Tisagenlecleucel Versus Standard of Care in Adult Patients With Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma: A Randomized, Open Label, Phase III Trial (BELINDA)
Phase: PHASE3
Conditions: Non-Hodgkin Lymphoma
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
CTL019, tisagenlecleucel, Kymriah® 
Clinical Trial Protocol CCTL019H2301 / NCT03570892
Tisagenlecleucel versus standard of care in adult patients 
with relapsed or refractory aggressive B-cell non-Hodgkin 
lymphoma: A randomized, open label, phase III trial 
(BELINDA) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2016-002966-29 
Version number: 
02 (Clean) 
Development phase: 
III 
Document status: 
Final 
Release date: 
18-Mar-2020
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 1.0 (01-Dec-2017) 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 8 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 15 
Amendment 2 (18-Mar-2020) ........................................................................................... 17 
Amendment 01-CN.01 (28-Oct-2019) .............................................................................. 22 
Amendment 1 (22-Feb-2019) ............................................................................................ 23 
Protocol summary .............................................................................................................. 35 
1 
Introduction ....................................................................................................................... 42 
1.1 
Background ............................................................................................................ 42 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment ................................................................................................ 42 
1.1.2 
Historical experience with viral gene therapies .................................... 46 
1.1.3 
Overview of tisagenlecleucel ................................................................ 47 
1.2 
Purpose .................................................................................................................. 50 
2 
Objectives and endpoints ................................................................................................... 51 
3 
Study design ...................................................................................................................... 54 
4 
Rationale ............................................................................................................................ 55 
4.1 
Rationale for study design ..................................................................................... 55 
4.1.1 
Rationale for lymphodepletion .............................................................. 57 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 57 
4.3 
Rationale for choice of comparator drugs ............................................................. 58 
4.4 
Purpose and timing of interim analyses ................................................................. 59 
4.5 
Risks and benefits .................................................................................................. 59 
4.5.1 
Identified safety risks with the use of tisagenlecleucel ......................... 59 
4.5.2 
Potential safety risks ............................................................................. 67 
4.5.3 
Other risks ............................................................................................. 70 
5 
Population .......................................................................................................................... 71 
5.1 
Inclusion criteria .................................................................................................... 71 
5.2 
Exclusion criteria ................................................................................................... 73 
6 
Treatment ........................................................................................................................... 75 
6.1 
Study treatment ...................................................................................................... 75 
6.1.1 
Investigational and control drugs .......................................................... 75 
6.1.2 
Tisagenlecleucel pre-infusion evaluation .............................................. 77 
6.1.3 
Additional safety procedures prior to tisagenlecleucel infusion ........... 78 

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6.1.4 
Additional study treatments .................................................................. 79 
6.1.5 
Treatment arms...................................................................................... 80 
6.1.6 
Treatment duration ................................................................................ 81 
 
 81 
6.2 
Other treatment(s) .................................................................................................. 82 
6.2.1 
Concomitant therapy ............................................................................. 82 
 
 83 
6.3 
Participant numbering, treatment assignment, randomization .............................. 84 
6.3.1 
Participant numbering ........................................................................... 84 
6.3.2 
Treatment assignment, randomization .................................................. 84 
6.4 
Treatment blinding ................................................................................................ 85 
6.5 
Dose modification .................................................................................................. 85 
6.5.1 
Follow-up for toxicities ......................................................................... 85 
6.6 
Additional treatment guidance ............................................................................... 87 
 
 87 
6.6.2 
Recommended treatment for adverse events ......................................... 87 
6.6.3 
Emergency breaking of assigned treatment code .................................. 92 
6.7 
Preparation and dispensation ................................................................................. 92 
6.7.1 
Handling of study treatment and additional treatment .......................... 92 
7 
Informed consent procedures ............................................................................................ 93 
8 
Visit schedule and assessments ......................................................................................... 94 
8.1 
Screening ............................................................................................................. 130 
8.1.1 
Eligibility screening ............................................................................ 131 
8.1.2 
Information to be collected on screening failures ............................... 132 
8.2 
Participant demographics/other baseline characteristics ..................................... 132 
8.3 
Efficacy ................................................................................................................ 133 
8.3.1 
Transmission of efficacy data to BIRC ............................................... 137 
8.3.2 
Non-expedited review - timepoints without locally determined 
progression or stable disease ............................................................... 137 
8.3.3 
Expedited review - timepoints with locally determined progression 
or stable disease ................................................................................... 138 
8.4 
Safety ................................................................................................................... 139 
8.4.1 
Laboratory evaluations ........................................................................ 140 
8.4.2 
Electrocardiogram (ECG) ................................................................... 141 
8.4.3 
Pregnancy and fertility ........................................................................ 143 
8.4.4 
Spirometry ........................................................................................... 143 
8.4.5 
Other safety evaluations ...................................................................... 143 

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8.4.6 
Appropriateness of safety measurements ............................................ 143 
8.5 
Additional assessments ........................................................................................ 143 
8.5.1 
Patient reported outcomes (PRO)........................................................ 143 
8.5.2 
Pharmacokinetics/ Cellular Kinetics ................................................... 146 
 
 157 
8.5.4 
Imaging ............................................................................................... 164 
8.5.5 
Survival follow-up .............................................................................. 164 
8.5.6 
Other assessments ............................................................................... 164 
9 
Study discontinuation and completion ............................................................................ 164 
9.1 
Discontinuation .................................................................................................... 164 
9.1.1 
Discontinuation of study treatment ..................................................... 164 
9.1.2 
Criteria for premature patient discontinuation from the study ............ 165 
9.1.3 
Withdrawal of informed consent ......................................................... 166 
9.1.4 
Lost to follow-up ................................................................................. 167 
9.1.5 
Early study termination by the sponsor ............................................... 167 
9.1.6 
Criteria for stopping or pausing the study ........................................... 167 
9.2 
Study completion and post-study treatment ........................................................ 168 
10 Safety monitoring and reporting ...................................................................................... 169 
10.1 
Definition of adverse events and reporting requirements .................................... 169 
10.1.1 
Adverse events .................................................................................... 169 
10.1.2 
Serious adverse events ........................................................................ 171 
10.1.3 
SAE reporting...................................................................................... 172 
10.1.4 
Adverse events of special reporting requirements .............................. 173 
10.1.5 
Pregnancy reporting ............................................................................ 173 
10.1.6 
Reporting of study treatment errors .................................................... 173 
10.2 
Additional safety monitoring ............................................................................... 174 
10.2.1 
Liver safety monitoring ....................................................................... 174 
10.2.2 
Renal safety monitoring ...................................................................... 175 
10.2.3 
Data Monitoring Committee ............................................................... 175 
10.2.4 
Steering committee .............................................................................. 175 
10.2.5 
Blinded independent review committee (BIRC) ................................. 176 
10.2.6 
Follow up of secondary malignancy ................................................... 176 
11 Data collection and database management ...................................................................... 176 
11.1 
Data collection ..................................................................................................... 176 
11.2 
Database management and quality control .......................................................... 177 
11.3 
Site monitoring .................................................................................................... 177 

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12 Data analysis and statistical methods .............................................................................. 178 
12.1 
Analysis sets ........................................................................................................ 178 
12.1.1 
Screened Set ........................................................................................ 178 
12.1.2 
Infused Set ........................................................................................... 178 
12.1.3 
Full Analysis Set ................................................................................. 178 
12.1.4 
Safety Set ............................................................................................ 179 
12.1.5 
Per-Protocol Set .................................................................................. 179 
12.1.6 
Cellular Kinetic Analysis Set .............................................................. 179 
12.2 
Participant demographics and other baseline characteristics ............................... 179 
12.3 
Treatments ........................................................................................................... 179 
12.4 
Analysis of the primary endpoint ........................................................................ 180 
12.4.1 
Definition of primary endpoint ........................................................... 180 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 180 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 181 
12.4.4 
Sensitivity and supportive analyses .................................................... 181 
12.5 
Analysis of secondary endpoints ......................................................................... 182 
12.5.1 
Efficacy and/or pharmacodynamic endpoints ..................................... 183 
12.5.2 
Safety endpoints .................................................................................. 185 
12.5.3 
Patient reported outcomes ................................................................... 188 
12.5.4 
Cellular kinetics .................................................................................. 190 
 
 190 
12.5.6 
Efficacy in sub-populations................................................................. 193 
 
 193 
 
 193 
 
 193 
12.7 
Interim analyses ................................................................................................... 193 
12.8 
Sample size calculation........................................................................................ 193 
12.8.1 
Primary endpoints ............................................................................... 193 
13 Ethical considerations and administrative procedures .................................................... 194 
13.1 
Regulatory and ethical compliance ...................................................................... 194 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 194 
13.3 
Publication of study protocol and results............................................................. 194 
13.4 
Quality control and quality assurance.................................................................. 195 
14 Protocol adherence .......................................................................................................... 195 
14.1 
Protocol Amendments ......................................................................................... 195 
15 References (available upon request) ................................................................................ 196 

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16 Appendices ...................................................................................................................... 205 
16.1 
Appendix 1:  Assessment algorithms for hepatitis B and C status at screening .. 205 
16.2 
Appendix 2: Guidelines for efficacy evaluation in non-Hodgkin-Lymphoma 
studies .................................................................................................................. 206 
16.2.1 
Introduction ......................................................................................... 206 
16.2.2 
Methodologies ..................................................................................... 206 
16.2.3 
Definitions ........................................................................................... 207 
16.2.4 
Efficacy assessments ........................................................................... 209 
16.2.5 
Data handling and programming conventions .................................... 221 
16.2.6 
Appendices .......................................................................................... 222 
16.3 
Appendix 3:  Modified data reporting by study period ....................................... 224 
16.4 
Appendix 4: Liver event and laboratory trigger definitions and follow-up 
requirements ........................................................................................................ 225 
16.5 
Appendix 5: Specific renal alert criteria and actions and event follow-up .......... 228 
 
List of tables 
Table 1-1 
Phase III trials in relapsed/refractory DLBCL ...................................... 44 
Table 2-1 
Objectives and related endpoints .......................................................... 51 
Table 4-1 
Clinical signs and symptoms associated with CRS............................... 61 
Table 4-2 
Cytokine Release Syndrome Grading ................................................... 61 
Table 4-3 
Immune effector Cell-Associated Neurotoxicity Syndrome 
(ICANS) Grading .................................................................................. 63 
Table 4-4 
Immune effector Cell-associated Encephalopathy (ICE) score ............ 64 
Table 6-1 
Defined risk factors and risk groups of International Prognostic 
Index (IPI) ............................................................................................. 85 
Table 6-2 
CRS management .................................................................................. 88 
Table 6-3 
Definition of high dose vasopressor use ............................................... 89 
Table 8-1 
Visit evaluation schedule pre-screening to randomization ................... 96 
Table 8-2 
Visit evaluation schedule for Arm A (patients randomized to 
tisagenlecleucel treatment strategy) ...................................................... 99 
Table 8-3 
Visit evaluation schedule for Arm B (patients randomized to SOC 
treatment strategy) ............................................................................... 112 
Table 8-4 
Visit evaluation schedule for patients who cross over from Arm B 
(SOC) to Arm A (tisagenlecleucel) ..................................................... 118 
Table 8-5 
Imaging or disease assessment collection plan ................................... 137 
Table 8-6 
ECOG performance status grade ......................................................... 139 
Table 8-7 
Physical assessments ........................................................................... 140 

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Table 8-8 
Laboratory assessments – Central Assessments ................................. 141 
Table 8-9 
Laboratory Assessments – Local Assessments ................................... 141 
 
 147 
Table 8-11 
Validated analytical methods and limit of quantification associated 
with the cellular kinetic analytes and immunogenicity assessments .. 148 
Table 8-12 
Tisagenlecleucel cellular kinetics by qPCR in peripheral blood 
collection log for patients in screening to randomization, Arm A, 
and in patients that cross over from Arm B to Arm A. ....................... 150 
 
 
 
 152 
Table 8-14 
Tisagenlecleucel cellular kinetics by q-PCR in bone marrow 
aspirate collection log for patients in screening to randomization, 
Arm A, and for patients that cross over from Arm B to Arm A. ........ 153 
Table 8-15 
Tisagenlecleucel cellular kinetics by q-PCR in CSF .......................... 153 
Table 8-16 
Humoral Immunogenicity serum sample collection for patients in 
screening to randomization, and Arm A, and in patients that cross 
over from Arm B to Arm A................................................................. 154 
Table 8-17 
Cellular Immunogenicity peripheral blood sample collection log 
for patients in screening to randomization, and Arm A, and in 
patients that cross over from Arm B to Arm A. .................................. 155 
Table 8-18 
Tisagenlecleucel cellular kinetics by qPCR in tocilizumab treated 
patients during CRS in Arm A and in patients that crossover from 
Arm B to Arm A ................................................................................. 156 
 
 
 160 
 
 161 
 
 
 
 162 
 
 
 163 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 174 
Table 16-1 
Five Point Scale (5PS) ........................................................................ 207 
Table 16-2 
Radiological response assessment ....................................................... 212 
Table 16-3 
Overall disease response ..................................................................... 215 
Table 16-4 
Censoring reasons ............................................................................... 219 
Table 16-5 
Options for event dates used in PFS, EFS, TTP, DOR ....................... 220 

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Table 16-6 
Data reporting adverse events, concomitant medications, and 
laboratory values ................................................................................. 224 
Table 16-7 
Liver event and laboratory trigger definitions .................................... 225 
Table 16-8 
Follow up requirements for liver events and laboratory triggers ........ 225 
Table 16-9 
Specific renal alert criteria and actions ............................................... 228 
Table 16-10 
Follow up of renal events .................................................................... 228 
List of figures 
Figure 1-1 
Tisagenlecleucel chimeric antigen receptor design ............................... 48 
Figure 3-1 
Study design .......................................................................................... 55 
 

