are both CD19 expressing B cell malignancies, and preliminary data from 
patients with DLBCL show that CTL019 therapy has potent anti-tumor activity.
The purpose of this study will be to determine the safety and efficacy of CTL019 in 
adults with relapsed or refractory DLBCL and to monitor all patients exposed to 
CTL019 for 5 years following CTL019 infusion.
Primary Objective(s) 
and Key Secondary 
Objective
To evaluate the efficacy of CTL019 therapy, defined as overall response rate (ORR), 
which includes complete response (CR) and partial response (PR) based on the 
as determined by a central 
independent review committee. (Cheson et al 2014)
Secondary Objectives

Evaluate safety of CTL019

Evaluate time to response (TTR)

Evaluate duration of overall response (DOR)

Evaluate event free survival (EFS)

Evaluate progression free survival (PFS)

Evaluate overall survival (OS)

Evaluate safety and efficacy in histological and molecular subtypes

Characterize the in vivo cellular PK profile (levels, persistence, trafficking) of 
CTL019 transduced cells into target tissues (blood, bone marrow, cerebral spinal 
fluid (CSF) and other tissues if available)

Describe the incidence of immunogenicity to CTL019

Describe presence of RCL


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Study design
This is a single arm, open-label, multi-center, phase II study to determine the efficacy 
and safety of CTL019 in patients ≥ 18 years with relapsed or refractory diffuse large 
B-cell lymphoma (DLBCL). The study will have the following sequential phases: 
Screening, Pre-Treatment, Treatment and Primary follow-up, Secondary follow-up, 
and Survival follow-up. The total duration of the study is 5 years. Efficacy will be 
assessed until progression; safety will be assessed throughout the full duration of the 
study. Patients will be monitored for delayed adverse events for up to 15 years after 
last CTL019 infusion in a separate destination protocol per the health authority 
guidelines. Approximately 100 patients will be enrolled to allow for 80 patients to be 
treated in the main study cohort. Further to this main cohort an additional cohort 
(Cohort A) will evaluate the impact of manufacturing site on clinical outcome.
Approximately 18 patients will be enrolled in the additional cohort to allow for 15
patients to be treated. This cohort will assess the clinical profile (safety and efficacy, 
PK) of CTL019 manufactured at the Fraunhofer Institut für Zelltherapie (Leipzig, 
Germany). After the amendment 5 of the protocol, approximately 10 additional 
Japanese patients will be enrolled, to allow for at least 6 additional patients to be 
treated (total 9 treated in Japan).
At the beginning of the trial, a safety run-in stage will be conducted to enroll at least 
three patients to assess the acute safety profile and product characteristics of the 
Novartis manufactured CTL019 cell product. The initial patients will be enrolled in this 
trial subsequently with minimum interval between CTL019 infusions of 14 days. Full 
safety profiles and product characteristics of these patents following lymphodepleting
chemotherapy and CTL019 infusion will be reported to the Health Authorities.
Population
The target population is comprised of adults ≥ 18 years with relapsed or refractory 
DLBCL not eligible for HSCT. A minimum of 25 patients in each of the two most 
common molecular subtypes of DLBCL: GC and ABC type will be treated in the main 
cohort. 
Inclusion criteria
1. Written informed consent must be obtained prior to any screening procedures
2. Patients must be ≥18 years of age
3. Histologically confirmed DLBCL (by central pathology review before enrollment).
a. Sufficient FFPE tumor samples must be available for histological and 
molecular subtype testing along with a corresponding pathology report. A 
recent tumor sample obtained for the purpose of this study must be submitted 
however if not clinically feasible, an archival tumor biopsy from the most 
recent relapse may be submitted instead. Excisional biopsies should be 
submitted wherever possible; in cases where this is not possible, a core 
needle biopsy is allowable. Fine needle aspiration (FNA) is not allowed.
4. Relapsed or refractory disease after ≥2 lines of chemotherapy, including rituximab 
and anthracycline, and either having failed autologous HSCT, or being ineligible 
for or not consenting to autologous HSCT
5. Measurable disease at time of enrollment:
a. Nodal lesions greater than 20 mm in the long axis, regardless of the length of 
the short axis
b. Extranodal lesions (outside lymph node or nodal mass, but including liver and 
spleen) ≥ 10 mm in long AND short axis
For detailed information please refer to Section 14.1 Appendix 1: Guidelines for 
efficacy evaluation in diffuse large B cell lymphoma and follicular lymphoma studies 
6. Life expectancy ≥12 weeks
7. ECOG performance status that is either 0 or 1 at screening
8. Adequate organ function:
a. Renal function defined as:
●
A serum creatinine of ≤1.5 x ULN OR
●
eGFR ≥ 60 mL/min/1.73 m2
b. Liver function defined as:
●
ALT ≤ 5 times the ULN for age


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●
Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert–
Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome 
may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 
1.5 x ULN
c. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 
dyspnea and pulse oxygenation > 91% on room air
d. Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or 
MUGA
e. Adequate bone marrow reserve without transfusions defined as:
●
Absolute neutrophil count (ANC) > 1.000/mm3
●
Absolute lymphocyte count (ALC) > 300/mm3, and absolute number of 
CD3+ T cells >150/mm3
●
Platelets ≥ 50.000//mm3
●
Hemoglobin > 8.0 g/dl
9. Must have an apheresis product of non-mobilized cells accepted for 
manufacturing
10. Women of child-bearing potential, defined as all women physiologically capable 
of becoming pregnant, and all male participants must use highly effective 
methods of contraception for at least 12 months following CTL019 infusion and 
until CAR T cells are no longer present by PCR.
Highly effective contraception methods include:
●
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception
●
Female 
sterilization 
(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.
●
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.
●
BOTH of the following forms of contraception must be utilized:
a. 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 hormonal vaginal ring or transdermal hormonal 
contraception AND
b. Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
●
Use of intrauterine devices (IUDs) is excluded due to increased risks of infection 
and bleeding Placed IUDs may remain in place but additional measures of 
contraception are mandated. Additionally, drugs that induce cytochrome P450 
(CYP) enzymes can increase the clearance of sex hormones that are eluted by 
the devices and reduce contraceptive efficacy; given the poly-pharmacy for these 
patients this presents a real risk of device failure and possible resultant 
inadvertent conception.
●
In case of use of oral contraception women should have been stable on the same 
pill for a minimum of 3 months before taking study treatment.
11. Sexually active males must use a condom during intercourse for 12 months the 
tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR 
on two consecutive tests. qPCR test results will be available upon request. A 
condom is required for all sexually active male participants to prevent them from 
fathering a child AND to prevent delivery of study treatment via seminal fluid to 
their partner after treatment as they should not father a child in this period. A 
condom is required to be used also by vasectomized men (as well as during 
intercourse with a male partner or sterile female partner) as WBCs are a normal 
part of semen and transmission of CTL019 transduced cells may occur.


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Exclusion criteria
1. Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 
therapy
2. Treatment with any prior gene therapy product
3. Active CNS involvement by malignancy
4. Prior allogeneic HSCT
5. Eligible for and consenting to autologous HSCT
6. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of 
infusion
7. Investigational medicinal product within the last 30 days prior to screening
Note: Investigational therapies must not be used at any time while on study until the 
first progression following CTL019 infusion
8. The following medications are excluded:
●
Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to
leukapheresis and > 72 hours prior to CTL019 infusion. However, the following 
physiological replacement doses of steroids are allowed: <12 mg/m2/day 
hydrocortisone or equivalent
●
Immunosuppression: Any immunosuppressive medication must be stopped ≥ 2
weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could 
include check point inhibitors (monoclonal antibodies and small molecule 
modulators).
●
Antiproliferative therapies other than lymphodepleting chemotherapy within 2 
weeks of leukapheresis and 2 weeks prior to infusion
●
Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase 
inhibitors, and hydroxyurea) must be stopped > 72 hour prior to leukapheresis 
and > 72 hours prior to CTL019 infusion
●
Other cytotoxic drugs, including low dose daily or weekly maintenance 
chemotherapy, must not be given within 2 weeks prior to leukapheresis and 
within 2 weeks prior to CTL019 infusion.
●
Fludarabine may be associated with prolonged lymphopenia. This should be 
taken into consideration when evaluating the optimal timing for leukapheresis.
●
Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 
half-lives of the respective antibody, whichever is longer. Note: Rituximab is 
excluded within 4 weeks prior to infusion
●
CNS disease prophylaxis must be stopped > 1 week prior to CTL019 infusion 
(e.g. intrathecal methotrexate)
9. Prior radiation therapy within 2 weeks of infusion
10. Active replication of or prior infection with hepatitis B or active hepatitis C (HCV 
RNA positive)
11. HIV positive patients
12. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood 
culture positive ≤ 72 hours prior to infusion)
13. Unstable angina and/or myocardial infarction within 6 months prior to screening
14. Previous or concurrent malignancy with the following exceptions:
●
Adequately treated basal cell or squamous cell carcinoma (adequate wound 
healing is required prior to study entry)
●
In situ carcinoma of the cervix or breast, treated curatively and without evidence 
of recurrence for at least 3 years prior to the study
●
A primary malignancy which has been completely resected and in complete 
remission for ≥ 5 years
15. Pregnant or nursing (lactating) women
16. Intolerance to the excipients of the CTL019 cell product
17. Cardiac arrhythmia not controlled with medical management
18. Removed
19. Prior treatment with any adoptive T cell therapy


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20. Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary 
cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma 
(PMBCL), EBV positive DLBCL of the elderly, Richter’s transformation, and 
Burkitt lymphoma
21. Patients with active neurological auto immune or inflammatory disorders (e.g. 
Guillain-Barre Syndrome, Amyotrophic Lateral Sclerosis)
Investigational and 
reference therapy
A single target dose of 5 x 108 of viable autologous CTL019 transduced T cells will 
be administered via intravenous infusion.
Efficacy assessments
Imaging (CT or MRI, PET-CT or dedicated PET), physical examination, bone 
marrow biopsy, B-Symptoms
Safety assessments
Adverse events and laboratory anomalies (type, frequency and severity)
Selected adverse events
Immunogenicity assessments (Humoral and cellular)
Detection of replication competent lentivirus
Detection of monoclonal or oligoclonal vector integration 
PKs
Pharmacokinetic assessments planned for this trial include:

Characterization of CTL019 PK (e.g. Cmax, Tmax, AUCs, etc.) in blood, bone 
marrow and other relevant tissues if available by quantitative Polymerase Chain 
Reaction (qPCR) and/or flow cytometry.
Data analysis
Primary endpoints:
The primary analysis will be carried out after 80 treated patients have completed at 
least 3months of follow-up or have discontinued due to any reason. Selected 
efficacy and safety analysis will be updated annually. A final Clinical Study Report 
(CSR) will be produced once all patients complete or discontinue from the study. 
The primary efficacy endpoint, ORR will be analyzed based on the data observed 
by IRC in the full analysis set (FAS). 
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 that the 
ORR is greater than 20% at overall one-sided 2.5% level of significance, powered 
for ORR of 38%. The ORR will be summarized along with the 2-sided 95% exact 
Clopper-Pearson confidence intervals. 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.
Sensitivity analyses will be performed on the Enrolled Set, the per-protocol set 
(PPS) and with all patients who satisfy all clinical eligibility criteria (excluding the 
inclusion criteria that pertains to the patient’s accepted apheresis product) using the
same method as described above. Additional sensitivity analysis will be performed 
using the ORR as assessed by local investigators in the FAS population.
One interim analysis is planned when approximately 50 patients with DLBCL are 
treated and followed up for 3 months. If the lower bound of 99.08% exact 
confidence interval for ORR is greater than 20% then statistical significance can be 
declared. If the predicted probability of success (i.e., positive result at the end of the 
study) is less than 10% then the study may be terminated due to futility.
Secondary endpoints:
Analysis of secondary 
 endpoints will be descriptive and may include 


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summary statistics such as means, standard deviations, 95% confidence intervals, 
if applicable, Kaplan-Meier curves and median time to event will be presented for 
time-to-event variables (DOR, TTR, EFS, PFS and OS), if appropriate. 
Pharmacokinetics parameters will be descriptively summarized and will include 
geometric and arithmetic means, SD, CV% and CV% geometric-mean, median, 
minimum, and maximum (for Tmax only median, minimum and maximum will be 
presented). PK parameters will be summarized by best overall response.
Sample size: In two retrospective studies in relapsed and refractory DLBCL patients 
receiving 2nd or 3rd line therapies, the observed ORR were 14% and 20% 
(Seshadri et al 2008, Elstrom et al 2010). In a recent prospective clinical trial with 
ibrutinib in patients who had a median of 3 prior lines of therapy, the ORR in the 
ABC subtype (N=29) was 40% and in the GC subtype (n=20) 5% leading to an 
overall ORR of 21.7% (Wilson et al 2012).
Based on the null hypothesis of ORR ≤ 20% and alternative hypothesis of 
ORR>20%, 80 patients in the primary analysis will provide 94% power to 
demonstrate statistical significance at one sided 0.025 level of significance, if the 
underlying ORR is 38%. In this setting, an ORR of 24/80=30% will be needed to 
claim success.
Assuming approximately 20% enrolled patients will not be infused due to reasons 
such as 
, worsening of patient’s condition, etc., at least 100 
patients need to be enrolled to ensure 80 patients are treated.
Key words
Relapsed/refractory DLBCL, CTL019


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Non-Hodgkin Lymphomas (NHL) comprise a heterogeneous group of malignancies. Estimated 
new cases are 70,800 and deaths are 18,990 in the United States (US) for 2014 (National Cancer 
Institute 2014). There were 66,371 lymphoid malignancies registered in 2000-2002 by 44 
European cancer registries (Sant et al 2010). NHL are classified according to the current WHO 
classification (WHO 2008) into immature lymphoid neoplasms, mature B-cell neoplasms, T-
cell and NK-cell neoplasms, and post-transplant lymphoproliferative disorders (PTLD). Mature 
B-cell lymphomas are further classified into indolent lymphomas (e.g. multiple myeloma, CLL) 
and aggressive lymphomas (e.g. diffuse large B-cell lymphoma (DLBCL). DLBCL is the most 
frequent lymphoma subtype, representing 30-35% of all non-Hodgkin lymphomas (NHL) 
(Ghielmini et al 2013). Estimated incidence in the European Union is 3–4/100 000/year, 
increasing with age from 0.3/100 000/year (35–39 years) to 26.6/100 000/year (80– 84 years) 
(Tilly H 2012). About 10,000 deaths per year are due to DLBCL in the US (National Cancer 
Institute).
Most patients with localized DLBCL can be cured with conventional combination immuno-
chemotherapy or with combined–modality therapy. For patients with advanced-stage disease, 
the majority of patients can be cured with doxorubicin-based combination chemotherapy and 
rituximab (e.g. R-CHOP). Prognosis depends on individual risk factors. The International 
Prognostic Index (IPI) for aggressive NHL (diffuse large cell lymphoma) includes five 
significant risk factors prognostic of OS:
1. Patient age (≤60 years vs. >60 years)
2. Serum lactate dehydrogenase (LDH) (normal vs. elevated)
3. ECOG performance status (0 or 1 vs. 2–4)
4. Stage (stage I or stage II vs. stage III or stage IV)
5. Extranodal site involvement (0 or 1 vs. 2–4)
Patients with ≥2 risk factors after age-adjustment have a poor prognosis with a 5 year OS-rate 
of 21-46%. Age- and stage-adjusted modifications are used for younger patients with localized 
disease (Moller et al 2013). Very recently a revised IPI, the NCCN-IPI, has been proposed to 
better reflect the individual patient’s risk in the rituximab era. Very similar to the original IPI, 
five prognostic factors were identified:
1. Patient age (>40 to ≤60 vs. >60 to ≤75 vs. >75 years)
2. Normalized serum LDH (>1 to ≤3 vs. >3 x ULN)
3. ECOG performance status (≥2)
4. Ann Arbor Stage (Stage ≥III)
5. Extranodal site involvement (Disease in bone marrow, CNS, liver/GI tract, or lung)
The NCCN-IPI can discriminate four prognostic groups: low (0-1), low-intermediate (2-3), 
high-intermediate (4-5), and high (6-8).
DLBCL is a heterogeneous disease with several molecular subtypes. Subtypes were identified 
by molecular profiling based on biologic similarity to normal stages of B-cell development, 


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dividing DLBCL into germinal center-like (GC), activated B-cell-like (ABC) tumors, and 
primary mediastinal large B cell lymphoma (PMBCL) (Lenz et al 2008) (Alizadeh et al 2000). 
The turnaround time for gene expression profiling (GEP) is not useful for initiation of therapy 
in most DLBCL patients. There are immunohistochemistry (IHC) algorithms, which 
approximate the GEP. These IHC models predict a 3-year overall survival (OS) of 85% in GC 
tumors compared to 65% in ABC tumors (Hans et al 2004).
Despite overall improvement in outcomes of DLBCL, approximately one-third of patients will 
develop relapsed/refractory (r/r) disease that remains a major cause of morbidity and mortality. 
Refractory disease is defined as a <50% decrease in lesion size with induction therapy or the 
appearance of new lesions (Cheson et al 2007). Progressive or relapsed disease reflects the 
appearance of new lesions after attainment of complete remission (CR) (Cheson et al 2007). 
Relapsed and refractory patients have a poor prognosis, particularly those who do not respond 
to 2nd line chemotherapy (Friedberg 2011). Left untreated, life expectancy is 3 to 4 months, 
similar to what is seen in patients not responding to 2nd line chemotherapy (Elstrom et al 2010).
While approximately 60% of patients with r/r DLBCL remain sensitive to conventional 2nd-line 
salvage immunochemotherapy, <10% have prolonged disease-free survival. (Gisselbrecht et al 
2010) Patients with r/r DLBCL responding to 2nd-line immunochemotherapy and undergoing 
subsequent high-dose chemotherapy and stem cell transplantation (HSCT) maintain their 
response over longer time (3-year PFS 39% in patients with HSCT vs. 14% for patients without 
HSCT) (Gisselbrecht et al 2010) (Sehn 2012). Patients relapsing within 12 months of rituximab-
containing 1st-line therapy have a particularly poor prognosis even with HSCT (Gisselbrecht et 
al 2010). Without HSCT, chemotherapy provides only short-term disease control in r/r DLBCL. 
For transplant candidates who fail second line therapy or who relapse post-transplant, prognosis 
is grave. Molecular analysis of biopsies from the CORAL trial in 2nd line DLBCL (Gisselbrecht 
et al 2010) showed equal distribution of GC vs. non-GC DLBCL (Thieblemont et al 2011).
In summary, treatment options for patients who do not respond to 2nd line salvage therapy or 
who relapse after autologous HSCT are only palliative and overall survival (OS) is 3-4 months. 
Novel therapies are urgently needed for this patient population.
Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a key component of B 
cell receptor (BCR) signaling has preferential activity in the ABC subtype. The survival of ABC 
but not GC DLBCL cell lines is sustained by "chronic active" B cell receptor (BCR) signaling. 
Gain-of-function mutations affecting the BCR subunit CD79B occur in 21% of ABC but only 
5% of GC DLBCL tumors. An open-label Phase II study (NCT01325701) with ibrutinib in 
patients who had a median of 3 prior lines of therapy, reported an ORR in the ABC subtype 
(N=29) of 40% compared to 5% in the GC subtype (n=20) leading to an overall ORR of 21.7% 
(Wilson et al 2012). Rituximab, a chimeric monoclonal antibody against CD20, improves the 
survival of both the GC and non-GC subtypes analyzed by Hans algorithm (Fu et al 2008). 
Based on current experience, CTL019 is expected to be effective in the different molecular 
DLBCL subtypes.
1.1.1
Historical experience with retroviral gene therapies
To date, malignant cell transformation after vector-mediated insertional mutagenesis has been 
observed in three clinical entities (X-linked Severe Combined Immunodeficiency [SCID-X1], 
Chronic Granulomatous Disease [CGD], and Wiskott-Aldrich Syndrome [WAS]) which have 


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involved the use of first-generation gamma-retroviral vectors harboring long terminal repeats 
(LTRs) with strong enhancer/promoter sequences (Hacein-Bey-Abina et al 2003, Howe et al 
2008, Boztug et al 2010, Stein et al 2010, Persons and Baum 2011). In contrast, data from 
lentiviral vector trials have demonstrated more polyclonal patterns of vector insertion (Cartier 
et al 2009, Biffi et al 2011), with the exception of the first patient reported from a thalassemia 
trial (Cavazzana-Calvo et al 2010). Importantly, despite a very high transduction efficiency 
achieved using lentiviral vectors, molecular clonality studies have not indicated any reasons for 
concern, to date, in published clinical trials (Schambach et al 2013).
Retroviral vectors are useful gene delivery vehicles because they insert a deoxyribonucleic acid 
(DNA) copy of their genome into the host cell. However, insertion of vector sequences is 
distributed throughout the cellular genome and insertion has the potential to up-regulate, 
dysregulate, or knockout local gene expression. Thus, there has always been a theoretical risk 
of insertional oncogenesis resulting from disruption of normal function of genes that control 
cell growth. This risk has been realized in a clinical trial utilizing murine-derived retroviral 
vectors to transfer the γ signaling chain to stem cells of infants with SCID-X1 (Hacein-Bey-
Abina et al 2003). A total of 4 of 9 children in that trial have developed integration site-induced 
cancers, and one of those children died after relapse. In a parallel study where the same disease 
load and target cells were used, no tumorigenesis was observed at first, suggesting that minor 
differences, such as vector envelope and stem cell growth factors, might be relevant in long 
term safety of integrating vectors (Gaspar et al 2004). However, in December of 2007, one of 
the 10 children treated in that study also developed insertion-mediated oncogenesis (Howe et al 
2008). Today, the causes of insertional oncogenesis remain poorly understood, but in the SCID-
X1 studies, a common integration site, LMO-2, is observed in at least 3 of the 5 patients. In 
general, the target cell, vector, and disease payload are considered major factors contributing to 
the risks of vector-induced tumors. However, there is insufficient data to date to support the 
relative contribution of each of these factors in assuring safety of retroviral gene transfer.
Lentiviral vectors are a major subset of retroviral vectors, but demonstrate distinct integration 
patterns compared to oncoretroviral vectors which have been the predominant vector to date for 
gene transfer studies. The integration pattern of lentiviral vectors tends to be inside active 
transcription units as opposed to upstream in the locus control region where the insertion would 
have a greater chance of up-regulating gene expression. In addition, lentiviral vectors have no 
enhancer activity in their long terminal repeat (LTRs) regions and have lower levels of poly-A 
read-through, all factors which may improve gene transfer safety (Zaiss et al 2002). Thus, it 
may be that lentiviral vectors are a safer alternative to oncoretroviral vectors for gene transfer. 
Animal models have provided supporting evidence for this (Montini et al 2006). As lentiviral 
vectors are also superior for gene transfer, it is anticipated that these vectors will ultimately 
replace oncoretroviral vectors for stable gene transfer.


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In direct contrast to oncoretroviral vectors, lentiviral vectors have not been shown to be 
oncogenic in nature except for a single study in neonatal mice where direct injection for liver 
delivery was performed (Themis et al 2005). The oncogenesis in this study may be associated 
with a vector element that can be modified to reduce such a risk (Schambach et al 2006), and 
also may be unique to the animal model used in that study. A newer study in tumor prone mice 
comparing the tumorigenicity of retroviral vectors to lentiviral vectors demonstrated that 
lentiviral vector gene transfer into hematopoietic stem cells of up to an average of 6 copies per 
cell was not tumorigenic in contrast to retroviral vectors at an average copy number of 3 per 
cell (Montini et al 2006). It is notable that T cell leukemia is not a recognized side effect of 
human immunodeficiency virus (HIV) lentiviral infection.
More recently, retroviral and lentiviral safety has been demonstrated in modified T cell gene 
therapy trials. A long-term retrospective study of >500 patient-years of collective patient 
samples tested for at least 11 years after infusion from three clinical trials using gamma-
retroviral modified T cells to express CD4zeta chimeric antigen receptor (CAR) did not show 
evidence of transgene silencing, atypical gamma-retroviral integration patterns, or clonal 
expansion (Scholler et al 2012). A favorable safety profile was also determined for a 
conditionally replicating HIV-derived lentivirus that delivered HIV envelope antisense to 
patient T cells. In two separate treatment cohort analyses, no evidence for insertional 
mutagenesis or enrichment of vector copies near proto-oncogenes was observed (Levine et al 
2006, and Wang et al 2009). These data represent follow-up after 21-36 months (Levine et al 
2006) and 28-32 weeks (Wang et al 2009). Another group reported no apparent risk of vector 
related AEs following 263 infusions of autologous, lentiviral transduced T cells with a long 
ribonucleic acid (RNA) antisense to HIV-1 envelope (McGarrity et al 2013). More recently ex 
vivo lentiviral transduced hematopoietic stem cells were used to correct an inherited storage 
disease in three children and in an inherited WAS in 3 children with follow up for up to 24 
months and 20-32 months, respectively. Lentiviral integration studies showed sustained gene 
marking with polyclonal engraftment of transduced cells with no evidence of aberrant clonal 
expansion, no evidence of in vivo selection of clones carrying integrations near oncogenes and 
therefore no evidence of vector-induced genotoxicity (Biffi et al 2013, Aiuti et al 2013).
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of 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).
Adoptive T-cell therapy for cancer involves the infusion of native or genetically modified 
mature T cells that have the capacity to recognize and possibly eliminate the patient’s malignant 
cells. In particular, chimeric antigen receptor-based approach involves engineering T cells with 
sequences that encode antibody-based antigen recognition moieties linked to signaling domains. 


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Unlike T cell receptors (TCR), CARs allow the T cells to specifically target and destroy tumor 
cells in a Major Histocompatibility Complex (MHC) independent manner (Mellman et al 2011).
A promising target antigen for B cell malignancies is CD19, a cell-surface protein whose 
expression is restricted to B cells and their precursors (Sadelain et al 2003, 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, 4-1BB plus 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 
transfected 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) joined by a peptide linker of about 15 residues in length (Mullaney 
et al 2001).
Figure 1-1
CTL019 chimeric antigen receptor design


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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 et al 
2014). It is anticipated that CTL019 may offer a therapeutic alternative for patients with r/r B 
cell malignancies, including DLBCL, 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. For further information refer to the [CTL019 Investigator’s 
Brochure].
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).
1.2.1.2
Clinical experience
At the National Cancer Institute, 10 patients with NHL (4 DLBCL, 4 PMBCL, 2 low grade 
lymphomas) have received CAR modified CTLs directed against CD19. (Recombinant DNA 
Advisory Committee (RAC) meeting 2013). Response rate was 70% (DLBCL: 1 CR, 2 PR, 1 
SD; PMBCL: 1 CR, 1 PR, 1 SD, 1 NE; Other: 2 PR). At the University of Pennsylvania 
(UPENN), a Phase II trial with CTL019 in 30 heavily pretreated, relapsed/refractory NHL 
patients including 9 with DLBCL has started in January 2014. To date fourteen patients (9 
DLBCL, 5 FL) have been treated with CTL019. Most patients had early clinical responses, with 
2 out of 2 patients evaluated with CT showing PET-negative CRs. One patient progressed 
before response assessment. In ALL, across both children and adults, more than 85% of patients 
have achieved a complete response (CR) within 28 days of infusion (Grupp SA 2013, 
unpublished data as of February 19th, 2014). In CLL, the response rate has been lower, and no 
relapses have yet been observed in patients who achieve CR (Porter DL 2013, unpublished data 
as of February 19th, 2014).In patients with severe CRS, tocilizumab was administered with rapid 
(within hours) resolution of fevers and hemodynamic instability. Patients achieving a complete 
remission (CR) also experienced B-cell aplasia and hypogammaglobulinemia, which was 
supported with periodic intravenous immune globulin infusions (Grupp et al 2013). For further 
information refer to the [CTL019 Investigator’s Brochure].


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There are currently 5 ongoing human treatment studies using CTL019 therapy (Table 1-1).
Results from these ongoing clinical trials of CTL019 in r/r CLL and r/r adult and pediatric ALL 
have shown promising and durable anti-tumor efficacy (Porter et al 2011, Grupp et al 2013, 
Maude et al 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 allogeneic 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.
As of January 2015, 26 patients (18 DLBCL, 8 FL) have been enrolled in the University of 
Pennsylvania (UP) phase II trial (UPCC13413), and 20 patients have been treated with CTL019 
(5x108 CTL19+ cells). Overall response rate (ORR) at three months after CTL019 infusion in 
18 evaluable patients (12 DLBCL, 6 FL) was 67%, with 6 patients showing PET-negative CRs 
(5 DLBCL, 1 FL), and 6 patients showing disease progression. Six patients progressed before 
response assessment. Although data is preliminary in terms of duration of response, all 
responding patients so far remain in remission up to 280 days. (Schuster et al. ASH 2014, 
abstract 3087). Other investigators have also reported their results in CLL, NHL and ALL with 
autologous anti-CD19 CARs (Davila et al 2014, Brentjens et al 2011, Kochenderfer et al 2012).
To date, no vector related AEs have been seen with higher CTL019 transgene levels of 
expression or persistence, with the longest periods of observation being 9, 10, and 22 months 
in three pediatric patients with r/r ALL and 12, 22, 42 and 43 months in 4 adult patients with r/r 
CLL as of March 2014.
Post-infusion monitoring for RCL in these trials with University of Pennsylvania manufactured 
CTL019 (CART-19) therapy has shown no Vesicular Stomatitis Virus, Glycoprotein (VSV-G) 
by quantitative Polymerase Chain Reaction (q-PCR) (test for RCL) detectable in any of the 
patient samples at time points up to 2 years (7 patients from UPCC03712 trial; 16 patients form 
UPCC04409 trial, 11 patients from CHP959 trial).
Clinical Cellular Kinetics (Pharmacokinetics)
r/r ALL
Based on preliminary data, following infusion of CTL019, a rapid expansion occurs with a 
median Tmax occurring around 9-10 days as measured by qPCR (copies of CTL019 transgene) 
and flow cytometry (% of CD3+/CTL019+ and % CD3/CD8+ CTL019) in patients with a best 
response of CR or CRi. The mean half-life in the CR/CRi patients (n=35) were reported to be 
approximately 32 days measured by PCR. The mean overall exposure (AUC28d) was 
approximately 12.4 and 15.5-fold lower in NR patients (n=3) compared with CR/CRi (n=46) 
for % of CD3+/CTL019+ and % CD3/CD8+ CTL019, respectively, signifying the roles of both 
expansion and persistence for eliciting clinical response. AUC84d and Cmax also tended to be 
higher for CR/CRi patients compared to NR as measured by both qPCR and flow cytometry. 
Bone marrow concentrations of CTL019 (quantified as CD3+/CTL019+%) were measurable at 
1 month post-CTL019 infusion in 40 of 46 CR/CRi pediatric ALL patients, and within those 
patients by 3 months measurable in 24 of 46 patients sampled showing trafficking of CTL019 
to the bone marrow space as measured by flow cytometry. Bone marrow data was limited in 


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NR patients (n=2) with very low levels by 1 month. Trafficking of CTL019 cells has also been 
demonstrated into the cerebral spinal fluid (CSF) in this patient population (Grupp 2013).
CLL
Rapid expansion occurs with a median Tmax occurring around 13 days post infusion in CLL 
patients with a best response of CR or CRi as measured by qPCR (copies of CTL019 
transgene) and flow cytometry (% of CD3+/CTL019+ and % CD3/CD8+ CTL019). Limited
data from preliminary analysis suggests that Tmax may be slightly delayed (ranges from 17.0 
-28.0 days) in CLL patients achieving a PR/ PRi/NR/PD in Study A2201 relative to CR/CRi 
patients. Based on limited data there appears to be a trend for a longer CTL019 half-life in 
CR/CRi CLL patients compared with PRi and PRi/NR/PD patients, this trend is consistent
with results observed in other indications (e.g. ALL).
 
 
 
 
Clinical Safety
Adult r/r ALL
As of January 2015, 18 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 21 to 66 years. CRS was seen in 16 of 18 patients. Twelve patients 
(66.7%) had grade 3 or 4 CRS and nine (75%) of these patients required anti-cytokine therapy 
with tocilizumab.
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.
Adult r/r B-NHL
At the University of Pennsylvania (UP), a Phase II trial with CTL019 in heavily pretreated, 
relapsed/refractory NHL patients has started in January 2014 (UPCC13413). This trial includes 
adult patients with relapsed or refractory NHL including diffuse large B-cell lymphoma 
(DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). As of January 2015, 
26 patients (18 DLBCL, 8 FL) have been enrolled, and 20 patients have been treated with 
CTL019 (5x108 CTL19+ cells). All patients developed fever following T cell infusion, 
attributed to cytokine release syndrome (CRS). CRS was detected in 15 patients: 13 patients 
with grade 2 CRS, 1 patient with grade 3, and 1 patient with grade 4 CRS. One patient received 
steroids and tocilizumab for grade 4 CRS. CRS occurred within the first week of T cell infusion 
in all patients. Neurologic toxicity was observed in 11 pts (1 grade 3 encephalopathy that 


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resolved with corticosteroids; 1 grade 3 dysarthria and grade 3 ataxia). There was no treatment-
related mortality (Schuster et al. ASH 2014, abstract 3087).
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.
Table 1-1
Summary of ongoing human studies as of January 2015
Study
Patients 
infused
Population
Infusion Schedule
Median CTL019 
transduced cells
UPCC04409, Phase 
I
20
(14 CLL 
and 6 ALL)
r/r CD19+ adult 
leukemia/lymphoma
Day 0; 10%
Day 1; 30%
Day 2; 60%
1.4 x 108
CHP959, Phase I
43
(42 ALL)
r/r CD19+ pediatric 
leukemia/lymphoma
Day 0; 10%
Day 14; 30%
Day 28; 60%
Later amended to 
Day 0, 1 and optional 
Day 14 (or later)
3.5 x 106/kg body weight 
UPCC03712, Phase 
II
28
r/r CLL
Day 0; 100%
Low dose cohort (14):
2.1 x 107
High dose cohort (14):
2.6 x 108
UPCC21413, Phase 
II
12
r/r ALL
Day 0; 100%
5 x107
UPCC13413, Phase 
II
26 enrolled
(18 DLBCL 
and 8 FL)
NHL:
Follicular (FL), 
Mantle Cell (MCL) & 
Diffuse Large B-Cell 
(DLBCL)
Day 0; 100%
5 x108
14BT022, Phase II
15
r/r ALL
Day 0; 100 %
5.0 x 106/kg body 
weight
For further information regarding clinical experience with CTL019, refer to the [CTL019 Investigator’s Brochure]
2
Rationale
2.1
Study rationale and purpose
Current therapies for DLBCL consist of combination chemotherapies with CD20-targeting 
immunotherapies. While over 50% of patients reach long-lasting complete remissions, 
approximately one-third of patients are refractory to therapy or will relapse after initial response. 
These patients have a poor prognosis, especially if they do not respond to or are not eligible for 
salvage regimen including HSCT.
The B-cell marker CD19 has emerged as a target for DLBCL treatment in the past years. 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 vast majority of DLBCL expresses CD19 


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(Kimura et al 2007). We have developed chimeric antigen receptor (CAR) T cells to target 
CD19+ cells (CTL019). 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. Data from 
patients with B-cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), 
and other CD19 expressing B cell lymphomas show that CTL019 therapy has potent anti-tumor 
activity.
As of January 2015, 26 patients (18 DLBCL, 8 FL) have been enrolled in the University of 
Pennsylvania (UP) phase II trial (UPCC13413), and 20 patients have been treated with CTL019 
(5x108 CTL019+ cells). Overall response rate (ORR) at three months after CTL019 infusion in 
18 evaluable patients (12 DLBCL, 6 FL) was 67%, with 6 patients showing PET-negative CRs 
(5 DLBCL, 1 FL), and 6 patients showing disease progression. Six patients progressed before 
response assessment. Although data is preliminary in terms of duration of response, all 
responding patients so far remain in remission up to 280 days. (Schuster et al. ASH 2014, 
abstract 3087).
If CTL019 has preferential activity in a subtype of DLBCL is currently unknown. Since the 
mechanism of action of CTL019 is independent of BCR signaling, it is anticipated that patients 
with GC and ABC subtype and patients failing ibrutinib will equally respond to CTL019. In 
addition, a cross-resistance with CD20-targeted therapies such as rituximab is not expected.
Figure 2-1
Mechanisms of actions of rituximab, ibrutinib and CTL019 in B 
lymphocytes:
The monoclonal antibody rituximab targets CD20 on the cell surface, activates complement mediated
cytotoxicity, opsonic phagocytosis also known as antibody-dependent cell-mediated cytotoxicity 
(ADCC) and direct lysis by NK cells. Ibrutinib targets the intracellular Bruton’s tyrosine kinase and 
interferes with cell signaling, inhibits the activating signal for PI3K and for NFkB, an inhibitor of 
apoptosis. CTL019, CAR modified T-cells targeting CD19, lead to cytokine release, T-cell proliferation 


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and activation of macrophages, neutrophils and other lymphocytes. Preclinical models are being 
investigated to determine the effects of ibrutinib on CTL019.
In summary, novel therapies for relapsed or refractory DLBCL are urgently needed. Targeting 
CD19 by CAR expressing T-cell therapy has been shown to be effective eliminating very 
advanced B-cell malignancies and has the potential to induce complete remissions in patients 
otherwise beyond treatment. This trial will therefore assess the clinical activity of CTL019 in 
patients with relapsed/refractory DLBCL measured as overall response rate.
2.2
Rationale for the study design
This is a 5 year single arm, multi-center, phase II study to determine the efficacy and safety of 
CTL019 in adult patients with relapsed or refractory DLBCL. A single arm therapy study design 
is supported by the absence of effective therapies in this setting, and high unmet medical need. 
This study will enroll approximately 100 patients to allow 80 patients treated in the main cohort. 
Approximately 18 patients will be enrolled in cohort A to allow for 15 patients to be treated. 
After the amendment 5 of the protocol, approximately 10 additional Japanese patients will be 
enrolled, to allow for at least 6 additional patients to be treated (total 9 treated in Japan). After 
assessment of eligibility, patients qualifying for the study will be enrolled and start 
lymphodepleting chemotherapy, i.e. fludarabine and cyclophosphamide, or bendamustine for 
patients with cyclophosphamide resistance, as indicated per protocol, followed by a single dose 
of CTL019 transduced cells.
Previous clinical data with CTL019 therapy has been generated using cell product manufactured 
at the Cell and Vaccine Production Facility (CVPF) at the University of Pennsylvania. This trial 
will utilize product manufactured at a Novartis manufacturing facility. A limited safety run-in 
stage will be conducted at the beginning of this trial. These patients will be included in the total 
targeted patient population.
The efficacy of CTL019 will be evaluated through the primary endpoint of ORR as determined 
by an Independent Review Committee (IRC) assessment, including CR and PR, until 
progression or relapse for up to 5 years. The choice of ORR as the primary endpoint is based 
on 
evidence 
that 
ORR 
is 
a 
standard 
outcome 
measurement 
in 
DLBCL 
(Cheson et al 2007). Objective response is the most predictive factor of outcome after 
autologous HSCT (i.e. after salvage therapy) (Johnston et al 2008). For patients not responding 
to the first salvage regimen, the outcome is extremely poor, with a median OS of approximately 
4 months (Elstrom et al 2010, Friedberg 2011).
Safety will be monitored throughout the trial. Per Health Authority guidelines (FDA, EMA) for 
gene therapy products or advanced therapy medicinal products that utilize integrating vectors 
(e.g. lentiviral vectors), all patients treated with CTL019 must be monitored for specific 
toxicities for up to a total of fifteen years, irrespective of their response to CTL019. All patients 
will be monitored in this trial for five years, followed by semiannual and annual safety 
assessments in a separate long-term safety follow-up protocol (CCTL019A2205B) for 
additional ten years. The purpose of this is to assess the risk of acute and delayed AEs suspected 
to be related to CTL019 therapy, and to monitor for replication competent lentivirus (RCL).
During the “treatment and primary follow-up phase” all adverse events will be collected for the 
first 12 months only. After 12 months, if a patient is still in the primary follow-up phase, only 


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protocol defined adverse events and adverse events of special interest will be collected. Patients 
completing or discontinuing from this primary follow-up phase will have an “End of Treatment 
and Primary Follow-Up Visit”. 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 data on delayed adverse events, in line with HA recommendation for gene therapy 
products. Patients not entering or finishing the secondary follow-up will be followed in a 
separate long-term safety follow-up protocol (LTFU, CCTL019A2205B). It is anticipated that 
patients may leave the primary follow-up and move to secondary follow-up for the following 
reasons (Figure 2-2):
1. Progression of disease/relapse
2. Pursuing HSCT while in remission
3. Withdrawal from the primary follow up
Figure 2-2
Expected flow of patients in CTL019C2201
Based on current clinical experience with CTL019 therapy acute toxicities are expected in the 
first 28 days after single infusion of CTL019 cells. Expected acute toxicities include elimination 
of normal CD19 positive B cells, cytokine release syndrome (CRS)/macrophage activation 
syndrome (MAS) associated with the onset of antitumor responses mediated by large numbers 
of activated T cells, tumor lysis syndrome (TLS), and toxicities associated with the 
lymphodepleting chemotherapy conditioning regimen used with adoptive T-cell therapy. For 
more details and guidance on management of these toxicities refer to Section 6.2.4.2.1. These 
acute toxicities, with the exception of B cell depletion or aplasia, are all typically reversible and 
resolved within several weeks to months of CTL019 infusion.
Potential long-term toxicities of CTL019 therapy may include continued B cell aplasia with 
increased risk of infections if CTL019 cells persist. Other potential toxicities may include 
insertional site oncogenesis, expression of replication competent lentivirus (RCL) detection, 
and potential effects of maternal CTL019 cells on pregnancy outcome. RCL, autonomous 
proliferation of infused CTL019 T cells, and insertional site oncogenesis during the CTL019 
therapy trials have not been observed to date.
Collection of such long term effects of CTL019 cell therapy will help to further define the risk-
benefit profile of CTL019 in patients with B cell malignancies. These observations will also 


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serve to provide further guidance to patients, health care providers and investigators of such 
risks and their detection and management.
Patients that complete or discontinue from this study will be requested to consent to the LTFU 
study, CCTL019A2205B, to meet health authority guidelines.
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. More than 40 patients with myeloma have been treated with 
CARs and lymphopenia after lymphodepleting chemotherapy, and observed improved 
engraftment (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).
As of January 2015 in the ongoing CTL019 lymphoma study UPCC13413, all 20 patients 
infused with CTL019 cells received a lymphodepleting chemotherapy prior to adoptive transfer 
of T cells. Five patients received a lymphodepleting regimen consisting of bendamustine, nine 
patients received cyclophosphamide, one patient received fludarabine and cyclophosphamide, 
two patients received EPOCH; one patient received lenalidomide + CHOP, and two patients 
received cyclophosphamide in combination with radiation therapy (Schuster et al. ASH 2014, 
abstract 3087). Similarly, in ongoing CTL019 pediatric and adult ALL studies, most patients 
infused with CTL019 received a lymphodepleting conditioning regimen prior to adoptive 
transfer of T cells.
For further information regarding clinical experience with lymphodepletion prior to CTL019 
infusion, refer to the [CTL019 Investigator’s Brochure].
2.3
Rationale for dose and regimen selection
The dose selected for this trial is a single infusion of 5 x 108 CTL019 cells based on available 
data collected in patients with CLL, ALL and non-Hodgkin’s lymphoma (NHL) indicating it is 
well tolerated. A clear relationship between response and dose of infused transduced CTL019 


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cells has not been established in data collected to date in patients with CLL, ALL, and non-
Hodgkin’s lymphoma but will be explored further in this trial. This is likely the consequence of 
the ability of CTL019 transduced cells 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, and 
across diseases. Additional considerations in this dose selection will have to take into account 
the manufacturing feasibility of producing adequate numbers of CTL019 transduced cells and 
important differences in toxicity profile across indications.
Animal studies supported 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 dosing in the pilot study CTL019B2102J/UPCC04409 was divided 
among three split infusions: 10%, 30% and 60% of the total cell dose (up to 5x109). In this 
study, autologous CART-19 transduced cells were administered to 20 patients with 
relapsed/refractory CD19+ B-cell malignancies (14 CLL and 6 ALL). While the target cell dose 
was 5x109, the acceptable range was 1.5 x107 to 5 x109 CART-19 cells. Of the 11 patients that 
had a CR, 7 patients received a single infusion (approximately 5x108 cells) due to the onset of 
fevers, yet CRs were observed with either 1 to 3 infusions. Thus, patients responded both after 
a single infusion and after multiple infusions of CART-19 cells.
Based on results from study CTL019B2102J/UPCC04409, the target dose levels of 1-5x107 and 
1-5x108 CART-19 transduced cells were selected for a subsequent dose optimization study in 
CLL (study CTLA019A2201/UPCC03712). Patients with heavily pretreated CLL frequently 
have a significantly lower percentage of CD3+ cells in leukapheresis products than patients 
with other types of hematologic malignancy. Lentiviral transduction and expansion therefore 
could be limited in the setting of reduced CD3+ cells. As observed in the phase I study, 
manufacturing success rates declined to approximately 50% when targeting 109 or more CART-
19 cells. Targeting 108 or fewer cells has not been an issue from a manufacturing standpoint. A 
single infusion of CART-19 cells in the dose optimization study (CTL019A2201/UPCC03712) 
was clinically well tolerated and responses have been seen with both dosing schemas. The most 
recent data update from this dose optimization study in CLL have not shown a discernible 
difference with regards to incidence or severity of CRS or any other toxicity between the low 
and the high dose schedules tested (i.e. 1-5x107 vs 1-5x108). Of the 26 patients dosed to date, 
14 have experienced CRS (6 in the high dose and 8 in the low dose arm, respectively). CRS 
cases have occurred several days post CTL019 infusion and have been generally mild to 
moderate and manageable. No treatment related deaths have been noted in either arm. Notably, 
in patients with CLL achieving CR or a lasting PR, the number of infused CTL019 transduced 
cells has ranged from 1.4 x 107 to 1.1 x 109 cells. This two-log-fold difference did not support 
a statistically significant dose response relationship in spite of a numerically higher response 
rate amongst patients dosed in the high dose arm. Thus far, 8 out of 23 assessable patients have 
responded (4 CR and 4 PR), including 5 (50%) responders in the high dose arm and 3 (23%) 
responders in the low dose arm (p=0.37).
In the ongoing trial UPCC13413 in adult patients with relapsed or refractory NHL (including 
diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma 
(MCL)), treated patients have received a single dose of 5 x 108 CTL019 transduced cells 


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(translating into a median dose of 5.8 x 106/ kg (range: 3.7 – 8.9 x 106) CTL019 transduced 
cells).
Unique adverse events following T cell infusion included cytokine release syndrome (CRS) and 
neurologic disturbances. CRS occurred within the first week of T cell infusion, and there were 
no episodes of delayed CRS. Neurologic toxicity was observed in 11 pts: Three patients 
developed transient delirium (1 grade 2, 2 grade 3) and one patient developed a possibly related, 
grade 5 encephalopathy. Like in CLL, preliminary data suggest no dose-response or dose-
toxicity relationship became obvious (18 evaluated patients January 2015).
Data from the adult ALL trials previously supported a safe and efficacious dose range of 1.4 x 
107 to 1.1 x 109 CTL019 transduced cells. However, 3 patients with adult r/r ALL in study 
UPCC21413 died within 16 days post-CTL019 infusion possibly related to CTL019 infusion 
(in the presence of concomitant infectious complications in all three instances). After health 
authority consultation, the dose for treatment of patients with adult ALL in study UPCC21413 
was reduced to 1 to 5 x 107 transduced CAR T cells. No deaths have occurred in ongoing 
pediatric ALL trials. In pediatric ALL patients, clinical responses were seen after the infusion 
of CTL019 transduced cell doses ranging from 1.1 to 18.1 x 106 transduced CTL019 cells/kg 
body weight with an age range of 5 to 22 and a weight range of 18.3 to 122.0 kg. Toxicity as 
assessed by severity of CRS appears to correlate with pre-infusion tumor burden in pediatric 
ALL but not with transduced CTL019 cell numbers within the range of cell doses studied. 
Therefore, the targeted CTL019 cell dose for pediatric ALL patients is 2 to 5 x 106 CTL019 
transduced cells per kg body weight with a maximum dose of 2.5 x 108 CTL019 transduced 
cells (non-weight adjusted). Based on the current safety profile, no dose modifications were 
instituted in other indications than ALL.
It is important to note that the severity and incidence of CRS induced by similar CTL019 dosing 
schemas differs between adult ALL and CLL or NHL and therefore, dose selection for the latter 
indications should be based on toxicity and efficacy data observed in trials for patients with 
CLL or NHL. It is important to note that no deaths have been reported to date amongst more 
than 50 patients with CLL or NHL treated in clinical trials at the University of Pennsylvania. 
This is likely because the use of doses ranging from 1 to 5x108 cells in CLL or NHL (the dose 
range used to treat approximately two thirds of patients) has been associated with less frequent 
and more attenuated forms of CRS compared with those induced by the same dose range in 
adult ALL. Furthermore, in the dose optimization study in CLL, the highest dose range tested 
(1 to 5x108) renders numerically higher response rates compared with the lower dose range (1 
to 5x107).
In summary, based on clinical experience from past and ongoing trials in r/r CLL and NHL at 
the University of Pennsylvania, where the upper range of the target dosing tested in study 
CTL019A2201/UPCC03712 (i.e. 1-5x108) was effective and safe, a target dose of 5 x 108
CTL019 viable transduced cells has been chosen for further development in CLL and NHL. 
The allowable dose range is 1-5x108 viable transduced cells.
2.4
Rationale for choice of combination drugs
Not applicable.


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2.5
Rationale for choice of comparators drugs
Not applicable.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary:
Refer to Section 10.4
Evaluate the efficacy of CTL019 therapy in the main cohort
Overall response rate (ORR), which includes complete response (CR) and 
partial response (PR) as determined by IRC assessment in the full analysis 
set (FAS) of the main cohort
In addition sensitivity analyses will be performed using the local investigator 
response assessments
Key secondary:
Refer to Section 10.5.1
Not applicable
Not applicable
Other secondary:
Refer to Section 10.5.2
Evaluate safety of CTL019
Type, frequency and severity of adverse events and laboratory abnormalities
Evaluate time to response
Time to response, i.e. time between date of CTL019 infusion until first 
documented response (CR or PR) 
Evaluate duration of overall response (DOR) 
Duration of response, i.e. the time from achievement of CR or PR, whichever 
occurs first, to relapse or death due to DLBCL
Evaluate event free survival (EFS)
EFS, i.e. the time from date of CTL019 infusion to the date of first 
documented disease progression or relapse, new treatment for lymphoma or 
death due to any cause
Evaluate progression free survival (PFS)
PFS, i.e. the time from date of CTL019 infusion to the date of first 
documented disease progression or death due to any cause
Evaluate overall survival (OS)
OS, i.e., the time from date of CTL019 infusion to the date of death due to 
any cause
Evaluate efficacy and safety in histological and molecular 
subgroups (GC, ABC, other)
ORR, PFS, OS, EFS, DOR and AEs in histological and molecular subtypes
Characterize the in vivo cellular PK profile (levels, 
expansion, persistence) of CTL019 transduced cells into 
target tissues (blood, bone marrow, cerebral spinal fluid 
and other tissues if available), summarized by clinical 
response
- PK parameters: Cmax, Tmax, AUCs, T1/2, Clast, Tlast and/or other relevant 
PK parameters in peripheral blood, bone marrow, as appropriate
Characterize immunogenicity (pre-existing (pre-dose) and 
post-infusion) in patient treated with CTL019
-Summary of immunogenicity(cellular and humoral)


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Objective
Endpoint
Analysis
Describe presence of RCL
- RCL by VSV-g q-PCR
Evaluate efficacy and safety in cohort A
ORR, PFS, OS, EFS, DOR and AEs in cohort A 
Evaluate the Overall response rate for all patients treated
ORR in all patients treated


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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 adult patients with relapsed or refractory DLBCL. The study will have the following 
sequential phases for all patients: Screening (Section 7.1.1), Pre-treatment, Treatment and 
Primary follow-up, Secondary follow-up, and Survival follow-up.
Efficacy for all patients will be evaluated using CT/MRI based on the Lugano Classification 
(updated Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma; Cheson et al 2014; Barrington et al 2014)
 
 If local health authorities require the use of specific imaging modalities 
(e.g., MRI) and/or a different imaging schedule for disease response assessment purposes a 
decision will be made on a case by case basis upon discussion between Novartis and the 
Investigator. Efficacy will be assessed at Day 28 and months 3, 6, 9, 12, 18, 24 months and then 
every 12 months for 5 years until documented disease relapse or disease progression. PET-CT 
will be performed at baseline and at Month 3. Due to the mechanism of action of CTL019, the 
Day 28 assessment should be interpreted in context of other clinical parameters that suggest 
true progression rather than pseudo-progression due to inflammatory changes and tumor 
swelling (De Velasco et al 2015).
. Although clinical guidelines (ESMO and NCCN) do not recommend routine imaging in 
patients in CR for longer than 2 years, in the context of this clinical trial an extended efficacy 
follow up by CT/MRI is justified.
At the beginning of the trial, a safety run-in stage will be conducted to enroll at least three 
patients to assess the acute safety profile and product characteristics of the Novartis 
manufactured CTL019 cell product. The initial patients will be enrolled in this trial 
subsequently with minimum interval between CTL019 infusions of 14 days. Full safety profiles 
and product characteristics of these patients following lymphodepleting chemotherapy and 
CTL019 infusion will be reported to the Health Authorities. The acute and subacute toxicity 
profile for CTL019 cell product manufactured at the University of Pennsylvania has been 
established in patients with r/r B-NHL with only low grade CRS observed in patients with 
DLBCL.
The data to be reported will include demographics, lymphodepleting chemotherapy, total and 
CTL019 transduced viable T cell doses, AE/ Serious Adverse Events (SAEs), standard 
laboratory data (hematology and chemistry) and CTL019 cellular PK.
For the purpose of safety onboarding of new sites, after the above safety run-in stage has been 
completed, a staggered approach will also be utilized at each new respective site (with no prior 
experience administering CTL019) and will occur as follows:

1st patient infusion, wait 14 days

2nd patient infusion, wait 14 days

Following completion of this staggered enrollment of the first two patients, the new site 
may then proceed with infusion of patients without staggering the patients.


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Safety will be assessed throughout the study.
One additional cohort has been added to the original main study cohort (80 patients treated with 
CTL019 manufactured at the Novartis manufacturing facility in Morris Plains, USA).
The additional cohort A will enroll approximately 18 patients to allow at least 15 patients 
infused with CTL019 manufactured at the Fraunhofer Institut für Zelltherapie. After the 
amendment 5 of the protocol, approximately 10 additional Japanese patients will be enrolled, 
to allow for at least 6 additional patients to be treated (total 9 treated in Japan).
Figure 4-1
CTL019C2201 study design
4.1.1
Leukapheresis assessment
Non mobilized leukapheresis products collected from the patient prior to study entry (historical) 
may be usable for CTL019 manufacturing if collected at an appropriately certified apheresis 
center and the product is accepted for manufacturing. If a historical leukapheresis product is not 
available, an apheresis procedure will be scheduled for cell procurement prior to final 
enrollment. 
 
 
 
Sample sentinel vials collected from the leukapheresis will be sent to Novartis manufacturing 
prior or together with the leukapheresis product.
For guidelines on optimal patient timing of apheresis collection, please refer to the
Leukapheresis Key Requirements within the [Leukapheresis, Cryopreservation&Scheduling
Manual].


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Following informed consent, information on the patient’s leukapheresis product will be 
transferred to Novartis manufacturing. Novartis manufacturing will then evaluate the patient’s 
apheresis product for acceptance. Final enrollment is defined as the point at which the patient 
meets all clinical inclusion/exclusion criteria, and the patient’s leukapheresis product is 
accepted for manufacturing.
Please refer to the Leukapheresis
Key
Requirements
within
the
[Leukapheresis, 
Cryopreservation&SchedulingManual] on the recommended procurement, as well as handling 
and shipment procedures of the apheresis samples to the designated manufacturing facility.
4.2
Definition of end of the study
The end of study is defined as the last patients 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: progression 
of disease, 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 from the 
date of infusion on all patients under a separate long term follow-up (LTFU) protocol as 
recommended by health authority guidance for patients treated with gene therapies. All patients 
who either complete or prematurely discontinue from the study will be enrolled in this 
destination protocol at the time of study completion/discontinuation (a separate informed 
consent form will be provided for this protocol; Section 7.1.7).
Patients may continue to be followed under the current protocol for survival, pregnancy 
outcomes and secondary malignancy, which can be conducted via a form or telephone contact 
until Last Patient Last Visit (LPLV) as defined above or until they choose to enroll into the long 
term follow-up protocol (CCTL019A2205B), whichever occurs first.
4.3
Early study termination
The study can be terminated at any time for any reason by the sponsor, Novartis, or if any of 
the stopping criteria described in Section 6.2.4.1.1 are met. Should this be necessary, the patient 
should be seen as soon as possible and the same assessments should be performed as described 
in Section 7 for a discontinued or withdrawn patient. The investigator may be informed of 
additional procedures to be followed in order to ensure adequate patient consideration is given 
to the protection of the patient’s interests. For patients who have received CTL019 infusion, a 
long term post-study follow-up for delayed AEs including monitoring for lentiviral 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.


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5
Population
5.1
Patient population
The study will enroll adult patients ≥ 18 years with relapsed or refractory DLBCL, having failed 
2 or more lines of therapy and not eligible for HSCT. A minimum of 25 patients in each of the 
two most common subtypes of DLBCL: GC and ABC type will be treated in the main study 
cohort. Patients with T cell rich/histiocyte rich large B cell lymphoma (THRBCL), primary 
cutaneous DLBCL, primary mediastinal B cell lymphoma (PMBCL), EBV positive DLBCL of 
the elderly, Richter’s transformation, and Burkitt lymphoma are not allowed.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. 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 have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures
2. Patients must be ≥18 years of age
3. Histologically confirmed DLBCL at last relapse (by central pathology review before 
enrollment).
a. Sufficient FFPE tumor samples must be available for histological and molecular 
subtype testing along with a corresponding pathology report. A recent tumor sample 
obtained for the purpose of the study must be submitted however if not clinically 
feasible, an archival tumor biopsy from the most recent relapse may be submitted 
instead. Excisional biopsies should be submitted wherever possible; in cases where 
this is not possible, a core needle biopsy is allowable. Fine needle aspiration (FNA) is 
not allowed.
4. Relapsed or refractory disease after ≥2 lines of chemotherapy, including rituximab and 
anthracycline, and either having failed autologous HSCT, or being ineligible for or not 
consenting to autologous HSCT
5. Measurable disease at time of enrollment:
a. Nodal lesions greater than 20 mm in the long axis, regardless of the length of the short 
axis
b. Extranodal lesions (outside lymph node or nodal mass, but including liver and spleen) 
≥ 10 mm in long AND short axis
For detailed information please refer to Section 14.1 Guidelines for efficacy 
evaluation in in diffuse large B cell lymphoma and follicular lymphoma studies 
6. Life expectancy ≥12 weeks
7. ECOG performance status that is either 0 or 1 at screening


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8. Adequate organ function:
a.
Renal function defined as:

A serum creatinine of ≤1.5 x ULN OR

eGFR ≥ 60 mL/min/1.73 m2
b. Liver function defined as:

ALT ≤ 5 times the ULN for age

Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert–Meulengracht 
syndrome; patients with Gilbert-Meulengracht syndrome may be included if their 
total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
c.
Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and 
pulse oxygenation > 91% on room air
d. Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA
e. Adequate bone marrow reserve without transfusions defined as:

Absolute neutrophil count (ANC) > 1.000/mm3

Absolute lymphocyte count (ALC) >300/ mm3, and
absolute number of CD3+ T cells >150/mm3

Platelets ≥ 50.000/mm3

Hemoglobin > 8.0 g/dl
9. Must have an apheresis product of non-mobilized cells accepted for manufacturing.
10. Women of child-bearing potential defined as all women physiologically capable of 
becoming pregnant, and all male participants must use highly effective methods of 
contraception for at least 12 months following CTL019 infusion and until CAR T cells are 
no longer present by qPCR on two consecutive tests.
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (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.

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.
BOTH of the following forms of contraception must be utilized:

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 hormonal vaginal ring or transdermal hormonal contraception

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
Use of intrauterine devices (IUDs) is excluded due to increased risks of infection and bleeding. 
Placed IUDs may remain in place but additional measures of contraception are mandated.


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Additionally, drugs that induce cytochrome P450 (CYP) enzymes can increase the clearance of 
sex hormones that are eluted by the devices and reduce contraceptive efficacy; given the poly-
pharmacy for these patients this presents a real risk of device failure and possible inadvertent 
resultant conception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
11. Sexually active males must accept to use a condom during intercourse for 12 months after 
treatment as they should not father a child in this period. A condom is required to be used 
also by vasectomized men (as well as during intercourse with a male partner or sterile 
female partner) as WBCs are a normal part of semen and transmission of CTL019 
transduced cells may occur.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 
therapy
2. Treatment with any prior gene therapy product
3. Active CNS involvement by malignancy
4. Prior allogeneic HSCT
5. Eligible for and consenting to autologous HSCT
6. Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
7. Investigational medicinal product within the last 30 days prior to screening
Note: Investigational therapies must not be used at any time while on study until the first 
progression following CTL019 infusion.
8. The following medications are excluded:
a.
Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to 
leukapheresis and > 72 hours prior to CTL019 infusion. However, the following 
physiological replacement doses of steroids are allowed: <12 mg/m2/day 
hydrocortisone or equivalent
b. Immunosuppression: Any other immunosuppressive medication must be stopped ≥ 
2 weeks prior to leukapheresis and ≥2 weeks prior to CTL019 infusion. This could 
include check point inhibitors (monoclonal antibodies and small molecule 
modulators).
c.
Antiproliferative therapies other than lymphodepleting chemotherapy within 2 
weeks of leukapheresis and 2 weeks prior to infusion

Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase 
inhibitors, and hydroxyurea) must be stopped > 72 hour prior to leukapheresis 
and > 72 hours prior to CTL019 infusion

Other cytotoxic drugs, including low dose daily or weekly maintenance 
chemotherapy, must not be given within 2 weeks prior to leukapheresis and 
within 2 weeks prior to CTL019 infusion.


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
Fludarabine may be associated with prolonged lymphopenia. This should be 
taken into consideration when evaluating the optimal timing for leukapheresis 
collection.
d. Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-
lives of the respective antibody, whichever is longer. Note: Rituximab is excluded 
within 4 weeks prior to infusion.
e.
CNS disease prophylaxis must be stopped > 1 week prior to CTL019 infusion (e.g. 
intrathecal methotrexate)
9. Prior radiation therapy within 2 weeks of infusion
10. Active replication of or prior infection with hepatitis B or active hepatitis C (HCV RNA 
positive)
11. HIV positive patients
12. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture 
positive ≤ 72 hours prior to infusion)
13. Unstable angina and/or myocardial infarction within 6 months prior to screening
14. Previous or concurrent malignancy with the following exceptions:
a. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is 
required prior to study entry)
b. In situ carcinoma of the cervix or breast, treated curatively and without evidence of 
recurrence for at least 3 years prior to the study
c. A primary malignancy which has been completely resected and in complete remission 
for ≥ 5 years
15. Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive 
potential must have a negative serum or urine pregnancy test performed within 24 hours 
before lymphodepletion
16. Intolerance to the excipients of the CTL019 cell product
17. Cardiac arrhythmia not controlled with medical management
18. Removed
19. Prior treatment with any adoptive T cell therapy
20. Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary 
cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV 
positive DLBCL of the elderly, Richter’s transformation, and Burkitt lymphoma
21. Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain-
Barré Syndrome, Amyotrophic Lateral Sclerosis)
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 


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to a transmembrane region derived from the CD8 receptor, which is linked to an intracellular 
bipartite signaling chain of TCR-ζ (or CD3-ζ) and 4-1BB intracellular signaling domains. The 
extracellular scFv with specificity for CD19 is derived from a mouse monoclonal antibody. T 
cells which are enriched from a patient leukapheresis unit are expanded ex vivo using 
commercially available magnetic beads that are coated with anti-CD3 and anti-CD28 
monoclonal antibodies. The cells are transduced with the CD19 CAR lentiviral vector which 
ensures that only peripheral white blood cells enriched for lymphocytes are exposed to the 
vector. The residual non-integrated vector is washed away during the process. CTL019 cells 
will be expanded ex vivo for up to 10 days. At the end of the culture, the CTL019 cells are 
depleted of magnetic beads, washed, concentrated, and cryopreserved. Results from a release 
testing procedure are required prior to release of the product for infusion.
6.1.1
Dosing regimen
The target dose of CTL019 transduced cells for adult patients will consist of a single infusion 
of 5 x 108 viable CTL019 transduced cells, which will be administered via intravenous infusion. 
The acceptable dose range is considered as 1 - 5x108 viable CTL019 transduced cells.
6.1.1.1
Lymphodepleting chemotherapy
It is anticipated that many patients will have been receiving chemotherapy for relapsed or 
resistant disease. Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy 
cycle is planned. The use of any additional chemotherapy prior to the recommended 
lymphodepleting chemotherapy will be at the discretion of the investigator and dependent on 
the patient’s disease burden. 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.
When given, lymphodepleting chemotherapy should be started 14 to 5 days before CTL019 
infusion (D1) to allow for at least 48 hours from last dose of lymphodepleting chemotherapy to 
CTL019 infusion. The chemotherapy start date will vary based on the selected chemotherapy. 
The purpose of this chemotherapy is to induce lymphopenia in order to facilitate engraftment 
and homeostatic expansion of CTL019 cells. For lymphodepleting chemotherapy, 
cyclophosphamide-based regimens are the agents of choice as there is the most experience with 
the use of these agents in facilitating adoptive immunotherapy. The proposed lymphodepleting 
regimen is:

Fludarabine (25 mg/m2 intravenously [i.v.] daily for 3 doses) and cyclophosphamide (250 
mg/m2 i.v. daily for 3 doses starting with the first dose of fludarabine)
If there was previous grade IV hemorrhagic cystitis with cyclophosphamide, or the patient 
demonstrated resistance to a previous cyclophosphamide-containing regimen, then the 
following regimen should be used:

Bendamustine 90 mg/m2 i.v. daily for 2 days
Note: Female patients of childbearing potential must have a negative pregnancy test (urine or 
serum) within 24 hours prior to the start of lymphodepleting therapy. If the patient does not 
require lymphodepleting therapy, she should still have a negative pregnancy test at the required 
visit that takes place 14 to 5 days before CTL019 infusion (see Table 7-1).