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List of abbreviations 
5PS 
5 point scale 
AAIPI 
Age-adjusted international prognostic index 
ABC 
Activated B-cell 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALC 
Absolute lymphocyte count 
ALK 
Anaplastic Lymphoma Kinase 
ALL 
Acute Lymphoblastic Leukemia 
ALP 
Alkaline phosphate 
ALS 
Amyotrophic lateral sclerosis 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
ASH 
American Society of Hematology 
AST 
Aspartate aminotransferase 
ASTCT 
American Society of Transplantation and Cellular Therapy 
ATC 
Anatomical therapeutic chemical 
AUC 
Area under the curve 
AV block 
Atrioventricular block 
B-ALL 
B-cell acute lymphoblastic leukemia 
 
 
BEAM 
Carmustine, Etoposide, Cytarabine, Melphalan 
BIRC 
Blinded Independent Review Committee 
BM 
Bone marrow 
BOR 
Best overall response 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary artery bypass graft 
CAR 
Chimeric antigen receptor 
CCG 
CRF Completion Guidelines 
CD19 CART 
CD 19 redirected chimeric antigen receptor T cell 
CDS 
Core data sheet 
CFR 
Code of Federal Regulations 
CHOP 
Cyclophosphamide, doxorubicin, vincristine, prednisone 
CI 
Confidence Interval 
CK 
Cellular kinetics 
CKAS 
Cellular kinetic analysis set 
Clast 
Concentration last 
CLL 
Chronic Lymphocytic Leukemia 
Cmax 
Maximum concentration 
CMO&PS 
Chief Medical Office and Patient Safety 
CMR 
Complete metabolic response 
CMV 
Cytomegalovirus 
 
 
CNS 
Central Nervous System 
CORAL 
Collaborative Trial in Relapsed Aggressive Lymphoma 
CR 
Complete Response 

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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 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CT 
Computed tomography 
CTC 
Common toxicity criteria 
CTCAE 
Common terminology criteria for adverse events 
CV% 
Coefficient of Variation (%) 
DFS 
Disease free survival 
DHAP 
Dexamethasone, high dose, cytarabine (Ara-C, cisplatin (platinum) 
DILI 
Drug induced liver injury 
DLBCL 
Diffuse large B-cell lymphoma 
DLCO 
Diffusing capacity carbon monoxide 
DMC 
Data monitoring committee 
DNA 
Deoxyribonucleic acid 
DOR 
Duration of Response 
DRESS 
Drug reaction with eosinophilia and systemic symptoms 
EBV 
Epstein-Barr virus 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EEG 
Electroencephalography 
EFS 
Event free survival 
eGFR 
Estimated Glomerular Filtration Rate 
ePRO 
Electronic patient reported outcome 
EQ-VAS 
EuroQoL visual analogue scale 
EQ-5D 
EuroQoL 5 dimensions 
EMA 
European Medicines Agency 
EOS 
End of study 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
EWB 
Emotional Well-Being 
FACT-G 
Functional assessment of cancer therapy general 
FACT-Lym 
Functional assessment of cancer therapy lymphoma 
FACT-LymS 
Functional assessment of cancer therapy lymphoma subscale 
FACT-TOI 
Functional assessment of cancer therapy total outcome index 
FACT-TS 
Functional assessment of cancer therapy total score 
FAS 
Full analysis set 
FDA 
Food & Drug Administration 
FDG 
Fluorodeoxyglucose 
FEV1 
Forced expiratory volume in one second 

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FH 
Fleming-Harrington 
FISH 
Fluorescence in situ hybridization 
FL 
Follicular lymphoma 
FL3B 
Follicular lymphoma grade 3B 
FNA 
Fine needle aspirate 
FPFV 
First Patient First Visit 
FWB 
Functional well-being 
GBS  
Guillain-Barre syndrome 
GCB 
Germinal center B-cell 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony stimulating factor 
GDP 
Gemcitabine, dexamethasone, cisplatin 
GemOx 
Gemcitabine, oxaliplatin 
GEP 
Gene expression profiling 
GGT 
Gamma glutamyl transferase 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte macrophage-colony stimulating factor 
GVHD 
Graft versus host disease 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HDCT 
High dose chemotherapy 
HIV 
Human immunodeficiency virus 
HL 
HLH 
Hodgkin lymphoma 
Hemophagocytic lymphohistiocytosis 
HR 
Hazard ratio 
HR 
Heart rate 
HRQoL 
Health related quality of life 
HSC 
Hematopoietic stem cell 
HSCT 
Hematopoietic stem cell transplantation (refers to both allogenic SCT and autologous SCT) 
HSV 
Herpes simplex virus 
i.v. 
Intravenous(ly) 
IB 
Investigator’s brochure 
ICE 
Ifosfamide, carboplatin, etoposide 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
ICU 
Intensive care unit 
IDO 
Indoleamine 2,3-dioxygenase 
IEC 
Independent ethics committee 
IFN-g 
Interferon gamma 
Ig 
Immunoglobulin 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IMP 
Investigational medicinal product 
IN 
Investigator notification 

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INR 
International normalized ratio 
IPI 
International prognostic index 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
IT 
Intrathecal 
ITP 
Autoimmune thrombocytopenia/thrombocytopenic purpura 
ITT 
Intent to treat 
IUD 
Intrauterine device 
IUS 
Intrauterine System 
IWRS 
Interactive web response system 
LD 
Lymphodepletion 
LDH 
Lactate dehydrogenase 
LDi 
Longest diameter 
LFT 
Liver function tests 
LISA 
Lentivirus insertion site analysis 
LLOQ 
Lower 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 
MAS 
Macrophage activation syndrome 
MCHC 
Mean corpuscular hemoglobin concentration 
MCS 
Mental component summary 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
MMc 
Maternal microchimerism 
mPFS  
Median progression free survival 
MRA 
Magnetic resonance angiography 
MRD 
Minimum residual disease 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCIC-CTG 
National Cancer Institute of Canada Clinical Trials Group 
NE 
Norepinephrine equivalent 
NGS 
Next generation sequencing 
NHL 
Non-Hodgkin’s Lymphoma 
NK 
Natural killer cell 
NMR 
No metabolic response 
NOS 
Not otherwise specified 
NYHA 
New York Heart Association 
ORR 
Overall response rate 
OS 
Overall survival 
PB 
Peripheral blood 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase Chain Reaction 

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PCS 
Physical component summary 
PD 
Progressive disease or Pharmacodynamics 
 
 
 
 
PET 
Positron emission tomography 
PFS 
Progression free survival 
PK 
Pharmacokinetics 
PMBCL 
Primary mediastinal large B-cell lymphoma 
PMD 
Progressive metabolic disease 
PML 
Progressive multifocal leukoencephalopathy 
PMR 
Partial metabolic response 
PPD 
Perpendicular diameter 
PPS 
Per-protocol set 
PR 
Partial response 
PRO 
Patient reported outcome 
PT 
Preferred term or Prothrombin time 
PTLD 
Post-transplant lymphoproliferative disorders 
PWB 
Physical Well-Being 
q12hr 
Every 12 hours 
QA 
Quality Assurance 
QMS 
Quality Management System 
qPCR 
Quantitative polymerase chain reaction 
QTcF 
QT interval correction formula 
R 
Rituximab 
r/r 
Relapsed or refractory 
RAP 
Reporting and analysis plan 
RCL 
Replication competent lentivirus 
RD 
Relapsed disease 
RNA 
Ribonucleic acid 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan 
SC 
Steering committee 
scFv 
Single chain variable fragment 
SCT 
Stem cell transplantation 
SD 
Stable Disease 
SDi 
Shortest diameter 
SF-36 
Short Form 36 health survey 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvic transaminase 
SNP 
Single nucleotide polymorphism 
SOC 
System organ class or Standard of care 
SPD 
Sum of the product of the diameters 
SUSAR 
Suspected unexpected serious adverse reactions 
SUV 
Standardized uptake value 
SWB 
Social well being 
T1/2 
Time to half life 
TBIL 
 Total bilirubin 

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TCR 
T cell receptor 
TdP 
Torsades de pointes 
T/HRBCL 
T-cell/Histiocyte-rich B-cell Lymphoma 
Tlast 
Timepoint of last measurable concentration 
TLS 
Tumor lysis syndrome 
Tmax 
Time to peak concentration 
TNF 
Tumor necrosis factor 
TPR 
Timepoint response 
TTP 
Time to progression 
TTCR 
Time to complete response 
TTR 
Time to response 
ULN 
Upper limit of normal 
UNK 
Unknown 
US 
Ultrasound 
USPI 
United States Prescribing Information 
VH 
Heavy Chain Variable Domain 
VL 
Light Chain Variable Domain 
VSV 
Vesicular Stomatitis Virus 
VSV-G 
Vesicular Stomatitis Virus/Glycoprotein 
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 
Screening 
(Baseline) Efficacy 
Assessment 
The assessment is done within 4 weeks of randomization. If multiple assessments are 
performed then the one closest temporally to randomization will serve as baseline 
assessment. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study subject or patient 
(Optional) Bridging 
Therapy 
Rituximab based therapy given prior to tisagenlecleucel infusion 
Cohort 
A specific group of subjects fulfilling certain criteria and generally treated at the same 
time 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
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 
within approved indication/dosage 
Period 
A subdivision of the study timeline; divides stages into smaller functional segments such 
as screening, baseline, titration, washout, etc. 
Personal Data 
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes subject identifier information, study 
information and biological samples. 
Premature 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 
Randomization 
Point or time when patients have met all clinical eligibility and are assigned to Arm A 
(optional bridging chemo + lymphodepleting chemotherapy + tisagenlecleucel) or Arm B 
(SOC) 
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 
Subject Number 
A number assigned to each subject upon signing the informed consent. This number is 
the definitive, unique identifier for the subject and should be used to identify the subject 
throughout the study for all data collected, sample labels, etc. 
Variable 
A measured value or assessed response that is determined from specific assessments 
and used in data analysis to evaluate the drug being tested in the study 

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

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Amendment 2 (18-Mar-2020)  
Amendment rationale  
As of 25-Feb-2020, 107 participants out of 318 planned participants have been randomized on 
the study.  
The main purpose of this amendment is: 
1. To incorporate time to response as a secondary endpoint on the study, as this is an 
important aspect to describe the efficacy outcome for both study arms. 
2. To incorporate feedback from the data monitoring committee regarding the pre-infusion 
evaluation criteria in Section 6.1.2 to clarify the previously written criteria. This was 
important to guide investigators to a more thorough review of pre-infusion criteria due 
to patient safety findings when rapidly progressing patients have been infused. These 
clarifications have already been implemented with a dear investigator letter, and are now 
being adopted into the protocol. 
In addition, other changes and clarifications were made after consultation with the study 
steering committee to clarify certain eligibility criteria and some aspects of study conduct.  
These changes were aimed to improve study recruitment and compliance, while still 
maintaining safe and effective research in the desired study population with unmet medical 
need.  
Key changes include:  
• Changes were made to the inclusion criteria to allow patients who have suboptimal 
response (not CR) to first line therapy. This is consistent with NCCN guidelines and this 
population would be expected to have a similar prognosis to the current population 
(NCCN v1, 2019).   
• Changes were made to safety reporting criteria in Section 10.1.3 due to inconsistency 
with the modified data reporting in Section 16.3 Appendix 3. 
• Rituximab washout periods were removed as there is no clear scientific evidence of 
rituximab inhibiting the mechanism of action of tisagenlecleucel, and the long half life 
of rituximab makes it impossible to sufficiently remove this drug from the body with 
any reasonable amount of washout. The removal of this washout improves patient safety 
and removes the burden of modifying bridging and SOC chemotherapy regimens before 
infusion. 
• Additional changes were made based on feedback received from investigators and to 
clarify questions and address obstacles to protocol compliance observed to date.   
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. 
Significant changes are listed below: 
• Protocol summary section updated to align with content of protocol body.  

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• Table 2-1 was updated to include a secondary objective/endpoint for time to response 
(TTR).  
• Section 3 Study Design updated: 
• Arm A paragraph sentence was deleted:  “In order to comply with the 4 week washout 
period for rituximab therapy prior to tisagenlecleucel infusion (see Section 6.2.2), 
rituximab may need to be omitted from the last cycle of bridging chemotherapy.”  
• Arm B sentence clarified: “... patients with PR FDG+ disease, SD or PD per local 
assessment may request manufacturing  
• Table 4-1 Neurologic  was deleted from the clinical signs and symptoms associated with 
CRS. 
• Section 4.5.2.4 sentence deleted to align with IB, “The use of tocilizumab a monoclonal 
antibody against the IL-6 receptor, can exacerbate demyelinating disease, and therefore its 
use is to be used with precaution in such conditions [Actermra® USPI].” 
• Section 4.5.3.1 clarified that qPCR tests are available upon request 
• Section 5 sentence added for clarification “Central lab must be used to confirm eligibility 
of all lab parameters listed in Section 5.1 and Section 5.2.” 
• Section 5.1 Inclusion criteria updated: 
• Inclusion Criteria #3 was updated to include “PR” after at least 6 cycles of first line 
treatment, a new biopsy must be submitted.  
• Inclusion Criteria #4 was updated to include patients who received other anti-CD20 
antibody besides rituximab 
• Inclusion Criteria #6 was updated to ensure patients with active disease are included 
in the trial.  
• Inclusion Criteria #8c was updated to align with reference manual  
• Section 5.2 Exclusion criteria was updated: 
• Exclusion criteria #3 updated to note that treatment for second line “systemic” 
lymphoma is excluded. Updated sentence to include local irradiation is permitted. 
• Exclusion criteria #4 deleted parenthetical example as asymptomatic disease is not 
necessarily a sign of no active CNS involvement  
• Section 6.1.1 Investigational and control drugs updated: 
• Investigational Drug section clarified that “Patients that crossover to arm A after 
failing treatment with SOC chemotherapy may use any type of bridging therapy at the 
investigator’s discretion and are not restricted to the four bridging therapies specified 
in the protocol Section 3 and Section 6.1.1.” (similar change made in Section 6.1.4 
and 6.1.7) 
• Section 6.1.2 Pre-infusion evaluation updated based on DMC recommendation: 
• Added sentence: “In case of any doubt on fulfillment of pre-infusion evaluation 
criteria, the medical monitor may be contacted. The investigator will be required to 
sign the tisagenlecleucel pre-infusion checklist stating fulfillment of pre-infusion 
criteria within 24 hours prior to tisagenlecleucel infusion. Criteria must continue to be 
monitored after the form is signed until the time of infusion in case of any worsening 
of status which would preclude tisagenlecleucel infusion.” 