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6.1.1.2
CTL019 infusion
The CTL019 cell product will be prepared and released by the manufacturing facility to the 
study site approximately 4-5 weeks after manufacturing has commenced, provided all required 
safety and quality release criteria have been met. Upon receipt of the cryopreserved CTL019 
cell product, an inventory must be performed and a drug receipt log filled out and signed by the 
person accepting the shipment. The cryopreserved CTL019 cell product should be kept in the 
vapor phase of liquid nitrogen until CTL019 infusion. For details on the cryopreserved 
components, and the specific storage and handling requirements of the CTL019 cell product, 
see the [Investigational Product Handling Manual].
Prior to CTL019 infusion the following criteria must be met:
1. All patients must undergo a rapid influenza diagnostic test within 10 days prior to the 
planned CTL019 infusion. If the patient is positive for influenza, 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 the patient is asymptomatic.
For patients residing in the United States, Canada, Europe and Japan, influenza testing is 
required during the months of October through May (inclusive). For patients residing in 
the southern hemisphere such as Australia, influenza testing is required during the months 
of April through November (inclusive). For patients with significant international travel, 
both calendar intervals above may need to be considered.
2. Patient should not experience a significant worsening in clinical 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. CTL019 infusion should be 
delayed in such cases.
3. Rapidly progressing patients, or patients experiencing laboratory abnormalities after 
enrollment, that in the opinion of the treating investigator or PI may impact patient safety 
or the patients’ ability to receive the CTL019 infusion, may have their infusion delayed 
until both the treating investigator and PI determine it is clinically appropriate to proceed 
with the CTL019 infusion.
4. Patients experiencing toxicities from their preceding lymphodepleting chemotherapy will 
have their infusion schedule delayed until these toxicities have resolved. 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: Cardiac arrhythmia not controlled with medical management
c. Hypotension requiring vasopressor support
d. Uncontrolled active infection, as evidenced by positive blood cultures for bacteria, 
fungus, or PCR positivity for viral DNA in blood within 72 hours of CTL019 cell 
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5. Following lymphodepleting chemotherapy patients must not have progressive disease in 
order to receive CTL019 infusion, as this will potentially put them at an unacceptable risk 
for severe CRS. Patients should not receive CTL019 infusion if they exhibit significant 
progression of disease following lymphodepleting chemotherapy as evidenced by:
a. Significant increase in nodal disease
b. Significant increases in extranodal areas
c. Occurrence of new lymphoma manifestations
d. Clinical evidence of CNS disease
6. If patients are taking any of the following medications, their infusion must be delayed 
until the medications have been stopped according to the below:
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. Antiproliferative therapies other than the protocol specified lymphodepleting therapy 
must have been stopped ≥ 2 weeks prior to CTL019 infusion
c. Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase 
inhibitors, and hydroxyurea) must be stopped > 72 hour prior to leukapheresis and > 
72 hours prior to CTL019 infusion. Other cytotoxic drugs, including low dose daily or 
weekly maintenance chemotherapy, must not be given within 2 weeks prior to 
leukapheresis and within 2 weeks prior to CTL019 infusion.
d. Immunomodulatory drugs must be stopped ≥ 2 weeks prior to infusion. This could 
include check point inhibitors (monoclonal antibodies and small molecule 
modulators).
e. Antibodies including anti-CD20 therapy must be stopped ≥ 4 weeks prior to infusion 
or 5 half-lives of the respective antibody prior to infusion, whichever is longer. Note: 
Rituximab is excluded within 4 weeks prior to infusion.
f.
CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 infusion (e.g. 
intrathecal methotrexate).
Patients experiencing toxicities from their preceding chemotherapy will have their CTL019 
infusion delayed until the above toxicities have been resolved. If any of the above criteria are 
not met and a period of delay is 4 or more weeks from completing lymphodepleting 
chemotherapy and the WBC>1000/µL, the patient will need to be re-treated with 
lymphodepleting chemotherapy, and these criteria will need to be re-established prior to 
CTL019 infusion.
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 will receive prophylactic allopurinol, or a non-allopurinol alternative (e.g. febuxostat). 
Infection prophylaxis should follow local guidelines dictated only by the preceding 
lymphodepleting chemotherapy. Infection prophylaxis per se for CTL019 is not recommended.


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The site must confirm that two doses of tocilizumab are on site prior to CTL019 infusion
and one dose of siltuximab (if available in country) must be accessible within 24 hours of 
infusion for administration in order to manage suspected toxicities. (see Section 6.2.4.2.1
for details).
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 another H1 
antihistamine. These medications can be repeated every 6 hours as needed. Non-steroidal anti-
inflammatory medication may be prescribed if the patient continues to have fever not relieved 
with acetaminophen 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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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.
Supportive care:
Local guidelines will be followed for the supportive care of 
immunosuppressed and chemotherapy treated patients including infection management. All 
blood products administered should be irradiated. Immunosuppressive medications, including 
steroids, should not be administered unless life threatening circumstances arise.
6.1.2
Ancillary treatments
As side effects from T cell infusions can include fever, chills and/or nausea, all patients should 
be pre-medicated with acetaminophen or paracetamol and diphenhydramine or an H1 
antihistamine, as described above in Section 6.1.1.2. If fever develops please follow your 
institutional guidelines for patients with fever/neutropenia and strongly consider admission for 
close observation.
6.1.3
Rescue medication
Rescue medications are medications given for severe CRS due to CTL019 therapy 
(Figure 6-1). CTL019 administration may require tocilizumab (recommended dose 8 mg/kg 
i.v.), steroids, and siltuximab (11 mg/kg IV over 1 hour) for the treatment of suspected CRS 
toxicities as described below in Section 6.2.4.2.1.
The site must confirm that two doses of tocilizumab are on site and available for 
administration prior to CTL019 infusion and one dose of siltuximab (if available in 
country) must be accessible within 24 hours of infusion. (see Section 6.2.4.2.1 for details).
All rescue medications (except for tocilizumab or siltuximab), including steroids given to treat 
CRS, must be listed on the concomitant medication CRF. Tocilizumab or siltuximab therapy 
administration should be reported on the “Dose Administration Record - Tocilizumab” or “Dose
Administration record - Siltuximab” eCRF, respectively. Steroids given to treat CRS must be 
listed on the concomitant medication CRF.
6.1.4
Guidelines for continuation of treatment
Not applicable
6.1.5
Treatment duration
A single dose of CTL019 transduced cells will be given.
6.2
Dose escalation guidelines
Not applicable
6.2.1
Starting dose rationale
Not applicable


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6.2.2
Provisional dose levels
Not applicable
6.2.3
Guidelines for dose escalation and determination of MTD/RP2D/RDE
Not applicable
6.2.3.1
Implementation of Dose Escalation Decisions
Not applicable
6.2.3.2
Intra-Patient dose escalation
Not applicable
6.2.4
Definitions of dose limiting toxicities (DLTs) in a phase II study
6.2.4.1
Toxicity management, stopping rules and study termination
It is expected that AEs will occur frequentlyin this population based on the underlying advanced
malignancy and that these can be SAEs. Therefore, there is no specific occurrence of SAEs
that define a stopping rule, but the review of SAEs will form the basis for potential early
stopping of the study. 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 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 the sponsor’s discretion and may include reasons such as 
low recruitment, protocol violations, or inadequate data recording.
6.2.4.1.1 Criteria for stopping or pausing the study
During the safety run-in stage the study will be paused, and health authorities notified, if at 
least one of the following events occur:

Life-threatening (grade 4) toxicity attributable to protocol therapy that is unmanageable, 
unexpected and unrelated to chemotherapy and attributable to CTL019 therapy. High 
fevers, hypotension, hypoxia, disseminated intravascular coagulation, encephalopathy 
(e.g. lethargy, confusion, aphasia, seizures), intensive care unit (ICU) admission, dialysis 
and mechanical ventilation are expected. The expected side effects can also result in grade 
4 liver toxicity, nephrotoxicity and other organ involvement

Death suspected to be related to CTL019 therapy
After the safety run-in stage the study may be paused pending notification of the health 
authorities and the DMC for investigation and possible protocol amendment if any patient 
experiences any of the following events within three weeks of the CTL019 cell infusion:


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
Life-threatening (grade 4) toxicity attributable to protocol therapy that is unmanageable, 
unexpected and unrelated to chemotherapy and attributable to CTL019 therapy.

High fevers, hypotension, hypoxia, disseminated intravascular coagulation, 
encephalopathy (e.g. lethargy, confusion, aphasia, seizures), intensive care unit 
(ICU) admission, dialysis and mechanical ventilation are expected. The expected 
adverse effects can also result in grade 4 liver toxicity, nephrotoxicity and other organ 
involvement.

Death suspected to be related to CTL019 therapy

Any patient develops uncontrolled T cell proliferation beyond 8 weeks from CTL019 
cell product infusion that does not respond to management

Any patient develops detectable replication competent lentivirus (RCL) during the study

The Investigator, Sponsor, DMC, or any independent review board or regulatory body
decides for any reason that patient safety may be compromised by continuing the study

The Sponsor decides to discontinue the development of the intervention to be used in this
study
6.2.4.2
General toxicity management considerations
Patients treated with CTL019 should not donate blood, organs, tissues, sperm, oocytes and cells.
6.2.4.2.1 Expected toxicities
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.
Cytokine Release Syndrome (CRS) / Macrophage Activation Syndrome (MAS)
Data from CTL019 treated patients experiencing CRS show marked elevations in IL-6 and IFN-
g. The symptoms generally occur 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. Renal failure/renal injury, hyperbilirubinemia 
and increased ALT or AST can also occur. Supportive care and anti-cytokine therapy have been 
used for effective management of CRS. Prompt responses to tocilizumab have been seen in 
most patients; Several patients with a suboptimal response to the first dose of tocilizumab have 
received a second or third dose of tocilizumab with CRS resolution. In patients with incomplete 
resolution of CRS after several doses of tocilizumab, CRS resolution has been observed 
following siltuximab administration. 
 
 
 
Fatal outcomes 


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associated with CRS have been observed in adult ALL patients in the context of current 
significant clinical infections. Findings from study UP13413 could imply a higher risk to 
develop CRS in patients with bone marrow involvement (Schuster, unpublished data). 
Accordingly, patients with lymphoma involving the bone marrow should be monitored even 
more closely for signs of CRS.
A detailed treatment algorithm has been established with clear criteria for CRS management 
and guidance on when to administer tocilizumab and siltuximab as presented below in
Figure 6-1 and must be followed by investigators. Tumor necrosis factor (TNF alpha) 
antagonists have been used with CTL019 associated CRS with little evidence for efficacy. 
Given the apparent lack of activity combined with their immunosuppressive effects, TNF 
antagonists are not recommended. This approach was designed to avoid life-threatening 
toxicities, while attempting to allow the CTL019 transduced cells to establish a proliferative 
phase which appears to correlate with tumor response. Patients will be required to remain 
proximal to the treating site for the first 21 days.
The management of CRS is based solely upon clinical parameters as described in Figure 6-1
below. 
 
 Cases of transient left ventricular dysfunction, as assessed by echocardiogram 
(ECHO), have been reported in some patients with severe (Grade 4) CRS. Therefore 
consideration should be given to monitoring cardiac function, by ECHO, during severe CRS, 
especially in cases with prolonged severe hemodynamic instability, delayed response to high 
dose vasopressors, and/or severe fluid overload.
Clinically significant coagulopathy is often seen with moderate to severe CRS (Grade 3 and 4) 
and may continue as CRS is beginning to clinically resolve. Coagulation parameters (PT, aPTT, 
and fibrinogen) should be more frequently monitored in this setting. CTL019 associated 
coagulopathy with or without clinical bleeding and hypofibrinogenemia is strongly 
recommended to be managed with cryoprecipitate of fibrinogen concentrate in addition to 
routine blood product support.CTL019 related CRS can be associated with neurologic events. 
Two types of neurologic events with respect to timing of onset have been observed. Onset of 
neurologic events can be concurrent with high fevers during the development and maximal 
grade of CRS. Delayed onset of neurologic events can also occur as CRS is resolving or after 
CRS has completely resolved. Consideration should be given to monitoring for neurologic 
events during and after resolution of CRS.
A modification of the Common Terminology Criteria for Adverse Events (CTCAE) CRS 
grading scale has also been established to better reflect CTL019-therapy-associated CRS as 
presented in Table 6-1.
Specific CRFs have been developed for the capture of CRS elements, severity, management 
and response to intervention.


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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” vasopressor1 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: IV infusion over 1 hour
●
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:
Consider other diagnosis causing clinical deterioration (i.e. sepsis, adrenal insufficiency)
If no improvement within 1st dose of tocilizumab within 12 to 18 hours, consider steroids (plan rapid taper
after hemodynamic normalization):
2 mg/kg methylprednisolone as an initial dose, then 2 mg/kg per day. As steroids are tapered quickly, 
monitor for adrenal insufficiency and need for hydrocortisone replacement
If no response to steroids within 24 hours, consider 2nd dose of Tocilizumab (dosed 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, adrenal insufficiency)
If no response to steroids and 2nd dose of tocilizumab within 24 hours or further clinical deterioration, 
consider siltuximab 11 mg/kg IV over 1 hour (if available in country).
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, adrenal insufficiency)
In ongoing CRS despite prior therapy, consider anti-T cell therapies such as cyclophosphamide, anti-
thymocyte globulin, or alemtuzumab
Hemodynamic and respiratory support
1 See specific definition of “high dose” vasopressors in Table 6-2 below


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Table 6-1
CTL019 therapy associated grading for cytokine release syndrome: 
The Penn Grading Scale for Cytokine Release Syndrome (PGS-CRS)
●
Marked elevations in IL-6, interferon gamma and less intensely TNF
●
Symptoms occur 1 to 14 days after cell infusion
●Symptoms may include: high fever, rigors, myalgia, arthralgia, nausea, vomiting, anorexia, fatigue, 
headache, hypotension, encephalopathy, dyspnea, tachypnea and hypoxia
1
2
3
4
Mild reaction: Treated 
with supportive care such 
as antipyretics and 
antiemetics.
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 vasopressors, 
coagulopathy requiring 
fresh frozen plasma 
(FFP) or cryoprecipitate
or fibrinogen concentrate, 
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 vasopressors 
(see Table 6-2) or 
hypoxia requiring 
mechanical ventilation.


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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 Vasopressin and Septic Shock Trial (VASST) 
formula)
If on combination vasopressors (not 
vasopressin)
Norepinephrine equivalent of ≥ 20 mcg/min (using VASST formula)
Vasopressin and Septic Shock Trial (VASST) Equivalent Equation:
Norepinephrine equivalent dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + [epinephrine
(mcg/min)] + [phenylephrine (mcg/min) ÷10]
Criteria from Russell et al (2008)
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 ≥ 4.5 mg/dL 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 IV fluids and 
rasburicase if uric acid levels remain elevated, and consider in hospital monitoring.


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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 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).
Neurological adverse reactions
Neurological events, including events indicative of encephalopathy and delirium of non-
infectious origin, have been observed in patients following various types of T cell directed 
therapy including CTL019 and other CAR-T cell therapies of other institutions. The 
pathophysiology for neurological events, in particular in case of late events, is not fully 
understood but thought to be related to generalized T-cell mediated inflammation rather than 
direct toxicity of CAR-T-cells on the brain (Tey 2014). Some of the neurological events 
observed may be related to CRS, but whether this results from systemic cytokines crossing the 
blood brain barrier and engaging cytokine receptors in the brain or from direct cytokine 
production in the CNS is not clear (Maus et al 2014). There are no obvious predictors of 
neurologic toxicity. Confounders, such as preceding or newly induced anti-cancer treatment 
regimens, might be involved.
Early neurological events are the second most-common adverse reaction associated with CAR-
T therapies. In attempt to standardize the assessment of these events, the CARTOX working 
group has suggested the name CART-cell- related- encephalopathy syndrome (CRES) (Neelapu 
et al 2018). This syndrome is described as a toxic encephalopathy with a wide range of variable 
symptoms such as aphasia, confusion, delirium, tremors, occasionally seizures and rarely life-
threatening cerebral edema. The manifestation of CRES is biphasic, with the first phase 
occurring concurrently with cytokine release syndrome (CRS) symptoms typically within the 
first 5 days after CAR-T-cell therapy, and the second phase after CRS subsides. Delayed 
neurological events with seizures or episodes of confusion 3-4 weeks following CAR-T-cell 
therapy have been reported to occur in approximately 10% of patients.
In clinical trials, the majority of neurological events following CTL019 infusion were observed 
within 8 weeks, however, neurological events with later onset > 8 weeks and not in the context 
of CRS have also been reported. Most neurological events observed within 8 weeks were 
transient or self-limiting in nature. Frequently, encephalopathy, confusional state and delirium 
were observed. Other manifestations include a multifarious set of signs and symptoms including 
seizures, aphasia, speech disorder, and tremor. Some of the events are severe and may have a 
life-threatening outcome. 


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Notably, the onset of neurological events after CTL019 infusion can be concurrent with CRS, 
following resolution of CRS or in the absence of CRS. The incidence appeared to be greater 
with higher CRS severity and prior history of CNS leukemia and history of other prior CNS 
diseases. Encephalopathy typically occurred after peak CRS symptoms and tended to be self-
limiting with some exceptions. Delayed onset of neurological events may also occur as CRS is 
resolving or after CRS has completely resolved.
The causality assessment of neurological events in patients treated with CTL019 can be 
confounded, as CNS toxicity can be associated with chemotherapy used for lymphodepletion 
and the presence of co-morbid conditions such as CRS, fever and infections.
Prolonged depletion of normal B cells and hypogammaglobulinemia
Based on previous clinical experience, it is likely that CTL019 therapy will result in B cell
depletion and hypogammaglobulinemia. Experience with CTL019 therapy shows that patients 
with persistent B cell aplasia demonstrate hypogammaglobulinemia which has been managed 
with immunoglobulin therapy. In the event of hypogammaglobulinemia, patients should be
considered for immunoglobulin therapy per local clinical practice guidelines.
Infections and infectious complications
Depletion of B cells with resulting hypogammaglobulinemia is expected as a result of CTL019 
on target effects. CTL019 related hypogammaglobulinemia is typically managed with 
immunoglobulin replacement therapy dependent upon age specific, disease specific and local 
institutional guidelines. Immunoglobulin replacement during the study period will be recorded. 
In general B cell aplasia and hypogammaglobulinemia, of various causes, can be associated 
with increased rates of infection. Such infections are typically sinopulmonary but other sites 
and types of infections have also been reported.
Institutional guidelines for vaccination (e.g. pneumococcus) should be followed before starting 
CTL019 therapy. No live vaccines should be used in CTL019 recipients or prospective 
recipients as the lack of effective B cells after infusion makes the likelihood of a systemic 
infection considerable and the value negligible.
Other potential complications of B cell
aplasia include progressive multifocal 
leukoencephalopathy (PML) and reactivation of hepatitis B virus.
For the first 12 months of the study, all data on infections will be collected for patients in the 
primary follow-up. After 12 months for CTL019 treated patients or if patients move to the 
secondary follow-up, 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
Viral Reactivation
Patients with active hepatitis B or active hepatitis C have been excluded from clinical studies 
with CTL019, because of the potential risk of viral reactivation and the risk of fulminant 
hepatitis, hepatic failure and fatal outcome. HIV positive patients have been also excluded, 
because of the possible effect on HIV viral suppression. 


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In addition, there is currently no experience with manufacturing CTL019 for patients testing 
positive for HBV, HCV and HIV. Patients are to be screened for any active HBV, HCV or HIV 
infection prior to leukapheresis.
Subjects with active hepatitis B or hepatitis C or subjects with HIV confirmed by serology will 
not be enrolled in the study.
Hematological disorders including cytopenias
The etiology of cytopenias is multifactorial, likely reflecting a combination of effects from the
underlying disease, cytotoxicity from prior anticancer treatment, bridging chemotherapy during
the CTL019 manufacture waiting time and conditioning lymphodepleting chemotherapy just
prior to CTL019 infusion in addition to the CAR-T cell therapy per se, which is frequently
associated with B-cell aplasia as on-target effect. Prolonged hematological cytopenias and
hematological disorders are considered a sequelae.
6.2.4.2.2 Potential toxicities
Cerebral Edema
Five fatal cases of cerebral edema occurred in the ROCKET study in adult ALL treated with 
JCAR015 and were characterized by a rapid evolution soon after JCAR15 infusion appeared to 
be resistant to anti-cytokine treatment, and ensued brain death within 1-2 days after diagnosis. 
 
 
No fatal cerebral edemas have been reported following CTL019 infusion in the clinical 
development program or the post-marketing setting to date that would resemble the clinical 
course reported for JCAR015. JCAR015 presents a different construct of an anti-CD19 CAR-
T-cell product compared to CTL019.
Replication-competent lentivirus (RCL) testing
Replication-competent lentivirus (RCL) may be generated during CTL019 manufacturing using 
a lentiviral vector to encode anti-CD19 CAR or subsequently after introduction of vector 
transduced viable T cells into the patient. However, RCL resulting from manufacturing is highly 
unlikely since elements are incorporated in the design of the vector system that minimize vector 
recombination and generation of RCL. Furthermore, the vector used to transduce the product 
undergoes sensitive assays for detection of RCL. Thus patients will only receive cell products 
that meet RCL release criteria considered sufficient to confirm the absence of RCL in CTL019
and the negligible probability of de novo generation of any RCL. None of the subjects tested in 
the development program showed evidence of RCL. However, generation of an RCL following 
CTL019 infusion remains a theoretical possibility. The development of RCL could pose a risk 
to patients and therefore, monitoring for RCL will be conducted during the course of the trial 
(see Product Handling Manual for a description of the assays). Blood samples for RCL testing 
will be collected as per Table 7-1. If blood samples test are negative through Month 12, all 
samples taken after Month 12 will be stored for potential future testing. Additional, unscheduled 
samples for RCL testing, for persistence testing of CAR transgene sequences, and/or for B and 
T-cell enumeration can be collected anytime on a case-by-case basis. If a positive RCL assay 


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result is obtained from a patient blood specimen, (as detected by Vesicular Stomatitis 
Virus/Glycoprotein (VSV-G) qPCR, for example) the Investigator will be informed and the 
patient rescheduled for a retest of the DNA test. , 
As per guidance for gene therapy medicinal products, patients exposed to CTL019 will be 
monitored for 15 years following last treatment for vectors persistence and RCL within the 
long-term follow-up study. In case of suspected secondary malignancies, as per the guidance 
“Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent 
Retrovirus During Product Manufacture and Patient Follow-up” (FDA 2020), biopsy sample of 
neoplastic tissues or relevant autopsy tissues will be collected for RCL testing.
Secondary malignancies (including vector insertion site oligo/monoclonality)
Secondary malignancies in cancer patients, i.e., newly occurring malignancies other than the 
primary malignancy (e.g., T-cell and non-T-cell hematological malignancies, solid tumors), can 
be increased as a result of both previous chemotherapy and radiation therapy exposure and 
partly due to increased rates within families (Friedman et al 2010). The rate of new malignancy 
detection following CTL019 therapy will need to take into account these additional 
confounding risk factors.
Transduction of a patient’s T cells with the lentiviral vector could lead to insertional 
mutagenesis resulting in an uncontrolled T-cell proliferation and an oncogenic effect that could 
result in a T-cell and non-T-cell malignancies. 
Ruella et al. (2018) reported a B-cell ALL patient treated in an early clinical study at the 
University of Pennsylvania (UPenn) / Children’s Hospital of Philadelphia with CTL019 as 
manufactured by UPenn. The patient showed an initial response to treatment and relapsed 9 
months after infusion with CD19-negative leukemia cell that aberrantly expressed the anti-
CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during 
CAR-T cell manufacture at Penn and its product bound in cis to the CD19 epitope on the surface 
of leukemic cells, masking it from recognition by and conferring resistance to the CAR-T. 
 
 
 
 
CTL019 uses third generation self-inactivating lentiviral vector to safeguard against the 
potential oncogenic effects. Insertional mutagenesis was evaluated in two lentivirus insertion 
site analysis (LISA) studies where 12 batches of manufactured patient product ready for 
infusion and two batches of product manufactured from healthy donor cells were analyzed. The 
results indicate that there was no preferential integration near genes of concern, no preferential 
sites of integration (hot spots), and no preferential outgrowth of cells harboring integration sites 
of concern.
CTL019 is based on autologous, fully differentiated T cells and therefore the carcinogenicity 
risk is considered to be low in comparison to genetic modification or repair such as HSC gene 
therapy. In a recent review of CAR-T cell therapies, Bonifant et al (2016) as well as Mohanlal 
et al (2016) discussed that to date no cases of malignant transformation have been reported for 


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genetic modification of T cells and that there currently is no evidence for vector-induced 
immortalization, clonal expansion, or enrichment for integration sites near genes implicated in 
growth control or transformation. This is supported by the results of the lentivirus insertion site 
analysis (LISA) studies performed during the development of CTL019.
Theoretically, CAR-positive viable T cells could proliferate without control of normal 
homeostatic mechanisms. In pre-clinical studies (Milone et al 2009) and clinical experience to 
date (Porter et al 2011, Grupp et al 2013, Maude et al 2014), CAR-positive viable T cells have 
only proliferated in response to physiologic signals or upon exposure to CD19 antigen. In the 
context of 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 either harmful 
depending on the extent of proliferation or beneficial, since clonal dominance of adoptively 
transferred T cells has been associated with tumor reduction in adoptive transfer trials (Dudley 
2002, Dudley 2005).
All secondary malignancy should be managed/treated according to current medical practice and 
local standard of care. 
For the follow-up of secondary malignancy, please refer to Section 8.10.
CTL019
6.2.5
Criteria for discontinuing a patient’s participation in the study
If a patient develops a condition that precludes CTL019 infusion after enrollment but before 
infusion, the patient will be prematurely discontinued. This will be done at the judgment of
the PI, and could include for example, the occurrence of an intercurrent illness requiring the 
institution of systemic immunosuppression.
6.2.6
Concomitant Therapy
Clinically significant prescription and nonprescription medication, excluding vitamins, and 
herbal and nutritional supplements, and procedure-related (inpatient or outpatient) medications
taken by the patient during the 30 days prior to screening will be recorded. At every visit 
following the screening visit up to the month 60 visit, concomitant medications will be recorded 
in the medical record and on the appropriate CRF.
During selected trial phases concomitant medication collection will be modified as outlined in
Appendix 3: CTL019 Modified Data Reporting- Treatment and Primary Follow Up Phase,
Appendix 4: CTL019 modified data reporting – Secondary Follow Up Phase, CRF Completion 
Guidelines (CCGs), and Table 6-3 below. Modified collection of concomitant medications 
during these periods are designed to capture CTL019-related toxicity, severity, interventions 
and response/resolution following intervention. Any additions, deletions, or changes of these 
medications will be documented.


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Table 6-3
Concomitant medication reporting by study period
Study period
Inpatient/ICU
Outpatient
Pre-treatment period (ICF to LD chemo/pre-infusion)
Modified
Modified
Treatment period (LD chemo/pre-infusion through M12)
Modified
All concomitant medications
Post-treatment period (after M12 through M60)
Modified
Modified
The following guidelines must be adhered to during the study:

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 long acting G-CSF 
should not be given within 10 days of CTL019 infusion. The effects of granulocyte colony 
stimulating factor (G-CSF) on the other hand, are unknown.

Steroids or other immunosuppressant drugs should NOT be used as pre-medication for 
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
The following medications are excluded:
a.
Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to leukapheresis 
and > 72 hours prior to CTL019 infusion. However, the following physiological 
replacement doses of steroids are allowed: <12 mg/m2/day hydrocortisone or equivalent
b. Immunosuppressive therapies: Any drug used for immunosuppression must be stopped ≥ 
2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include 
check point inhibitors (monoclonal antibodies and small molecule modulators).
c.
Antiproliferative therapies other than lymphodepleting chemotherapy within 2 weeks of 
leukapheresis and 2 weeks prior to infusion.

Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, 
and hydroxyurea) must be stopped > 72 hour prior to leukapheresis and > 72 hours prior 
to CTL019 infusion

Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, 
must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to 
CTL019 infusion.

Fludarabine may be associated with prolonged lymphopenia. This should be taken into 
consideration when evaluating the optimal timing for apheresis collection.
Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of 
the respective antibody, whichever is longer. Note: Rituximab is excluded within 4 weeks prior 
to infusion.


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d. CNS disease prophylaxis must be stopped > 1 week prior to CTL019 infusion (e.g. 
intrathecal methotrexate)
e.
Investigational therapies must not be used at any time while on study until the first 
progression following CTL019 infusion.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
Not applicable
6.3.2
Follow-up for toxicities
6.3.2.1
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational treatment, a standardized process for identification, monitoring and evaluation 
of liver events has to be followed.Liver events are divided into two categories:

Liver events of special interest (AESI) which consist of elevated transaminases and/or 
bilirubin (elevated liver function tests (LFTs))

Medically significant liver events which are considered as serious adverse events (SAEs) 
and which consist of marked elevations of LFTs and / or pre-specified adverse events.
Please refer to Appendix 5 Section 14.5.1 for complete definitions of liver events.
Any liver event which meets the criteria for “medically significant” event as outlined in 
Appendix 5 Section 14.5.1 should follow the standard procedures for SAE reporting as 
described in Section 8.2.
Every liver event as defined in Appendix 5 Section 14.5.1 should be followed up by the 
investigator or designated personal at the trial site as summarized below. Detailed information 
is outlined in Appendix 5 Section 14.5.2. .

Repeating the LFT to confirm elevation as appropriate

Hospitalization of the patient if appropriate

A causality assessment of the liver event via exclusion of alternative causes (e.g., disease, 
co-medications)

An investigation of the liver event which needs to be followed until resolution.
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded on appropriate CRF pages.
For additional details please refer to Section 6.2.4
6.3.2.2
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with total bilirubin increase may be indicative 
of potential DILI and should be considered as clinically important events.


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The threshold for potential DILI may depend on the subject’s baseline AST/ALT and total 
bilirubin value; subjects meeting any of the following criteria will require further follow-up as 
outlined below:

For subjects with normal ALT and AST and total bilirubin value at baseline: AST or ALT 
> 3.0 x ULN combined with total bilirubin > 2.0 x ULN

For subjects with elevated AST or ALT or total bilirubin value at baseline: [AST or ALT > 
3 x baseline] OR [AST or ALT > 8.0 x ULN], whichever occurs first, combined with [total 
bilirubin > 2.0 x baseline AND > 2.0 x ULN]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be
considered and their role clarified before DILI is assumed as the cause of liver injury.
A detailed history, including relevant information such as review of ethanol consumption,
concomitant medications, herbal remedies, supplement consumption, history of any preexisting
liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT,
prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase. If
available, testing of Glutamate Dehydrogenase (GLDH) is additionally recommended.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT,
MRI, or duplex sonography.
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of
cholestasis. Cholestasis is defined as an ALP elevation > 2.0 x ULN with R value < 2 in
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in
participants with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury.
Table 6-4 provides guidance on specific clinical and diagnostic assessments which can be
performed to rule out possible alternative causes of observed LFT abnormalities.


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Table 6-4
Disease
Assessment 
Hepatitis A, B, C, E
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-HCV, HCV 
RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
Antinuclear Antibodies (ANA) & Anti-
Smooth Muscle Antibody (ASMA) titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic steatohepatitis
Ultrasound or MRI
Hypoxic/ischemic hepatopathy
Medical history: acute or chronic 
congestive heart failure, hypotension, hypoxia, hepatic venous occlusion. 
Ultrasound or MRI.
Biliary tract disease
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs old)
Caeruloplasmin
Hemochromatosis
Ferritin, transferrin
Alpha-1 
antitrypsin deficiency
Alpha-1-antitrypsin
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes / glycogenic hepatitis).
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of a serious adverse event (SAE) and should be 
reported as SAE using the term “potential treatment-induced liver injury.” All events should be 
followed up with the outcome clearly documented.
6.3.2.3
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:
1. Serum creatinine increase ≥ 25% compared to baseline during normal hydration status
2. Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR new onset dipstick 
proteinuria ≥ 3+ OR new onset dipstick hematuria ≥ 3+ (after excluding menstruation, 
urinary tract infection, extreme exercise, or trauma)
Renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first assessment 
(select as applicable: for Phase 2 and Phase 3).
Every renal laboratory trigger or renal event should be followed up by the investigator or 
designated personnel at the trial site as summarized in Section 14.6.1 (Specific Renal Alert 
Criteria and Actions) in Appendix 6.
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Upon informed consent completion, the patient will initiate screening. Each patient is identified 
in the study database by a Subject Number (Subject No.), that is assigned sequentially at each 
site by IRT when the patient is first enrolled for screening and is retained as the primary 


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Protocol No. CCTL019C2201
identifier for the patient throughout his/her entire participation in the trial. The Subject No. 
consists of the four digit Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential three digit patient number suffixed to it, so that each subject 
is numbered uniquely across the entire database.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject 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 entered into the appropriate CRF page.
IRT must be notified within 2 days that the patient was not treated.
6.4.2
Treatment assignment
This is a single-arm open-label study. Patients will be enrolled and assigned to treatment upon 
confirmation of all clinical eligibility criteria by the investigator, and acceptance of the 
leukapheresis product for manufacturing.
6.4.3
Treatment blinding
This is an open-label study.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol No. CCTL019C2201


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Protocol No. CCTL019C2201
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments through the end of the Treatment and Primary Follow-up 
phase (Section 7.1.1, Section 7.1.2 and 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 an 
observational 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 when the patient discontinued from the Treatment and Primary Follow-
Up Phase since CTL019 infusion. For example, if the patient discontinued from the Treatment 
and Primary Follow-Up phase at Month 10, the first visit in the Secondary Follow-Up Phase 
will be Month 12. Table 7-2 lists all of the assessments through the end of the Secondary 
Follow-up phase (Section 7.1.4).
In each table, required assessments are indicated with an “X” at the visits when they are 
performed. The letter (D) in Table 7-1 and Table 7-2 under the category column indicates the 
assessments that will have data entered into the clinical database and (S) is for assessments that 
will have data remain as source documentation. All data obtained from these assessments must 
be supported in the patient’s source documentation.
No CRF will be used in the patient’s source documentation.