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• Evaluation #1 updated to include detail on rising LDH values and ECOG performance 
status changes 
• Evaluation #4 updated note to specify the tests “HBV, HCV, and HIV” 
• Section 6.2.1 clarified investigator discretion in use of drugs with known risk of QTc 
prolongation and/or ‘Torsades de Pointes” 
•
  
 
 
 
  
• Section 6.3.2 clarified refractory and relapse definition for stratification 
• Section 6.6.2.1 updated tocilizumab availability to align with latest RMP 
• Section 8 Visit Schedule and Assessments was updated to provide more clarity on study 
phasing and survival follow-up details 
• Table 8-1 Visit evaluation schedule pre-screening to randomization updated: 
• At screening Spirometry, ECHO/MRA/MUGA, ECG assessments are (allowed up to 
4 weeks prior to randomization) 
• Footnote 4 added 
• Table 8-2 Visit evaluation schedule for Arm A (patients randomized to tisagenlecleucel 
treatment strategy) updated: 
• Pre-infusion criteria evaluation was updated to clarify the requirement to complete 
mandatory signed form within 24 hours prior to tisagenlecleucel infusion 
 
 
• Footnote 3 sentence addition  
• Table 8-3 Visit evaluation schedule for Arm B (patients randomized to SOC treatment 
strategy updated: 
• Updated visit HSCT Day to HSCT Day 1 
• Renamed “End of Treatment and Follow-up” to “End of Treatment and Primary 
Follow-up” 
• Footnote 3 sentence addition  
• Table 8-4 visit evaluation schedule for patients who cross over from Arm B (SOC) to Arm 
A (tisagenlecleucel) updated: 
• Changed Visit Safety and Efficacy Follow-up visits to be timed based on crossover 
visit date” 
• Pre-infusion criteria evaluation was updated to clarify the requirement to complete 
mandatory signed form within 24 hours prior to tisagenlecleucel infusion 
 
  
• Footnote 3 sentence addition 
• Footnote 7 corrected as BIRC confirmed imaging is not done after crossover  
• Section 8.1 Screening updated: 

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• Added Cardiac and Lung function evaluation. 
 
 
 
• Sentence updated to allow rescreening upon consultation and agreement with the 
medical monitor. 
• Section 8.1.1 added sentence: Novartis will supply a stratification form which must be 
signed and returned prior to randomization  to ensure adequate documentation of 
stratification factors. 
• Section 8.3 Efficacy updated to: 
• “Efficacy assessment should be also performed before initiation of new anticancer 
therapy in all patients if there has not already been an adequate imaging assessment 
demonstrating BIRC-confirmed SD/PD.”  
• Added sentence: “The crossover visit should also mark the end of the treatment and 
primary follow-up visit for patients in Arm B.” 
• Disease characterization at baseline and evaluation of efficacy point 4 updated to 
CNS Brain Imaging (CT/MRI and/or diagnostic lumber puncture with CSF cytology 
(mandatory at screening and at discretion of the Investigator to evaluate CNS disease 
thereafter) 
 
• Imaging assessments section sentence rephrased for clarification of CNS disease 
assessment 
• Sentence “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.” deleted from this section and moved to 
Section 8.5.3 with new wording 
• Table 8-8 updated to include RCL by VSV-g q-PCR 
• Section 8.4.2, 8.4.2.1and 8.4.4 updated to allow ECG, cardiac imaging and spirometry 
already completed during the regular care of the participant within 4 weeks prior to 
randomization; including before signing the main study ICF can be considered as the 
screening assessments for this study. 
• Section 8.5.1 Patient reported outcomes (PRO) clarified that “The responses stored 
electronically in the database will be considered the source file.” Deleted the need to print 
a copy of the PRO questionnaires. 
• Table 8-16 and Table 8-17 footnote updated 
• Table 8-18 updated 

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• Sections 9.1.1, 9.1.2, 9.1.3 clarified study phasing and visits to complete upon 
discontinuation from each phase of the trial 
• Section 9.2 was reordered to clarify the study completion and post treatment study phasing 
• Section 10.1.3 SAE reporting was modified because it was not consistent with modified 
safety reporting in Section 16.3 
• Section 10.1.5 Pregnancy reporting sentence added according to updated global protocol 
template 
• Section 12.1.5 Updated protocol deviation to include “PR”. 
• Section 12.5 Updated to include “time to response (TTR) 
• Section 12.5.1.1 Overall response rate (ORR) sentence added: “A descriptive summary of 
patients’ disease response status at the Week 6 assessment will also be provided.” This is 
to characterize disease status after bridging therapy. 
• Section 12.5.1.3 Time to response (TTR) entire section was added to describe the Time to 
overall disease response. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  

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Summary of previous amendments  
Amendment 01-CN.01 (28-Oct-2019)  
Amendment rationale  
As of the release of this amendment, no subjects have been screened nor have received study 
treatment in 
. 
 
 
 
 
       
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
 
•
 
 
 
 
• Tisagenlecleucel, 
 
 assessments in PB in 
patients treated with tocilizumab 
 
 
• Peripheral blood (B and T cell levels) 
 
 
 
 

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•
 
 
 
 
 
 
 
•
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Amendment 1 (22-Feb-2019) 
Amendment rationale  
At the time of this amendment, no sites have yet been activated for the study.   

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The amendment was initiated in order to address feedback from multiple health authorities. 
There were several key updates that were required which could affect the conduct and 
management of the study: 
• Modification of the cytokine release syndrome (CRS) recommendations to the most up-to-
date approach on management of CRS and inclusion of neurotoxicity grading as per the 
America Society for Blood and Marrow Transplantation (ASBMT) consensus guidelines 
(Lee et al 2018) 
• Introduction of a new stratification factor of region to account for variety of 
implementation of standard of care treatment strategy across regions 
• Clarification of the crossover timelines following hemotopoetic stem cell transplant 
(HSCT) 
• Modification of serious adverse event (SAE) reporting requirement as per health authority 
commitment to require reporting of:  
• Progression of malignancy with fatal outcome as an SAE within 24 hours of 
awareness, if the following criteria are met: 
• Death within 30 days after tisagenlecleucel infusion, irrespective of causality to 
tisagenlecleucel  
• Death beyond 30 days after tisagenlecleucel infusion, if there is a least a possible 
causality to tisagenlecleucel  
• Several changes to the lab collection schedule to reduce the burden of cellular 
kinetic/
 collections, and to ensure adequate safety assessments during bridging 
chemotherapy 
• Clarifying language on the implementation of standard of care (SOC) therapy to reduce 
heterogeneity of arm B treatment across the study 
• The week 6 timepoint was changed to PET-CT and the window was widened to ± 2 weeks 
and language was added to ensure that this evaluation occurs after bridging chemotherapy 
and prior to tisagenlecleucel infusion 
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. Significant 
changes are listed below: 
• Section 1.1.2 was added to describe historical experience with viral gene therapies 
• Section 1.1.3 was updated with recent data on clinical experience, with new Section 
1.1.3.3 on Clinical efficacy and 1.1.3.4 on Clinical safety 
• Table 2-1 was updated to:  
• Clarify for all objectives whether the objective refers to Arm A and crossover, or 
all arms 
• Combine both objectives related to immunogenicity in Arm A to one objective 
 
 
  

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• Section 3 was updated to: 
• Clarify that patients with historical leukapheresis product do not need to undergo 
a new leukapheresis collection.   
• Add a stratification factor of Region (North America vs. Rest of World)  
• Clarify that every effort should be made to bring patients in a PR to transplant 
• Clarify language that ibrutinib and lenalidomide are only to be used in patients 
who are no longer eligible for HSCT 
• Clarify the allowable window of response assessments to be brought in line with 
the Visit Evaluation Schedules.  The week 6 timepoint window was also widened 
to ± 2 weeks to ensure that this evaluation occurs after bridging chemotherapy 
and prior to tisagenlecleucel infusion 
• Figure 3-1 was updated to clarify the different options available after week 6 and to update 
week 6 to PET-CT 
• Section 4.1 added a limit of 365 days after transplant was added for eligibility for 
crossover 
• Section 4.1 removed language related to CTL019 toxicity since it is not relevant to this 
section  
• Rationale for Lymphodepletion was moved from section 4.4 to 4.1.1 
• Section 4.2 clarified that chemotherapy regimens are not recommendations, but rather 
these are the only allowable treatments per protocol 
• Section 4.3 added Language was updated as in Section 3 to clarify that ibrutinib and 
lenalidomide are only to be used if the patient is no longer eligible for HSCT 
• Section 4.5 was updated with language regarding contraception requirements 
• Section 4.5.1.1 updated Cytokine Release Syndrome language including a definition of the 
date of resolution of CRS.  A description of grading of CRS was inserted to a new table 4-
2 (grading was previously discussed in Table 6-2).  
• Section 4.5.1.2 was updated to introduce the immune effector cell-associated neurotoxicity 
syndrome (ICANS) grading system, including the immune effector cell-associated 
encephalopathy ICE score , 
• Sections 4.5.1.5, 4.5.1.5.1, 4.5.1.6, 4.5.1.7, 4.5.1.8, 4.5.2.1, 4.5.2.2, 4.5.2.3, 4.5.2.4, and 
4.5.2.5 were updated with new program-standard risk language.  The sections previously 
labeled 4.6.1.7.1 (progressive multifocal leukoencephalopathy (PML)), 4.6.2.6 (New 
incidence or exacerbation of an existing neurological event), and 4.6.2.7 (graft versus host 
disease (GVHD)) were removed.   
• Section 4.5.3.1 was updated with language on pregnancy and to allow for unscheduled 
quantitative polymerase chain reaction (qPCR) collections in long term additional follow-
up to monitor for contraception requirements 

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• Section 4.5.3.2 was updated to clarify the management of SOC risks 
• Section 5.1 Inclusion criteria was updated 
• Inclusion Criteria #3 was updated to clarify that in some cases a biopsy after 
relapse/progression is not mandatory 
• Inclusion Criteria #5 was updated to state that intention to transplant and type of high 
dose chemotherapy (HDCT) regimen is documented in interactive response 
technology (IRT) only, not in the electronic case report form (eCRF) 
• Inclusion Criteria #8 was updated with slightly different bilirubin and oxygen 
saturation requirements 
• Section 5.2 Exclusion criteria was updated: 
• Exclusion Criteria #4 was updated to specify CNS involvement by disease under 
study 
• Exclusion Criteria #7 was updated to clarify as per Section 16.1 that patients with 
prior hepatitis B and C are allowed on study 
• Exclusion Criteria #8 was updated to remove reference to repeat testing, as this is 
included on the pre-infusion checklist 
• Exclusion Criteria #9 was updated with more clear language on infections 
• Exclusion Criteria #10 was updated to allow any patient with left ventricular ejection 
fraction (LVEF)  ≥45% at screening to be eligible for the study, regardless of testing 
within the past 6 months  
• Exclusion Criteria #11 was updated to clarify which prior malignancies are allowed 
• Exclusion Criteria #12 was updated to clarify that hypersensitivity to any drug 
product advised by the protocol is an exclusion 
• Exclusion Criteria #13 was updated to add cerebrovascular disorders 
• Exclusion Criteria #14 was changed to require a serum test, and removed reference to 
testing before study treatment, since this would not occur at the time of eligibility 
assessment 
• Exclusion Criteria #15 and #16 were updated to clarify the duration of contraception 
requirement for both arms 
• Exclusion Criteria #17 related to additional parallel investigational drug or device 
studies was removed, since this is already covered by Exclusion #6 
• Exclusion Criteria #17 (new) was added to clarify that patients who have a 
contraindication to study procedures should not be enrolled 
• Section 6.1.1 was updated to: 
• Statement was added that immunochemotherapy should start within 7 days of 
randomization 
• State that change in therapy is required if the response does not allow the patient to 
proceed to transplant 
• Clarify that patients should be given every possible chance to proceed to transplant 
• Clarify that ibrutinib and lenalidomide are only to be used if the patient is no longer 
eligible for transplant 

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• Clarify that transplant may occur after only 3 cycles of immunochemotherapy at 
investigator discretion 
• Add that HSCT date is recorded in IRT 
• Section 6.1.2 Pre-infusion evaluation checklist: 
• Check #4  
• Language regarding repeat of viral serology testing was moved from Section 8.1, 
since this language refers to a check done prior to infusion 
• Added additional check for clinically significant active infection 
• Check #6 and Check #9 were added 
• Check #7 was updated with the correct section referenced 
• Check #8 was updated to clarify that any northern hemisphere country should 
follow October through May for influenza testing 
• Section 6.1.3 was updated to allow for infection prophylaxis as per standard guidelines 
and the number of doses of tocilizumab that must be available after dosing was clarified 
• Section 6.1.4.2 specifies that tisagenlecleucel availability should be confirmed prior to 
starting lymphodepleting chemotherapy, and the timing of the lymphodepleting visit in 
patients not receiving lymphodepleting chemotherapy was updated 
• Section 6.1.5 was updated to: 
• Clarify that the tisagenlecleucel dosing is based on the viable cell count 
• Clarify that ibrutinib and lenalidomide are only to be used if the patient is no longer 
eligible for transplant 
 
  
 
 
 
 
 
 
 
• Section 6.2.1 was updated to refer to modified reporting criteria during certain trial 
periods 
 
 
 
 
 
 
 
  
• Section 6.3.2 was updated to reflect the new stratification factor 
• Section 6.5 was updated to clarify that modifications to drug combinations of the pre-
defined regimens should be approved by the Novartis global medical representative 
• Section 6.6.1.2 was updated to clarify that this section also applies to optional bridging 
immunochemotherapy and lymphodepleting chemotherapy 

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• Section 6.6.2.1 was updated to clarify that the availability of 4 doses of tocilizumab are 
required on site for each patient 
• Table 6-2 was updated to separate the grading of CRS from the management (grading was 
moved to Table 4-2).  Management recommendations were also updated  
 
 
 
• Section 6.6.2.4  was significantly shortened 
• Section 6.6.2.5 was updated to clarify time restrictions when live virus vaccinations can be 
given 
• Section 6.6.2.8, 6.6.2.9 and 6.6.2.10 were updated with most relevant management 
strategy 
• Section 6.6.2.11 (GVHD) was deleted 
• Section 6.6.3 was added (but described as not applicable) 
• Section 6.7.1.2 was added to replace part of section 6.7.1.1 with the standard process for 
disposal of tisagenlecleucel.      
• Section 6.7.1.3 was added to clarify handling of standard of care therapy 
• Section 8 was updated to: 
• 
to allow the possibility of additional monitoring assessment in accordance to local 
practice 
• 
to clarify the meaning of the (*) within the VES tables 
• Table 8-1 was updated to: 
• State that spirometry results are captured in the source only, not in the eCRF 
• Clarify the multiple gated acquisition (MUGA) scan  is an acceptable alternative to 
ECHO 
• Clarify that either computed tomography (CT)/magnetic resonance imaging (MRI) of 
brain or lumbar puncture can be used to confirm absence of CNS disease 
• Clarify that fertility assessment is only done at screening 
• Clarify that serum pregnancy test should be done prior to leukapheresis and is source 
documented only 
 
 
• Remove Bone marrow collections for cellular kinetics from the randomization visit 
• 
 
• Add peripheral blood cell levels assessment at screening, since this assessment is 
needed for Inclusion Criteria #8c 
• Table 8-2 was updated to: 
• Allow for multiple cycles of bridging chemotherapy with visits tied to cycles 
• Change the week 6 visit to PET-CT and move the Week 6 visit prior to 
lymphodepleting chemotherapy and after bridging chemotherapy, and widen the 

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window to ± 2 weeks.  Footnote 2 was added to specify the timing of this scan as pre-
infusion. 
• Update of visit names so that they are based on the actual date of infusion rather than 
an assumed Day 28 infusion 
• Add requirements to repeat physical examination, ECOG, vital signs, central 
hematology, and central chemistry on Day 1 and 15of each cycle of bridging 
chemotherapy and coagulation, pregnancy testing and weight on Day 1 of every cycle 
only.  Urine dipstick is done on Day 1 of the first cycle only  Footnote 1 was also 
added to clarify 
• Clarify that physical examination, performance status, and vital signs should be done 
at the lymphodepleting visit  
• Electrocardiogram (ECG) requirement was updated to only be on the day of infusion 
and otherwise as clinically indicated 
• Add ECHO/MRA/MUGA as clinically indicated 
• Add the ICANS grading and ICE score to assess neurotoxicity as per ASBMT 
consensus grading 
• Change the week 6 scan from CT to PET-CT 
• Clarify that CT scan is required at M6 only if PET-CT is not available 
• Clarify that either CT/MRI of brain or lumbar puncture are as clinically indicated 
• Changed cardiac enzyme testing to only as clinically indicated 
• Require serum pregnancy testing during bridging chemotherapy .  Duration of testing 
was updated to specify monthly testing for as long as contraception is required 
• Remove rituximab PK collections 
• Clarify humoral versus cellular immunogenicity and specify that these collections are 
only until M12 in long term additional follow-up 
• Clarify the location of additional tables on CRS and tocilizumab-related collections 
• Remove the lymphodepleting chemotherapy and 10 minutes post-dose collection for 
tisagenlecleucel cellular kinetics by qPCR 
 
 
 
 
 
  
• Add cerebral spinal fluid (CSF) collections for tisagenlecleucel for cellular kinetics by 
qPCR as clinically indicated (this was already described in Section 8.5.2) 
• Remove lab collections from survival follow-up visit 
• Remove ePRO from the week 8 (Infusion + 28d) visit 
• Add a footnote to explain the meaning of * as being related to the day of 
tisagenlecleucel infusion, in addition to footnotes on repeating of bridging 
chemotherapy cycles and the week 6 scan 
• Table 8-3 was updated to: 

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• Allow for multiple cycles of SOC chemotherapy.  Safety visits will be tied to the 
cycles of chemotherapy rather than to randomization.  
• Add visits related to HSCT with safety assessments, including conditioning, HSCT 
day, and HSCT +7, 14, 21, and 28 days  
• Widen the window for the week 6 visit to ±2 weeks and change from CT to PET-CT 
• Add section headers to describe the types of assessments listed below each section  
• Add requirements to repeat physical examination, ECOG, vital signs, central 
hematology, and central chemistry on Day 1 of each cycle of bridging chemotherapy 
and coagulation, pregnancy testing and weight on Day 15 of every cycle.  Footnote 1 
was also added to clarify  
• Add M18 performance status assessment 
• Change requirement of ECG, cardiac enzymes, and ECHO/MRA/MUGA to as 
clinically indicated, and then repeated at crossover 
• Clarify that CT scan is required at M9 and M12, and only at M6 if PET-CT is not 
available 
• Clarify that either CT/MRI of brain or lumbar puncture are as clinically indicated 
• Update pregnancy testing during chemotherapy treatment to be with serum testing 
• Specify the duration of pregnancy testing to be monthly throughout the study until the 
end of contraception requirements per local label 
• Add viral serology testing at the crossover visit 
• Add peripheral blood B cell levels to the table (to align with the collections as 
described in Sections 8.5.2.1 and Section 8.5.3) 
• ePRO was removed from the Week 8 visit, as the Week 8 visit no longer exists  
• Footnote was added to clarify repeating of immunochemotherapy cycles 
• Table 8-4 was updated to: 
• Allow for multiple cycles of bridging chemotherapy with visits tied to cycles 
• Change the week 6 visit to PET-CT and move the Week 6 visit prior to 
lymphodepleting chemotherapy and after bridging chemotherapy, and widen the 
window to ± 2 weeks.  Footnote 2 was added to specify the timing of this scan, which 
may be prior to tisagenlecleucel infusion or after depending on the availability of 
product. 
• Update of visit names so that they are tied to the date of infusion rather than an 
assumed Day 28 infusion 
• Add requirements to repeat physical examination, ECOG, vital signs, central 
hematology, and central chemistry on Day 1 of each cycle of bridging chemotherapy 
and coagulation, pregnancy testing and weight on Day 15 of every cycle.  Footnote 1 
was also added to clarify  
• Clarify that physical examination, performance status, and vital signs should be done 
at the lymphodepleting visit  
• Update ECG requirement to be only on the day of infusion and as clinically indicated 
• Add ECHO/MRA/MUGA as clinically indicated  

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• Add the ICANS grading and ICE score to assess neurotoxicity as per ASBMT 
consensus grading 
• Changed cardiac enzyme testing to only as clinically indicated 
• Duration of pregnancy testing was updated to specify monthly testing for as long as 
contraception is required 
• Remove Rituximab PK collections\ 
• Clarify humoral versus cellular immunogenicity and specify that these collections are 
only until M12 in long term additional follow-up 
 
 
• Remove lab collections from the survival follow-up visits 
 
 
s  
• Add CSF collections for tisagenlecleucel for cellular kinetics by qPCR as clinically 
indicated ( to align with the collections as described in Section 8.5.2) 
 
 
 
• Remove ePRO from the week 8 (Infusion + 28d) visit and from Day 1 
• Add a footnote to explain the meaning of * as being related to the day of 
tisagenlecleucel infusion, in addition to footnotes on repeating of bridging 
chemotherapy cycles and the week 6 scan 
• Section 8.1 was updated to: 
• Remove language on repeat viral serology testing before infusion, as it was added to 
section 6.1.2 
• Clarified that serum pregnancy testing is required prior to leukapheresis 
• Align pre-leukapheresis lab values with Inclusion Criteria #8 
• Clarify that only patients who are having manufacture of tisagenlecleucel will send 
the leukapheresis material to the manufacturing facility 
• Section 8.1.1 was updated to clarify the timing of information on leukapheresis being sent 
to the manufacturing facility, to clarify that the assessment of eligibility is by investigator 
judgement, and to add language on the new stratification factor 
• Section 8.3 was updated to: 
• Clarify that all randomized patients (even those that don’t receive study treatment) 
should have efficacy assessments, and that all patients should have an efficacy 
assessment prior to starting new anticancer therapy 
• Added language on patients who have stable disease (SD)/progressive disease (PD) at 
the Week 12 visit, while they are still waiting for tisagenlecleucel infusion 
• Clarified allowable methods of CNS disease assessment 
• Change the Week 6 scan from CT to PET/CT 
• Clarify the timing of the Week 6 assessment in Arm A, Arm B, and crossover patients 

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• Clarify which scan should be treated as the baseline for patients that crossover to arm 
A 
• Clarify in table 8-5 that there is only one tumor biopsy required at screening, and that 
week 6 is PET-CT 
• Update table 8-5 to include the option of brain CT/MRI or lumbar puncture mandated 
at baseline 
• Section 8.3.3 was updated to: 
• Simplify language regarding the need for expedited review 
• Update the window of week 6 to +/- 2 weeks 
• Add a limit of 365 days after transplant was added for eligibility for crossover 
• Clarify what should occur after an investigator submits a scan for SD/PD 
confirmation, based on the blinded independent review committee (BIRC) response 
• Table 8-8 was split into Table 8-8 and Table 8-9 which specifies which assessments are 
done locally and which are central 
• Section 8.4.2.2 was updated to change the timing of cardiac enzyme collection 
• Section 8.4.3 was updated to simplify language on pregnancy 
• Section 8.5.2 was updated to: 
• Remove Rituximab PK 
•
 
 
• Clarify that patients who crossover will also be assessed for cellular kinetics  
• Table 8-11 was updated to remove Rituximab PK 
• Table 8-12 was updated with new visit naming as per VES, and with new scheduled 
timepoint relative to infusion, and lymphodepleting and 10 minutes post-dose collection 
was removed. A footnote was also added to clarify the collection of qPCR samples for 
monitoring of contraception requirements.  
 
 
 
• Table 8-14 was updated to reduce the frequency of collection, and update new scheduled 
timepoint relative to infusion for qPCR bone marrow collections 
 
 
• Table 8-15 was updated to reduce the frequency of collection 
• Table 8-16 was updated with new visit naming as per VES, and with new scheduled 
timepoint relative to infusion and clarified to refer to humoral testing.  Sample numbers 
for long term additional follow-up were clarified in a footnote 
• Table 8-17 was updated with new visit naming as per VES, and with new scheduled 
timepoint relative to infusion and clarified to refer to cellular testing. Sample numbers for 
long term additional follow-up were clarified in a footnote. 
• The table on Rituximab PK was removed 

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• Section 8.5.3 was updated to clarify the requirements for tumor biopsy 
 
 
 
 
 
 
 
 
 
 
• Section 9.1.5 updated language on early study termination 
• Section 10.1.1 removed language on reporting of disease progression as an SAE, and 
updated language on changes to study treatment .  The language on when standard versus 
modified reporting of adverse events (AEs) would be required as per study period was 
also clarified and condensed.  A new statement was added to allow for collection of key 
components of CRS events to allow for grading in alternative grading scales 
• Section 10.1.2 was updated with new language on reporting of disease progression as an 
SAE 
• Section 10.1.4 was also added to allow for SAE reporting as per health authority request 
• Section 10.1.5 was updated with pregnancy reporting requirements 
• Section 10.2.3 was updated to clarify that the DMC will not assess efficacy 
• Section 12.1 was updated to align with the CTL019 Project statistical analysis plan (SAP).  
A new “infused set” was defined, and the safety set was clarified. The anti-cytokine PK 
set was removed, since this assessment is not done in this study  
• Section 12.4.1 was updated to allow for a definition of the week 12 assessment window to 
be included in the SAP rather than the protocol   
• Section 12.4.2 was updated with clarifying language on the hypothesis and stratification 
• Section 12.4.3 was updated to remove missing tumor assessment as a censoring reason, 
and the definition of new anticancer therapy was clarified to also include any anti-
neoplastic therapy given after HSCT 
• Section 12.4.4 was updated to clarify the log-rank tests to be used, to add a sensitivity 
analysis counting missing assessment as a censoring reason, and to add all stratification 
factors as subgroup analyses as well.  In addition, a sensitivity analysis for event free 
survival(EFS) per BIRC irrespective of new anti-cancer therapy for lymphoma was added 
• Section 12.5 was updated with the new stratification factor, define the maximum time for 
crossover, and to further explain potential methods for overall survival (OS) sensitivity 
analysis. A further sensitivity analysis for overall response rate (ORR) was added using 
evidence of disease at the Week 6 assessment.  
• Section 12.5.2 was updated to align with the project level CTL019 SAP with clarification 
of safety time periods and analysis.  A sensitivity analysis was also added for grading of 
CRS and neurotoxicity on alternative grading scales (e.g. ASBMT) 
• Section 12 removed all reference to rituximab PK and tocilizumab PK 
• Section 15 references were added/remove as appropriate 