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Protocol No. CCTL019C2201
Table 7-1
Primary visit evaluation schedule
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Obtain Informed 
Consent
D
7.1.1
X
IWRS/IRT 
Registration
S
X
X
X
X
Patient history
Demography
D
7.1.1
X
Inclusion/exclusion 
criteria
D
5.2
5.3
X
Medical history
D
7.1.1
X
Prior antineoplastic 
therapy
D
7.1.1
X
Prior/concomitant 
medications
D
6.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications 
(selected)
D
6.2.6
X
X
X
X


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Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Antineoplastic 
therapies after 
CTL019 infusion
D
7.1.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central confirmation 
of diagnosis and 
subtype 
determination (FFPE 
tumor biopsy)
D
7.2.1
X
Physical assessments
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Performance status
D
7.2.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Pulse oximetry
D
7.2.2.2
X
X
X
X
X
X
X
MUGA/ECHO
D
7.2.2.6
X
Electrocardiogram 
(ECG)
D
7.2.2.6
X
X
Intervention
Leukapheresis
D
4.1.1
X
Leukapheresis pre-
evaluation and 
acceptance
S
4.1.1
X
Lymphodepleting 
chemotherapy
D
6.1.1.1
X
CTL019 infusion 
prerequisite 
assessment
S
6.1.1.2
X
CTL019 transduced 
cell infusion
D
6.1.1.2
X


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Efficacy assessments
B-symptoms
D
7.2.1
X
X
X
X M3 
&M6 
only
X
X
X
X
X
Imaging (CT/MRI)
D
7.2.1
X
X (if no 
PET-
CT)
X
X
M3 
(if no 
PET 
CT) & 
M6 
only
X
X
X
X
Imaging (PET-CT) 
D
7.2.1
X 
(within 
4
weeks
prior to 
infusion
)
X
M3 
only


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Local response 
assessment
D
7.2.1
X
X
X 
M3 & 
M6 
only
X
X
X
X
Bone marrow biopsy 
and/or aspirate 
D
7.2.1
X
X only if 
CR and if 
prior BM 
involvemen
t
X M3 
only
At time of radiological CR
CSF cytology
D
7.2.1
X
As clinically indicated
CNS Imaging 
(CT/MRI)
S
7.2.1
As clinically indicated


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Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Safety assessments
Adverse events
D
8.1
8.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Protocol defined 
Adverse events and 
AEs of special 
interest, including 
new malignancies
D
8.1
8.2
X
X
X
X
Pregnancies
D
7.2.2
X
X
X
X
X
X
Laboratory 
assessments
Hematology
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central flow 
cytometry before 
leukapheresis 
(peripheral blood)
D
7.1.1
X


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Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Central flow 
cytometry (fresh 
leukapheresis 
product) 
D
7.1.1
X
Pregnancies
D
7.2.2.5
X
X
X
X
X
Serum or Urine 
pregnancy test
S
7.2.2.5
X
X
X 
(Ser
um)
Viral serology (CMV, 
EBV, HIV, HbsAg, 
HBsAb, HBcAb, HCV 
RNA)
D
7.2.2.5
X
Coagulation (PT, 
aPTT, INR, 
fibrinogen, D-dimer)
D
7.2.2.5
X
X
X
X
X
Serum 
immunoglobulin 
levels (IgG, IgA, IgM)
D
7.2.2.5
X
X
X
X
X 
M3 
&M6 
only
X
X 


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Urinalysis
D
7.2.2.5
X
Rapid Influenza
(A and B) Testing
D
6.1.1.2
7.1.2
7.2.2.5
Within 10 days 
of infusion


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
CTL019 PK, 
 and safety assessments
Serum 
(immunogenicity, 
cytokines, etc.)
D
7.2.3
7.2.4
X
X
X
X
X
X
X
X
X
X
X 
M3 
&M6 
only
X
M12 
only
X 
M24 
only
X 
M3
6 
onl
y
X


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
CTL019 
 
 
 
 
 
 
D
7.2.3
see (Table 7-14, Table 7-15)
CTL019 
pharmacokinetics by 
qPCR (peripheral 
blood)
D
7.2.3
X
X
X
X
X
X
X
X
X
X
X 
M2 
M3 
M6 
only
X
X
X
X
X
CTL019 
pharmacokinetics by 
flow cytometry 
(peripheral blood)
D
X
X
X
X
X
X
X
X
X
X
M2
M3
M6
Only
X
X 
M18 
only
X


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Tumor biopsy 
D
7.2.3
7.2.4
X
X M3 
only
As clinically indicated
CTL019 
pharmacokinetics -
CSF (CTL019 PK, 
)
D
7.2.3
X
As clinically indicated
CTL019 
pharmacokinetics -
Bone marrow 
(CTL019 PK by 
qPCR)
D
7.2.3
X
X only if 
CR
X M3 
only
As clinically indicated
CTL019 
pharmacokinetics -
Bone marrow (flow 
cytometry)
D
7.2.3
X
X only if 
CR
X 
M3 
only
As clinically indicated


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
RCL by VSV-g q-
PCR
D
7.2.2.5
X
X 
M3 
&M6 
only
X 
M12 
only
X 
M24
only
X
X
Leukapheresis 
sample for correlative 
studies
D
7.1.2
X
CTL019 cell product 
sample for correlative 
studies
D
7.1.2
X


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Phase
Category
Protocol Section
Screening
Pre-Treatment
Treatment and Primary Follow-up
Survival Follow-up after 
study completion
Visit Name
Enrollment/Pre-
Lymphodepleting 
Chemotherapy
Pre-infusion
Infusion
Post-infusion
End of Treatment and 
Primary Follow-up
Study day
W-8 to W-4
W-3 to D-8
W-2 to 
D-5
D -1
D1
D2
D4 ±1d
D 7 ±1d
D 11 ±1d
D 14 ±1d
D 17 ±1d
D 21 ±3d
D 28 ±7d
M2 M3 M4 M5 
M6 ±14d
M9 M12 ±14d
M18 M24 ±14d
M30 M42 M54 
±14d
M36 M48 ±14d
M60 ±14d
q 3m
Survival follow-up
D
7.1.5
For all patients who receive a CTL019 infusion, follow-up for survival every 3 months until end 
of study or enrolling into the long term follow-up, whichever comes first. If a patient misses a 
quarterly scheduled visit where survival status is required, or if the time-point does not align 
with a scheduled visit, survival status can be obtained via phone contact
X
End of phase 
disposition
D
n/a
X
X
X


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Amended Protocol Version 06 (Clean)
Protocol No. CCTL019C2201
Table 7-2
Secondary follow-up visit evaluation schedule (for patients who end their primary follow up before M60)
Phase
Category
Protocol Section
Secondary Follow-up
Survival Follow-up
after study completion
Visit Name
Post-infusion
End of Secondary 
Follow-up
Study day
M2 
±14d
M3 
±14d
M6 
±30d
M9 
±30d
M12 
±30d
M18 
±60d
M24 
±60d
M30 
±60d
M36 
±60d
M42 
±60d
M48 
±60d
M54 
±60d
M60 
±60d
q 
3m
Concomitant medications (selected)
D
6.2.6
X
X
X
X
X
X
X
X
X
X
X
X
X
Antineoplastic therapies after CTL019 
infusion 
D
7.1.5
X
X
X
X
X
X
X
X
X
X
X
X
X
IWRS/IRT Registration
S
X
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
Performance status
D
7.2.2.4
X
X
X
X
X
X
X
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
Efficacy assessments
Current status of primary malignancy
(only until patient progresses)
D
7.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety assessments
Protocol defined Adverse events and 
AEs of special interest, including new 
malignancies
D
8.1
8.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancies
D
7.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum or Urine Pregnancy Test
S
7.2.2.5
X
X
X
X
X
X 
(Serum)
Hematology (CBC & differential)
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X


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Phase
Category
Protocol Section
Secondary Follow-up
Survival Follow-up
after study completion
Visit Name
Post-infusion
End of Secondary 
Follow-up
Study day
M2 
±14d
M3 
±14d
M6 
±30d
M9 
±30d
M12 
±30d
M18 
±60d
M24 
±60d
M30 
±60d
M36 
±60d
M42 
±60d
M48 
±60d
M54 
±60d
M60 
±60d
q 
3m
Serum (immunogenicity, cytokines, etc.)
D
7.2.3
7.2.4
X
X
X
CTL019 transgene persistence 
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
Peripheral blood (B and T cell levels in 
blood by flow cytometry)
D
7.2.2.5
X
X
X
X
X
X
X
RCL by VSV-g q-PCR
D
7.2.2.5
X
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
End of phase disposition
D
n/a
X


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7.1.1
Screening phase
After informed consent/assent is obtained, blood tests and assessments to determine eligibility 
as outlined below are performed.
Patients who have signed an informed consent/assent will be registered in the IRT system and 
undergo a routine lymphoma staging workup including:
a. Demography
b. Medical history and prior/concomitant medications and antineoplastic therapies
c. Tumor biopsy. A FFPE tumor sample obtained for the purpose of this study must be 
submitted, however if not clinically feasible, an archival tumor biopsy at most recent 
relapse may be submitted instead. Excisional biopsies should be submitted wherever 
possible; in cases where this is not possible, a core needle biopsy is allowable. Fine needle 
aspiration (FNA) is not allowed. If possible, an additional fresh frozen biopsy sample 
should be obtained for exploratory analysis.
d. Central pathology assessment of tumor biopsy

subtype determination
e. Physical Examination (PE) including height, weight, vital signs, extramedullary disease 
assessment and CNS symptom assessment
f.
Performance status (ECOG)
g. Pulse oximetry
h. MUGA or ECHO
i.
ECG
j.
B-symptom assessment
k. Imaging (CT/MRI). Local assessment will be used to determine eligibility
l.
Bone marrow biopsy and/or aspirate
m. CSF cytology
n. CNS Brain Imaging (MRI/CT) (if clinically indicated)
o. Hematology
p. Chemistry Panel
q. Serum pregnancy test (if female of childbearing potential)
r.
Viral serology (CMV, EBV, HIV, HbsAg, HBsAb, HBcAb, HCV RNA). If HIV screening 
test is positive then a confirmatory HIV test is required to be performed as per current 
local guidelines (see Appendix 2 for interpretation of Hepatitis B results)
s.
Coagulation panel
t.
Serum immunoglobulin levels (IgG, IgA, IgM)
u. Flow cytometry
v. Urinalysis
x. Adverse events


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The below assessments do not need to be repeated if performed in the context of the 
leukapheresis protocol [CCTL019B2206] or if performed as part of clinical routine within 4 
weeks of the signature of the CCTL019C2201 ICF:
a. Central flow cytometry
b. Serum immunoglobulin levels (IgG, IgA, IgM)
c. Viral serology (CMV, EBV, HIV, HbsAg, HBsAb, HBcAb, HCV RNA). If HIV screening 
test is positive then a confirmatory HIV test is required to be performed as per current 
local guidelines (see Appendix 2 for interpretation of Hepatitis B results)
7.1.1.1
Criteria for repeating screening procedures prior to CTL019 infusion
In the event that the time between screening assessment and the enrollment exceeds 8 weeks 
the following must be repeated: ECHO/MUGA, ECG, performance status assessment,
Complete Blood Count with differential and Platelet Count, Chemistry Panel, Coagulation 
Panel, Urinalysis, Serum Pregnancy test.
In the event that the time between screening assessment and enrollment exceeds 12 weeks, the 
below screening procedures must be repeated in addition to the above:
a. Physical Examination (PE) including height, weight, vital signs, extramedullary disease 
assessment and CNS symptom assessment
b. Pulse oximetry
c. Imaging (PET-CT or FDG-PET+CT/MRI)
d. Bone marrow biopsy and/or aspirate only if suspected or known bone marrow 
involvement
e. CSF cytology only if suspicion of CNS involvement
f.
CNS Brain Imaging (MRI/CT) (if clinically indicated)
7.1.1.2
Eligibility screening and enrollment
For detailed enrollment procedures, including use of Interactive Response Technology (IRT), 
please refer to the IRT User Manual.
Only following informed consent to study CCTLC2201 information on the patient’s apheresis 
product will be transferred to Novartis manufacturing. Novartis manufacturing will then 
evaluate the patient’s apheresis product for acceptance. For sites performing the leukapheresis 
as part of this protocol leukapheresis can only be performed after patient consent has been 
obtained.
Enrollment is defined as the point at which a patient meets all clinical inclusion/exclusion 
criteria and the patient’s apheresis product is accepted for manufacturing. The patient is then 
enrolled using the same Subject No. assigned at screening by the site investigator or designated 
staff. Once assigned, the Subject No. must not be reused for any other patient and the Subject 
No. for that individual must not be changed. If a screened patient is not enrolled for any reason, 
the specific reason will be entered into the clinical database.


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IRT will continuously monitor the enrollment of different molecular DLBCL subtypes to ensure 
that a minimum of 25 patients are treated in each of the GC and ABC subtypes.
IRT Registration: To document screening and enrollment into the study, the IRT will be 
contacted initially after informed consent/assent is obtained and again after eligibility is 
confirmed. Furthermore infusion of CTL019 must be confirmed in the IRT system within 24 
hours of infusion.
7.1.1.3
Information to be collected on patients not enrolled
The reason for not being enrolled will be entered in the clinical database. The demographic 
information, informed consent, Inclusion/Exclusion pages and any adverse events leading to 
subject discontinuation must also be completed for patients not enrolled. No other data will be 
entered into the clinical database for patients who are not enrolled.
7.1.2
Pre-treatment phase
For details of assessments, refer to Table 7-1.
Enrollment/Pre-chemotherapy evaluation visit (W-3 to D-8)
Prior to start of lymphodepleting therapy (the day before or on the day of the scheduled
lymphodepleting chemotherapy regimen is to begin) the patient will undergo blood collection 
for safety 
ssessments 
 
, humoral & cellular immunogenicity and RCL by VSV-G qPCR. In addition, 
adverse events and prior/concomitant medications will be reviewed. Viably frozen 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-5) It is anticipated that many patients will 
have been receiving chemotherapy for relapse or resistant disease. Prior to CTL019 cell infusion 
and after apheresis, one cycle of lymphodepleting therapy is planned, if patients are not already
lymphopenic. The use of additional chemotherapy prior to the recommended preinfusion 
lymphodepleting therapy will be at the discretion of the investigator and dependent on the 
patient’s disease burden. 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, 
however a visit should still occur during this time window, and required assessments should be 
completed.
At this visit patients will undergo blood test for hematology and chemistry, a pregnancy test (all 
female patients of childbearing potential), rapid influenza testing and in addition, the patients 
weight, adverse events and prior/concomitant medications will be reviewed. For patients who 
do receive lymphodepleting therapy, this visit should occur within 24 hours of starting 
lymphodepleting chemotherapy.
Lymphodepleting therapy should be started 14 to 5 days before CTL019 infusion (D1) to allow 
for at least 48 hours from last dose of lympodepleting therapy to CTL019 infusion. The purpose 
of the lymphodepleting therapy is to induce lymphopenia in order to facilitate engraftment and 
homeostatic expansion of CTL019 cells. Fludarabine (25 mg/m2 i.v. daily for 3 doses) and 
cyclophosphamide (250 mg/m2 i.v. daily for 3 doses starting with the first dose of fludarabine) 


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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.
Note: All patients must undergo a rapid influenza diagnostic test 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 signs and symptoms are present, CTL019 infusion should be delayed until 
the patient is asymptomatic.
For patients residing in the United States, Canada, Europe and Japan, influenza testing is 
required during the months of October through May (inclusive). For patients residing in the 
southern hemisphere such as Australia, influenza testing is required during the months of April 
through November (inclusive). For patients with significant international travel, both calendar 
intervals above may need to be considered.
A PET-CT (or CT/MRI and dedicated FDG PET when PET-CT not available) must be 
performed within four weeks prior to scheduled infusion of the CTL019 product, and should be 
scheduled as close to CTL019 infusion as possible. This imaging assessment will form the 
baseline for all subsequent efficacy evaluations. B-symptoms will also be evaluated at that time.
Pre-infusion visit (D-1)
On the day prior to the scheduled CTL019 infusion, patients will undergo a physical exam 
(including vital signs), a performance status assessment, blood collection for safety
assessments and humoral & cellular immunogenicity. In addition, adverse events 
and prior/concomitant medications will be reviewed.
If at this point the patient does not enter the study, this must be indicated in the IRT system.
7.1.3
Treatment and primary follow-up phase
For details of assessments, refer to Table 7-1.
Infusion visit (D1)
Infusions will begin 2 to14 days after completion of lymphodepleting chemotherapy.
The day of (but prior to) the CTL019 infusion, patients will undergo a physical examination 
including weight, a performance status assessment, pulse oximetry, ECG, and blood tests 
including chemistry, a CBC with differential, and coagulation panel. Final CTL019 infusion 
pre-requisites (including an ECG and a rapid influenza test) will be checked prior to infusion 
(per Section 6.1.1.2).
CTL019 transduced T cells will be given as a single dose with a target of 5 x 108 CTL019 
transduced cells. Vital signs will be monitored before and following CTL019 infusion (per 
Section 6.1.1.2). An additional 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.


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For all patients who receive a CTL019 infusion, additional follow-up will be made to 
determine survival every 3 months. If a patient misses a quarterly scheduled visit where 
survival status is required, or if the quarterly time-point where survival status is required does 
not align with a scheduled visit, survival status can be obtained via phone contact, and the 
survival eCRF must be entered.
Post-infusion visits: D2, D4±1d, D7±1d, D11±1d, D14±1d, D17±1d, D21±3d
At the intervals following infusion listed above, patients will undergo one or more of the 
following: blood tests including chemistry, hematology, coagulation, serum immunoglobulin, 
humoral & cellular immunogenicity, 
 flow cytometry (b cells, 
 and CD19 assessment), a physical exam (with vital signs), performance status 
assessment and pulse oximetry. In addition, adverse events and prior/concomitant medications 
will be reviewed.
Weekly sample collections for serum cytokines, CTL019 PK, 
 
 are mandated during the first 28 days following CTL019 infusion. However, 
as the time-course and rapidity of CRS development varies among patients, additional 
unscheduled samples for these markers may also be collected as needed, if it is clinically 
feasible.
 
 
 
 
 
Please note that results of cytokine analyses are NOT to be used for clinical management 
decisions of CRS. A detailed treatment algorithm has been established with clear criteria for 
CRS management (see Figure 6-1).
For details of assessments at each visit, refer to Table 7-1.
Post-infusion visit (D28 ±7d)
Patients will undergo blood collection for hematology, chemistry, coagulation, serum 
immunoglobulins, cytokines, flow cytometry (B cells, 
 and CD19 assessment) 
humoral and cellular immunogenicity, and CTL019 PK,
 
Patients will also have their B-symptoms assessed, Imaging (CT/MRI) assessments 
performed, a physical examination (including vital signs, weight) and a performance status 
assessment. If at this visit the patient has a radiological CR based upon imaging assessments, a 
bone marrow biopsy needs to be performed in patients that had prior bone marrow involvement
to confirm the CR. Due to the mechanism of action of CTL019, the Day 28 assessment should 
be interpreted in context of other clinical parameters that suggest true progression rather than 
pseudo-progression due to inflammatory changes and tumor swelling (De Velasco et al 2015).
Adverse events and prior/concomitant medications will be reviewed.
For details of assessments, refer to Table 7-1.


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Post-infusion visits M2±14d, M3±14d, M4±14d, M5±14d, M6±14d
At the intervals following infusion listed above, patients will undergo one or more of the 
following: blood collection for hematology, chemistry, serum immunoglobulins, flow 
cytometry (B cells, 
 and CD19 assessment), cytokines, humoral & cellular 
immunogenicity and CTL019 PK, 
 and RCL by 
VSV-G qPCR. In addition, at the intervals following infusion listed above patients will undergo 
one or more of the following: a physical exam (including vital signs and weight), a performance 
status assessment, B-symptom assessment, Imaging (CT/MRI) assessment, PET-CT (or 
dedicated FDG PET when PET-CT not available) (Month 3 only) a bone marrow biopsy and/or 
aspirate (Month 3 only), 
. 
 
 
 
Adverse events and prior/concomitant medications will be reviewed. Any pregnancies 
will be reported.
For details of assessments required at each specific 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 and CTL019 PK. In addition, patients will undergo a physical exam 
(including vital signs and weight), performance status assessment, B-symptom assessment, 
Imaging (CT/MRI) assessment. Adverse events and prior/concomitant medications will be 
reviewed. Any pregnancies will be reported.
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 cells, 
 and CD19 assessment), cytokines, 
humoral & cellular immunogenicity and CTL019 PK, 
 RCL by VSV-G qPCR. In addition, patients will undergo a physical exam (including 
vital signs and weight), a performance status assessment, B-symptom assessment, Imaging 
(CT/MRI) assessment, 
. 
Adverse events and prior/concomitant medications will be reviewed. Any pregnancies will be 
reported.
Patients with CD19 CART 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 6 month 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, Sponsor 


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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.
For details of assessments, refer to Table 7-1.
Post-infusion visit M18 ±14d and M24 ±14d
At the intervals following infusion listed above, patients will undergo one or more of the 
following: blood collection for hematology, chemistry, flow cytometry (B cells, 
 
and CD19 assessment), cytokines, humoral & cellular immunogenicity and CTL019 PK, 
, and RCL by VSV-G qPCR (Month 24 only). In 
addition, at the intervals following infusion listed above patients will undergo one or more of 
the following: a physical exam (including vital signs and weight), a performance status 
assessment, B-symptom assessment, Imaging (CT/MRI) assessment 
 
. Protocol defined adverse events, adverse 
events of special interest (including new malignancies) and selected concomitant medications 
will be reviewed. Any pregnancies will be reported.
For details of assessments required at each specific visit, refer to Table 7-1.
Post-infusion visits M30 ±14d, M42 ±14d, M54 ±14d
At the intervals following infusion listed above, patients will undergo one or more of the 
following: blood collection for hematology, chemistry, flow cytometry. In addition, at the 
intervals following infusion listed above patients will undergo one or more of the following: a 
physical exam (including vital signs and weight), a performance status assessment and B-
symptom assessment. Protocol defined adverse events, adverse events of special interest 
(including new malignancies) and selected concomitant medications will be reviewed. Serum 
or urine pregnancy test will be done for WOCBP until contraception is no longer required. 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, [CCTL019A2205B], 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.
For details of assessments required at each specific visit, refer to Table 7-1.
Post-infusion visits M36 ±14d and M48 ±14d
At the intervals following infusion listed above, patients will undergo one or more of the 
following: blood collection for hematology, chemistry, flow cytometry (B cells, 
 
and CD19 assessment), cytokines, humoral & cellular immunogenicity and CTL019 PK, 
, and RCL by VSV-G qPCR. In addition, at the 
intervals following infusion listed above patients will undergo one or more of the following: a 
physical exam (including vital signs and weight), a performance status assessment, B-symptom 
assessment, Imaging (CT/MRI) assessment 
 
. Protocol defined adverse events, adverse events of special interest (including 
new malignancies) and selected concomitant medications will be reviewed. Serum or urine 


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pregnancy test will be done for WOCBP until contraception is no longer required. Any 
pregnancies will be reported.
For details of assessments required at each specific visit, refer to Table 7-1.
7.1.3.1
End of treatment and primary follow-up (EOT) visit (M60 ±14d) 
including premature withdrawal
The End of Treatment and Primary Follow-Up (EOT) visit for each patient will be 60 months 
(5 years) from the date of their infusion if they complete all scheduled visits. If a patient 
discontinues early from the primary follow-up, a visit should be scheduled as soon as possible, 
at which time all of the assessments listed for the Month 60 visit will be performed. An End of 
Treatment and Primary Follow-Up Disposition Case Report/ Record Form (CRF) page should 
be completed, giving the date and reason for stopping the treatment and primary follow-up 
phase.
During the End of Treatment and Primary Follow-Up visit, patients will undergo the following: 
blood collection for hematology, chemistry, serum immunoglobulins, CTL019 PK, 
 flow cytometry (B cells, 
), cytokines and RCL by VSV-G
qPCR. In addition, patients will undergo a physical exam (including vital signs and weight), 
performance status assessment, B-symptom assessment, Imaging (CT/MRI) assessment, 
 
. Protocol defined adverse events, adverse events of 
special interest (including new malignancies) and selected concomitant medications will be 
reviewed. A Serum pregnancy test will be done for WOCBP until contraception is no longer 
required. Any pregnancies will be reported.
Following completion of the Treatment and Primary Follow-Up, patients will be followed for 
survival until the end of the study as defined in Section 4.2 (Section 7.1.5) or patients will be 
enrolled in the long term follow-up (LTFU) study, whichever occurs first. Patients who 
discontinue or withdraw from the Treatment and Primary Follow-Up early for any reason will 
be asked to continue the study in the Secondary Follow-up Phase through Month 60.
7.1.3.2
Criteria for premature patient withdrawal from treatment and primary 
follow-up phase
Patients must be followed according to the visit schedule for the Treatment and Primary Follow-
Up to ensure adequate data are collected for the proper assessment of study primary and 
secondary objectives. 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:

Disease progression/Relapse after remission,

Pursuing HSCT while in remission, or

Patient voluntary withdrawal from the primary follow-up.
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients lost to follow up should be recorded as such on the CRF. For 
patients who are lost to follow-up, the investigator should show “due diligence” by 


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documenting in the source documents steps taken to contact the patient, e.g., dates of telephone 
calls, registered letters, etc.
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. protocol defined 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 discontinues from the Treatment and Primary Follow-Up 
phase at Month 10, the first visit in the Secondary Follow-Up Phase will be Month 12.
For details of assessments, refer to Table 7-2. 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, serum immunoglobulins, humoral immunogenicity, cytokines, CTL019 PK, 
flow cytometry (B cells, 
) and RCL by VSV-G qPCR. In addition, patients will 
undergo a physical exam (including weight), vital signs, and a performance status assessment. 
Protocol defined adverse events, adverse events of special interest (including new malignancies) 
and selected prior/concomitant medications will be reviewed. Serum or urine pregnancy test 
will be done between M30 and M54, and a serum pregnancy test at M60 for WOCBP until 
contraception is no longer required. Any pregnancies will be reported. Efficacy will be assessed 
until patient progresses. For these patients, relapse status of primary malignancy will be 
assessed at each visit.
In the event a patient cannot attend any visit during the secondary follow-up, the investigator 
should attempt to contact the patient by phone to determine, at a minimum, primary malignancy 
status and survival status.
For details of assessments, refer to Table 7-2.
Additional follow-up will be made to determine survival status for patients every 3 months. If 
a patient misses a quarterly scheduled visit where survival status is required, or if the quarterly 
time-point where survival status is required does not align with a scheduled visit, survival status 
can be obtained via phone contact, and the survival eCRF must be entered.
7.1.4.1
Criteria for premature patient withdrawal from the study
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients lost to follow up should be recorded as such on the CRF. For 
patients who are lost to follow-up, the investigator should show “due diligence” by 
documenting in the source documents steps taken to contact the patient, e.g., dates of telephone 
calls, registered letters, etc.
Patients may be withdrawn from the study if any of the following occur:
a. The patient is lost to follow-up
b. Patient noncompliance with study therapy and/or clinic appointments
c. Voluntary withdrawal; a patient may remove himself/herself from the study at any time 
without prejudice.


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d. Termination of the study by the sponsor or the health authorities
Novartis will continue to retain and use all research results that have already been collected for 
the study evaluation. All biological samples that have already been collected may be retained 
and analyzed at a later date (or as required by local regulations).
7.1.5
Survival follow-up phase
For all patients who complete the primary follow-up or prematurely discontinue from the 
primary or secondary follow-up phase, every attempt should be made to follow the patients to 
determine survival every 3 months post-CTL019 infusion until the end of study as defined in 
Section 4.2, or until the patient is enrolled in the long term follow-up (LTFU), whichever occurs 
first. Survival status can be obtained via phone contact with the patient.
7.1.6
Long-term follow-up
As a single administration study, patients are followed on study for 5 years post-infusion for 
safety and efficacy evaluations. A long term post-study follow-up for lentiviral vector safety 
will continue under a separate destination protocol. Patients will continue to be followed until 
15 years post-CTL019 infusion per health authority guidelines.
Under the long term follow-up protocol, semiannual and annual evaluations will be performed 
on all patients who have received a CTL019 cell product infusion as recommended by the FDA 
and EMA in accordance with the relevant guidelines. All patients who either complete the study 
or prematurely discontinue post-CTL019 infusion will be automatically enrolled in this 
destination protocol at the time of study completion/discontinuation (separate informed 
consent/assent forms will be provided for this protocol). One to two times a year patients will 
visit the clinical site for a physical exam and medical history (including concomitant 
medications and adverse events) with careful attention to features possibly related to lentiviral 
associated events such as new malignancies, new incidence or exacerbation of a pre-existing 
neurologic disorder, new incidence or exacerbation of a prior rheumatologic or other 
autoimmune disorder, or new incidence of other hematologic disorders. In addition, labs will 
be drawn to evaluate routine safety endpoints, CTL019 vector persistence and RCL.
7.1.7
Discontinuation of study treatment
Not applicable as patient will only receive 1 dose of CTL019 at Day 1
7.1.8
Withdrawal of consent
Patients may voluntary withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not want any further visits or assessments, and does not want any further study 
related contact.
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).
If a patient withdraws consent, the investigator must make every effort (e.g. telephone, e-mail, 
letter) to determine the primary reason for this decision and record this information.


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7.1.9
Follow up for safety evaluations
Please refer to Section 7.1.4 and Section 7.1.6.
7.1.10
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show “due diligence” by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow-up should be recorded as such on the appropriate 
disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Efficacy assessments will be performed as indicated in Table 7-1, and as clinically indicated 
until relapse or progression. Efficacy evaluation will be based on recommendations by the 
International Malignant Lymphomas Imaging Working Group (Cheson et al 2014; Barrington 
et al 2014) and detailed as an appendix to the protocol (Guideline for Efficacy Evaluation in 
DLBCL and FL studies, version 2).
An Independent Review Committee (IRC) appointed by Novartis will review data related to 
disease response assessment according to the Guideline for Efficacy Evaluation in DLBCL and 
FL studies, version 2. Radiological imaging will be transmitted by the sites to the imaging 
Contract Research Organization (CRO) designated by Novartis to undergo quality checks and 
central review by the IRC. Clinical data such as, physical exam, bone marrow results, B-
symptoms, pathology/histology and cytology results; as well as, information regarding prior 
interventions, pre-existing radiographic findings that may mimic metastatic disease at 
baseline/screening and on-study interventions will be transmitted to the imaging CRO for 
review by a medical oncologist/hematologist. Further details regarding the IRC assessment will 
be provided in the IRC charter. The central review of the scans will be carried out in a blinded 
fashion. The decision regarding patient management will remain with the local investigator. 
Enrollment eligibility will be determined by the local staging assessment of the required images 
obtained during screening. Imaging studies used to determine eligibility must be submitted to
the IRC.
Disease characterization at baseline and evaluation of efficacy during study rely on the 
following:

Central pathology assessment

Molecular subtype determination by central laboratory

Imaging

Bone marrow biopsy or aspirate


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
CSF cytology

B-symptoms

Physical exam
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The results of the central evaluations 
will be used for primary analysis purposes. The local investigator’s assessment will be used 
for treatment decision making. Any imaging assessments already completed during the 
regular work-up of the patient within 8 weeks prior to start of screening , including before 
signing the main study ICF, can be considered as the screening images for this study. Any 
imaging assessments obtained after infusion cannot be considered baseline images.
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable (non-index) lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment.
A PET-CT (or CT/MRI and FDG PET when PET-CT not available) must be performed within 
four weeks prior to scheduled infusion of the CTL019 product, and should be scheduled as 
closely as possible to CTL019 infusion and at Month 3. The CT component of the PET-CT may 
be used in lieu of a standalone CT/MRI, only if the CT component is of similar diagnostic 
quality as a contrast enhanced CT performed without PET. If contrast enhanced PET-CT is not 
available, a standard FDG-PET must be performed and a standalone diagnostic CT/MRI should 
be performed in addition to the FDG-PET scan. If independent CT and PET scanners are used, 
and the subject is receiving both scans on the same day, the PET must be performed prior to the 
CT with IV contrast as to not compromise PET results. The PET-CT acquisition methodology 
(e.g., administration of intravenous contrast) should remain consistent between baseline and
Month 3 for any given patient.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. It is recommended to verify disease progression by PET-CT.


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Table 7-3
Imaging or disease assessment collection plan
Procedure
Screening/Pre-infusion
Post-infusion Assessment
PET-CT with contrast enhanced 
CT
Mandated within 4 weeks prior to 
scheduled infusion of CTL019 
product 
Mandated at Month 3
Dedicated FDG PET
Mandated if no PET-CT available
within 4 weeks prior to scheduled 
infusion of CTL019 product 
Mandated at Month 3 if no PET CT 
available
CT/MRI (Chest, Abdomen, Pelvis, 
Neck)
Mandated to determine study 
eligibility
Mandated within 4 weeks prior to 
scheduled infusion of CTL019 
product if no PET-CT available or if 
the CT component of the PET-CT 
scan is not of diagnostic quality
Mandated at Day 28, Months 6, 9, 
12, 18, 24, 36, 48 and 60 and as 
clinically indicated
Mandated at Month 3 if no PET-CT 
available
Due to the mechanism of action of 
CTL019, the Day 28 assessment 
should be interpreted in context of 
other clinical parameters that 
suggest true progression rather 
than pseudoprogression due to 
inflammatory changes and tumor 
swelling.
CNS Imaging (CT/MRI)
As clinically indicated
As clinically indicated
Bone marrow aspirate and biopsy 
DLBCL cells
Mandated
Mandated at time of radiological 
CR in patients with baseline bone 
marrow disease and as clinically 
indicated
Mandated at Month 3 in all patients
Tumor biopsy (FFPE) for central 
pathology assessment and DLBCL 
subtype determination
Mandated
n/a
CSF Cytology
Mandated
As clinically indicated
The status of primary malignancy based on clinical routine assessments will be recorded for 
patients with ongoing response during follow up. The CD19 status at time of relapse should be 
recorded.
7.2.2
Safety and tolerability assessments
For patients in the primary follow-up, safety will be monitored by assessing immunogenicity 
against CTL019, lab abnormalities, physical examination, ECG, and vital signs, as well as 
collecting adverse events continuously until Month 12. After Month 12 only selected AEs 
(protocol defined AEs) will be collected.
For patients in the secondary follow-up, only selected AEs (protocol defined) will be collected.
For complete details on AE collection, reporting and adverse events of special interest, refer to 
Section 8.
For all patients either in the primary or the secondary follow-up, any pregnancies will need to 
be reported and followed-up.