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• Section 16.1 was updated with new eligibility algorithms for hepatitis B and C.    
• Section 16.3 was updated with new modified reporting requirements, and also clarified 
that standard reporting resumes again for patients that crossover to arm A 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 

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Protocol summary 
Protocol number 
CCTL019H2301 
Full Title 
Tisagenlecleucel versus standard of care in adult patients with relapsed or 
refractory aggressive B-cell non-Hodgkin lymphoma: A randomized, open label, 
phase III trial (BELINDA) 
Brief title 
Tisagenlecleucel in adult patients with aggressive B-cell non-Hodgkin lymphoma 
Sponsor and Clinical 
Phase 
Novartis - Phase III 
Investigation type 
Biological 
Study type 
Interventional 
Purpose and rationale 
Current front-line therapies for diffuse large B-cell lymphoma (DLBCL) and other 
aggressive B-cell non-Hodgkin lymphoma (NHL) (e.g. Follicular lymphoma grade 
3B (FL3B), primary mediastinal large B cell lymphoma (PMBCL), T cell 
rich/histiocyte rich large B cell lymphoma, DLBCL associated with chronic 
inflammation, intravascular large B-cell lymphoma, anaplastic lymphoma kinase 
positive (ALK+) large B-cell lymphoma) consist of combination chemotherapies 
with CD20-targeted immunotherapies. While over 50% of patients reach long-
lasting complete response (CR) with initial therapy, approximately one-third of 
patients are refractory (i.e. do not achieve a response) to therapy or will relapse or 
progress after initial response. These patients have poor prognosis, especially if 
they are refractory or have an early relapse (i.e., within 12 months of last therapy) 
even if the patient receives high dose chemotherapy and autologous 
hematopoietic stem cell transplant (HSCT). Novel therapies for relapsed/refractory 
(r/r) DLBCL and other aggressive B-cell lymphomas are highly needed. 
The B-cell marker CD19 has emerged as a target for B-cell lymphoma 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 (Kimura et al 2007). 
Targeting CD19 by chimeric antigen receptor (CAR) T cell therapy has been 
shown to be effective at eradicating malignant cells from very advanced B-cell 
malignancies and to have the potential to induce durable complete responses in 
patients lacking effective treatment options. Data from patients with B-cell Acute 
Lymphoblastic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and other 
CD19 expressing B cell lymphomas show that tisagenlecleucel therapy has potent 
anti-tumor activity. 
This phase III study will compare the efficacy and safety of tisagenlecleucel 
treatment strategy against the current SOC (standard second line salvage 
chemotherapy including autologous HSCT in suitable patients), in poor prognosis 
patients with aggressive B-cell NHL after failure of frontline rituximab- and 
anthracycline-based therapy. 
The two treatment strategies being compared are 
• 
Tisagenlecleucel after optional bridging chemotherapy and lymphodepleting 
(LD) chemotherapy 
• 
Standard of care chemotherapy followed by autologous HSCT  
Primary Objective 
The primary objective of this study is to compare tisagenlecleucel treatment 
strategy to SOC treatment strategy with respect to delaying the composite event 
of disease progression(PD)/stable disease (SD) at or after the Week 12 
assessment; or death at any time, i.e. event free survival (EFS) as assessed by a 
blinded independent review committee (BIRC). 

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Secondary Objectives 
• 
To compare tisagenlecleucel treatment strategy to SOC treatment strategy 
with respect to EFS by local investigator. 
• 
To compare tisagenlecleucel treatment strategy to SOC treatment strategy 
with respect to overall survival (OS). 
• 
To compare tisagenlecleucel treatment strategy to SOC treatment strategy 
with respect to overall response rate (ORR) and duration of response (DOR) 
by BIRC and local investigator. 
• 
To compare tisagenlecleucel treatment strategy and SOC treatment strategy 
with respect to time to response (TTR). 
• 
To evaluate safety and tolerability of tisagenlecleucel treatment strategy 
versus SOC treatment strategy. 
• 
To compare patient reported outcomes (PROs) of health-related quality of life 
(HRQoL) in both treatment arms. 
• 
Evaluate efficacy and safety of both treatment arms in histological subgroups 
(e.g DLBCL, not otherwise specified (NOS), FL3B, other) and molecular 
subgroups (e.g. germinal center B-cell (GCB), activated B-cell (ABC), other) 
• 
To assess the patients treated with tisagenlecleucel (in Arm A or after 
crossover) treatment strategy with respect to the following objectives: 
• 
Characterize the in vivo cellular kinetics of tisagenlecleucel transduced 
cells into target tissues (blood, bone marrow, cerebral spinal fluid (CSF) 
and other tissues if available), as measured by quantitative polymerase 
chain reaction (qPCR) summarized by clinical response in patient 
receiving tisagenlecleucel therapy in arm A or after crossover. To 
characterize the incidence and prevalence of tisagenlecleucel 
immunogenicity (humoral and cellular) and impact on cellular kinetics, 
efficacy, and safety in patients receiving tisagenlecleucel therapy in arm 
A or after crossover  
• 
Assess presence of replication competent lentivirus (RCL) in patients 
receiving tisagenlecleucel in Arm A or after crossover. 
Study design 
This is a randomized, open label, multicenter phase III trial comparing the 
efficacy, safety, and tolerability of tisagenlecleucel to SOC in adult patients with 
aggressive B-cell NHL after failure of rituximab and anthracycline containing first 
line immunochemotherapy. Failure of frontline therapy is defined as refractoriness 
(lack of complete response or progression during therapy) or relapse/progression 
within 365 days of last dose of first line therapy (in patients who achieved CR on 
first line therapy). 
Screened patients may undergo non-mobilized leukapheresis for autologous T 
cell collection soon after obtaining informed consent (unless historical product is 
to be used). During the screening period, no lymphoma-specific therapy is allowed 
prior to randomization. During randomization, patients will be stratified by: 
(a) Remission duration - refractory to front line therapy or relapsed < 6 months 
from last dose of first line immunochemotherapy v. relapsed 6 - 12 months) 
(b) International prognostic index (IPI) score (< 2 versus ≥ 2, The International 
Non-Hodgkin's Lymphoma Prognostic Factors Project (1993); Moskowitz 
(1999)). 
(c) Region (North America vs Rest of World) 
Eligible patients will be randomized into: 
Arm A: (tisagenlecleucel treatment strategy): Patients will receive 
lymphodepletion chemotherapy followed by infusion of tisagenlecleucel. Use 
of platinum-based bridging chemotherapy prior to lymphodepletion therapy is 
allowed. 
Arm B: (standard of care treatment strategy): Patients will receive platinum-
based immunochemotherapy followed in responding patients by HDCT and 
autologous HSCT. 
Tumor and response assessments will be performed during the screening period 
(baseline within 2 weeks of randomization), 6 weeks after randomization (± 2 

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weeks), 12 weeks after randomization (± 1 week), 6 months after randomization 
(± 2 weeks), every 3 months thereafter (± 2 weeks) for the first year, every 6 
months (± 2 weeks) for the second year, and annually thereafter (± 2 weeks) up to 
5 years after randomization. 
Crossover from arm B to arm A is allowed after confirmed SD/PD by BIRC at any 
time at or after the Week 12 assessment up until 1 year after autologous HSCT. 
Population 
The study will randomize approximately 318 patients age 18 or greater. 
Key Inclusion criteria 
1. 
Histologically confirmed (by local histopathological assessment), aggressive 
B-cell NHL at relapse/progression or PR after front line therapy. For patients 
with relapse/progression if biopsy after relapse/progression is not available or 
it is not clinically feasible to obtain a new biopsy, an archival tumor biopsy 
from the initial diagnosis may be submitted. For patients in PR after at least 6 
cycles of first line treatment, a new biopsy must be submitted. Aggressive B-
cell NHL is heretofore defined by the following list of subtypes (Swerdlow et al 
2016):  
• 
DLBCL, NOS, 
• 
FL grade 3B, 
• 
Primary mediastinal large B cell lymphoma (PMBCL), 
• 
T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL), 
• 
DLBCL associated with chronic inflammation, 
• 
Intravascular large B-cell lymphoma, 
• 
ALK+ large B-cell lymphoma, 
• 
B-cell lymphoma, unclassifiable, (with features intermediate between 
DLBCL and classical Hodgkin Lymphoma (HL)), 
• 
High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 
rearrangements, 
• 
High-grade B-cell lymphoma, NOS 
• 
HHV8+ DLBCL, NOS 
• 
DLBCL transforming from follicular lymphoma 
• 
DLBCL transforming from marginal zone lymphoma 
• 
DLBCL, leg type 
2. 
Relapse or progression within 365 days from last dose of anti-CD20 antibody 
and anthracycline containing first line immunochemotherapy or refractory 
(have not achieved a CR). 
3. 
Patient is considered eligible for autologous HSCT as per local investigator 
assessment. Note: Intention to transplant and type of high dose 
chemotherapy (HDCT) regimen will be documented in the Interactive 
Response Technology (IRT) system. 
4. 
Disease that is both active on PET scan (defined as Deauville score of 4 or 5) 
and measurable on CT scan defined as: 
a. 
Nodal lesions >15 mm in the long axis, regardless of the length of the 
short axis, and/or 
b. 
Extranodal lesions (outside lymph node or nodal mass, but including liver 
and spleen) >10 mm in long AND short axis 
5. 
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 
6. 
Adequate organ function: 
Renal function defined as: 
a. 
Serum creatinine of ≤1.5 x upper limit of normal (ULN), OR estimated 
glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 
Hepatic function defined as: 
b. 
Alanine Transaminase (ALT) and Aspartate Transaminase (AST) ≤ 5 × 
ULN 

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c. 
Total Bilirubin ≤1.5 × ULN with the exception of patients with Gilbert 
syndrome who may be included if their total bilirubin is ≤3.0 × ULN and 
direct bilirubin ≤1.5 × ULN 
Hematologic Function (regardless of transfusions) defined as: 
d. 
Absolute neutrophil count (ANC) >1000/mm3 
Only for patients with non-historical apheresis: 
e. 
Absolute lymphocyte count (ALC) >300/mm3 or  
f. 
Absolute number of CD3+ T cells >150/mm3 
g. 
Platelets ≥50000/mm3 
h. 
Hemoglobin >8.0 g/dl 
Adequate pulmonary function defined as: 
i. 
No or mild dyspnea (≤ Grade 1) 
j. 
Oxygen saturation measured by pulse oximetry > 90% on room air 
k. 
Forced expiratory volume in 1 s (FEV1) ≥50% or carbon monoxide 
diffusion test (DLCO) ≥50% of predicted level 
7. 
Must have a leukapheresis material of non-mobilized cells available for 
manufacturing. Note: Please refer to Section 6.2.2, Section 8.1 
(Leukapheresis) for prohibited concomitant medications and washout times to 
ensure adequate collection as well as the
 
] for specific collection procedures. 
Key Exclusion criteria 
1. 
Prior treatment with anti-CD19 therapy, adoptive T cell therapy, or any prior 
gene therapy product 
2. 
Treatment with any systemic lymphoma-directed second line anticancer 
therapy prior to randomization.  Only steroids and local irradiation are 
permitted for disease control.   
3. 
Patients with active central nervous system (CNS) involvement by disease 
under study are excluded, except if the CNS involvement has been effectively 
treated and local treatment was >4 weeks before randomization 
4. 
Prior allogeneic HSCT 
5. 
Uncontrolled acute life threatening infection 
6. 
Any of the following cardiovascular conditions: 
a. 
Unstable angina, myocardial infarction, coronary artery bypass graft 
(CABG), or stroke within 6 months prior to screening, 
b. 
Left ventricle ejection fraction  (LVEF) <45% as determined by 
echocardiogram (ECHO) or magnetic resonance angiography (MRA) or 
multigated acquisition (MUGA) at the screening assessment. 
c. 
New York Heart Association (NYHA) functional class III or IV 
(Chavey et al 2001), at screening or within the past 12 months. 
d. 
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
complete left bundle branch block, high-grade atrioventricular (AV) block 
(e.g., bifascicular block, Mobitz type II) and third degree AV block unless 
adequately controlled by pacemaker implantation. 
e. 
Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or 
inability to determine the QTcF interval 
f. 
Risk factors for Torsades de Pointes (TdP), including uncorrected 
hypokalemia or hypomagnesemia, history of cardiac failure, or history of 
clinically significant/ symptomatic bradycardia, or any of the following: 
i. Long QT syndrome, family history of idiopathic sudden death or 
congenital long QT syndrome 
ii. Concomitant medication(s) with a “Known Risk of Torsades de 
Pointes” per crediblemeds.org that cannot be discontinued or 
replaced by safe alternative medication. 
7. 
Patients with active neurological autoimmune or inflammatory disorders 
(e.g., Guillain-Barré Syndrome (GBS), Amyotrophic Lateral Sclerosis 

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(ALS)) and clinically significant active cerebrovascular disorders (e.g., 
cerebral edema, posterior reversible encephalopathy syndrome (PRES)) 
Study treatment 
• 
Arm A: A single dose of 0.6 to 6.0 × 108 of CAR-positive viable autologous 
tisagenlecleucel transduced T cells administered via i.v. infusion after 
optional bridging chemotherapy and LD chemotherapy 
• 
Arm B: SOC with intent to transplant (autologous HSCT) per local guidelines 
Efficacy assessments 
• 
Imaging (CT or MRI, PET-CT or PET), 6 weeks after randomization (± 2 
weeks), 12 weeks after randomization (± 1 week), 6 months after 
randomization (± 2 weeks), and every 3 months thereafter (± 2 weeks) for the 
first year, every 6 months (± 2 weeks) for the second year, and annually 
thereafter (± 2 weeks) up to 5 years after randomization, 
• 
physical examination 
• 
bone marrow biopsy 
 
 
 
 
 
 
 
 
 
 
  
Pharmacokinetic 
assessments 
 
 
• 
Cellular kinetics by qPCR (blood, bone marrow, CSF if available) 
• 
Immunogenicity (blood) 
 
Key safety assessments 
Adverse events (AEs and laboratory abnormalities (type, frequency and severity). 
All patients treated with tisagenlecleucel will be monitored for specific toxicities for 
up to a total of 15 years post infusion, irrespective of their response to 
tisagenlecleucel. All patients who receive tisagenlecleucel will be monitored in this 
trial for 5 years after randomization, followed by semiannual and  annual safety 
assessments in a separate long-term follow-up protocol (CCTL019A2205B) for an 
additional ten years. All patients not receiving tisagenlecleucel will be followed for 
safety until 56 days after the last dose of study treatment.  Adverse event 
collection will restart upon crossover for patients that crossover to arm A.    
Other assessments 
• 
Time to definitive deterioration in 36 item short form health survey (SF-36v2), 
Functional Assessment of Cancer Therapy Lymphoma (FACT-Lym), and 
EuroQol Visual Analogue Scale (EQ-VAS) 
Data analysis 
Approximately 318 patients will be randomized in a 1:1 ratio to either 
tisagenlecleucel therapy or SOC therapy. During randomization, patients will be 
stratified by: 
a. 
remission duration (refractory to front line therapy or relapsed <6 months v. 
relapsed at 6 -12 months inclusive)  
b. 
International prognostic index score (IPI, <2 versus ≥2). 
c. 
Region (North America vs. Rest of World) 
Analysis sets: 
• 
The Full Analysis Set (FAS) comprises all randomized patients. According to 
the intent to treat principle, patients will be analyzed according to the 
treatment and strata they have been assigned to during the randomization 
procedure. 
• 
The Safety Set includes all patients to whom study treatment has been 
assigned by randomization. Patients will be analyzed according to 
randomized treatment. 