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7.2.2.1
Physical Examination
A complete evaluation will generally include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities and vascular and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History CRF page. Any lesions, detected during a physical exam at any time-
point that are not detectable by imaging should be recorded on the Tumor Evaluation CRF page 
as a non-targeted lesion and does not need to be recorded on the Adverse Event CRF page. 
Significant new findings, other than new lesions, that begins or worsens after informed consent 
must be recorded on the Adverse Event CRF page.
7.2.2.2
Vital Signs
Vital signs include temperature, blood pressure, pulse, respiratory rate, and pulse oximetry. 
Pulse oximetry will be performed only at Screening, Day 1 (prior to infusion) through Day 14. 
After the patient has been sitting for five minutes, with back supported and both feet placed on 
the floor, systolic and diastolic blood pressure will be measured using an automated validated 
device, with an appropriately sized cuff. In case the cuff sizes available are not large enough 
for the patient’s arm circumference, a sphygmomanometer with an appropriately sized cuff may 
be used.
Vital signs (temperature, respiration rate, pulse, pulse oximetry, and blood pressure) will be 
taken prior to, during and immediately after the infusion and then approximately every 15 
minutes for one hour and then every hour for the next two hours, or until these signs are 
satisfactory and stable.
7.2.2.3
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 according to Table 7-1.
7.2.2.4
Performance status
At visits according to Table 7-1, the ECOG performance scale index will be used to evaluate 
the performance status of the patients.
Table 7-4
ECOG Performance status grade
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead


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7.2.2.5
Laboratory evaluations
Laboratory assessments will be performed according to Table 7-1 and Table 7-2. Note: 
Additional assessments should be performed between visits as clinically indicated and to follow 
AEs or CTL019 expected events. For all laboratory assessments that occur on Day 1, these 
should be performed prior to CTL019 infusion unless indicated otherwise.
Table 7-5
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCHC, MCV, Platelets, Red blood cells, White blood cells with 
complete differential (Basophils, Eosinophils, Lymphocytes, Atypical Lymphocytes, 
Monocytes, Neutrophils , Lymphoblasts, Plasma cells, Prolymphocytes, Myelocytes, 
Metamyelocytes, and Promyelocytes)
Chemistry
Glucose, Blood Urea Nitrogen (BUN), Creatinine, eGFR, Sodium, Potassium, Calcium, 
Total Protein, Albumin, Total Bilirubin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), 
Magnesium, Phosphorus, LDH, 
 and Uric Acid
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, pH, Protein, Specific Gravity)
If macroscopic panel is abnormal then perform microscopic panel (Red Blood Cells, White 
Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Coagulation
Prothrombin time (PT) or International normalized ratio (INR), activated Partial 
thromboplastin time (aPTT), fibrinogen, and D-dimer
Pregnancy 
screen for 
WOCBP
Serum and urine pregnancy test is required as long as contraception is required. Refer to 
Table 7-1 and Table 7-2 for the timepoints. 
Influenza
Rapid Influenza A & B Test
Viral Serology
Cytomegalovirus (CMV), Epstein-Barr Virus ( EBV), Hepatitis C Virus RNA, Hepatitis B 
surface antigen (HbsAg), Hepatitis B surface antibody (HBsAb), Hepatitis B core antibody 
(HBcAb), HIV test (if an initial HIV screening test is positive then a confirmatory HIV test is 
required to be performed as per current local guidelines)
Additional 
assessments
Serum immunoglobulin levels (IgG, IgA, IgM)
CTL019 PK will be quantified by q-PCR and flow cytometry in peripheral blood and bone 
marrow.
 
 
 
 Replication competent 
lentivirus (RCL) will be detected by q-PCR for VSV-G in peripheral blood. See Table 7-6. If 
negative after the first year, samples will be collected and stored but not analyzed unless 
requested for safety purposes.
Table 7-6
Central clinical laboratory parameters collection plan
Test Category
Test Name/Method
CD19 testing
Immunohistochemistry or flow cytometry
DLBCL and subtype determination
Immunohistochemistry
Bone marrow aspirate/biopsy
Flow cytometry or immunohistochemistry 


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Test Category
Test Name/Method
RCL (VSV-G)
VSV-g q-PCR (whole blood)
Cytokines
Serum cytokine panel, PD1, PDL1 (peripheral blood, CSF)
Immunogenicity 
Incidence and prevalence (pre-existing) of immunogenicity against 
CTL019 (peripheral blood and serum)
CTL019 pharmacokinetics
CTL019 PK by q-PCR or flow cytometry (peripheral blood, bone marrow 
aspirate)
Additional assessments
Serum immunoglobulin levels (IgG, IgA, IgM) (Secondary follow-up only)
Refer to the [Laboratory Manual] for more detailed instructions for the collection, handling, 
and shipment of PK
samples.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed at:

Screening

Infusion-Day 1 (prior to infusion)
The date and time of the ECG and the following parameters will be collected and assessed: 
QTcF, PR, QT and QRS interval in msec, heart rate (bpm).
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History CRF page. Clinically significant findings must be discussed 
with Novartis prior to enrolling the patient in the study. New or worsened clinically significant 
findings occurring after informed consent must be recorded on the Adverse Events CRF page.
7.2.2.6.2 Cardiac imaging – MUGA (multiple gated acquisition) scan or 
echocardiogram (ECHO)
An ECHO/MUGA test is required to be completed at screening. Clinically significant 
abnormalities present when the patient signed the informed consent should be reported on the 
Medical History CRF page. Clinically significant findings must be discussed with Novartis 
prior to enrolling the patient in the study. New or worsened clinically significant findings 
occurring after informed consent must be recorded on the Adverse Events CRF page. Patients 
must have a left ventricular ejection fraction (LVEF) ≥ 45% to be included into the study.


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7.2.3
Cellular Kinetics and Pharmacokinetics
Blood and BM sampling for PK evaluations will be performed at specified time-points. All 
collections of PK blood samples will be recorded on the appropriate PK blood collection CRF 
page. Refer to the [Laboratory Manual] for details on sample handling and shipment.
Table 7-7
CTL019 pharmacokinetics by q-PCR in peripheral blood collection log
Cycle
Day*
Scheduled time 
point relative to 
dosing
PK DRID 
(CTL019)*
PK 
Sample 
No. 
(CTL019)
Blood 
Volume 
(mL)
1
W-3 to D-8 
Enrollment/Pre-
Chemotherapy
Pre-dose
201
201
6
1
D1 10 minutes ± 5 
minutes post-infusion
0.167h post-dose (±5 
min)
201
202
6
1
D2
24h (+/-6h)/D2
201
203
6
1
D4±1d
72hD4
201
204
6
1
D7±1d
D7
201
205
6
1
D11±1d
D11
201
206
6
1
D14±1d
D14
201
207
6
1
D17±1d
D17
201
208
6
1
D21±3d
D21
201
209
6
1
D28±7d
D28
201
210
6
1
M2±14d
M2
201
211
6
1
M3±14d
M3
201
212
6
1
M6±14d
M6
201
213
6
1
M9±14d
M9
201
214
6
1
M12±14d 
M12 
201
215
6
1
M18±14d
M18
201
216
6
1
M24±14d 
M24
201
217
6
1
M30±14d 
M30
201
218
6
1
M36±14d 
M36
201
219
6
1
M42±14d 
M42 
201
220
6
1
M48±14d 
M48
201
221
6
1
M54±14d 
M54
201
222
6
1
M60±14d 
M60
201
223
6
1
Unscheduled PK 
samples related to CRSa
201
2001
6
1
Unscheduled (PK 
samples related to safety 
events, relapse) b
201
3001
6
1
Unscheduled (PK 
samples at relapse)c
201
6001
6
*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


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Cycle
Day*
Scheduled time 
point relative to 
dosing
PK DRID 
(CTL019)*
PK 
Sample 
No. 
(CTL019)
Blood 
Volume 
(mL)
 
bUnscheduled PK samples related to other non-CRS safety events are uniquely, sequentially 
numbered 3001, 3002, etc.
cIn the event patient relapses, an unscheduled PK sample should be collected along with 
corresponding immunogenicity sample (refer to Table 7-12 and Table 7-13)
Note: If RCL testing was negative through Month 12, all samples taken after Month 12 will be stored 
for potential future testing.
Table 7-8
CTL019 pharmacokinetics by flow cytometry in peripheral blood 
collection log
Cycle
Day*
Scheduled time point 
relative to dosing
PK DRID 
(CTL019)*
PK Sample No. 
(CTL019)
Blood 
Volume 
(mL)
1
W-3 to D-8 
Enrollment/Pre-
chemotherapy 
evaluation
Pre-dose
201
301
2
1
D1 10 minutes 
± 5 minutes 
post-infusion
0.167h post-dose (±5 min)
201
302
2
1
D4±1d
72hD4
201
303
2
1
D7±1d
D7
201
304
2
1
D11±1d
D11
201
305
2
1
D14±3d
D14
201
306
2
1
D17±1d
D17
201
307
2
1
D21±3d
D21
201
308
2
1
D28±7d
D28
201
309
2
1
M2±14d
M2
20 1
310
2
1
M3±14d
M3
201
311
2
1
M6±14d
M6
201
312
2
1
M9±14d
M9
201
313
2
1
M12±14d (EOT) 
M12
201
314
2
1
M18±14d
M18
201
315
2
1
M60±14d 
M60
201
316
2
1
Unscheduled 
PK samples 
related to CRSa
201
4001
2
1
Unscheduled 
(PK samples 
related to safety 
events, relapse)
b
201
5001
2
1
Unscheduled 
(PK samples at 
relapse)c
201
7001
2


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Cycle
Day*
Scheduled time point 
relative to dosing
PK DRID 
(CTL019)*
PK Sample No. 
(CTL019)
Blood 
Volume 
(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
 
 
bUnscheduled anytime PK samples related to other non-CRS safety events will be uniquely, 
sequentially numbered 5001, 5002, etc.
cIn the event patient relapses, an unscheduled PK sample should be collected along with 
corresponding immunogenicity sample (refer to Table 7-12 and Table 7-13)
Table 7-9
CTL019 pharmacokinetics by q-PCR in bone marrow aspirate 
collection log
To be completed only if bone marrow examined
Cycle
Day*
Scheduled time point 
relative to dosing
PK DRID 
(CTL019)*
PK Sample 
No. 
(CTL019)
Sample 
Volume (mL)
1
W-8 to W-4 
Screening
Pre-dose/screening
201
401
2
1
M3±14d
M3
201
402
2
1
Unscheduled 
(e.g. at time of 
radiological CR, 
related to 
relapse) a
201
403
2
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
a.Unscheduled time points begin with 403, 404, 405 series
Table 7-10
CTL019 pharmacokinetics by flow cytometry in bone marrow aspirate 
collection log
To be completed only if bone marrow examined
Cycle
Day*
Scheduled time point 
relative to dosing
PK DRID 
(CTL019)*
PK Sample 
No. (CTL019)
Sample 
Volume (mL)
1
W-8 to W-4 
Screening
Pre-dose/screening
201
501
2
1
M3±14d
M3
201
502
2
1
Unscheduled 
(e.g. at time of 
radiological CR, 
related to 
relapse) a
201
503
2
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
a.Unscheduled time points begin with 503, 504, 505 series"


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Table 7-11
CTL019 pharmacokinetics by q-PCR in CSF biopsy or other tissue log
To be completed only if CSF collection performed.
Day/ Scheduled Time Point*
Sample Volume
W-8 to W-4 Screening
4-8 mL
Unscheduled (e.g. related to relapse) 
4-8 mL
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
Table 7-12
Immunogenicity serum sample collection log
Day/ Scheduled Time Point*
Sample volume
W-3 to D-8 Enrollment/Pre-chemotherapy evaluation
**
D14±1d
**
D28±7d
**
M3±14d
**
M6±14d
**
M12±14d 
**
Unscheduled (at relapse)***
**
Unscheduled (e.g. related to safety events)
**
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
** Aliquots are derived from the serum cytokine collections; refer to Table 7-17.
***In the event patient relapses, an unscheduled immunogenicity sample should be collected along 
with corresponding PK sample (refer to Table 7-7, Table 7-8)
Table 7-13
Immunogenicity whole blood sample collection log
Day/ Scheduled Time Point
Sample volume
W-3 to D-8 Enrollment/Pre-chemotherapy evaluation
**
D14±1d
**
D28±7d
**
M3±14d
**
M6±14d
**
M12±14d 
**
Unscheduled (at relapse)***
Unscheduled (e.g. related to safety events)
**
*All measurement times are relative to date of CTL019 infusion unless otherwise specified.
 
***In the event patient relapses, an unscheduled immunogenicity sample should be collected along with 
corresponding PK sample (refer to Table 7-7, Table 7-8)


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Table 7-14
 CTL019 Pharmacokinetics (PK), 
 
 treated patients during CRS
Day/ 
Scheduled 
Time 
Point*/**
Dose 
Reference 
ID
Sample 
Number
Sample 
Volume 
(serum) 
CTL019 
Dose 
Reference 
ID
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
201
--
--
--
--
D1 1h ± 15 
min post 
infusion
101
2
5 mL
201
251
2 mL
351
2 mL
D2 ± 2h
101
3
5 mL
201
252
2 mL
352
2 mL
D3 ± 4h
101
4
5 mL
201
253
2 mL
353
2 mL
D7 ± 1d
101
5
5 mL
201
254
2 mL
354
2 mL
D1 (pre-
dose; 
second 
infusion)
101
6
5 mL
201
255
2 mL
355
2 mL
D1(5-15 
minutes post 
second 
infusion)
102
7
5 mL
201
--
--
--
--
D2 ± 2h 
from second 
infusion
102
8
5 mL
201
256
2 mL
356
2 mL
D3 ± 4 hours 
(post second 
infusion)
102
9
5 mL
201
257
2 mL
357
2 mL
D7±1d (post
second 
infusion)
102
10
5
201
258
2 mL
358
2 mL
D1 (5-15 
minutes pre-
dose; 
additional 
infusion)
102
11
5 mL
201
259
2 mL
359
2 mL
D1 (5- 15 
minutes post 
additional 
infusion
103
12
5 mL
201
--
--
--
--
D2 ± 2 hours
103
13
5 mL
201
260
2 mL
360
2 mL
D3 ± 4 hours
103
14
5 mL
201
261
2 mL
361
2 mL
D7 ± 1d
103
15
5 mL
201
262
2 mL
362
2 mL
Additional***
104,105
16, 17, 
18, 19, 
20
5 mL
201
263, 264, 
265, 266
2 mL
363, 364, 
365, 366
2 mL
*All measurement times are relative to 
infusion unless otherwise specified. A serum 
sample collected at D -1 for cytokine analysis (see Table 7-17 would serve as the baseline sample.
**Samples may be collected as needed dependent upon administration of
if clinically 
feasible.
Unscheduled CTL019 PK sample collections related to CRS as specified in Table 7-7 will cease once 


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Day/ 
Scheduled 
Time 
Point*/**
Toci Dose 
Reference 
ID
Toci 
Sample 
Number
Toci 
Sample 
Volume 
(serum) 
CTL019 
Dose 
Reference 
ID
CTL019 
PK by 
qPCR 
Sample 
Number^
Sample 
Volume
(whole 
blood)
CTL019 
PK by 
flow 
cytometry 
Sample 
Number^
Sample 
Volume
(whole 
blood)
^PK collections for CTL019 measured by qPCR will be numbered starting with 251 series and PK 
collections measured by flow cytometry will be numbered starting with a 351 series
 
Table 7-15
 CTL019 PK 
 treated 
patients during CRS
Day/ 
Scheduled 
Time 
Point*/**
Dose 
Reference 
ID
Sample 
Number
Sample 
Volume 
(serum) 
CTL019 
PK by 
qPCR 
Sample 
Number
Sample 
Volume
(whole 
blood)
CTL019 PK 
by flow 
cytometry 
Sample 
Number
Sample 
Volume
(whole 
blood)
D1 (5-15 
minutes post 
infusion)
301
401
5 mL
--
--
--
--
D1 1 hour ± 
15 min post 
infusion
301
402
5 mL
501
2 mL
701
2 mL
D2 ± 2 hours
301
403
5 mL
502
2 mL
702
2 mL
D3 ± 4 hours
301
404
5 mL
503
2 mL
703
2 mL
D7 ± 1d
301
405
5 mL
504
2 mL
704
2 mL
D1 (pre-dose; 
additional 
infusion)
301
406
5 mL
505
2 mL
705
2 mL
D1(5-15 
minutes post 
additional 
infusion)
302
407
5 mL
--
--
--
--
D2 ± 2 hours 
from 
additional 
infusion
302
408
5 mL
506
2 mL
706
2 mL
D3 ± 4 hours
302
409
5 mL
507
2 mL
707
2 mL
D7 ± 1d
302
410
5 mL
508
2 mL
708
2 mL
Additional***
303, 304
411, 412, 
413, 414, 
415
5 mL
509, 510, 
511, 512
2 mL
709,710, 
711, 712
2 mL
*All measurement times are relative to
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 o
 if clinically feasible.
Unscheduled CTL019 PK sample collections related to CRS as specified in Table 7-7, Table 7-8, and will 
cease once PK/PD sample collections related to
administration commence, if 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/assent will be recorded in the 
patient’s source documents. New or worsening adverse events prior to starting study 
treatment (i.e. lymphodepleting chemotherapy or the pre-infusion visit if the lymphodepleting 
chemotherapy is not given per Section 6.1.1.1) are required to be recorded in the Adverse Events 
CRF if they meet one of the following criteria:

All infections

All clinical AEs grade ≥ 3

All laboratory abnormalities deemed clinically significant by the investigator

All AEs related to a study procedure

All AEs leading to study discontinuation

All SAEs meeting criteria outlined in Section 8.2.2
Concomitant medications during the pre-screening period will also follow modified reporting 
criteria as described in Appendix 3.
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, regardless of causality will be recorded in the Adverse Events CRF up to 
the Month 12 visit.
Adverse event monitoring should be continued through the Month 60 (EOT) visit. Following 
the Month 12 visit, and through the Month 60 visit, adverse events should only be reported 
to Novartis and recorded in the Adverse Events CRF if it meets one of the following criteria:

Events leading to death

Events related to a study procedure

Infections:

Serious or opportunistic infections that fulfill one of the following criteria:


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
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
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event.
Adverse events will be assessed according to the Medical Dictionary for Regulatory Authorities
(MedDRA) and the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, 
with the exception of CRS, which will follow Table 6-1. If CTCAE grading does not exist for 
an adverse event, the severity of mild, moderate, severe, and life-threatening, corresponding to
Grades 1 - 4, will be used. CTCAE Grade 5 (death) will not be used in this study; 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)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)
7. Whether it is serious, where a serious adverse event is defined as in Section 8.2.1


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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.
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 within 28 days after CTL019 infusion. These adverse events are mostly due to CRS 
and MAS, although there may be some contribution from the preceding lymphodepleting 
chemotherapy (neutropenia fever, cytopenias). CRS/MAS toxicity is an ‘on-target’ effect 
resulting from the expected CTL019 cell expansion, activation and tumor cell killing.
A typical inpatient or ICU day can generate hundreds of data points and many therapeutic dose 
changes throughout a given day. These inpatient events and days are not scheduled protocol 
defined visits although they are anticipated to occur in some patients. Revised inpatient data 
capture will be utilized for this study to systematically collect subsets of patient data to describe 
the management of safety events associated with CTL019 therapy for the purpose of:
1. Adequately informing physicians and patients of the expected risks of CTL019 and the 
recommended interventions to manage these risks
2. Health authority submission
This is done through a targeted collection of concomitant medications and laboratory data and 
CRS CRFs specifically designed to capture CTL019-related toxicity, severity, interventions and 
response/resolution following intervention. Details can be found in the CRF Completion 
Guidelines (CCGs) and Appendix 3 and 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 sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities that do not meet the definition of an adverse event should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A medication for the lab abnormality may be required by the protocol 
in which case the lab abnormality would still, by definition, be an adverse event and must be 


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reported as such. Whenever possible, a diagnosis, rather than a symptom should be provided 
(e.g. anemia instead of low hemoglobin).
8.1.4
Adverse events of special interest
An adverse event of special interest (AESI, serious or non-serious) is one of greater scientific 
and medical concern specific to CTL019. The current defined AESIs for CTL019 include 
Cytokine Release Syndrome, Tumor Lysis Syndrome, Neutropenic fever, Cytopenia >28 days, 
drop in cardiac ejection fraction, neurotoxicity, hepatic events (Section 6.3), and infections.
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

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

All malignant neoplasms (secondary malignancies, not disease progression of the study 
indication) will be assessed as serious under “medically significant.”
Progression of the underlying malignancy with fatal outcome must be reported as a SAE within 
24 hours of awareness, if the following criteria are met: 

Deaths beyond 30 days after CTL019 infusion, if there is a least a possible causality 
to CTL019

Non-fatal disease progression should not be reported as AE.
8.2.2
Reporting
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 


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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.
8.2.2.1
Screening/pre-treatment
Any SAEs experienced during the screening/pre-treatment phase (from the time of patient 
providing informed consent/assent until the patient begins study-related treatment) should 
ONLY be reported to Novartis and be captured in the CRF and safety database if the event 
meets at least one of the following criteria:

All events leading to death.

All pulmonary or cardiac abnormalities

All infections

All events related to a study procedure

Any AE reportable for this study period that also meets criteria for serious

Any substantial change in the status of the patient that precludes the patient from 
proceeding to study treatment (e.g. GVHD, rapid progression of malignancy, marked 
decline in performance status)

Any other substantial change in the status of the patient that the investigator deems may 
have a potential impact on the patients during lymphodepletion and CTL019 treatment
8.2.2.2
Study-related treatment to Month 12
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.
8.2.2.3
Month 12 to Month 60
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 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 
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
Positive RCL test result

Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a 
location near a known human oncogene

New malignancy (T-cell & non T-cell), other than the primary malignancy

Progressive multifocal leucoencephalopathy (PML)

Hepatitis B reactivation
In addition, at the specific request of a National Health Authority, the following SAEs will be 
reported in an expedited manner:

Any SAE related to a study procedure

All occurrences of CRS grade ≥ 3 (to be reported to National Health Authority on a 
monthly basis)

All occurrences of Neurologic toxicity ≥ 4

All deaths regardless of attribution following lymphodepleting chemotherapy and/or 
CTL019 infusion
8.2.2.4
Post-treatment protocol
Any SAEs experienced after the Month 60 (EOT) visit should only be reported to Novartis Drug 
Safety and Epidemiology (DS&E) 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.
In addition, semiannual and annual evaluations will be performed for up to 15 years from the 
date of infusion on all patients under a separate long term follow-up (LTFU) protocol as 
recommended by health authority guidance for patients treated with gene therapies. All patients 
who either complete or prematurely discontinue from the study will be enrolled in this 
destination protocol at the time of study completion/discontinuation (a separate informed 
consent form will be provided for this protocol; Section 7.1.7).
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
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If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis DS&E department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same treatment that 
this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable
8.4
Contraception
The contraceptive measures outlined in this section for WOCBP and sexually active males are 
the effective ones and they replace those presented in the Inclusion Criteria section.
WOCBP
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant, must use highly effective methods of contraception for at least 12 months following 
CTL019 infusion and until CAR T cells are no longer present by qPCR on two consecutive tests. 
qPCR test results will be available upon request. Highly effective contraception methods 
include:
●
Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception
●
Female sterilization (surgical bilateral oophorectomy with or without hysterectomy), total 
hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment.
●
Male sterilization (at least 6 months prior to screening). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient.
●
Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or 
other forms of hormonal contraception that have comparable efficacy (failure rate <1%), 
for example hormone vaginal ring or transdermal hormone contraception. In case of use of 
oral contraception women should have been stable on the same pill for a minimum of 3 
months before enrollment into this study.
NOTE: If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
Sexually active males
Sexually active males must use a condom during intercourse for 12 months after the CTL019
infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. qPCR 


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test results will be available upon request. A condom is required for all sexually active male 
participants to prevent them from fathering a child AND to prevent delivery of study treatment 
via seminal fluid to their partner.
8.5
Pregnancies
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy follow up in this study will end after birth or after any adverse pregnancy outcome 
associated with the end of the pregnancy. In case of live birth the newborn will be followed up 
until 12 months of age to detect any developmental issue or abnormality that would not be seen 
at birth. Pregnancy outcomes must also be collected for the female partners of any males who 
received 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 the Novartis Chief Medical Office and Patient Safety (CMO&PS). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship between the investigational treatment and pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
8.6
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 IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.7
Data Monitoring Committee
A data monitoring committee (DMC) will be established prior to the enrollment of the first 
patient. The DMC will be responsible for reviewing the safety and efficacy results from the 
interim analysis as well as overseeing safety data at regular intervals. Enrollment will not be 
interrupted in between the interim analysis data cutoff date and a DMC review of the interim 
analysis data and determination on whether to proceed with 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 adult hematologist/oncologist) and one biostatistician.
There will be an initial meeting with the DMC to have agreement on their roles and 
responsibilities and potential data format and procedures that will be reviewed during the course 
of the study. The first DMC safety review meeting will be held when approximately the first 5 
patients have been treated for at least 1 month or at least 6 months after the first patient is 
enrolled, whichever occurs first. Subsequent safety reviews will occur every six months, unless 
otherwise requested by the Chairman of the DMC. Additional meetings will be held by DMC 


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or sponsor’s requests at the time of some safety issues occurrence, especially when serious 
events (e.g., death) occur on the study or safety notifications regarding the study treatment come 
out.
Detailed recruitment status and interim safety reports will be provided to the DMC on a regular 
basis.
Further details regarding the constitution of the DMC and its specific roles will be provided in 
the DMC charter prior to the enrollment of the first patient.
8.8
Steering Committee
The steering committee (SC) will be established comprising investigators participating in the 
trial, Novartis representatives from the Clinical Trial team and not members of the DMC. The 
SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter.
8.9
Independent Review Committee (IRC)
An IRC will be established to review data related to disease response assessments during the 
Treatment and Primary Follow-up Phase and determine response and relapse for the primary 
analysis. An IRC charter will detail the IRC data flow and review process in alignment with the 
response definitions in Section 14.1. Patient management will be based upon local investigator 
assessments. The designation of response 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.
8.10
Follow-up of Secondary Malignancy
For patients treated with CTL019, treating physician/healthcare providers should contact 
Novartis if the patient develops a secondary malignancy. 
Upon clinical confirmation of a secondary malignancy, blood samples should be collected for 
CAR-transgene and RCL. 
Novartis strongly recommends collection of a portion of a biopsy (e.g., bone marrow, solid 
tumor) from the secondary malignancy (if applicable and previously collected as standard of 
care in diagnosing or treating the secondary malignancy) for analysis, such as CAR-transgene 
and RCL. Additional details for sample handling and shipping are outlined in the laboratory 
manual.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects 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 subject 
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.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, 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.


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9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
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 eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
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 80 patients have received CTL019 infusion in the 
main cohort and completed 3 months from study day 1 infusion or discontinued earlier. Selected 
efficacy and safety analysis will be updated annually. A final Clinical Study Report (CSR) will 
be produced once all patients complete the study.
10.1
Analysis sets
The analysis sets to be used are defined as below. The FAS will be used as the primary efficacy 
analysis set. The Safety Set will be used for all the safety analysis. The Pharmacokinetic 
Analysis Set (PAS) will be used for the pharmacokinetics analysis.
All tables and listings will be presented by one treatment arm of CTL019.


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10.1.1
Screened Set
The Screened Set comprises all patients who have signed informed consent and screened in the 
study.
10.1.2
Enrolled Set
The enrolled set comprises all patients who are enrolled in this study. Enrollment is defined as 
the point at which the patient meets all inclusion/exclusion criteria, and the patients’ apheresis 
product is accepted for manufacturing.
10.1.3
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received an infusion of CTL019
10.1.4
Safety Set
The Safety Set comprises all patients who received infusion of CTL019.
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:

Diagnosis of disease other than DLBCL at baseline;

Missing or incomplete documentation of disease at baseline;
In addition, patients who receive a dose less than the minimum dose of 1×108 CTL019 
transduced viable T cells will also be excluded. The detailed exclusion criteria of PPS will be 
determined and documented in the study Report and Analysis Plan (RAP) prior to primary 
analysis.
10.1.6
Pharmacokinetic analysis set
The CTL019 pharmacokinetic analysis set (PAS) consists of patients in FAS who have at least 
one sample providing evaluable pharmacokinetic (PK) data. The PAS will be used for 
summaries (tables and figures) of PK data.
 
 
 
Note that patients may 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.


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10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data will be listed by patient and/or summarized descriptively 
by cohort 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 their prior treatment response:

Primary refractory: Patients who have never achieved CR prior to study

Relapse without HSCT: Patients without SCT, had a CR from other therapy and relapsed 
prior to the study

Relapse disease after prior autologous SCT
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The total cells infused (cells) and total CTL019 transduced viable T cells infused (cells) will be 
listed and summarized by cohort 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. 
 
10.4
Primary objective
The primary objective of the study is to evaluate the efficacy of CTL019 therapy as measured 
by overall response rate (ORR) rate, which includes complete response (CR) and partial 
response (PR) as determined by IRC assessment in the FAS for the main cohort.
In addition, sensitivity analysis will be performed using the local investigator response 
assessments instead of the IRC assessment.
10.4.1
Variable
The primary endpoint is the ORR as determined by IRC assessment. The ORR is defined as the 
proportion of patients with a best overall disease response of CR or PR, where the best overall 
disease response is defined as the best disease response recorded from CTL019 infusion until 
progressive disease or start of new anticancer therapy, whichever comes first.
The overall response at each assessment is determined as in Table 10-1. For time points when 
both FDG-PET and CT are available, the FDG-PET assessment overrules the CT response.


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Table 10-1
Overall response assessment
FDG-PET based response
CT-based response
CMR/CR
Complete Metabolic Response 
(CMR)
(All of the following)
Complete Radiologic Response 
(CR)
(All of the following)
Index 
nodal/extranodal 
(including splenic 
and hepatic 
lesions)
Score 1 or 2 with or without a 
residual mass on 5-PS
Residual masses allowed if no 
PET-avid
Nodal Disease: ≤ 1.5 cm in LDi
Extranodal Disease: Absent
Non-index
(including splenic 
and hepatic 
lesions)
Absent
Spleen
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease 
in marrow. Normal by morphology; 
if indeterminate, IHC/FLOW 
negative.
Normal by morphology; if 
indeterminate, IHC/FLOW negative.
PMR/PR
Partial Metabolic Response 
(PMR)
(All of the following)
Partial Remission (PR)
(All of the following)
Index 
nodal/extranodal 
(including splenic 
and hepatic 
lesions)
Score of 3, 4 or 5 with reduced 
uptake compared to baseline with 
respect to SUV intensity or extent. 
This may apply to the specific hot 
spot and/ or overall the subject. It is 
expected that there will be residual 
mass(es) present.
≥ 50% decrease from baseline in SPD 
of all index lesions
Non-index
(including splenic 
and hepatic 
lesions)
No increase
Spleen
> 50% decrease from baseline in 
enlarged portion of spleen (value > 13 
cm)
New lesions
None
None
Bone marrow
●
Residual uptake higher than 
uptake in normal marrow but 
reduced compared with baseline
●
Persistent focal changes in the 
marrow with nodal response,
Not applicable
NMR/SD
No Metabolic Response
(NMR)
(All of the following)
Stable Disease
(SD)
(All of the following)
Index 
nodal/extranodal 
(including splenic 
and hepatic 
lesions)
Score of 3, 4 or 5 with no significant 
change in FDG uptake from 
baseline
<50% decrease from baseline in SPD 
of all index lesions
No criteria for PD are met
Non-index
(including splenic 
and hepatic 
lesions)
No progression


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FDG-PET based response
CT-based response
Spleen
No progression
New lesions
None
None
Bone marrow
No change from baseline
Not applicable
PMD/PD
Progressive Metabolic Disease 
(PMD)
(At least one of the following)
Progressive disease
(PD)
(At least one of the following)
Index 
nodal/extranodal 
(including splenic 
and hepatic 
lesions)
Score of 3, 4 or 5 with increased 
uptake compared to the visually 
determined nadir with respect to 
SUV intensity or extent. This may 
apply to the specific hot spot and/ 
or overall the subject.
and/or
●
New FDG-avid foci consistent 
with lymphoma
●
Consider biopsy or interval scan 
if etiology of new lesions uncertain
PPD Progression:
An individual node/lesion must be 
abnormal with:
●
LDi > 1.5 cm AND
●
Increase by >= 50% from PPD 
nadir AND
●
An increase in LDi or SDi from 
nadir
●
≥ 0.5 cm for lesions ≤ 2.0 cm
●
≥ 1.0 cm for lesions > 2.0 cm
Non-index
(including splenic 
and hepatic 
lesions)
Unequivocal Progression
Spleen
Progression of existing splenomegaly
New or Recurrent splenomegaly
New lesions
Regrowth of previously resolved 
lesions
New node > 1.5 cm in any axis
New extranodal site > 1.0 cm in any 
axis
New extranodal site < 1.0 cm in 
longest axis and 
unequivocal/attributable to lymphoma.
Any size assessable disease 
unequivocal/attributable to lymphoma
Bone marrow
New/recurrent FDG-avid foci
New/recurrent involvement
†PET 5PS: 1, no uptake above background; 2, uptake mediastinum; 3, uptake > mediastinum but liver; 4, 
uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake 
unlikely to be related to lymphoma. SPD: Sum of the Products of Diameters; LDI: Longest transverse Diameter 
of a lesion; PPD: Product of perpendicular diameters
A patient will have a best overall disease response of CR if they had CR as overall disease 
response for at least one of the assessments.
A patient will have a best overall disease response of PR if at least one overall response of PR 
is available (and the patient would not qualify for CR).
A best overall disease response of SD will be declared when at least one SD assessment is 
available at least 4 weeks after CTL019 infusion (and the patient would not qualify for CR or 
PR).
A patient will have a best overall disease response of PD if the progressive disease was observed 
less than 14 weeks after CTL019 infusion (and the patient does not qualify for CR, PR or SD).