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• 
The cellular kinetic analysis set consists of all patients who receive at least 
one dose of tisagenlecleucel and for whom at least one concentration value 
was available. 
Statistical analysis: The primary endpoint is event free survival (EFS), defined 
as the time from the date of randomization to the date of the first documented 
disease progression or stable disease at or after the week 12 assessment by 
BIRC or death at any time. The primary efficacy objective is considered to be met 
if the null hypothesis, i.e. the survival functions for EFS in the two arms are 
identical, can be rejected based on a one-sided stratified log-rank test at 2.5% 
level of significance. Distribution of EFS will be estimated using the Kaplan-Meier 
method. The median EFS along with 95% confidence intervals (CIs) will be 
presented by treatment group. The Cox regression model stratified by the 
randomization stratification factors will be used to estimate the hazard ratio (HR) 
of EFS, along with the 95% confidence interval. There will be no interim analysis 
for EFS. The analysis for EFS will be performed when at least 200 EFS events in 
the FAS have been documented by the BIRC. 
Sample size: The 9 month EFS rate is estimated to be 22.32% in SOC arm 
based on the ORCHARRD study and is assumed to be 40% in tisagenlecleucel 
arm. Due to delayed tisagenlecleucel infusion of 6 weeks and ignoring SD/PD at 
week 6, we assume piecewise hazard rate in both treatment arms. The hazard 
ratio between two arms during the first 6 weeks is assumed to be 1 and 0.61 after 
6 weeks. Given those assumptions, a total of 200 EFS events are required to 
have 92% power at an one-sided 2.5% level of significance to reject the null 
hypothesis (i.e. the survival functions for EFS in the two arms are identical), using 
a stratified log-rank test with equal weights. 
Considering a recruitment period of approximately 21 months using staggered 
enrollment rate of 2, 10, 16 patients in the first 3 months followed by 17 patients 
thereafter, and assuming 15% drop out rate, a total of approximately 318 patients 
will need to be randomized to the two treatment arms in a 1:1 ratio. 
Overall survival (OS) is a secondary endpoint and is defined as the time from 
date of randomization to date of death due to any cause will only be formally 
tested between the two treatment arms, if the primary endpoint (EFS by BIRC) is 
significant. A maximum of two analyses are planned for OS: i) an interim analysis 
at the time of the primary analysis for EFS (provided EFS is significant) and ii) a 
final analysis approximately 5 years after randomization of the first patient if OS is 
not significant at the time of the primary analysis. The median OS along and the 
proportion of patients alive at 6,12 weeks, 6, 12, 18, 24, 36, 48, 60 months with 
95% CIs will be presented by treatment group. OS will be compared between the 
two treatment groups using a log-rank test stratified by randomization stratification 
factors. 
Safety: The assessment of safety will be based mainly on the incidence rates of 
AEs, their severity and seriousness, and laboratory assessments. Other safety 
data (e.g., physical assessments, electrocardiograms (ECGs), vital signs) will be 
summarized. For all comparative safety analyses, the safety set will be used. 
Patient reported outcomes: Time to definitive deterioration for SF-36 v2 
(physical and mental components), FACT-Lym (general score [G], lymphoma 
subscale [LymS], trial outcome index [TOI], total score [TS]), and EQ-VAS will be 
summarized using Kaplan-Meier methods. The estimated Kaplan-Meier plots will 
be provided and the unstratified log-rank test will be the primary method to 
compare the time to first deterioration between the two treatment groups. For SF-
36 v2, a score decrease of 3 points or higher must be held to be considered 
“deteriorated”. For FACT-Lym, a score decrease of 3 points or higher in FACT-G, 
2.9 points or higher in LymS, 5.5 points or higher in TOI, and 6.5 points or higher 
in TS must be held to be considered “deteriorated” For EQ-VAS, a score decrease 
of 7 points or higher must be held to be considered “deteriorated”. 
Summary statistics will be reported for each of items and scales over time by 
treatment arm. Repeated measures mixed-effects model will be carried to 
compare the two groups with respect to the change from baseline. Rates of 
improvement will be evaluated from baseline to each time point and will be 

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compared between the two treatment groups using chi-square test. For the 
Euroqol 5 dimension (EQ-5D) health state profiles, the proportions of patients 
reported having “no”, “slight”, “moderate”, “severe”, or “extreme” problems at each 
time point will be reported. 
Cellular kinetics: Descriptive statistics will be summarized by month 3 response 
for all patients who receive tisagenlecleucel. 
Cellular kinetics in patients that receive tocilizumab for CRS management: 
For patients who received tocilizumab for cytokine release syndrome (CRS) 
management, the concentrations (transgene levels of tisagenlecleucel) will be 
summarized by time points, relative to time of tocilizumab dose. The cellular 
kinetic parameters will be presented with and without the use of tocilizumab. 
Key words 
Relapsed/refractory, NHL, tisagenlecleucel, CTL019 

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1 
Introduction 
1.1 
Background 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Non-Hodgkin Lymphomas (NHL) comprise a heterogeneous group of malignancies. Estimated 
new cases are 72,240 and deaths are 20,140 in the United States (US) for 2017 (Siegel et al 
2017). In Europe, for 2012, there were an estimated 93,500 new cases and 37,800 deaths due to 
NHL (Ferlay et al 2015). 
The 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid 
tumors (Jaffe 2009), updated in 2016 (Swerdlow et al 2016), represents the established 
guidelines for the diagnosis of malignant lymphomas. The classification is based on the 
recognition of distinct diseases according to a combination of morphology, immunophenotype, 
genetic, molecular, and clinical features. Lymphoid neoplasms are stratified according to cell 
lineage and derivation from precursor or mature lymphoid cells into: immature lymphoid 
neoplasms, mature B-cell neoplasms, T cell and natural killer (NK)-cell neoplasms, and post-
transplant lymphoproliferative disorders (PTLD). Mature B-cell lymphomas are further 
classified into indolent lymphomas (e.g. multiple myeloma, follicular lymphoma – except for 
FL3B that is considered as an aggressive subtype-) and aggressive lymphomas (e.g. diffuse 
large B-cell lymphoma [DLBCL], Burkitt lymphoma, primary mediastinal large B cell 
lymphoma [PMBCL], T cell rich/histiocyte rich large B cell lymphoma [T/HCBCL], DLBCL 
associated with chronic inflammation, intravascular large B-cell lymphoma, ALK+ large B-cell 
lymphoma). DLBCL is the most frequent lymphoma subtype, representing 30-40% of all NHLs 
for western countries (Chiappella et al 2016, Al-Hamadani et al 2015). Estimated incidence in 
the European Union is 3.8/100,000/year, increasing with age (reaching a maximum after 75 
years) and with considerable variation across European countries (Sant et al 2010, Tilly et al 
2015). For the US, the incidence for the 2002-2011 period of was 6.9/100,000/year; also 
increasing with age (32.7/100,000/year after 65 years) (Howlader et al 2011) 
The prognosis of patients with DLBCL and other B-cell aggressive lymphomas depends on 
individual risk factors. The International Prognostic Index (IPI) for aggressive NHL includes 
five risk factors independently prognostic of overall survival (OS) (The International Non-
Hodgkin's Lymphoma Prognostic Factors Project 1993): 
• Patient age (≤60 years vs. >60 years) 
• Serum lactate dehydrogenase (LDH) (normal ≤ 1 × ULN vs. elevated > 1 × ULN) 
• ECOG performance status (0 or 1 vs. ≥ 2) 
• Stage (stage I or stage II vs. stage III or stage IV) 
• 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 from diagnosis are used for younger patients 
with localized disease (Moller et al 2003). A revised IPI, the National Comprehensive Cancer 
Network International Prognostic Index (NCCN-IPI), has been proposed to better reflect the 

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individual patient’s risk in the rituximab era (Zhou et al 2014). Very similar to the original IPI, 
five prognostic factors were identified: 
• Patient age (>40 to ≤60 vs. >60 to ≤75 vs. >75 years) 
• Normalized serum LDH (>1 to ≤3 vs. >3 x ULN) 
• ECOG performance status (0 or 1 vs. 2–4) 
• Ann Arbor Stage (stage I or stage II vs. stage III or stage IV) 
• Extranodal site involvement, that is, disease in bone marrow, CNS, liver/gastrointestinal 
(GI) tract, or lung (yes vs. no) 
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 based on gene expression 
profiling (GEP) and based on biologic similarity to normal stages of B-cell development 
classified into: i) germinal center-B-cell-like (GCB; CD10+, or BCL6+, IRF4/MUM1-), ii) 
activated B-cell-like (ABC), iii) primary mediastinal large B cell lymphoma (PMBCL) and iv) 
type 3 (unclassifiable) DLBCL (Swerdlow et al 2016, Lenz et al 2008, Alizadeh et al 2000). 
The GCB and ABC subtypes arise from B-cells at different stages of differentiation (GCB 
originates from germinal center B-cells, whereas ABC arises from post-germinal-center B-cells 
transitioning into plasma cells) and differ in their clinical outcome. GEP is not routinely used, 
however, immunohistochemistry (IHC)-based algorithms predict a 5-year OS of 76% in GCB 
tumors compared to 34% in ABC tumors (Hans et al 2004). Indeed, inferior survival for ABC 
DLBCLs was also observed in patients treated with rituximab and CHOP chemotherapy (Lenz 
et al 2008). 
Frontline treatment of patients with newly diagnosed DLBCL and other B-cell aggressive NHL 
is generally tailored based on age, age-adjusted IPI and feasibility of dose intensified 
approaches (Tilly et al 2015). The combination of rituximab (anti-CD20) with anthracycline-
based chemotherapy (e.g., cyclophosphamide, doxorubicin, vincristine and prednisone [R-
CHOP]) given every 21 days represents the standard frontline treatment for most patients with 
DLBCL. Despite most patients being cured with conventional frontline immunochemotherapy, 
around one-third will not respond (i.e., will not achieve a CR or PR) or will relapse or progress 
after treatment. More than half of all these treatment failures include non-responding and 
relapsing patients within a year after the standard frontline immunotherapy (early relapsed). 
These patients have a poor prognosis, particularly those who do not respond to second-line 
chemotherapy (Sarkozy and Coiffier 2015, Coiffier et al 2016, Friedberg 2011, Elstrom et al 
2010). Patients who achieve at least a partial response to second-line therapy have a 35-50% 
chance of long-term survival, whereas those with stable or progressive disease exhibit less 
favorable outcomes with a median OS of around 3.5 months (Elstrom et al 2010, van den Neste 
et al 2016), similar to the expected survival of approximately 4 months for patients left untreated 
(Elstrom et al 2010, van den Neste et al 2016). 
For patients with relapsed or refractory (r/r) DLBCL and other aggressive B-cell lymphomas 
with adequate performance status (defined by age and absence of major organ dysfunctions), 
the European Society for Medical Oncology (ESMO) and NCCN clinical treatment guidelines 
recommend a salvage regimen with rituximab (R) and platinum-based chemotherapy, followed 
in responsive patients by high-dose chemotherapy and autologous hematopoietic stem cell 

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transplant (HSCT) (Tilly et al 2015, NCCN v1 2019). The most frequently used salvage 
regimens for these patients include R-DHAP (R-dexamethasone, cytarabine, cisplatin), R-ICE 
(R-ifosfamide, carboplatin, etoposide) or R-GDP (R-cisplatin, gemcitabine, dexamethasone) 
(Tilly et al 2015, NCCN v1 2019). Response rates to these conventional salvage 
immunochemotherapies is over  60%, including about 30% of complete responses (Coiffier et 
al 2016). Patients refractory or relapsing within 12 months of first-line therapy have a 
particularly poor prognosis even with autologous HSCT (Gisselbrecht et al 2010). Without 
autologous HSCT, chemotherapy provides only short-term disease control in these patients 
(Elstrom et al 2010). 
Three studies are relevant to underline the medical need in patients failing first-line treatment 
(Table 1-1). 
Table 1-1 
Phase III trials in relapsed/refractory DLBCL 
Trial (N randomized) 
CORAL (n=400)3,4 
LY.12 (n=619)2 
ORCHARRD (n=447)1 
Treatment Arm 
R-ICE 
R-DHAP 
GDP 
DHAP 
R-DHAP 
O-DHAP 
N treated 
197 
191 
303 
302 
223 
222 
 