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If a patient does not qualify for CR, PR, SD or PD, then their best disease response will be 
Unknown (UNK).
See Section 14.1 for details of disease response criteria.
10.4.2
Statistical hypothesis, model, and method of analysis
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 that ORR is greater than 20% at 
overall one-sided 2.5% level of significance, i.e.,
H0: p ≤ 0.2 vs. Ha: p>0.2
The ORR will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence 
intervals. 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 or equal to 20% can be rejected.
The primary efficacy endpoint, ORR will be analyzed based on the data observed in the FAS.
10.4.3
Handling of missing values/censoring/discontinuations
Patients in this study who are of unknown clinical response will be treated as non-responders. 
See also the Novartis guideline for efficacy evaluation in DLBCL and FL studies 
 
 (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: < 40 years, ≥40 years to <65 years, ≥ 65 years

Gender: Male, Female

Race: Asian, Black, Caucasian, Native American, Other, Pacific Islander, Unknown

Ethnicity: Hispanic or Latino, Chinese, Indian, Japanese, Mixed ethnicity, Other

Prior response status: Primary refractory, relapse without SCT, relapse after SCT

IPI at enrollment: <2 risk factors, ≥2 risk factors

Number of prior lines of anti-neoplastic therapy: ≤2 lines, 3 to4 lines, >4 lines

Stage of disease at baseline: I/II, III/IV.
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.


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10.5
Secondary objectives
10.5.1
Key secondary objective(s)
Not applicable because no formal hypothesis testing is planned other than for the primary 
objective.
10.5.2
Other secondary efficacy objectives
IRC assessment will be used in the main analysis of secondary endpoints that involve disease 
response.
10.5.2.1 Duration of overall response (DOR)
Duration of response (DOR) applies only to patients whose best overall disease response was 
CR or PR. It is defined as the time from the date of first documented disease response (CR or 
PR) to the date of first documented progression or death due to DLBCL. If a patient has not had 
an event, duration of overall response is censored at the date of the last adequate assessment.
In case a patient does not have progression or death due to DLBCL prior to data cutoff, DOR
will be censored at the date of the last adequate assessment on or prior to the earliest censoring 
event. The censoring reason could be:

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (also see below for handling HSCT)

Event documented after at least two missing tumor assessments

Adequate assessments no longer available
In the main analysis of DOR, death due to reason other than DLBCL will be considered as a 
competing risk event to other events of interest (progression or death due to DLBCL). In this 
analysis, the median response duration as well as proportion of patients without events 
following response (progression or death due to DLBCL) at 3, 6, 9, 12 months, etc. will be 
presented with 95% confidence intervals using the cumulative incidence function (CIF). 
Distribution of DOR will also be estimated using the Kaplan-Meier method in which death due 
to reason other than DLBCL will be censored.
As HSCT is an important treatment option in responding patients, it is appropriate to consider 
the date of HSCT as censoring date, instead of censoring at the last tumor assessment date. If a 
patient received HSCT after a CR or PR, relapse or survival status after HSCT will be recorded 
on the corresponding follow-up eCRFs, although data on individual disease response 
components (e.g. CT scan) will not be collected. In such cases, the date of relapse or death (if 
due to DLBCL) after HSCT will be used for the calculation of DOR as a sensitivity analysis.
Distribution of DOR will be estimated using the Kaplan-Meier method and the median response 
duration as well as proportion of patients without event at 3, 6, 9, and 12 months will be 
presented along with 95% confidence interval.


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In addition, the DOR may be separately summarized for patients with best overall response of 
CR and those with best overall response of PR.
10.5.2.2 DOR will be analyzed by cohort as well as for all treated patients 
combined in FAS.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

Disease progression or relapse

New anticancer therapy for lymphoma, excluding HSCT
In case a patient does not have any of the above events prior to data cutoff, EFS is censored at
the last adequate response assessment date on or prior to the earliest censoring event (except 
for HSCT). The censoring reason could be

Ongoing without event

Lost to follow-up

Withdrew consent

HSCT (see below for handling of HSCT)

Event after at least two missing scheduled disease assessment

Adequate assessments no longer available
In the main analysis of EFS, patients who proceed to HSCT after CTL019 infusion will be censored 
at the time of HSCT. In addition, a sensitivity analysis of EFS will be performed without censoring 
for HSCT.
The distribution function of EFS will be estimated using the KM method. The median EFS 
along with 95% confidence intervals will be presented if appropriate.
EFS will be analyzed by cohort as well as for all treated patients combined in FAS.
10.5.2.3 Progression free survival (PFS)
Progression-free survival (PFS) is defined as the time from the date of first CTL019 infusion to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of the last adequate 
assessment.
In case a patient does not have progression or death prior to data cutoff, PFS will be censored at
the date of the last adequate assessment on or prior to the earliest censoring event. The 
censoring reason could be:

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (see below for handling of HSCT)

Event documented after at least two missing tumor assessments

Adequate assessments no longer available


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In the main analysis of PFS, patients who proceed to HSCT after CTL019 infusion will be censored 
at the time of HSCT. In addition, a sensitivity analysis of PFS will be performed without censoring 
for HSCT.
PFS will be estimated using the Kaplan-Meier method and the median PFS as well as proportion 
of patients without event at 3, 6, 9, and 12 months will be presented along with 95% confidence 
interval.
PFS will be analyzed by cohort as well as for all treated patients combined in FAS.
10.5.2.4 Time to response
Time to overall disease response (CR or PR) is defined as the time from the date of CTL019 
infusion to the date of first documented disease response (CR or PR). The analysis will include 
all responders.
Time to response will be estimated using the Kaplan-Meier method and the median time to 
response will be presented along with a 95% confidence interval.
10.5.2.5 Time to response will be analyzed by cohort as well as for all treated 
patients combined in FAS.Overall survival (OS)
Overall survival (OS) is the time from date of first CTL019 infusion to date of death due to any 
reason. If a death has not been observed by the date of analysis cutoff, OS will be censored at 
the date of last contact.
OS will be assessed in all patients (FAS). The distribution function of OS will be estimated 
using the Kaplan Meier (KM) method. The median OS and the proportion of patients alive at 3, 
6, 12, 18, 24, 36, 48 and 60 months with 95% confidence intervals will be presented.
OS will be analyzed by cohort as well as for all treated patients combined in FAS.
10.5.2.6 Efficacy in histological and molecular subgroups
ORR, PFS, OS, EFS, and DOR will be descriptively summarized in histological subtypes (NOS, 
other) and molecular subtypes (GC, ABC and other).
10.5.2.7 Overall response rate in all treated patients
Overall response rate in all treated patients in FAS will be summarized along with the 95% 
confidence interval.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used, unless otherwise specified. All listings and 
tables will be presented by one treatment arm of CTL019.
The overall observation period will be divided into three mutually exclusive segments:


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
Pre-treatment period: from day of patient’s informed consent to the day before first 
lymphodepleting chemotherapy dose or the pre-infusion visit if the lymphodepleting 
chemotherapy is not given.

Lymphodepleting period (note: this period only applies to patients who received 
lymphodepleting chemotherapy): from the first day of lymphodepleting chemotherapy

to the day before infusion of CTL019, for patients who received infusion, or

to the earlier of date of discontinuation and 30 days after last dose of lymphodepleting 
chemotherapy for patients who didn’t receive infusion of 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.
Adverse events that begin or worsen after informed consent should be recorded in the patient’
s source documents. New or worsening adverse events prior to starting study treatment (i.e. 
lymphodepleting chemotherapy or the pre-infusion visit if the lymphodepleting chemotherapy 
is not given per Section 6.1.1.1) are not required to be recorded in the CRF unless it is an SAE 
meeting criteria outlined in Section 8.1.2 or SAE meeting criteria outlined in Section 8.2.2. 
Once the patient begins lymphodepleting chemotherapy or the pre-infusion visit, all new or 
worsening adverse events will be recorded in the Adverse Event CRF. Summary tables for 
adverse events will be provided for AEs that started or worsened during the post-infusion period, 
i.e. the CTL019-treatment-emergent AEs. In addition, AEs that started or worsened during the 
lymphodepleting period will be summarized for all patients who received lymphodepleting 
chemotherapy. All safety data (including those from the pre-treatment period) will be listed 
along with the period (as defined in Section 10.5.3.1) of the starting date of AE.
The incidence of CTL019 treatment-emergent adverse events (new or worsening during the 
post-infusion period) will be summarized by primary 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 and serious adverse events will be listed by patient and tabulated by primary system 
organ class and preferred term.
Adverse events of special interest (AESI)
The current search criteria of AESI are based on limited experience from ongoing clinical 
studies without an accurate assessment of causality. AESI and the search criteria of AESI will 
be updated prior to reporting. AESI that occur within 8 weeks of the CTL019 infusion will be 
summarized by group term and preferred term.


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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 and biochemistry and 
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)
All laboratory data will be listed with valued flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges.
 
 
10.5.3.4 Immunogenicity
Humoral immunogenicity assessment will include evaluation of pre-existing (pre-treatment) 
and post-treatment anti-CTL019 antibodies and to examine the incidence of immunogenicity 
with treatment, together with antibody titers, as a secondary endpoint. Data may be further 
fractionated to determine proportion of patients who make transient versus sustained antibody 
responses. The assay for humoral immunogenicity will be a cell-based assay, detecting 
antibodies that bind to a Jurkat cell line transfected with the CTL019 construct. This cell line 
stably expresses the complete CTL019 sequence and can be used to detect antibodies that bind 
to any epitope on the extracellular domain of the protein. 
 
 
 
10.5.3.5 Other safety data
Vital signs will be collected as clinically needed. Presence of detectable RCL will be tested by 
VSV-G at scheduled assessments in Table 7-1 and Table 7-2. All safety data will be listed.
10.5.3.6 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: < 40 years, ≥ 40 years to <65 years, ≥ 65 years

Gender: Male, Female

Race: Asian, Black, Caucasian, Native American, Other, Pacific Islander, Unknown


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
Ethnicity: Hispanic or Latino, Chinese, Indian, Japanese, Mixed ethnicity, Other

Prior HSCT therapy yes or no

Histological (NOS, other) and molecular subgroups (GC, ABC, other)
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.
Summary for AE will be separately performed for each cohort and for all patients combined in 
safety set.
10.5.4
Pharmacokinetics
CTL019 concentrations in peripheral blood (and bone marrow and CSF if available) will be 
listed, graphed and summarized by time points as assessed by the following:

CTL019 transgene levels as measured by q-PCR

CTL019 transduced cells measured by flow cytometry of CD3-positive
 
The PK parameters listed in Table 10-2 along with other relevant PK parameters will be 
estimated, if feasible, from the individual concentration versus time profiles using a non-
compartmental approach within the modeling program Phoenix® (Pharsight, Mountain View, 
CA) and reported by best response category. The non0-quantifiable concentrations will be 
imputed to zero for PK concentration summaries wand will not be included for estimation of 
PK parameters. Results reported but deemed unreliable will be flagged and excluded from the 
summaries and PK parameter derivations.
Table 10-2
Noncompartmental pharmacokinetic parameters
Parameter
Definition
AUC 0 - Tmax
The AUC from time zero to Tmax in peripheral blood (%*days or days*copies/ µg)
AUC Tmax - 28d 
and/or AUCTmax-
84d
The AUC from time Tmax to day 28 and/or AUCTmax-84dor other disease assessment 
days, in peripheral blood (%*days or days*copies/ µg)
AUC 0 - 28d 
and/or AUC0-
84dand M3 
The AUC from time zero to day 28 and/or day 84 and or other disease assessment days, 
in peripheral blood (%*days or days*copies/ µg)
Cmax
The maximum (peak) observed in peripheral blood or other body fluid drug concentration 
after single dose administration (% or copies/ µg)
Tmax
The time to reach maximum (peak) peripheral blood or other body fluid drug 
concentration after single dose administration (days)
T1/2
The half-life associated with the elimination phase slope of a semi logarithmic 
concentration-time curve (days) in peripheral blood
Clast
The last observed quantifiable concentration in peripheral blood (% or copies/µg)
Tlast
The time of last observed quantifiable concentration in peripheral blood (days)


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Descriptive statistics of PK parameters will be summarized by arithmetic and geometric means, 
standard deviation, CV%, CV% geometric mean minimum, median and maximum. For Tmax 
only minimum, median and maximum will be presented. PK parameters will also be 
summarized by best overall response.
 
 
 
 
 
If there is sufficient data available additional summaries and/or model-based analyses relating 
exposure to clinical response, CRS grade or other endpoints of interest may be considered. 
Further details will be provided in the RAP. 
 
 
 Population PK and/or PKPD methods including covariate analysis may be utilized if 
supported by the data, and may be summarized in a report separate from the CSR.
 
 
Descriptive statistics of key PK parameters will be separately summarized for each cohort as 
well as for all treated patients in the Pharmacokinetic Analysis Set.


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10.7
Interim analysis
One interim analysis for futility and overwhelming efficacy is planned for the study when 
approximately 50 patients of the planned 80 (62.5%) in the main cohort have received CTL019 
infusion and the last patient has completed 3 months from study day 1 infusion or discontinued 
earlier. An α-spending function according to Lan-DeMets (O’Brien-Fleming), as implemented 
in EAST 6.3, will be used to construct the efficacy stopping boundary (Lan and DeMets 1983). 
Based on this choice of α-spending function, if the interim analysis is performed with 50 
patients, the lower bound of the 2-sided 99.08% exact confidence interval for ORR will need to 
be greater than 20% to declare statistical significance. As a result, an ORR of 19/50=38% will 
be needed to claim success at interim analysis. At the final analysis when 80 patients are treated 
and followed for at least 3 months, 2-sided 95.28% exact CI will be used correspondingly, 
requiring an ORR of 24/80=30% to claim success.
The futility stopping boundary will be determined based on the predicted probability of success 
at the final analysis. The study may be stopped for futility if the posterior predictive probability 
of claiming success at the end of the study, i.e. observing at least 24 responders out of 80 total 
patients, is found to be smaller than 10% based on the data from interim analysis. Based on a 
non-informative prior (Beta (1,1)) on the probability of success, if less than or equal to 12 
responders are observed from 50 patients in the interim analysis, then the Bayesian predictive 
probability of observing at least 24 responders from 80 patients at the end of the study will be 
less than 10%.


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In case the actual number of patients included in the interim analysis cut-off date is not exactly 
equal to the planned 50 patients, the efficacy and futility boundaries will be re-calculated based 
on the actual number of patients using the pre-specified α-spending function and predicted 
probability of success criteria, respectively.
The above decision rules will be used by the DMC, to make recommendations to continue or 
stop the trial. The DMC will also review safety data periodically.
The operating characteristics of certain scenarios are summarized in Table 10-3 below.
Table 10-3
Simulated scenarios for interim and final analysis
Scenario
Simulated probability 
(%) to claim success at 
interim analysis
Simulated probability (%) to 
stop for futility at interim 
analysis
Simulated probability (%) to 
claim success at interim or 
final analysis
p=0.20 (H0)
0.3
81.04
2.1
p=0.30
13.86
22.36
52.18
p=0.38 
54.49
2.66
93.64
p=0.50
96.60
0.05
99.95
10,000 simulations were performed for each scenario using R 3.0.2.
10.8
Sample size calculation
In two retrospective studies in relapsed and refractory DLBCL patients receiving 2nd or 3rd 
line therapies, the observed ORR were 14% and 20% (Seshadri et al 2008, Elstrom et al 2010). 
In a recent prospective clinical trial with ibrutinib in patients who had a median of 3 prior lines 
of therapy, the ORR in the ABC subtype was 40% and in the GC subtype 5% leading to an 
overall ORR of 21.7% (Wilson et al 2012).
Based on the null hypothesis of ORR ≤ 20% and alternative hypothesis of ORR >20%, 80 
patients in the primary analysis will provide 94% cumulative power to demonstrate statistical 
significance, using a 2-look Lan-DeMets group sequential design with O’Brien-Fleming type 
boundary and an exact CI at one-sided cumulative 0.025 level of significance, if the underlying 
ORR is 38%. In this setting, an ORR of 24/80=30% will be needed to claim success.
Assuming approximately 20% enrolled patients will not be infused due to reasons such as 
manufactory failure, worsening of patient’s condition, etc., at least 100 patients need to be 
enrolled in the main cohort to ensure 80 patients are treated and hence will be used for the 
primary analysis. At least 25 patients in each of the GC and ABC DLBCL subtypes will be 
treated in the main cohort.
10.9
Power for analysis of key secondary variables
Not applicable because no formal hypothesis testing is planned other than for the primary 
objective.


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11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information.
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.


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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.
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 subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ 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 subject 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 electronic CRFs 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 Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.


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


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Stamenkovic I and Seed B (1988) CD19, the earliest differentiation antigen of the B cell lineage, 
bears three extracellular immunoglobulin-like domains and an epstein-barr virus-related 
cytoplasmic tail. J Exp Med; 168:1205-1210
Stein S, Ott MG, Schultze-Strasser S, et al (2010) Genomic instability and myelodysplasia with 
monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous 
disease. Nat Med; 16(2):198-204
Sullivan KM, Storb R, Buckner CD, et al (1989) Graft-versus-host as adoptive immunotherapy 
in patients with advanced hematologic neoplasms. N Engl J Med; 320(13):828-834
Surh CD, Sprent J (2000) Homeostatic T cell proliferation: how far can T cells be activated to 
self-ligands? J Exp Med; 192(4):F9-F14
Tedder T, Isaacs C (1989) Isolation of cDNAs encoding the CD19 antigen of human and mouse 
B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol; 143(2):717-
717
Tey SK (2014) Adoptive T-cell therapy: adverse events and safety switches. Clin Transl 
Immunology; 3(6):e17
Themis M, Waddington SN, Schmidt M, et al (2005) Oncogenesis following delivery of a 
nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Mol Ther; 12(4):763-771
Thieblemont C, Briere J, Mounier N, et al (2011) The germinal center/activated B-cell 
subclassification has a prognostic impact for response to salvage therapy in relapsed/refractory 
diffuse large B-cell lymphoma: a bio-CORAL study. J Clin Oncol; 29(31):4079-87
Tilly H, Vitolo U, Walewski J, et al (2012) Diffuse large B-cell lymphoma (DLBCL): ESMO 
clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncon 23(Suppl7):vii 
78-82
van Stipdonk MJ, Lemmens EE, and Schoenberger SP (2001) Naïve CTLs require a single brief 
period of antigenic stimulation for clonal expansion and differentiation. Nat Immunol; 
2(5):423-429
Wang GP, Levine BL, Binder GK, et al (2009) Analysis of lentiviral vector integration in HIV+ 
study patients receiving autologous infusions of gene modified CD4+ T cells. Mol Ther; 
17(5):844-850
 
Willemsen RA, Weijtens MEM, Ronteltap C, et al (2000) Grafting primary human T 
lymphocytes with cancer-specific chimeric single chain and two chain TCR. Gene Ther; 
7:1369-1377
Wilson WH, Jung SH, Porcu P, et al (2012) A Cancer and Leukemia Group B multi-center 
study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of 
outcome by molecular subtype. Haematologica; 97(5):758-765


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Wilson WH, Gerecitano JF, Goy A, et al (2012) The Bruton’s tyrosine kinase (BTK) inhibitor, 
ibrutinib (PCI-32765), has preferential activity in the ABC subtype of relapsed/refractory de 
novo diffuse large B-cell lymphoma (DLBCL): interim results of a multicenter, open-label, 
phase study. Blood;120:Abstract 686.
Zaiss AK, Son S, Chang LJ (2002) RNA 3’readthrough of oncoretrovirus and lentivirus: 
implications for vector safety and efficacy. J Virol; 76(14):7209-7219


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Appendices


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14.2
Appendix 2: Eligibility based on serologic markers for hepatitis B 
infection
Test
Results
HBsAg
+
-
-
-
-
HBcAb
Any
+
+
-
-
HBsAb
Any
-
+
+
-
Eligibility
Not Eligible
Not Eligible
Not Eligible
Eligible
Eligible
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 as the only positive marker: Protective – Indicates vaccination. These 
patients are eligible for this trial.
Anti-HBc positive (with or without HBsAb positive): Indicates prior infection and the 
possibility of recrudescent hepatitis B (including flare with acute liver failure). These patients 
are also at risk for viral reactivation. These patients are not eligible for this trial.
14.3
Appendix 3: CTL019 modified data reporting – Treatment and 
Primary Follow Up Phase
This guidance is used to determine whether or not an AE, SAE, Concomitant medication, or 
Laboratory result has to be recorded in the CRF during the relevant study period. Before using 
this guidance, the investigator should determine whether or not an adverse event is serious using 
the criteria found in the protocol Section 8, and then use the applicable row of this guidance to 
determine whether or not that event is to be recorded in the CRF.


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14.3.1
Adverse event (AE) and serious adverse event (SAE) reporting
Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment Period
(Starting from LD chemo/pre-
infusion visit)
Post-treatment Period
Through Month 12 Visit
After Month 12 Visit, through Month 60
Non-serious Adverse 
Events (AE)
Modified:
●
All infections
●
All laboratory abnormalities deemed 
clinically significant by the investigator
●
All clinical AEs grade ≥ 3
●
All AEs related to a study procedure
●
All AEs leading to study discontinuation
All, 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 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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14.3.2
Concomitant medication and laboratory reporting
Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment Period
(Starting from LD chemo/pre-infusion visit, 
through Month 12 )
Post-treatment Period
(After Month 12, through Month 60 )
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient
Concomitant 
medications
Modified:
Drugs:
Record all of the following medications:
●
Corticosteroids (including prophylactically for blood product 
administrations, physiologic replacement doses, high or stress 
doses, etc.)
●
Anti-seizure medications
●
Allopurinol, or non-allopurinol alternatives
●
Rasburicase
●
Immunoglobulin therapy
●
Any medication given therapeutically for an SAE
●
Vasopressors and cardiac inotropic agents (see below)
●
Narcotics and sedatives (see below)
●
Antineoplastic therapies (e.g. lymphodepleting chemotherapy)
●
Related to an AE or SAE defined as reportable for this period
Vasopressors and cardiac inotropic agents:
●
For dose, record only maximum daily rate (e.g. µg/kg/hr, mg/hr, 
etc.)
Narcotics and sedatives:
●
For dose, record only total daily dose
Blood products (e.g. red cells, platelets, FFP, cryoprecipitate):
●
Record all blood products, including prophylaxis
Electrolyte & vitamin replacement:
●
Record all electrolyte replacement if given for a clinically 
significant electrolyte disturbance and list these as an adverse 
event (AE).
All
Modified:
●
Related to an AE or SAE defined as reportable for 
this period
●
Mutagenic agents (including cytotoxic drugs)
●
Radiation & antineoplastic therapy (including SCT)
●
Immunoglobulin therapy
●
Immunosuppressive agents (including dose of 
steroids higher than physiologic replacement therapy 
doses of steroids (< 12 mg/m2/day hydrocortisone or 
equivalent)
●
Investigational therapy


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Pre-treatment period
(ICF to LD chemo/pre-infusion visit)
Treatment Period
(Starting from LD chemo/pre-infusion visit, 
through Month 12 )
Post-treatment Period
(After Month 12, through Month 60 )
Inpatient/ICU OR Outpatient
Inpatient/ICU
Outpatient
Inpatient/ICU OR Outpatient
●
Do not record prophylactic use of electrolyte or vitamin 
replacements
●
Do not record total parenteral nutrition (TPN) on concomitant 
medication CRF
Fluids:
●
Do not record fluid boluses and maintenance fluids
Antibiotics:
Record all antibiotics starting from day of infusion, even if given 
prophylactically
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 not clinically significant 
and treated prophylactically are NOT to be recorded (e.g. 
maintenance electrolyte replacement, platelets given without 
clinical bleeding)
All
Modified:
●
Record all scheduled labs (per Visit Evaluation 
Schedule)
●
Record all results (scheduled or unscheduled) for: 
LDH, Uric acid, 
 and fibrinogen (related to 
CRS/TLS/MAS)
●
Record all other laboratory values if they are ≥ 
Grade 3
●
For laboratory abnormalities reportable as AE/SAE, 
record laboratory results that support the event 
(scheduled or unscheduled)
●
For any AE/SAE that may be caused by a 
laboratory abnormality, the laboratory value(s) (any 
grade) must also be recorded (e.g. “muscle cramps” 
potentially caused by hypokalemia)
●
Laboratory abnormalities that are treated 
prophylactically are NOT to be recorded (e.g. 
maintenance electrolyte replacement, platelets 
given without clinical bleeding)


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14.4
Appendix 4: CTL019 modified data reporting – Secondary Follow Up Phase
Adverse Events/ Serious Adverse Events
Concomitant Medications
●
New incidence or exacerbation of a pre-existing neurological disorder
●
New incidence or exacerbation of a prior rheumatologic or other autoimmune disorder
●
New incidence of other hematologic disorders
●
Any severe adverse event or condition the investigator believes may have a reasonable relationship to 
CTL019 therapy
●
Any severe adverse event or condition that is unexpected
●
Positive RCL test result
●
Vector insertion site sequencing result with a mono-or oligoclonality pattern or in a location near a known 
human oncogene
●
New malignancy (T-cell & non T-cell), other than primary malignancy
●
Progressive multifocal leukoencephalopathy (PML)
●
Hepatitis B reactivation
●
Intravenous Immunoglobulin
14.5
Appendix 5: Liver event and Laboratory trigger Definitions and Follow-up Requirements
14.5.1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
LIVER LABORATORY TRIGGERS
ALT or AST > 5 x ULN
LIVER EVENTS
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBIL > 3 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBIL > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, abdominal pain, 
nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity*
If ALT or AST abnormal at baseline.                                                                ALT or AST > 3x baseline or > 300 U/L (whichever occurs first)


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14.5.2
Follow Up Requirements for Liver Laboratory Triggers - ALT, AST, TBL
ALT
TBL
Liver Symptoms
Actions
ALT increase without bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
Normal
For participants with 
Gilbert’s syndrome: No 
change in baseline TBL
None 

No change to study treatment

Measure ALT, AST, ALP, GGT, TBIL, INR, albumin, CK, 
and GLDH in 48-72 hours.

Follow-up for symptoms.
If elevated at baseline:
ALT > 2 x Baseline 
or > 300 U/L (whichever occurs ﬁrst)
If normal at baseline:
ALT > 5 x ULN
for more than two
weeks
Normal
For 
participants with
Gilbert’s
syndrome: No
change in
baseline TBL
None

Interrupt study drug

Measure ALT, AST, ALP, GGT, TBIL, INR, albumin, CK, 
and GLDH in 48-72 hours.

Follow-up for symptoms.

Initiate close monitoring and workup for competing 
etiologies.

Study drug can be restarted only if another etiology is 
identiﬁed and liver enzymes return to baseline.
If elevated at baseline:
ALT > 3 x
baseline
or > 300 U/L (whichever occurs ﬁrst) for 
more than two weeks
If normal at baseline:
ALT > 8 x ULN
Normal 
None
ALT increase with bilirubin increase:
If normal at baseline:
ALT > 3 x ULN
TBL > 2 x ULN
(or INR > 1.5) for 
participants with Gillbert’s 
syndrome: Doubling of 
direct bilirubin
None 

Interrupt study drug

Measure ALT, AST, ALP, GGT, TBIL, INR, albumin, CK, 
and GLDH in 48-72 hours.

Follow-up for symptoms.
If elevated at baseline:
ALT > 2 x
baseline


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ALT
TBL
Liver Symptoms
Actions
or > 300 U/L (whichever occurs ﬁrst)

Initiate close monitoring and workup for competing 
etiologies.

Study drug can be restarted only if another etiology is 
identiﬁed and liver enzymes return to baseline.
If normal at baseline:
ALT > 3 x ULN
Normal or elevated
Severe fatigue, 
nausea, vomiting, right 
upper quadrant pain
If elevated at baseline:
ALT > 2 x
Baseline or > 300 U/L (whichever 
occurs first).
14.6
Appendix 6: Specific Renal Alert Criteria and Actions and Event Follow-up
14.6.1
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Confirmed serum creatinine increase 25 – 49%
Consider causes and possible interventions
Follow up within 2-5 days
Serum creatinine increase ≥50% +
OR if <18 years old, eGFR ≤35 mL/min/1.73 m2
Consider causes and possible interventions 
Repeat assessment within 24-48 hours if possible 
Consider drug interruption or discontinuation unless other causes are diagnosed 
and corrected
Consider patient hospitalization and specialized treatment
New onset dipstick proteinuria ≥ 3+ OR
(Spot) urinary protein-creatinine ratio (PCR) ≥ 1g/g (or mg/ mmoL equivalent as 
converted by the measuring laboratory)
Consider causes and possible interventions 
Assess serum albumin & serum total protein
Repeat assessment to confirm 
Consider drug interruption or discontinuation unless other causes are diagnosed 
and corrected


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Renal Event
Actions
New onset hematuria ≥3+ on urine dipstick
Assess & document 
Repeat assessment to confirm 
Distinguish hemoglobinuria from hematuria 
Urine sediment microscopy 
Assess serum creatinine
Exclude infection, trauma, bleeding from the distal urinary tract/bladder, 
menstruation 
Consider bleeding disorder
+Corresponds to KDIGO criteria for Acute Kidney Injury
14.6.2
Follow up of renal events
Assess, document and record in the appropriate CRF
Urine dipstick and sediment microscopy evidence of DIN: crystals, red blood cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, 
tubular epithelial cells
Blood pressure and body weight
Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid
Urine output
Review and record possible contributing factors to the renal event (co-medications, other co-morbid conditions) and additional diagnostic procedures (MRI etc.) in the 
CRF.
Monitor patient regularly (frequency at investigator’s discretion) until: 
Event resolution: serum creatinine within 10% of baseline or PCR <1 g/g or albumin-creatinine ratio <300 mg/g)
or
Event stabilization: serum creatinine level with ± 10% variability over last 6 months or PCR stabilization at a new level with ± 50% variability over last 6 months
Analysis of urine markers in samples collected over the course of the renal event

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Statistical Analysis Plan - Addendum 2
CTL019C2201 
Clinical Development
CTL019 (tisagenlecleucel-T)
CCTL019C2201 / NCT02445248
A Phase II, single arm, multicenter trial to determine the 
efficacy and safety of CTL019 in adult patients with 
relapsed or refractory diffuse large B-cell lymphoma 
(DLBCL)
Statistical Analysis Plan
Amendment 3
Author:
, Statistician
Document type:
RAP Documentation
Document status:
Final 
Release date:
Jan 27, 2023
Number of pages:
55
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Statistical Analysis Plan - Addendum 2
CTL019C2201 
Document History
Version
Date
Changes
0.1
08/27/2015
First draft to CTT review
0.2
10/07/2015
Incorporating CTT comments, sent to LF head review
0.3
11/23/2015
Incorporating LFH review comments, sent to CSB review
1.0
01/19/2016
Final version
2.0
02/23/2017
Amendment 1
Updates related to protocol Amendment 4

Updated study design to align with protocol.

Clarified that the primary endpoint and secondary endpoints will 
be assessed in main cohort (US manufacturing). Additional 
analyses will also be done separately for cohort A (Fraunhoffer) 
and for both cohorts combined.

Updated the response evaluation criteria from 
 

Updated the timing of interim and primary analysis, changing 
the minimal follow up at the time of analysis from 6 months to 3 
months

Added Efficacy analysis set

Updated Per-Protocol set
Updates related to analyses included in Pediatric ALL BLA

Clarify the sensitivity analyses on enrolled patients

Added analysis for hematopoietic cytopenia

Updated PK analysis plan
Updates related to the interim analysis

Added scope of interim analysis (Section 6)

Clarified that interim efficacy analysis (except OS) will be 
conducted on EAS. 
Updates related to analyses in breakthrough application

Added analysis of ORR based on BOR ignoring CR/PR at day 
28

Added sensitivity analysis for ORR excluding patients with CR 
at baseline
Details/Clarification for Programming

Update partial date imputation rule for concomitant medication

Algorithm for censoring after missing two scheduled 
assessment

Algorithm for defining IPI risk factor category

Information for defining cohort, molecular subtype, double/triple 
hit subgroup
3.0
01/06/2017
Amendment 2

Updated definition of analysis sets for more clarity


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Statistical Analysis Plan - Addendum 2
CTL019C2201 
Version
Date
Changes

Added analysis population by endpoints in Section 6 to clarify 
the scope and presentation for primary and final analysis.