% 
% 
% 
% 
% 
% 
ORR in patients who received at least one cycle of salvage therapy regardless of time to relapse/resistance 
status 
CR + PR 
63.5 
62.8 
46.2 
44.7 
42.2 
37.8 
SD 
11.7 
11.5 
5.6 
6.0 
29.6 
28.8 
PD 
19.3 
18.3 
25.7 
28.8 
15.2 
17.6 
UNK 
5.1 
7.3 
22.5 
20.5 
13.0 
15.8 
Completed induction 
phase with CR/PR/SD 
74.7 
51.2 
69.2 
Patients receiving 
HSCT, % of all 
treated 
51.3 
55 
52.1 
49.3 
37.2 
33 
Outcome in Refractory and Relapsed within 12 months (early relapsed) from last therapy 
ORR, % in CR/PR (% 
in R > 12 mo) 
46.5 
(v. 88%) 
35.3 
(v. 70%) 
29 
(v. 67%) 
PFS, %* 
23£ 
(% not reported in R>12 mo) 
NA 
20 
(v. 50% in R > 12 mo; 
HR 0.32, p<0.0001)# 
EFS, %* 
20££ 
(v. 45% in R > 12 mo; 
p<0.001) 
NA 
NA 
OS, %* 
39££ 
(v. 64% in R>12 mo, 
p<0.001) 
NA 
30 
(v. 60% in R>12mo; 
HR 0.40, p<0.0001) ## 
Outcome in Refractory and Relapsed within12 months from last therapy with autologous HCT (vs no HSCT) 
PFS, %* / mPFS, mo 
(vs no HSCT)* 
39 / 18.7 
(v. 14 / 2.8)£ 
NA 
NA / 11.6 
(v. NA / 1.4) ### 
OS, %* / mOS, mo 
(vs no HSCT)* 
NA 
NA 
NA / Not Reached 
(v. NA / 7.1) ### 

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Trial (N randomized) 
CORAL (n=400)3,4 
LY.12 (n=619)2 
ORCHARRD (n=447)1 
NA: not available; R>12: relapsed after 12 months of front line 
* % of time related parameters by study presented at 3y for CORAL, 2y for ORCHARRD and 4y for LY. 12; 
£ Data for the 187 patients in CORAL study who received prior rituximab 
££ Data for all the patients in CORAL regardless of prior rituximab (n=228 refractory/early relapsed and 160 with 
late relapse) 
# median PFS (by BIRC, all pts regardless of arm): refractory/relapsed <12m: 1.5 mo vs R>12: 23.8 mo (Novartis 
unpublished internal data) 
## median OS (all pts regardless of arm): refractory/relapsed <12m: 10.0 mo vs R>12: not reached (Novartis 
unpublished internal data) 
### HSCT: performed in 25.6% of r/r <12m vs 58.9% in R>12 (Novartis unpublished internal data) 
1van Imhoff et al (2017). 2Crump et al (2014), 3Gisselbrecht et al (2010), 4van den Neste et al (2016). 
The ‘Collaborative Trial in Relapsed Aggressive Lymphoma’ (CORAL) study demonstrated 
that approximately 60% of patients with r/r DLBCL respond to second-line salvage 
immunochemotherapy (R-ICE or R-DHAP), and around 50% of patients receiving this salvage 
therapy can further receive HSCT (Gisselbrecht et al 2010) (Table 1-1). Data from this trial also 
showed that patients refractory or relapsing within 12 months of rituximab-containing first-line 
therapy had a particularly poor prognosis, with only 14% of patients not undergoing autologous 
HSCT being event free at 3 years (median progression free survival (mPFS) in these patients 
only 2.8 months). On the other hand, for refractory or early relapsing patients undergoing 
autologous HSCT, the 3-year PFS rate was 39% (and median PFS 18.7 months), highlighting 
the importance of autologous HSCT as treatment option in this patient population. Response 
rate was also lower in patients who were refractory or relapsing within 12 months of front line 
therapy (46.5% vs 87.5% in patients relapsing after 12 months of front line therapy). Another 
important finding from this trial is that patients not undergoing autologous HSCT can still be 
rescued and eventually transplanted with further chemotherapy (Gisselbrecht et al 2010, van 
den Neste et al 2016), data not shown in Table 1-1. Interestingly, 39% of patients not 
undergoing transplant after first salvage therapy (i.e., R-ICE or R-DHAP) responded after a 
second salvage therapy. Indeed, 31% of all patients receiving second salvage were eventually 
transplanted (87.5% auto / 12.5% allo) and 88% of these transplanted patients were alive at 1 
year (median OS not reached at the time of the analysis). On the other hand, patients with SD 
or PD after initial salvage therapy not responding to second salvage therapy have a dismal 
prognosis, with a median OS of only 3.4 months (van den Neste et al (2016), data not shown in 
Table 1-1) which highlights the need of developing new therapies for these patients. 
The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) LY.12 trial 
compared the efficacy GDP versus DHAP and subsequent consolidation by high dose 
chemotherapy/autologous HSCT in 619 patients with relapsed/refractory aggressive NHL 
(DLBCL, peripheral T cell lymphoma, and anaplastic large cell lymphoma were enrolled in this 
trial) (Crump et al 2014). As observed in CORAL trial, response rate was lower in patients who 
were refractory or had relapsed within 12 months from initial therapy (35.3% vs 70% in patients 
relapsing after 12 months of front line therapy) (Table 1-1). Outcome in patients refractory and 
relapsed within 12 months from last therapy according to HSCT are not available for this trial. 
The short term nature of disease control in many patients with r/r DLBCL and poor prognosis 
of early relapses was also confirmed in the ORCHARRD trial, which compared the anti-CD20 
directed antibody ofatumumab (O) plus DHAP versus rituximab (R) plus DHAP followed by 
autologous HSCT in patients with r/r DLBCL after first-line treatment (van Imhoff et al 2017). 

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All patients enrolled in this trial were refractory to or had relapsed following first-line treatment 
with rituximab and an anthracycline-based chemotherapy regimen and therefore, this study 
might represent the most relevant efficacy data of salvage therapy in the rituximab era. Of the 
447 randomized patients, 71% were refractory or early relapsed (i.e., did not achieve CR, 
progressed or experience response for < 12 months) after front line R-CHOP. As was seen in 
CORAL and LY.12 trials, these patients with refractory or early relapsed disease had a worse 
outcome when compared with patients relapsing after 12 months of initial therapy [ORR: 29% 
vs 67%, 2-year PFS: 20% vs 50% (HR 0.32, p<0.0001) and 2-year OS: 30% vs 60% (HR 0.40, 
p <0.0001)]. As expected, median PFS and OS values were also significantly higher in patients 
with late relapse (1.5 vs 23.8 months for PFS and 10.0 vs not reached for OS in refractory/early 
relapsed vs late relapsed patients). HSCT in this group of patients also increased the median 
PFS and OS when compared with the patients not able to be transplanted (median PFS in 
transplanted 11.6 months vs 1.4 months in non-transplanted; median OS in transplanted not 
reached vs 7.1 months in non-transplanted patients) (Table 1-1). These data confirm the poor 
prognosis of refractory and early relapsing patients after front line therapy and the unmet need 
for this patient population. 
The SCHOLAR-1 meta-analysis (n=636) has reported on the very poor outcome of patients 
with DLBCL refractory to anti-CD20 monoclonal antibody- and anthracycline-containing 
regimens (Crump et al 2017). In this meta-analysis, both the ORR and the OS were quite similar 
regardless of the number of prior lines and the refractory group (refractory after first line vs ≥  
second line vs relapse within 1 year of autologous HSCT): i) for ORR: 20 vs 26 vs 34%; ii) for 
median OS: 7.1 vs 6.1 vs 6.2 months.  
Concerning r/r FL3B and other aggressive B-cell lymphomas, these patients are also treated 
according to the DLBCL treatment algorithm and in particular the FL3B subtype is regarded as 
aggressive lymphoma, with a clinical behaviour very similar to DLBCL and with frequent 
histological transformation into DLBCL (Dreyling et al 2016, NCCN V1 2019). Indeed, this 
aggressive FL3B subtype is generally excluded from clinical trials exploring new therapies (e.g., 
obinutuzumab, idelalisib) for indolent NHL (Sehn et al 2015, Sehn et al 2016, Gopal et al 2014). 
In summary, after failure of rituximab containing first line therapy several chemotherapy 
salvage options are available but none of them seems to be superior from the others. Although 
all current treatment options have not been compared in a randomized setting, the observed 
results are quite consistent regardless of the line of therapy and particularly poor in the group 
of patients with refractory disease and early relapse (i.e., within 12 months of last therapy). This 
is as well supported by the recent SCHOLAR-1 meta-analysis, showing that the DLBCL 
population has homogeneous and consistently poor outcomes regardless of refractory group, 
line of therapy and disease stage (Crump et al 2017). 
In conclusion, refractory and early relapsed aggressive B-cell NHL represents a significant 
unmet medical need and thus novel therapies are urgently needed for this patient population. 
1.1.2 
Historical experience with viral gene therapies 
Retroviral vectors are highly effective gene delivery vehicles for inserting foreign genetic 
material into the host cell.  

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Lentiviral vectors, a major subset of retroviral vectors, demonstrate distinct integration patterns 
compared to other retroviral vectors, which have been predominantly used  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 (LTR) regions and have lower levels of poly-A 
read-through. These are all factors, which improve gene transfer safety (Zaiss et al 2002). Thus, 
lentiviral vectors appear a safer alternative to retroviral vectors, which is supported by animal 
models (Montini et al 2006). Lentiviral vector trials have demonstrated in general more 
polyclonal patterns of vector insertion (Cartier et al 2009, Biffi et al 2013).Importantly, despite 
a very high transduction efficiency achieved using lentiviral vectors, molecular clonality studies 
have not indicated any reasons for concern, to date, in published clinical trials (Schambach et 
al 2013).  
For further information refer to the [tisagenlecleucel Investigator’s Brochure]. 
1.1.3 
Overview of tisagenlecleucel 
Adoptive T cell therapy for cancer involves the infusion of native or genetically modified 
mature T cells that have the capacity to recognize and possibly eliminate the patient’s malignant 
cells. In particular, chimeric antigen receptor (CAR)-based approach involves engineering T 
cells with sequences that encode antibody-based antigen recognition moieties linked to 
signaling domains. CAR-T cells specifically target and destroy tumor cells in a Major 
Histocompatibility Complex (MHC) independent manner (Mellman et al 2011). 
A promising target antigen for B cell malignancies is CD19, a cell-surface protein whose 
expression is restricted to B cells and their precursors (Sadelain et al 2003, Porter et al 2011), 
with no expression on hematopoietic stem cells or non-B cell tissues. CAR-T cells targeting 
CD19 have been developed to target B cell malignancies. 
First generation CARs contain the T cell receptor (TCR) activation signal domain consisting of 
TCRζ. Second generation CARs contain costimulatory signaling domains as well: either CD28 
or 4-1BB. The 3rd generation CARs contain further advancements such as double costimulatory 
modules comprised of CD28, 4-1BB plus TCRζ (June 2007, June et al 2009, Kohn et al 2011). 
Tisagenlecleucel (CART-19, CTL019) is a second generation CAR-T cell product that uses 
autologous peripheral blood T cells that have been genetically modified ex vivo to target CD19 
on the surface of B cells. As shown in Figure 1-1, the CAR approach uses lymphocytes 
genetically programmed to express 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 and Pallavicini 2001). 

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Figure 1-1 
Tisagenlecleucel chimeric antigen receptor design 
 
Recent clinical trials of tisagenlecleucel in r/r CLL, r/r ALL, and r/r B-cell lymphomas have 
shown promising and durable anti-tumor efficacy (Porter et al 2011, Grupp et al 2013, Maude 
et al 2014, Schuster et al 2017). Consequently, tisagenlecleucel appears to be a therapeutic 
alternative for patients with B cell malignancies (including DLBCL) refractory to the current 
therapies. For further information refer to the [Tisagenlecleucel Investigator’s Brochure]. 
1.1.3.1 
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). The incorporation of costimulatory signaling modules such as CD28 and 4-
1BB in second generation CARs increases potency of the engineered T cells in pre-clinical 
studies (Finney et al 1998, Krause et al 1998, Eshhar et al 2001, Maher et al 2002, Finney et al 
2004, Friedmann-Morvinski et al 2005, Brentjens et al 2010). The pre-clinical data supporting 
CAR T cell persistence, expansion and anti-tumor efficacy have been published (Gross and 
Eshhar 1992, Milone et al 2009). 
1.1.3.2 
Clinical experience 
Tisagenlecleucel is investigated in several malignancies including r/r ALL, r/r diffuse large B-
cell lymphoma (DLBCL), r/r CLL, and follicular lymphoma (FL). Available data show 
encouraging anti-tumor efficacy with manageable toxicity (Grupp et al 2013, Porter et al 2011, 
Schuster et al 2017, Chong et al 2016, Maude et al 2018). 
For more details please refer to the [Tisagenlecleucel Investigator’s Brochure]. 
1.1.3.2.1 Cellular kinetics 
In adult r/r DLBCL patients from Study C2201, tisagenlecleucel typically exhibits an initial 
rapid expansion phase, achieving maximal expansion around Day 9 (D9), followed by a bi-
exponential decline. The persistence of tisagenlecleucel transgene in peripheral blood has been 