Updated definition of refractoriness.

Added additional analysis for response rate
o
Response rate at Month 3, 6 and 9
o
Comparative analysis between local and central review

Updated PK and immunogenicity analysis
o
Moved dose response analysis to SCP
o
Moved exposure response analysis to SCP
o
Miscellaneous updated analysis of PK and 
immunogenicity

Updated subgroup analysis
4.0
09/20/2017
Addendum 1

One subgroup analysis was added for primary endpoint of ORR as per 
FDA request.
o
Time from most recent relapse to CTL019 infusion: <=Median 
vs. >Median

New presentation of CRS information (including maximum CRS grade, 
time to onset of CRS; duration of CRS; time to Grade 3/4 CRS, 
concurrent infections
 selected 
complications,
 
5.0
01/29/2019
Addendum 2

Updated the language in AESI section to include all identified and 
potential risks.  The list of AESIs and their search criteria are provided 
in the program-level electronic Case Retrieval Strategy (eCRS) form.

One subgroup analysis was added for safety
o
Baseline total tumor volume: <=Median, >Median

Updated the subgroup categories of number of prior lines of anti-
neoplastic therapy from ‘<=2 lines, 3-4 lines, >=4 lines’ to ‘<=2 
lines, >2 lines’

Removed the Kaplan-Meier analysis of time to first CRS onset
6.0
01/24/2023
Amendment 3

Clarify scope for final CSR 

Update the analysis for cytopenia per product-level standard


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Statistical Analysis Plan - Addendum 2
CTL019C2201 
Table of contents
Document History ...............................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
1
Introduction .......................................................................................................................10
2
Study design, objectives and endpoints.............................................................................10
2.1
Study Design..........................................................................................................10
2.2
Study objectives and endpoints .............................................................................12
3
Definitions and general methodology ...............................................................................16
3.1
Definitions .............................................................................................................16
3.1.1
Study drug and study treatment.............................................................16
3.1.2
Date of first administration of lymphodepleting chemotherapy ...........16
3.1.3
Date of infusion of study drug ..............................................................16
3.1.4
Date of first study treatment..................................................................16
3.1.5
Study day...............................................................................................16
3.1.6
Baseline.................................................................................................16
3.1.7
Last contact date....................................................................................17
3.1.8
Lost to follow-up...................................................................................17
3.2
Data Included in the analysis.................................................................................17
3.3
Definitions of analysis sets....................................................................................18
3.4
Response evaluation for DLBCL...........................................................................19
3.4.1
Overall radiological response at each assessment.................................19
3.4.2
Overall disease response at each assessment ........................................19
3.4.3
Best Overall disease response...............................................................22
3.4.4
Disease response and response rate (ORR) at month X (X=3, 6 and 
9) ...........................................................................................................23
3.5
Time-to-event definitions.......................................................................................23
4
Statistical methods used in reporting.................................................................................24
4.1
General presentation of descriptive summaries.....................................................24
4.2
Cohort ....................................................................................................................24
4.3
Patient disposition..................................................................................................24
4.4
Background and demographic characteristics .......................................................24
4.4.1
Basic demographics data.......................................................................24
4.4.2
Medical history......................................................................................25
4.4.3
Prior anti-neoplastic therapy .................................................................25


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Statistical Analysis Plan - Addendum 2
CTL019C2201 
4.4.4
International Prognostic Index (IPI) factor ...........................................25
4.4.5
Others ....................................................................................................25
4.5
Protocol deviation summaries................................................................................26
4.6
Treatments (study treatment, rescue medication, other concomitant therapies, 
compliance)............................................................................................................26
4.7
Efficacy evaluation................................................................................................26
4.7.1
Primary efficacy endpoint.....................................................................26
4.7.2
Secondary efficacy................................................................................29
31
4.8
Safety evaluation ...................................................................................................32
4.8.1
Analysis set and reporting periods for the analyses..............................32
4.8.2
Adverse events (AEs)............................................................................32
4.8.3
Laboratory abnormalities ......................................................................34
4.8.4
Cytokine release syndrome and anti-cytokine therapies.......................35
4.8.5
Other safety data ...................................................................................36
4.8.6
Safety subgroup analysis.......................................................................36
4.9
Pharmacokinetic analysis.......................................................................................36
 
37
37
37
38
4.9.5
Immunogenicity ....................................................................................38
38
39
39
40
40
40
40
41
41
41
42
4.16
Determination of sample size ................................................................................42
4.17
Interim analyses.....................................................................................................42


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5
Additional analysis definitions and conventions...............................................................43
5.1
Response rate analyses ..........................................................................................43
5.2
Assessment date.....................................................................................................43
5.3
Time-to-event analyses..........................................................................................44
5.4
Duration of follow-up............................................................................................44
5.5
Time windows .......................................................................................................44
5.6
Handling of missing or partial dates......................................................................49
5.6.1
AE date imputation ...............................................................................49
5.6.2
Concomitant medication date imputation .............................................51
5.6.3
Incomplete date for anti-neoplastic therapies .......................................51
5.6.4
Incomplete assessment dates for disease assessment............................52
5.6.5
Incomplete date for relapse or last known date subject in remission....52
5.6.6
Incomplete date for death or last known date subject alive ..................52
5.6.7
Incomplete date for initial diagnosis.....................................................53
5.6.8
Date of hospitalization imputation........................................................53
5.7
Determination of missing scheduled disease assessments.....................................53
6
Scope and patient population of interim, primary and final analysis................................54
6.1
Interim analysis scope............................................................................................54
6.2
Analysis population for primary and subsequent analyses....................................54
7
References .........................................................................................................................55
List of tables
Table 2-1
Study objectives and endpoints.............................................................12
Table 3-1
Last contact date data sources...............................................................17
Table 3-2
Overall radiological response based on CT at each assessment ...........19
19
Table 4-1
Safety reporting periods ........................................................................32
Table 4-2
Noncompartmental pharmacokinetic parameters..................................37
45
Table 5-2
Time windows for PK...........................................................................47
48
Table 5-4
AE/treatment date abbreviations...........................................................49
Table 5-5
AE partial date imputation algorithm....................................................50
Table 5-6
AE/treatment date relationship and imputation legend.........................50
Table 5-7
AE imputation example scenarios.........................................................50
Table 6-1
Endpoints, analysis population and manufacturing facilities................54


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List of figures
Figure 2-1
Study design.........................................................................................11


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List of abbreviations
ABC
Activated B-cell
AE
Adverse Event
AESI
Adverse events of special interest
ATC
Anatomical Therapeutic Chemical 
AUC
Area Under the Curve 
BOR
Best overall response
CAR
Chimeric antigen receptor
CCG
CRF Completion Guidelines
CI
Confidence Interval 
CIF
Cumulative incidence function
Cmax
Maximum concentration 
CMR
Complete Metabolic Response
CR
Complete Response 
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CRP
C-Reactive Protein 
CRS
Cytokine Release Syndrome
CSF
Cerebral spinal fluid 
CSR
Clinical Study Report 
CT
Computed tomography 
CTC
Common toxicity criteria 
CTCAE
Common Terminology Criteria for Adverse Events
DLBCL
Diffuse large B-cell lymphoma 
DMC
Data monitoring committee 
DOR
Duration of Response
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic data capture
EFS
Event free survival
FAS
Full analysis set 
GC
Germinal center-like
HSCT
Hematopoetic stem cell transplantation
ICF
Informed consent form 
 
IPI
International Prognostic Index
IRC
Independent Review Committee 
IRT
Interactive Response Technology 
i.v.
Intravenous(ly) 
IWRS
Interactive Web Response System 
kg
Kilogram
KM
Kaplan Meier 
LLOQ
Lower Limit of Quantification 


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LOQ
Limit of Quantification 
LPLV
Last Patient Last Visit 
LTFU
Long Term Follow Up 
MedDRA
Medical Dictionary for Regulatory Authorities
mL
Milliliter
MRI
Magnetic Resonance Imaging 
MRT
Mean Residence Time 
ORR
Overall Response Rate 
OS
Overall Survival
PAS
Pharmacokinetic analysis set
PCR
Polymerase Chain Reaction
PD
Progressive disease
PD
Pharmacodynamics
PET
Positron emission tomography 
PFS
Progression Free Survival 
PK
Pharmacokinetics
PMR
Partial Metabolic Response
PPS
Per Protocol Set 
PR
Partial Response 
PT
Preferred Term
QOL
Quality of Life 
Q-PCR
Quantitative Polymerase Chain Reaction
r/r
Relapsed or refractory
RAP
Report and Analysis Plan 
RCL
Replication competent lentivirus
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SCT
Stem cell transplantation
SD
Stable Disease 
SOC
System Organ Class 
SPD
Sum of the product of the diameters 
 
Tlast
Time of the last measurable concentration
Tmax
Time to peak concentration 
TNC
Total nucleated cells 
TNF
Tumor Necrosis Factor 
ULOQ
Upper Limit of Quantification 
UNK
Unknown 
VSV-G
Vesicular Stomatitis Virus, Glycoprotein
WBC
White blood cells


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1
Introduction
This document describes the detailed statistical methodology for the study CTL09C2201: A 
Phase II, single arm, multicenter trial to determine the efficacy and safety of CTL019 in adult
patients with relapsed and refractory diffuse large B-cell lymphoma. The data will be analyzed 
by Novartis and/or a designated CRO. It is planned that the data from all centers that participate 
in this protocol will be used. Three analyses are planned:

Interim analysis: when 50 patients treated with CTL019 from US manufacturing facility 
(main cohort) have been followed for at least 3 months or discontinued earlier. No CSR 
will be written.

Primary analysis: when 80 patients treated with CTL019 from US manufacturing facility 
(main cohort) have been followed for at least 3 months or discontinued earlier. Interim 
CSR will be written to support filing.

Final analysis: when all patients treated with CTL019 have completed study or 
discontinued earlier. 
2
Study design, objectives and endpoints
2.1
Study Design
The target population is comprised of adult patients with relapsed or refractory Diffuse Large 
B Cell Lymphoma. The study will have the following sequential phases for all patients (see 
Figure 2-1): Screening, Pre-Treatment (cell product preparation and lymphodepleting 
chemotherapy), Treatment and Primary Follow-up, Secondary Follow-up, and Survival Follow-
up. Efficacy for all patients will be evaluated using CT/MRI based on the  
 
 
 
 Efficacy will be assessed at Day 28 and months 3, 6, 9, 12, 18, 24 
months and then every 12 months for 5 years until documented disease relapse or disease 
progression. PET-CT will be performed at baseline and at Month 3. Due to the mechanism of 
action of CTL019, the Day 28 assessment should be interpreted in context of other clinical 
parameters that suggest true progression rather than pseudo-progression due to inflammatory 
changes and tumor swelling (De Velasco et al 2015). Although clinical guidelines (ESMO and 
NCCN) do not recommend routine imaging in patients in CR for longer than 2 years, in the 
context of this clinical trial an extended efficacy follow up by CT/MRI is justified. Safety will 
be assessed throughout the study.
One additional cohort has been added to the original main study cohort (80 patients treated with 
CTL019 manufactured at the Novartis manufacturing facility in Morris Plains, USA).
The additional cohort A will enroll approximately 18 patients to allow at least 15 patients 
infused with CTL019 manufactured at the Fraunhofer Institut für Zelltherapie.


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Figure 2-1
Study design
Only following informed consent/assent and confirmation of all clinical eligibility criteria will 
the information of the patient’s apheresis product (“pre-qualification”) be transmitted 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 a patient meets all clinical 
inclusion/exclusion criteria and the patient’s apheresis product is accepted for manufacturing.
Prior to CTL019 cell infusion and after apheresis, one cycle of lymphodepleting therapy is 
planned, if patients are not already lymphopenic. The purpose of the chemotherapy is to induce 
lymphopenia in order to facilitate engraftment and homeostatic expansion of CTL019 cells. 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.
CTL019 infusion will be given 2 to 14 days after completion of lymphodepleting chemotherapy, 
if lymphodepleting chemotherapy is required. CTL019 transduced T cells will be given as a 
single dose with a target of 5 x 108 (range 1-5 x 108) autologous CTL019 transduced cells via 
intravenous infusion. 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.
Disease status, PK, 
 safety and survival will be assessed in the Treatment and 
Primary Follow-up phase for up to 5 years post CTL019 infusion. 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. protocol 
defined adverse events) up to 5 years after CTL019 infusion. For all patients who complete the 
primary follow-up or complete/prematurely discontinue from the primary or secondary follow-
up phase, attempts to follow-up will be made to determine survival every 3 months post-


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CTL019 infusion until end of study, or patient is enrolled in the long term follow-up study, 
whichever occurs first.
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.
2.2
Study objectives and endpoints
Objectives and related endpoints are provided in Table 2-1 and detailed in the study protocol.
Table 2-1
Study objectives and endpoints
Objective
Endpoint
Primary:
Evaluate the efficacy of CTL019 therapy in the 
main cohort
Overall response rate (ORR), which includes complete 
response (CR) and partial response (PR) as determined 
by IRC assessment in the full analysis set (FAS) of the 
main cohort
In addition sensitivity analyses will be performed using 
the local investigator response assessments
Key secondary:
Not applicable
Not applicable
Other secondary:
Evaluate safety of CTL019
Type, frequency and severity of adverse events and 
laboratory abnormalities
Evaluate time to response
Time to response, i.e. time between date of CTL019 
infusion until first documented response (CR or PR) 
Evaluate duration of overall response (DOR) 
Duration of response, i.e. the time from achievement of 
CR or PR, whichever occurs first, to relapse or death due 
to DLBCL
Evaluate event free survival (EFS)
EFS, i.e. the time from date of CTL019 infusion to the 
date of first documented disease progression or relapse, 
new treatment for lymphoma or death due to any cause
Evaluate progression free survival (PFS)
PFS, i.e. the time from date of CTL019 infusion to the 
date of first documented disease progression or death 
due to any cause
Evaluate overall survival (OS)
OS, i.e., the time from date of CTL019 infusion to the 
date of death due to any cause
Evaluate efficacy and safety in histological and 
molecular subgroups (GC, ABC, other)
ORR, PFS, OS, EFS, DOR and AEs in histological and 
molecular subtypes
Characterize the in vivo cellular PK profile (levels, 
expansion, persistence) of CTL019 transduced 
cells into target tissues (blood, bone marrow, 
cerebral spinal fluid and other tissues if available), 
summarized by clinical response
- PK parameters: Cmax, Tmax, AUCs, T1/2, Clast, Tlast 
and/or other relevant PK parameters in peripheral blood, 
bone marrow, as appropriate
Characterize immunogenicity (pre-existing (pre-
dose) and post-infusion) in patient treated with 
CTL019
-Summary of immunogenicity(cellular and humoral)


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Objective
Endpoint
Describe presence of RCL
- RCL by VSV-g q-PCR
Evaluate efficacy and safety in cohort A
ORR, PFS, OS, EFS, DOR and AEs in cohort A 
Evaluate the Overall response rate for all patients 
treated
ORR in all patients treated


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3
Definitions and general methodology
3.1
Definitions
3.1.1
Study drug and study treatment
Study drug is defined as CTL019 transduced cells.
Study treatment includes not only the study drug, i.e., CTL019 transduced cells, but also 
lymphodepleting chemotherapy.
3.1.2
Date of first administration of lymphodepleting chemotherapy
The date of first administration of lymphodepleting chemotherapy is defined as the first date 
when a non-zero dose of chemotherapy was administered and recorded on the “Concomitant 
Antineoplastic Therapy” eCRF for the indication “Lymphodepleting”. 
3.1.3
Date of infusion of study drug
The date of infusion of study drug is defined as the date when a non-zero dose of study drug 
(CTL019 transduced cells) was administered and recorded on the “Dosage administration 
record” eCRF. 
3.1.4
Date of first study treatment
For patients who received lymphodepleting chemotherapy, the date of first study treatment is 
the date of first administration of lymphodepleting chemotherapy (as defined in Section 3.1.2); 
for patients who did not receive lymphodepleting chemotherapy, the date of first study treatment 
is the date of infusion of study drug (as defined in Section 3.1.3). 
3.1.5
Study day
The study day will be calculated as the difference between the date of the assessment and the 
date of first infusion of CTL019 (Day 1) plus 1 for assessments on or after the date of first 
infusion. For assessment before the date of first infusion, the study day will be calculated as the 
difference between the date of the assessment and the date of first infusion of CTL019 (Day 1) 
(Note: if an event happens before the first day of CTL019 infusion then the study day will be 
negative.) For patients who did not receive CTL019 infusion, their study days will not be 
calculated.
The study day will be displayed in all relevant data listings.
3.1.6
Baseline
Baseline is the result of an investigation describing the “true” uninfluenced state of the patients.
For efficacy and safety evaluation, the last available assessment before CTL019 infusion is 
taken as “baseline” value or “baseline” assessment.
If patients have no value as defined above, the baseline results will be missing.


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3.1.7
Last contact date
The last contact date will be used for censoring of patients in the analysis of overall survival.
For patients not known to have died as of the analysis cut-off date, the last contact date should 
be derived as the latest date on or before the data cut-off date from the dates listed in the first 
column of Table 3-2. For each of the sources specific conditions listed in the second column of 
Table 3-1 have to be fulfilled to ensure that there was true contact with the patient.
No additional dates are allowed to be used, e.g. dates coming from concomitant medications, 
 etc. 
Table 3-1
Last contact date data sources
Source data
Conditions
Last date patient was known to be alive from 
Survival Follow-up page 
No condition
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from drug administration record 
Non-missing dose. 
Any specific efficacy assessment date if available
Evaluation is marked as ‘done’.
Laboratory/PK collection dates
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE
Non-missing verbatim term
Note: completely imputed dates will not be used to derive the last contact date.  Partial date’s 
imputation is allowed to be used for event (death) and for censoring date only if coming from 
Survival Follow-up eCRF page (see Section 5.5.6 for details).
3.1.8
Lost to follow-up
Patients will be considered as lost to follow-up for time to event analysis if the time between 
their last contact date and the analysis cutoff date is greater than or equal to 105 days (i.e., 3 
months plus 2 weeks, assuming 1 month = 30.4375 days).
3.2
Data Included in the analysis
Data from all participating centers will be combined for the analyses.
The primary analysis will be performed after approximately 80 patients from main cohort have 
received CTL019 infusion and completed 3 months from study day 1 infusion or discontinued 
earlier. One interim analysis for futility and overwhelming efficacy will be performed after 
approximately 50 patients from main cohort have received CTL019 infusion and the last patient 
has completed 3 months from study day 1 infusion or discontinued earlier. Each analysis will 
use all data in the database up to the analysis cutoff date, determined prior to database lock.
Selected efficacy and safety analysis will be updated annually. A final Clinical Study Report 
(CSR) will be produced once all patients complete or discontinue from the study. Analyses 


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supporting primary and secondary objectives will be updated in the final CSR. Details for 
statistical outputs selection will be reflected in the Tables, Figures and Listings Shells of the 
final CSR.
3.3
Definitions of analysis sets 
The analysis sets to be used are defined as below. Unless otherwise specified, the Efficacy 
analysis set (EAS) will be used for ORR, DOR and TOR. The Full analysis set (FAS) will be 
used for PFS, EFS and OS. The Safety Set will be used for all safety analyses, unless otherwise 
specified. The Pharmacokinetic analysis set (PAS) will be used for pharmacokinetics analyses.
Analysis population for different endpoints and different planned analysis are specified in 
Section 6.
Screened Set
The Screened Set comprises all patients who have signed informed consent/assent and screened 
in the study.
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 accepted for manufacturing. In case of protocol deviation such that patients are 
enrolled without meeting all inclusion/exclusion criteria, such patients will still be considered 
in the Enrolled Set, if the patients’ leukapheresis product is received and accepted by the
manufacturing facility.
Full Analysis Set (FAS)
The Full Analysis Set (FAS) comprises all patients who received infusion of CTL019. 
Efficacy Analysis Set (EAS)
The Efficacy Analysis Set comprises a subset of patients in FAS who received CTL019 infusion
at least 3 months (90 days) prior to data-cut date.
Safety Set
The Safety Set comprises all patients who received infusion of CTL019. Note that the Safety 
Set and FAS are the same for this study.
Per-Protocol Set (PPS)
The Per-Protocol Set (PPS) consists of a subset of the patients in the EAS (at time of interim 
and primary analysis) or FAS (at time of final analysis) who are compliant with major 
requirements of the study protocol.
Major protocol deviations leading to exclusion from the PPS include:

Diagnosis of disease other than DLBCL at baseline;

Missing or incomplete documentation of disease at baseline;


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In addition, patients who receive a dose less than the minimum target dose 1×108 CTL019 
transduced cells will also be excluded. 
Pharmacokinetic Analysis Set (PAS)
The CTL019 Pharmacokinetic Analysis set (PAS) consists of patients in FAS who have at least 
one sample providing evaluable cellular kinetic data. The PAS will be used for summaries 
(tables and figures) of cellular kinetic data.
 
3.4
Response evaluation for DLBCL
The DLBCL response guideline is outlined in the Protocol Appendix 1 - Guidelines for efficacy 
evaluation in diffuse large B cell lymphoma and follicular lymphoma studies 
(Based on 
), hereafter referred 
to as 
. 
3.4.1
Overall radiological response at each assessment
Overall radiological response at each assessment is calculated as shown in Table 3-2. Please 
refer to the 
 for details.
Table 3-2
Overall radiological response based on CT at each assessment 
Index lesions
Non-index lesions1
New lesions
Overall radiological response
CR
CR
No
CR
CR
SD
No
PR
PR
CR or SD
No
PR
SD
CR or SD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1 If no non-index lesions are present at baseline, then this column is not used in evaluating overall radiological 
response.
3.4.2
Overall disease response at each assessment


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3.4.3
Best Overall disease response
The best overall disease response (BOR) is the best disease response recorded from date of 
infusion until progressive disease or start of new anticancer therapy (including ASCT), 
whichever comes first, and will integrate metabolic and radiologic responses.
A patient will have a best overall disease response of CR if they had CR as overall disease response 
for at least one of the assessments.


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A patient will have a best overall disease response of PR if at least one overall response of PR is 
available (and the patient would not qualify for CR).
A best overall disease response of SD will be declared when at least one SD assessment is available 
at least 4 weeks after CTL019 infusion (and the patient would not qualify for CR or PR).
A patient will have a best overall disease response of PD if the progressive disease was observed 
less than 14 weeks after CTL019 infusion (and the patient does not qualify for CR, PR or SD).
If a patient does not qualify for CR, PR, SD or PD, then their best disease response will be Unknown
(UNK).
3.4.4
Disease response and response rate (ORR) at month X (X=3, 6 and 9)
Disease response at month X is defined as the overall disease response evaluated at month X 
within protocol specified window. Response will be imputed follow the order of the rules 
below:
1. If patient start new cancer therapy prior to month X, then the response will be imputed as 
UNK
2. If an PD was observed earlier, then the response will be imputed as PD
3. If month X evaluation is not available, then the response will be imputed as 

CR, if both previous and next evaluations are available and show CR.

PR, if previous evaluation shows PR and next evaluation shows PR or better.

UNK, Otherwise.
The denominator for calculating ORR and CR rate at month X will be based on the number of 
patients who had infused at least X months prior to the data cut-off.
3.5
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 assessments of the event are available, the date of CTL019 infusion
will be used as end date when time is to be censored at last post-baseline response assessment,
i.e. time to event variables will never be negative.
Often censoring time is determined based on date of adequate response assessment. Any 
response assessment is considered to be adequate if the assessment was performed and the 
outcome of the assessment was other than “unknown” or “not done”.


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4
Statistical methods used in reporting
4.1
General presentation of descriptive summaries
Categorical data (e.g., gender, race, etc.) will be summarized by means of contingency tables; 
a missing category will be included as applicable. Percentages will be calculated using the 
number of patients in the relevant population or subgroup as the denominator.  
Continuous data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum).
4.2
Cohort
Patient cohort will be identified by culture ID collected on ‘Cryopreservation of Cell Doses -
Primary Product’ CRF. Patients with culture ID started with ‘MP’ are from main cohort 
(manufactured by Morris Plain, USA) and patients with culture ID started with ‘FH’ are from 
cohort A (manufactured by Fraunhofer, Germany).
4.3
Patient disposition
Patient disposition will be summarized for the following phases: 1) screening phase for the 
Screened Set; 2) pre-treatment phase for the Enrolled Set, 3) treatment and primary follow-up 
phase for the FAS and 4) secondary follow-up phase for the FAS. The patient disposition for 
each phase as specified will be summarized for all patients who entered that phase. The number 
and percentage of patients in each of the categories as listed for “End of Phase Disposition 
eCRF” pages will be tabulated and listed. Patients who have entered any study phase but have 
not completed/discontinued will be listed as appropriate.
For the screening phase, the clinical eligibility criteria that were not met by patients will also 
be tabulated. In addition, the number and percentage of patients who enrolled in the long term 
follow-up study will be summarized.
In addition, a high level disposition summary including all phases will be provided for all 
screened patients.
Duration of primary follow-up and total duration of study follow-up will be summarized 
descriptively. The number of patients in the following categories of duration of follow-up will 
also be tabulated : <3 months, 3 months to <6 months, 6 months to <12 months, 12 months to 
<24 months, >=24 months.
4.4
Background and demographic characteristics
The Enrolled set will be used for all baseline disease characteristics and demographic 
summaries. Patients infused and patients not infused will be presented side by side.
4.4.1
Basic demographics data
Demographic and other baseline data will be listed by patient and/or summarized descriptively. 


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4.4.2
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms at 
the time of informed consent will be summarized and listed. Separate summaries will be 
presented for ongoing and historical medical conditions. The summaries will be presented by 
primary system organ class and preferred term. Medical histories are coded using the medical 
dictionary for regulatory activities (MedDRA) terminology.
4.4.3
Prior anti-neoplastic therapy
Number and percentage of patients with prior anti-neoplastic medications/therapies/surgeries
will be summarized. Prior anti-neoplastic medications will be summarized by ATC class, and 
preferred term. All prior anti-neoplastic medications, radiotherapies, surgeries and SCT will be 
listed. 
Patients will be classified by their prior treatment response:

Refractory to last line

Refractory to all lines: Patients who have never achieved CR or PR prior to study.

Not refractory to all lines: Patients who did not achieved CR or PR at the last line of 
therapy prior to study but have achieved CR or PR before.

Relapsed to last line: Patients had a CR or PR from last line of prior therapy and relapsed 
prior to the study
4.4.4
International Prognostic Index (IPI) factor
IPI were determined by the answers (Yes, No and Unknown) of first five questions on 
‘Prognostic Factors’ CRF

Age greater than 60 years old

ECOG performance status >=2

More than a site of extranodal disease

Elevated LDH > upper limit of normal

Disease stage III/IV
IPI factors are summarized by category, based on number (Y) of questions with “Yes” and 
number (N) of questions with “No”

>=2; if Y>=2

< 2;  if N>=4 

Unknown; otherwise  
4.4.5
Others
All other data collected at baseline will be listed.


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4.5
Protocol deviation summaries
The number and percentage of patients in the Full Analysis Set with any protocol deviation will 
be tabulated by the deviation category. Major protocol deviations leading to exclusion from the 
PPS will be summarized.
All protocol deviations will be listed.
4.6
Treatments (study treatment, rescue medication, other 
concomitant therapies, compliance)
The total cells infused (both cells) and total transduced CTL019 cells infused (both cells and
cells/kg) will be listed and summarized using descriptive statistics.
Patients will be categorized as below, within or above the prescribed dose range. Patients with 
dose interruptions, as recorded in the dosage administration record eCRF, will be summarized.
Because the study drug of CTL019 is administered via one time infusion, no specific 
compliance will be summarized other than the CTL019 dose administration.
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 ATC class and preferred term.
Antineoplastic therapies, including the lymphodepleting chemotherapies, received after 
enrollment but prior to infusion will be listed. Patients will also be summarized by the types of 
lymphodepleting chemotherapies received.
Transfusions during the study will be listed. 
Rescue medications are medications given for severe CRS due to CTL019 cells. 
 
 
 
4.7
Efficacy evaluation
4.7.1
Primary efficacy endpoint
The primary objective of the study is to evaluate the efficacy of CTL019 therapy as measured 
by overall response rate (ORR), which includes complete response (CR) and partial response 
(PR) as determined by IRC assessment in the FAS in main cohort (patients treated with CTL019 
from US manufacturing facility).
The study will be ongoing at the time of interim analysis and primary analysis, when 50 and 80 
patients respectively from main cohort had 3 month follow-up or discontinued earlier. Therefore
EAS will be used to assess the primary endpoint to these milestones to ensure that patients
included in the analysis had the opportunity to be followed-up for 3 months. 
FAS will be used for the final update of the primary endpoint after all infused patients in the
main cohort have been followed 3 months or discontinued earlier.
In addition, sensitivity analysis will be performed using the local investigator response 
assessments instead of the IRC assessment.


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4.7.1.1
Variable
The primary endpoint is the ORR as determined by IRC assessment. The ORR is defined as the 
proportion of patients with a best overall disease response of CR or PR, where the best overall 
disease response is defined as the best disease response recorded from CTL019 infusion until 
progressive disease or start of new anticancer therapy (including ASCT), whichever comes first.
Best overall response will be assigned according to the following order: 
1. CR 
2. PR
3. SD
4. PD
5. Unknown
The best overall disease response for a patient is always calculated, based on the sequence of 
overall disease responses. 
See also the Section 3.4.3 for details regarding the definition of overall disease response.
4.7.1.2
Statistical hypothesis, model, and method of analysis
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 that ORR is greater than 20% at 
overall one-sided 2.5% level of significance, i.e., 
H0: p ≤ 0.2 vs. Ha: p>0.2
The ORR will be summarized along with the 2-sided 95% exact Clopper-Pearson confidence 
intervals. Taking into account the interim analysis (see Section 4.16), the study will be 
considered successful if the lower bound of the 2-sided 95.28% exact confidence interval for 
ORR is greater than 20%, so that the null hypothesis that the ORR is less or equal to 20% can 
be rejected.
4.7.1.3
Handling of missing values/censoring/discontinuations
Patients in this study who are of unknown clinical response will be treated as non-responders. 
See also the Novartis guideline for efficacy evaluation in lymphoma studies (based on 
 
) (Protocol Appendix 1) for more details.
Other missing data are simply noted as missing on appropriate tables/listings.
The censoring rules for time to event endpoints are specified in the corresponding sections in 
Section 4.6.2.
 


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4.7.1.5
Subgroup analysis
Subgroup analyses will be performed on the following based on the patient’s baseline status: 

Age: < 40 years, ≥40 years to <65 years, ≥ 65 years

Gender: Male, Female

Race: White, Asian, Black, Other

Ethnicity: Hispanic or Latino,  Other

Prior response status: Refractory to last line, relapsed to last line

IPI at enrollment: <2 risk factors, ≥2 risk factors

Number of prior lines of anti-neoplastic therapy: <=2 lines, >2 lines

Stage of disease at baseline: I/II, III/IV

Prior HSCT therapy: yes or no 

Molecular subtype: GC, ABC and other.

Rearrangements in MYC/BCL2/BCL6 genes: Double/Triple hits, Other

Time from most recent relapse to CTL019 infusion: <=Median vs. >Median
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.
 
 
 
 


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4.7.2
Secondary efficacy
4.7.2.1
Key secondary objective
Not applicable. No formal hypothesis testing is planned other than for the primary objective.
4.7.2.2
Other secondary efficacy objectives
IRC assessment will be used in the main analysis of secondary endpoints that involve disease 
response. GAP analysis will be provided for time to event endpoints.
4.7.2.2.1 Duration of overall response (DOR)
Duration of response (DOR) applies only to patients whose best overall disease response was 
CR or PR. It is defined as the time from the date of first documented disease response (CR or 
PR) to the date of first documented progression or death due to DLBCL. If a patient has not had 
an event, duration of overall response is censored at the date of the last adequate assessment.
In case a patient does not have progression or death due to DLBCL prior to data cutoff, DOR
will be censored at the date of the last adequate assessment on or prior to the earliest censoring 
event. The censoring reason could be:

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (also see below for handling HSCT)

Event documented after at least two missing tumor assessments

Adequate assessments no longer available
In the main analysis of DOR, death due to reason other than DLBCL will be considered as a 
competing risk event to other events of interest (progression or death due to DLBCL). In this 
analysis, the median response duration as well as proportion of patients without events 
following response (progression or death due to DLBCL) at 3, 6, 9, 12 months, etc. will be 
presented with 95% confidence intervals using the cumulative incidence function (CIF). 
Distribution of DOR will also be estimated using the Kaplan-Meier method in which death due 
to reason other than DLBCL will be censored.
As HSCT is an important treatment option in responding patients, it is appropriate to consider 
the date of HSCT as censoring date, instead of censoring at the last tumor assessment date. If a 
patient received HSCT after a CR or PR, relapse or survival status after HSCT will be recorded 
on the corresponding follow-up eCRFs, although data on individual disease response 
components (e.g. CT scan) will not be collected. In such cases, the date of relapse or death (if 
due to DLBCL) after HSCT will be used for the calculation of DOR as a sensitivity analysis.
Distribution of DOR will be estimated using the Kaplan-Meier method and the median response 
duration as well as proportion of patients without event at 3, 6, 9, and 12 months will be 
presented along with 95% confidence interval.
In addition, DOR may be summarized separately for patients with best response CR and those 
with best response PR, if there are sufficient patients in each of these two groups.


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4.7.2.2.2 Event free survival (EFS)
Event free survival (EFS) is the time from date of first CTL019 infusion to the earliest of the 
following (note the definition of events is not exactly the same as the Novartis modified Cheson 
criteria):

Death from any cause

Disease progression or relapse (as defined in section 3.4.2)

New anticancer therapy for lymphoma, excluding HSCT
In case a patient does not have any of the above events prior to data cutoff, EFS is censored at
the last adequate response assessment date on or prior to the earliest censoring event. The 
censoring reason could be 

Ongoing without event

Lost to follow-up

Withdrew consent

HSCT (see below for handling of HSCT)

Event after at least two missing scheduled disease assessment

Adequate assessments no longer available
Patients who proceed to HSCT after CTL019 infusion will be censored at the time of HSCT in the 
main analysis of EFS. In addition, a sensitivity analysis of EFS will be performed without 
censoring for HSCT.
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.
4.7.2.2.3 Progression free survival (PFS)
Progression-free survival (PFS) is defined as the time from the date of first CTL019 infusion to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of the last adequate 
assessment.
In case a patient does not have progression or death prior to data cutoff, PFS will be censored at
the date of the last adequate assessment on or prior to the earliest censoring event. The 
censoring reason could be:

Ongoing without event

Lost to follow-up

Withdrew consent

New anticancer therapy (see below for handling of HSCT)

Event documented after at least two missing tumor assessments

Adequate assessments no longer available
In the main analysis of PFS, patients who proceed to HSCT after CTL019 infusion will be censored 
at the time of HSCT. In addition, a sensitivity analysis of PFS will be performed without censoring 
for HSCT.


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PFS will be estimated using the Kaplan-Meier method and the median PFS as well as proportion 
of patients without event at 3, 6, 9, and 12 months will be presented along with 95% confidence 
interval.
4.7.2.2.4 Time to response
Time to overall disease response (CR or PR) is defined as the time from the date of CTL019 
infusion to the date of first documented disease response (CR or PR). The analysis will include 
all responders.
Time to response will be estimated using the Kaplan-Meier method and the median time to 
response will be presented along with a 95% confidence interval.
The following time to response may be explored if there are sufficient patients in the 
corresponding patient group: time from PR to CR (for patients with PR followed by CR); time 
from date of CTL019 infusion to PR (for all patients who had PR, regardless of whether it’s 
followed by CR); Time from date of CTL019 infusion to CR (for patients who had CR)
4.7.2.2.5 Overall survival (OS)
Overall survival (OS) is the time from date of first CTL019 infusion to date of death due to any 
reason. If a death has not been observed by the date of analysis cutoff, OS will be censored at 
the date of last contact.
OS will be assessed in all patients (FAS). The distribution function of OS will be estimated 
using the Kaplan Meier (KM) method. The median OS and the proportion of patients alive at 
3, 6, 12, 18, 24, 36, 48 and 60 months with 95% confidence intervals will be presented.
4.7.2.2.6 Efficacy in histological and molecular subgroups
The clinical efficacy outcomes (ORR, PFS, OS, EFS and DOR) will be summarized 
descriptively for each of the histological and molecular subgroups, if there are at least 5 patients 
in each of the group: 

Histological subgroups: Diffuse Large B-cell lymphoma, not otherwise specified 
(NOS), Transformed lymphoma and other.

Molecular subgroups: germinal center (GC), activated B-cell (ABC) and other.
 


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4.8
Safety evaluation
4.8.1
Analysis set and reporting periods for the analyses
Table 4-2 summarizes the mutually exclusive safety reporting periods as well as the patients 
to be included in each of the segments. Note that the post-infusion period will be the main 
period of safety reporting (see Section 4.7.2 for details).
Table 4-1
Safety reporting periods
Period
Definition
Patients to be included
Pre-treatment period
From day of patient’s informed consent to 
the day before  first lymphodepleting 
chemotherapy dose or the pre-infusion visit 
if the lymphodepleting chemotherapy is not 
given
Screened patients
Lymphodepleting period 
(note: this period only 
applies to patients who 
received lymphodepleting 
chemotherapy)
From the first day of lymphodepleting 
chemotherapy
•
to the day before infusion of CTL019, 
for patients who received infusion, or
•
to the earlier of date of discontinuation 
and 30 days after last dose of 
lymphodepleting chemotherapy for patients 
who didn’t receive infusion of CTL019
All patients who received 
lymphodepleting 
chemotherapy
Post-infusion period
Starting at day of first CTL019 infusion until 
end of study
Safety Set
4.8.2
Adverse events (AEs)
Reporting of AEs (except for CRS) will be based on MedDRA (latest version per database lock)
and Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. The grading of 
CRS will be based on protocol specific grading scales (Protocol section 6.2.4.2, Table 6-1).
Summary tables for AEs will be provided for AEs that started or worsened during the post-
infusion period, i.e. the CTL019-treatment-emergent AEs. However, all safety data (including 
all observation periods as defined in Section 4.7.1) will be listed and with the period (as defined 
in Section 4.7.1) flagged for the starting date of the AE.
The incidence of CTL019-treatment-emergent AEs (new or worsening during the post-infusion 
period) will be summarized by system organ class, preferred term, severity (based on CTCAE 
grades), and relation to study drug. A patient with multiple CTC grades for an AE will be 
summarized under the maximum CTC grade recorded for the event. The frequency of CTC 
grade 3 and 4 AEs will be summarized separately.
Deaths and serious adverse events will be listed by patient and tabulated by primary system 
organ class and preferred term.


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Adverse events of special interest (AESI) include all important identified and potential risks 
of tisagenlecleucel. The list of AESIs and their search criteria will be updated on a regular basis 
at program level in the electronic Case Retrieval Strategy (eCRS) form. The most recent version 
of the eCRS form will be used for the reporting activity. 
Post-infusion period:
The following AE summaries will be produced for the Safety Set and displayed by timing of 
onset: Within 8 weeks post first tisagenlecleucel infusion, 8 weeks to 1 year post first 
tisagenlecleucel infusion, >1 year post first tisagenlecleucel infusion, and any time post first 
tisagenlecleucel infusion.

Adverse events, regardless of study drug relationship, by primary system organ class,
preferred term and maximum grade

Adverse events, suspected to be study drug related, by primary system organ class, 
preferred term and maximum grade

Deaths post infusion during study follow-up, by primary system organ class and preferred 
term

Serious adverse events, regardless of study drug relationship, by primary system organ 
class and preferred term and maximum grade

Serious adverse events, suspected to be study drug related, by primary system organ class 
and preferred term and maximum grade

Adverse events of special interest (AESI) based on identified risks, regardless of study 
drug relationship, by group term, preferred term and maximum grade 

Adverse events of special interest (AESI) based on identified risks, suspected to be study 
drug related, by group term, preferred term and maximum grade

Adverse events of special interest (AESI) based on potential risks, regardless of study 
drug relationship, by group term, preferred term and maximum grade 

Adverse events of special interest (AESI) based on potential risks, suspected to be study 
drug related, by group term, preferred term and maximum grade

Adverse events leading to study discontinuation, regardless of study drug relationship, by 
primary system organ class and preferred term

Non-Serious Adverse events, regardless of study drug relationship, by primary system 
organ class and preferred term
Lymphodepleting period:
In addition, AEs that started or worsened during the lymphodepleting period will be 
summarized for all patients in the Enrolled Set who received lymphodepleting chemotherapy. 
The following tables will be produced:

Adverse events, regardless of study treatment relationship by primary system organ class 
and preferred term

Serious adverse events, regardless of study treatment relationship by primary system 
organ class and preferred term

Adverse events, with suspected study treatment relationship by primary system organ 
class and preferred term


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
Serious adverse events, with suspected study treatment relationship by primary system 
organ class and preferred term
Pre-treatment period:
AEs that started or worsened during the pre-treatment period will be separately summarized for 
the Enrolled Set: 

Adverse events, by primary system organ class, preferred term and maximum grade

Serious adverse events, by primary system organ class and preferred term
Detailed information regarding the CRS will be summarized: maximum CRS grade, time to 
Grade 3/4 CRS, concurrent infections, 
 hypotension, use of 
fluid resuscitation, use of pressor support,
etc. If there is 
sufficient number of CRS events, separate summaries may be provided by best overall response.
4.8.3
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 and laboratory tests for 
Safety Set:

Shift tables using CTCAE grades to compare baseline to the worst post-infusion value
o
for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) 

Change from baseline to the worst post-infusion value, with descriptive statistics of baseline 
value, worst post-infusion value and the change.
The following listings will be provided for Enrolled Set.

Listing of patients with laboratory abnormalities of CTC grade 3 or 4 with the 
corresponding CTC grades and the classifications relative to the laboratory reference 
ranges. 

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges.
The shift tables will be generated by timing: Within 8 weeks post CTL019 infusion, >8 weeks 
to 1 year post CTL019 infusion, >1 year post CTL019 infusion, and any time post first 
tisagenlecleucel infusion.
In addition, percentage of patient with Grade 3 or 4 hematopoietic cytopenias 28 days post 
CTL019 infusion will be summarized. Among patients with Grade 3 or 4 hematopoietic 
cytopenias 28 days post CTL019 infusion, the timing of resolution to Grade 2 or below will be 
summarized via Kaplan-Maier method. Grading of cytopenias will be derived using lab results 


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in absolute lymphocytes (hypo), absolute neutrophils (hypo), hemoglobin (hypo), platelet count 
(hypo) or WBC (hypo) according to CTCAE 4.03. If a patient did not achieve resolution at the 
last lab assessment, timing of resolution will be censored at the last assessment. The median 
time to resolution and KM estimates of % unresolved cases at different time point (month 2,
month 3 and etc.) will be summarized. The same analysis (summary and timing of resolution
analysis) will also be generated for hematopoietic cytopenias 4 weeks post CTL019 infusion. 
The “4 weeks” is defined as the Week 4 visit day (i.e., Day 28) plus time window allowed per 
study protocol (i.e., 7 days).
The following listings will be provided for Enrolled Set.

Listing of patients with laboratory abnormalities of CTC grade 3 or 4 with the 
corresponding CTC grades and the classifications relative to the laboratory reference 
ranges. 

Listing of all laboratory data with values flagged to show the corresponding CTC grades 
and the classifications relative to the laboratory reference ranges.
4.8.4
Cytokine release syndrome and anti-cytokine therapies
To explore the relationship between CRS and other endpoints, the goal of this statistical analysis 
should be considered as the generation of new scientific hypotheses and observing new trends, 
since the studies are not adequately powered to propose a scoring system. 
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. 
Detailed information regarding the CRS will be summarized by disease response from IRC
assessment. Information summarized includes: maximum CRS grade, time to onset of CRS; 
duration of CRS; time to Grade 3/4 CRS, concurrent infections, 
 
, selected complications, 
, etc.
In addition, time to resolution of the first CRS will also be summarized using KM method for 
patients with CRS.  In case the end date of a CRS is missing, it will be censored / imputed as 
the minimum of the following dates: the cut-off date, end of study evaluation (i.e., completion 
of the last phase of the study), date of death (if applicable).
Peak cytokine level, time to high fever onset, CTL019 PK parameters (e.g. Cmax and AUC0-
d28), 
 
and CTL019 dose administered will be 
plotted against the maximum CRS grade using strip plot as appropriate. 
 
 
 


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4.8.5
Other safety data
Vital signs will be collected as clinically needed. Presence of detectable RCL will be tested by 
VSV-G at protocol scheduled assessments. All safety data will be listed.
4.8.6
Safety subgroup analysis
Key safety summaries for adverse events regardless of relationship to study drug by System 
Organ Class (SOC) and Preferred Term (PT), and AESI will be repeated on the Safety Set in 
the following subgroups:

Age: < 40 years, ≥ 40 years to <65 years, ≥ 65 years

Gender: Male, Female

Race: White, Asian, Black, Other

Ethnicity: Hispanic or Latino, Other

Prior HSCT therapy: yes or no 

Molecular subtype: GC, ABC and other.

Stage of disease at baseline: I/II, III/IV

Baseline total tumor volume: <=Median, >Median
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.
4.9
Pharmacokinetic analysis
PAS will be used for all 
 PK summaries (Table and figures).
The following parameters or concentration time profiles will be displayed graphically:
CTL019 concentration versus time in peripheral blood, bone marrow and CSF (if available) as 
determined by qPCR 
 
The cellular kinetic parameters (Table 4-2) were estimated from the individual concentration 
versus time profiles using a non-compartmental approach within Phoenix® (Pharsight, 
Mountain View, CA). Non-quantifiable concentrations imputed to zero were included 
exclusively for the estimation of partial AUCs (eg. AUC0-28d) using the conventional linear 
trapezoidal approach. The apparent half-life was derived from concentration time profiles on a 
semi-logarithmic scale and hence the imputed values cannot be included in the estimation. 
 
 
 When a 
geometric mean was presented, it was stated as such. A range of values was presented for 
selected variables. For Tmax, only median values and ranges were given.


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Table 4-2
Noncompartmental pharmacokinetic parameters
AUC 0 - Tmax
The AUC from time zero to Tmax in peripheral blood (% or copies/ µg x days)
AUC Tmax - 28d or 
M3 
The AUC from time Tmax to day 28 or M3 or other disease assessment days, in peripheral 
blood (% or copies/ µg x days)
AUC 0 - 28d or M3 
The AUC from time zero to day 28 or M3 or other disease assessment days, in peripheral 
blood (% or copies/ µg x days)
AUC0-180d
The AUC from time zero to 180 days in peripheral blood (% or copies/ µg x days)
Cmax
The maximum (peak) observed in peripheral blood or other body fluid drug concentration 
after single dose administration (% or copies/ µg)
Tmax
The time to reach maximum (peak) peripheral blood or other body fluid drug concentration 
after single dose administration (days)
T1/2
The half-life associated with the disposition phase  slopes (alpha, beta, gamma etc.) of a 
semi logarithmic concentration-time curve (days) in peripheral blood
Clast
The last observed quantifiable concentration in peripheral blood (% or copies/ µg)
Tlast
The time of last observed quantifiable concentration in peripheral blood (days)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.9.5
Immunogenicity
Humoral immunogenicity assessment will include prevalence of immunogenicity (patients with 
pre-existing antibodies that bind to CTL019) and incidence of immunogenicity (patients with 
treatment-induced or treatment-boosted antibodies that bind to CTL019), together with 
antibody titers. Data will be further fractionated to determine proportion of patients who make 
transient versus sustained antibody responses. The assay for humoral immunogenicity will be a 
cell-based assay, detecting antibodies that bind to a Jurkat cell line transfected with the CTL019 
construct. This cell line stably expresses the complete CTL019 sequence and can be used to 
detect antibodies that bind to any epitope on the extracellular domain of the protein.
Humoral immunogenicity:
The proportion of humoral immunogenicity positive and negative patients will be summarized 
by time points. Summary statistics will be presented for CTL019 cellular kinetic parameters for 
qPCR by anti-CTL019 antibody post-infusion status (positive or negative). 
A scatter plot of baseline anti-CTL019 antibodies versus qPCR AUC0-28d and Cmax will be 
presented along with the appropriate regression line and equation. In addition boxplots of anti-
CTL019 antibodies at enrollment by month 3 disease response will be presented. The same 
response categories will be used for a similar boxplot summarizing the maximum fold change 
of anti-CTL019 post-infusion.
The plot of CTL019 transgene concentration-time profile will be presented by post-infusion 
anti-CTL019 antibody status.
Cellular immunogenicity:
The cellular immunogenicity will be summarized by time points separated for CTL019 Pool 1 
Peptides and CTL019 Pool 2 peptides. The boxplot of maximum fold change of cellular 
immunogenicity by month 3 disease response will be presented. The scatter plot of maximum 
fold change versus qPCR AUC0-28d and Cmax will also be presented along with the 
appropriate regression line and equation.


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4.16
Determination of sample size
In two retrospective studies in relapsed and refractory DLBCL patients receiving 2nd or 3rd 
line therapies, the observed ORR were 14% and 20% (Seshadri et al 2008, Elstrom et al 2010). 
In a recent prospective clinical trial with ibrutinib in patients who had a median of 3 prior lines 
of therapy, the ORR in the ABC subtype was 40% and in the GC subtype 5% leading to an 
overall ORR of 21.7% (Wilson et al 2012).
Based on the null hypothesis of ORR ≤ 20% and alternative hypothesis of ORR >20%, 80 
patients in the primary analysis will provide 94% cumulative power to demonstrate statistical 
significance, using a 2-look Lan-DeMets group sequential design with O’Brien-Fleming type 
boundary and an exact CI at one-sided cumulative 0.025 level of significance, if the underlying 
ORR is 38%. In this setting, an ORR of 24/80=30% will be needed to claim success.
Assuming approximately 20% enrolled patients will not be infused due to reasons such as 
manufactory failure, worsening of patient’s condition, etc., at least 100 patients need to be 
enrolled to ensure 80 patients are treated and hence will be used for the primary analysis. At 
least 25 patients in each of the GC and ABC DLBCL subtypes will be treated.
4.17
Interim analyses
One interim analysis for futility and overwhelming efficacy is planned for the study when 
approximately 50 patients of the planned 80 (62.5%) in main cohort have received CTL019 
infusion and the last patient has completed 3 months from study day 1 infusion or discontinued 
earlier. An α-spending function according to Lan-DeMets (O’Brien-Fleming), as implemented 
in EAST 6.3, will be used to construct the efficacy stopping boundary (Lan and DeMets 1983). 


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Based on this choice of α-spending function, if the interim analysis is performed with 50 
patients, the lower bound of the 2-sided 99.08% exact confidence interval for ORR will need to 
be greater than 20% to declare statistical significance. As a result, an ORR of 19/50=38% will 
be needed to claim success at interim analysis. The study will continue to the planned final 
analysis even if success is claimed at interim analysis. At the final analysis when 80 patients 
are treated and followed for at least 3 months, 2-sided 95.28% exact CI will be used 
correspondingly, requiring an ORR of 24/80=30% to claim success.
The futility stopping boundary will be determined based on the predicted probability of success 
at the final analysis. The study may be stopped for futility if the posterior predictive probability 
of claiming success at the end of the study, i.e. observing at least 24 responders out of 80 total 
patients, is found to be smaller than 10% based on the data from interim analysis. Based on a 
non-informative prior (Beta (1,1)) on the probability of success, if less than or equal to 12 
responders are observed from 50 patients in the interim analysis, then the Bayesian predictive 
probability of observing at least 24 responders from 80 patients at the primary analysis will be 
less than 10%. 
Only the patients who have received CTL019 infusion and followed for at least 3 months or 
discontinued earlier will be included in the efficacy IA analyses.
In case the actual number of patients included in the interim analysis cut-off date is not exactly 
equal to the planned 50 patients, the efficacy and futility boundaries will be re-calculated based 
on the actual number of patients using the pre-specified α-spending function and predicted 
probability of success criteria, respectively.
The above decision rules will be used by the DMC, to make recommendations to continue or 
stop the trial. The DMC will also review safety data periodically.
The scope of interim analysis is provided in Section 6.
5
Additional analysis definitions and conventions
5.1
Response rate analyses
For the analyses of response rate (e.g, ORR), the rates will be summarized along with a 2-sided 
95% exact Clopper-Pearson confidence interval. Sample code is provided below.
PROC FREQ data=dataset;
TABLEES outcome/binomial(CL=exact);run;
/* outcome is the variable to indicate response or not, note that if the outcome is 
dichotomous variable, then the proportion of outcome=0 will be calculated.*/
5.2
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as:

the latest date of all radiological measurement dates (e.g. CT-scan (or MRI), and 
excluding both bone marrow biopsy and B-symptoms assessment), if the overall disease 
response at that assessment is CR/PR/SD/UNK,


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
the earliest date of all measurement dates (e.g. CT-scan (or MRI), including bone marrow 
biopsy, but excluding B-symptoms assessments) if the overall disease response at that 
assessment is PD.
5.3
Time-to-event analyses
For time-to-event analyses (DOR, RFS, EFS and OS), the survival function will be estimated 
using the Kaplan-Meier (product-limit) method as implemented in PROC LIFETEST (see 
examples below). Median survival will be obtained along with 95% confidence intervals
calculated from PROC LIFETEST output using the loglog option available within PROC 
LIFETEST, Kaplan-Meier estimates with 95% confidence intervals at specific time points will 
be summarized. 
PROC LIFETEST data=dataset METHOD=KM conftype=loglog;
TIME survtime*censor(1);
RUN;
/* survtime represents variable containing event/censor times; 
censor represents censoring variable (1=censored, 0=event); */
The time points can be expressed in weeks or in months depending on the time-to-event variable 
(e.g. overall survival might require a different scale than duration of response). If ‘months’ is 
used it should be noted that 1 month is defined as (365.25/12) =30.4375 days, which is not equal 
to 4 weeks.
In completing risk analysis, the cumulative incidence function (CIF) can be estimated following 
macro:
%CIF(data=dataset, out=est, time=survtime, status=status, event=1);
/* survtime represents variable containing event/censor times; 
status represents status variable (0=censored, 1= event of interest, 2= competing 
events); */
5.4
Duration of follow-up 
For time to event endpoints (DOR, EFS and OS), the follow up time (in months) is calculated 
as: 
Follow-up time = (Date of event or censoring – Date of first CTL019 infusion + 1)/30.4375. 
The study follow up duration (in months) will be calculated as (Analysis cut-off date – Date of 
first CTL019 infusion + 1)/30.4375).
5.5
Time windows
In order to summarize the 
 PK 
 data over time, 
assessments will be time-slotted using the following time windows. These windows will be 
based on the study evaluation schedule and should comprise a set of days “around” the nominal 
visits. As a general rule, the following steps are followed to determine the cutoffs for post-
baseline time windows:


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
Transform all scheduled assessment time points into study days, assuming 1 month = 
30.4375 days. Middle points of scheduled assessments are determined.

The time window associated with the previous assessment ends prior to the middle point; 
the time window associated with the latter assessment begins after the middle point. In 
case the middle point is an exact study day, it will belong to the previous assessment.

The time window of first post-baseline assessment starts with Day 2, unless otherwise 
indicated.
For PK 
, if more than one assessment is done within the Baseline time window, 
the last assessment in the baseline time window will be used. For all other time windows, the 
assessment closest to the planned assessment date will be used; if two or more assessments are 
equidistant from the planned date, then the mean value will be used.


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Table 5-2 shows the defined time windows for PK sample.
Table 5-2
Time windows for PK 
Time Window
Planned visit timing (Study 
day)
Time Window Definition (Study day)
CTL019 pharmacokinetics by q-PCR in peripheral blood 
W-3 to D-8 Enrollment/Pre-
Chemotherapy
Before Study Day 1
≤-1
D1 10 min ± 5 min post-infusion
1
1
D2
2
2
D4±1d
4
3 to 5
D7±1d
7
6 to 9
D11±1d
11
10 to 12
D14±1d
14
13 to 15
D17±1d
17
16 to 18
D21±3d
21
19 to 24
D28±7d
28
25 to 44
M2±14d
61
45 to 76
M3±14d
91
77 to 136
M6±14d
183
137 to 228
M9±14d
274
229 to 319
M12±14d
365
320 to 456
M18±14d 
548
457 to 639
M24±14d 
731
640 to 822
M30±14d 
913
823 to 1004
M36±14d 
1096
1005 to 1187
M42±14d 
1278
1188 to 1369
M48±14d
1461
1370 to 1552
M54±14d 
1644
1553 to 1734
M60±14d
1826
≥ 1735
CTL019 pharmacokinetics by flow cytometry in peripheral blood
W-3 to D-8 Enrollment/Pre-
Chemotherapy
Before Study Day 1
≤-1
D4±1d
4
1 to 5
D7±1d
7
6 to 9
D11±1d
11
10 to 12
D14±1d
14
13 to 15
D17±1d
17
16 to 18
D21±3d
21
19 to 24
D28±7d
28
25 to 44
M2±14d
61
45 to 76
M3±14d
91
77 to 136
M6±14d
183
137 to 228
M9±14d
274
229 to 319
M12±14d
365
≥ 320
CTL019 pharmacokinetics by q-PCR in bone marrow aspirate
CTL019 pharmacokinetics by flow cytometry in bone marrow aspirate


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CTL019 pharmacokinetics by q-PCR in lymph node biopsy
W-8 to W-4 Screening
Before Study Week -4
≤-1
M3±14d
91
60 to 136
CTL019 pharmacokinetics by q-PCR in CSF
W-8 to W-4 Screening
Before Study Week-4
≤-1
Immunogenicity serum sample (Humoral)
Immunogenicity peripheral blood sample (Cellular)
W-3 to D-8 Enrollment/Pre-
Chemotherapy
Before Study Day 1
≤-1
D14±1d
14
1 to 21
D28±7d
28
22 to 59
M3±14d
91
60 to 136
M6±14d
183
137 to 273
M12±14d
365
≥274
Study Day 1 = start date of CTL019
 


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5.6
Handling of missing or partial dates
For patients not known to have died prior to the cut-off date:

All events with start date before or on the cut-off date, and with end date missing or after 
the cut-off date will be reported as “continuing”. 

This approach applies, in particular, to AEs and concomitant medication reports. For these 
events, the end date will not be imputed and therefore will not appear in the listings. 
For patients known to have died prior to or on the cut-off date:

All events with start date before or on the cut-off date, and with end date missing or after 
the cut-off date will have the end date imputed to the death date. 

This approach applies, in particular, to AEs and concomitant medication reports. For these 
events, the imputed end date will not appear in the listings. 
5.6.1
AE date imputation
Date imputation is the creation of a new, complete date from a partial one according to an agreed 
and acceptable algorithm.  Missing date for AE will be handled according to rules specified 
below. A partial date is simply an incomplete date e.g. DDOCT2001: the days are missing from 
this DDMMMYYYY date.
Partial AE start dates, if left partial, would ultimately mean the following:
It would not be possible to place the AE in time.
Therefore the treatment/dosage at the time of the event would be unknown.
Therefore the event could not be reported/summarized appropriately – if at all.
Therefore it is important to perform date imputation to ensure that as many data events are 
represented as correctly as possible. Of course partial and/or missing dates should also be 
caught as edit checks and passed back to the investigator for resolution.
The following Table 5-5 explains the abbreviations used.
Table 5-4
AE/treatment date abbreviations 
Day
Month
Year
Partial Adverse Event 
Start Date
<not used>
AEM
AEY
Treatment Start Date 
(TRTSTD)
<not used>
TRTM
TRTY
The following matrix Table 5-6 describes the possible combinations and their associated 
imputations. In the light grey boxes the upper text indicates the imputation and the lower text 
the relationship of the AE start date to the treatment start date (TRTSTD).


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Table 5-5
AE partial date imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The following Table 5-7 is the legend to the above table.
Table 5-6
AE/treatment date relationship and imputation legend
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date to 
Treatment Start Date
Imputation Calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
The following Table 5-8 gives a few examples.
Table 5-7
AE imputation example scenarios
Partial
AE start date
Treatment
start date
Relationship
Imputation 
Calculation
Imputed Date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001


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Partial
AE start date
Treatment
start date
Relationship
Imputation 
Calculation
Imputed Date
ddNOV2001
20OCT2001
After
( A )
01NOV2001
Note, it may happen that the imputed AE start is after AE end date, in that case, imputed AE 
start=AE end date.
There will be no attempt to impute the following:

Missing AE start dates

AE start dates missing the year
Partial AE end date will be imputed as follows:

Imputed date = min (date of death if applicable, last day of the month), if day is missing;

Imputed date = min (date of death if applicable, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
Missing AE end date or AE end date after data cutoff will be imputed as follows:
All events with start date before or on the cut-off date, and with end date missing or after the 
cut-off date will have the end date imputed as the minimum of the cut-off date or date of death
or study evaluation completion date (if applicable). For these events, the imputed end date will 
not appear in the listings, instead, they will be reported as “continuing”.
5.6.2
Concomitant medication date imputation
The imputation of the start date and end date of concomitant medication will follow the same 
conventions as for AE date..
5.6.3
Incomplete date for anti-neoplastic therapies
Prior therapies
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication start date 
will be used with the exception that for scenario (B) will be replaced to be ‘start date of 
study treatment -1’.
End date:
Imputed date = min (start date of study treatment, last day of the month), if day is missing;
Imputed date = min (start date of study treatment, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end 
date as the imputed start date.


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If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
Post therapies
Start date:
Imputed date = max (last date of study treatment + 1, first day of the month), if day is 
missing;
Imputed date = max (last date of study treatment + 1, 01JAN), if day and month are missing.
End date: No imputation.
5.6.4
Incomplete assessment dates for disease assessment
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 5.2). If all measurement dates have no day 
recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
5.6.5
Incomplete date for relapse or last known date subject in remission 
The “Primary Malignancy Status” CRF will be used to track the relapse status for those patients 
who enter the secondary follow up phase while in remission.
If the day or month of date of relapse or last known date subject in remission is missing, it will 
be imputed to the minimal of date of assessment and the following:

Missing day:
15th day of the month and year 

Missing day and month:
July 1st  of the year
5.6.6
Incomplete date for death or last known date subject alive
If the day or month of death is missing from the death CRF, death will be imputed to the 
maximum of the full (non-imputed) last contact date (Section 3.1.7) and the following:

Missing day: 15th day of the month and year of death

Missing day and month: July 1st  of the year of death
If the day or month of last known date subject alive is missing in the survival CRF, it will be 
imputed to the maximum of the full (non-imputed) last contact date and the following:

Missing day: minimum of the date of assessment and 15th day of the month and year of 
last known date subject alive

Missing day and month: minimum of the date of assessment and July 1st of the year of 
last known date subject alive


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5.6.7
Incomplete date for initial diagnosis
If the day or month of initial diagnosis is missing, the date of initial diagnosis will be imputed 
to the minimum of the informed consent date -1 and the following:

Missing day: 15th day of the month and year

Missing day and month: July 1st  of the year
5.6.8
Date of hospitalization imputation
The imputation of the start and end date of hospitalization will follow the same conventions as 
for AE date.
5.7
Determination of missing scheduled disease assessments
For some time-to-event endpoints (i.e. DOR, PFS, EFS), classification of censoring or event 
can depend on the number of missing scheduled disease assessments. 
The protocol defined schedule of disease assessments is month 1, month 3, every 3 months till 
month 12, every 6 months till month 24, then every 12 months till month 60. Each assessment 
is expected to be performed at the scheduled time point plus or minus 2 weeks in general, i.e. 
the window is 4 weeks.
An event is considered as after 2 or more missing scheduled disease assessments if the distance 
between the last adequate non-PD assessment and the event is larger than the threshold, defined 
as two times the protocol specified interval between the disease assessments plus the protocol 
allowed window around the assessments. 
Given the multiple different assessment frequencies, the definition of “2 or more missing 
scheduled disease assessments” is simplified as follows:  
An event is considered as having occurred after 2 or more missing scheduled disease 
assessments if the distance between the last adequate non-PD assessment and the event is:

>98 days (i.e. 14 weeks) if there is no post-baseline non-PD assessment

>182 days (i.e. 2+3+1 months), if the last adequate non-PD assessment occurs on or 
before Day 45 (i.e. middle point of Month 1 and Month 3)

>213 days (i.e. 3+3+1 months), if the last adequate non-PD assessment occurs after Day 
45 and on or before Day 228 (i.e. middle point of Month 6 and Month 9)

>304 days (i.e. 3+6+1 months), if the last adequate non-PD assessment occurs after Day  
228 and on or before day 319 (i.e. middle point of Month 9 and Month 12)

>578 days (i.e. 6+12+1 months), if the last adequate non-PD assessment occurs after Day  
319 and on or before Day 456 (i.e. middle point of Month 12 and Month 18)

>760 days (i.e. 12+12+1 months), if the last adequate non-PD assessment occurs after 
Day  456


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6
Scope and patient population of interim, primary and final
analysis
6.1
Interim analysis scope
For the interim analysis conducted when at least 50 patients had followed for 3 months or 
discontinued earlier, no CSR will be written. First interpretable results (FIR) will be issued for 
main efficacy and safety results, including

Patient disposition

Demographics and baseline disease characteristics 

Prior/post antineoplastic therapy, concomitant medication

ORR, DOR, PFS, EFS for patients in EAS only and OS for all infused patients (FAS)

Sensitivity and subgroup analysis for ORR, except for ORR on PPS.

Bayesian predictive probability for success at primary analysis 

Dose administration

Death and Adverse events (all AE, SAE, AESI)

Detailed information about CRS

Lab results (shift table and resolution of cytopenias)

PK parameter and concentration summary

Other safety data (vital sign)
Details can be found in interim analysis TFL shells.
6.2
Analysis population for primary and subsequent analyses 
At the time of primary analysis, there are less than 15 infused patients in cohort A. No separate 
summary will be provided for cohort A. Patients from cohort A (Fraunhofer manufacturing) 
will be listed separately. Selected endpoints will be summarized for both cohorts combined as 
specified in Table 6-1.
Table 6-1
Endpoints, analysis population and manufacturing facilities
Endpoints
Enrolled 
but not 
infused
EAS/PAS
FAS/SAF
All
Main 
Cohort1
Cohort A1
All1
Main 
Cohort1
Cohort A1
All1
Disposition*
X
X
X
Demographics*
X
X
X
Baseline disease characteristics*
X
X
X
Medical History
X
X
X
Treatment*
X
X
X


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Time from enrollment to 
disc./infusion
X
X
X
ORR (including subgroups)*
X
DOR (including subgroups)*
X
TTR*
X
PFS*
X
X
EFS*
X
X
OS*
X
X
All Safety except AE
X
Adverse Event*
X
X
PK Summary*
X
X
X
1. Manufacturing facility: Main Cohort=Morris Plain; Cohort A= Fraunhofer; All=all manufacturing facilities 
* Key efficacy and safety endpoints.
Key efficacy and safety endpoints (marked by * in Table 6-1) in will be summarized by cohort 
separately as well as for both cohorts combined only after at least 15 patients in cohort A have 
been infused and followed for at least 3 month. 
7
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