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observed for up to 2 years (Schuster et al 2017). All responding patients demonstrated 
expansion of transgene levels. No clinically relevant impact of patient characteristics and prior 
therapy on expansion were observed. Moreover, cellular and humoral immunogenicity had no 
impact on the cellular kinetics or clinical outcome (Awasthi et al 2017). 
In adults with DLBCL or FL in study A2101J , median peak tisagenlecleucel expansion in blood 
occurred at 8 and 10 days after infusion in responders and non-responders, respectively. No 
difference was noted between peak CD8-tisagenlecleucel and peak CD4-tisagenlecleucel 
expansion in responders and non-responders. Among 16 patients in CR (including both DLBCL 
and FL), 14 had consistently detectable tisagenlecleucel DNA at 6 to 24 months post 
tisagenlecleucel infusion. Two DLBCL patients lost detectable tisagenlecleucel DNA, one at 3 
months and one at 4 months, yet both continue in complete response at 23 and 29 months, 
respectively. 
1.1.3.3 
Clinical Efficacy 
Two clinical trials with tisagenlecleucel in DLBCL patients failing or not being candidates to 
HSCT are ongoing with available data: 
CTL019A2101J (NCT02030834) (Schuster et al 2017): this is a single-arm, single-institution 
trial ongoing at University of Pennsylvania. Patients with CD19+ DLBCL or FL with no 
curative treatment options, who relapsed, or had residual disease after HSCT, or were not 
eligible for autologous or allogeneic HSCT, were eligible for the trial. Patients had to have 
partial response or stable disease to most recent therapy. The 6-month ORR in DLBCL patients 
was 50% (7/14 patients), with CR achieved in 6 patients (43%; 95% CI: 18-71%). Sustained 
remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with 
DLBCL who had a response (95% CI, 33 to 98) had maintained the response. 
CTL019C2201 (NCT02445248) (JULIET trial): In Study C2201 (adult patients with r/r 
DLBCL), the overall response rate (ORR) was 52% (40% CR ad 12% PR), and 65% of the 
patients were relapse-free at 12 months of follow up.  Median response duration has not been 
reached. Most CR patients remained in CR at 3 months (Schuster et al 2018).  
1.1.3.4 
Clinical Safety 
Section 4.5 outlines identified and potential safety risks of tisagenlecleucel, most of which occur 
within 8 weeks of infusion. 
Safety in adult r/r B-NHL  
In study C2201, among the 111 patients assessed for safety, within the first 8 weeks after 
infusion there were 58% with cytokine release syndrome (CRS) (14% Grade 3, 8% Grade 4), 
21% with neurological events (7% Grade 3, 5% Grade 4), and 34% with infections (18% Grade 
3, 2% grade 4). The median time to CRS onset was 3 days (range 1-51 days), median CRS 
duration was 7 days (range 2-30 days); 14% of patients required tocilizumab and 10% of 
patients required both tocilizumab and corticosteroids.  Three patients died within 30 days of 
tisagenlecleucel infusion. No deaths after infusion were attributed to tisagenlecleucel by the 
investigators (Schuster et al 2018). 

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In study A2101J, 28 patients (14 with DLBCL and 14 with FL) were treated with 
tisagenlecleucel. Sixteen (57%) patients developed CRS (18% Grade 3-4) and 11 (39%) patients 
developed neurotoxicity (11% Grade 3-4). There was one death (possibly related to 
tisagenlecleucel) in a patient with FL, who died 234 days after tisagenlecleucel infusion in 
pathological CR (Schuster et al 2017).  
For further information refer to the [Tisagenlecleucel Investigator’s Brochure].  
1.2 
Purpose 
Despite the fact that most patients with aggressive B-cell NHL, can be cured with conventional 
frontline immunochemotherapy (e.g., R-CHOP), around one-third of patients will not respond 
(i.e., will not achieve a CR or PR) or will relapse or progress after front-line treatment. More 
than half of all these treatment failures include patients not responding (refractory) or 
relapsing/progressing within a year after the standard frontline immunotherapy (defined as 
“early relapses”). These patients have a poor prognosis, particularly if they do not respond to 
further salvage immunochemotherapy or are not eligible for HSCT (Sarkozy et al 2015, Coiffier 
et al 2016, Friedberg 2011, Elstrom et al 2010). Novel therapies for refractory and early relapsed 
DLBCL patients are thus urgently needed. 
Given the activity of tisagenlecleucel in DLBCL patients after two or more prior therapies, this 
phase III trial aims at providing randomized assessment of the safety and efficacy of the 
treatment strategy with this novel agent against the current standard of care treatment strategy, 
with the potential to provide additional treatment options for this patient population. 

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2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objectives 
Endpoints 
Primary Objective 
 
To compare tisagenlecleucel treatment strategy to SOC treatment strategy with respect to delaying 
the composite event of disease progression / stable disease at or after the week 12 assessment; 
or death at any time. 
• 
EFS, defined as time from date of randomization to the date 
of first documented disease progression or stable disease at 
or after the week 12 (±1 week) assessment, as assessed by 
blinded independent review committee (BIRC) per Lugano 
criteria, or death at any time 
Secondary Objectives 
 
• 
To compare tisagenlecleucel treatment strategy to SOC treatment strategy with respect to 
EFS as assessed by local investigator. 
• 
EFS as assessed by local investigator 
• 
To compare tisagenlecleucel treatment strategy to SOC treatment strategy with respect to 
overall survival (OS). 
• 
OS: defined as the time from randomization to date of death 
• 
To compare tisagenlecleucel treatment strategy to SOC treatment strategy with respect to 
overall response rate (ORR) 
• 
To evaluate duration of response (DOR) by BIRC and local investigator.  
• 
To compare tisagenlecleucel treatment strategy and SOC treatment strategy with respect to 
time to response (TTR) 
The following endpoints will be evaluated by BIRC and 
investigator assessment per Lugano criteria: 
• 
ORR: overall response rate as per the Lugano criteria 
• 
Duration of response: time from the date of first documented 
response of CR or PR to the date of first documented 
progression (SD or PD at or after the week 12 (±1w) 
assessment will be considered progression) or death due to 
aggressive B-cell NHL 
• 
TTR:  time from the date of randomization to the date of a 
patient first achieved a response of CR or PR on or after the 
Week 12 assessment 
• 
To evaluate safety and tolerability of tisagenlecleucel treatment strategy versus SOC 
treatment strategy 
• 
Type, frequency and severity of serious and non-serious 
adverse events and laboratory abnormalities and 
discontinuations due to adverse events 
• 
To compare patient reported outcomes (PRO) of health-related quality of life (HRQoL) in both 
treatment arms. 
• 
Time to definitive deterioration in SF-36v2, FACT-Lym, and 
EQ-VAS 

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• 
Evaluate efficacy and safety of both treatment arms in histological subgroups (e.g. DLBCL, 
NOS, FL3B, other) and molecular subgroups (e.g. GCB, ABC, other) 
• 
EFS, OS and AE 
• 
To characterize the in vivo cellular kinetics of tisagenlecleucel transduced cells into target 
tissues (blood, bone marrow, cerebral spinal fluid and other tissues if available), as measured 
by qPCR summarized by clinical response in patients receiving tisagenlecleucel therapy in 
arm A or after crossover 
• 
Summary of qPCR detected tisagenlecleucel transgene 
concentrations in peripheral blood and bone marrow (and 
other tissue, if available), and cellular kinetic parameters 
from peripheral blood profile samples by time point and 
clinical response status 
• 
To characterize the incidence and prevalence of tisagenlecleucel immunogenicity (humoral 
and cellular) and impact on cellular kinetics, efficacy, and safety in patients receiving 
tisagenlecleucel therapy in arm A or after crossover 
• 
Summary of pre-existing and treatment induced 
immunogenicity (cellular and humoral) of tisagenlecleucel 
• 
Levels of pre-existing and treatment induced 
immunogenicity. Cellular kinetic parameters, concentration-
time profile by immunogenicity category (positive/negative), 
and efficacy (Month 3 response) 
• 
To assess presence of RCL in patients receiving tisagenlecleucel in arm A or after crossover 
• 
RCL by VSV-qPCR 

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3 
Study design 
This is a randomized, open label, multicenter phase III trial comparing the efficacy, safety, and 
tolerability of tisagenlecleucel treatment strategy to SOC treatment strategy in adult patients 
with aggressive B-cell NHL after failure of rituximab and anthracycline containing first line 
immunochemotherapy. Failure of frontline therapy is defined as refractoriness (lack of 
complete response or progression during therapy) or relapse/progression within 365 days of last 
dose of first line therapy (in patients who achieved CR on first line therapy). 
Screened patients may undergo non-mobilized leukapheresis for autologous T cell collection 
after obtaining informed consent (unless historical product is to be used). During the screening 
period, no lymphoma-specific therapy is allowed prior to randomization. During randomization, 
patients will be stratified by: 
(a) remission duration (refractory or relapsed < 6 months from last dose of first line therapy 
vs. relapsed 6 - 12 months inclusive)  
(b) international prognostic index (IPI) score (<2 versus ≥2, The International Non-Hodgkin's 
Lymphoma Prognostic Factors Project (1993), Moskowitz 1999) 
(c) Region (North America vs. Rest of World) 
Eligible patients will be randomized into: 
Arm A (tisagenlecleucel treatment strategy, tisagenlecleucel after optional bridging 
chemotherapy and LD chemotherapy): Patients will receive lymphodepletion chemotherapy 
(unless the patient has a significant cytopenia, see Section 6.1.4.2) followed by infusion of 
tisagenlecleucel. Use of platinum-based bridging chemotherapy (regimens include R-ICE, R-
GDP, R-DHAP, or R-GemOx, and can be adjusted as per local practice, see Section 6.1.1) after 
randomization and prior to starting lymphodepletion therapy is allowed.   
Arm B (standard of care treatment strategy, standard of care chemotherapy followed by 
transplant): Patients will receive platinum-based immunochemotherapy, followed in 
responding patients by HDCT and autologous HSCT. Every effort should be made to perform 
autologous HSCT in patients achieving a PR, if deemed in the patient’s best interest by the 
treating physician. Cells collected as part of the leukapheresis procedure cannot be used for 
stem cell transplant. A separate collection of cells will be needed if a patient proceeds to 
autologous HSCT. Patients with response that is not sufficient to allow HSCT should change 
therapy to one of the other immunochemotherapy regimens listed above at the investigator’s 
discretion in an attempt to achieve a sufficient response and then proceed to HSCT.  Only 
patients who are deemed no longer eligible for HSCT (e.g. adverse event, poor tolerance to 
immunochemotherapy, 
worsening 
of 
performance 
status) 
after 
two 
cycles 
of 
immunochemotherapy may proceed to lenalidomide or ibrutinib treatment at investigator 
discretion. If the assessment of SD or PD is confirmed by BIRC at Week 6, the investigator 
may request manufacturing of tisagenlecleucel (but not crossover). After receiving 12 weeks of 
SOC therapy, patients with PR FDG+ disease, SD or PD per local assessment may request 
manufacturing of tisagenlecleucel. Crossover can only occur following confirmation of SD/PD 
per BIRC at or after the Week 12 (±1 week) visit, until 1 year after autologous HSCT as detailed 
in Section 8.3.3. 

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Tumor and response assessments will be performed during the screening period (baseline within 
2 weeks of randomization), 6 weeks after randomization (± 2 weeks), 12 weeks after 
randomization (± 1 week), 6 months after randomization (± 2 weeks), every 3 months thereafter 
(± 2 weeks) for the first year, every 6 months (± 2 weeks) for the second year, and annually 
thereafter (± 2 weeks) up to 5 years after randomization. All patients who have stable 
disease/disease progression determined by the local investigator at any time per Lugano 
classification 2014 require an expedited central tumor response review by the BIRC. 
Figure 3-1 
Study design 
 
4 
Rationale 
4.1 
Rationale for study design 
This is a randomized, open label, multicenter phase III trial to determine the efficacy and safety 
of tisagenlecleucel treatment strategy in adult patients with r/r aggressive B-cell NHL after 
failure of rituximab and anthracycline containing frontline immunochemotherapy. 
The outcome of patients with refractory/early relapsed DLBCL treated with first salvage 
therapy is poor, particularly for those who do not respond to the salvage therapy, who have a 
median life expectancy of only 4 months (Elstrom et al 2010, van den Neste et al 2016, 

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Friedberg 2011). As shown by the SCHOLAR-1 meta-analysis (Crump et al 2016), patients 
with chemorefractory DLBCL have consistently poor outcomes, regardless of line of therapy, 
with a median survival of approximately 6 months. In the ORCHARRD trial the median OS of 
patients who entered the study with chemorefractory disease was around 10 months, 
significantly shorter than the median OS of patients enrolled with chemosensitive disease. 
These data support exploring the use of novel therapies in refractory/early relapsed DLBCL 
patients (Van Imhoff et al 2017). 
Event-free survival is an acceptable primary efficacy endpoint in the setting of aggressive 
diseases like DLBCL and has shown to be a robust surrogate endpoint for OS in frontline 
DLBCL trials evaluating immunochemotherapy (Shi et al 2016, Lee et al 2011). In this trial, 
EFS is defined as the time from date of randomization to death due to any cause for all patients 
or lack of response (i.e. PD or SD) at or after the week 12 (±1w) assessment. 
SD is considered as treatment failure in aggressive B-cell lymphoma and, as demonstrated by 
the analysis performed in the CORAL study in patients not responding to first and second 
salvage therapies (and eventually not receiving HDCT and HSCT), the expected survival is only 
3.4 months from the start of the second salvage therapy. The ORCHARRD study also showed 
that only 33% and 37% of patients in the two treatment groups (R-DHAP and O-DHAP 
respectively) were able to undergo stem cell transplant (van Imhoff et al 2017). The current 
goal of salvage therapy in r/r aggressive B-cell lymphoma patients after front line 
immunochemotherapy is to achieve a good quality response and perform HDCT and HSCT. As 
a general rule, if a response is not observed after 2-3 cycles of a first salvage therapy, the 
recommendation is to change to a new salvage therapy (2nd salvage) with the same objective of 
achieving a response and eventually perform HSCT. If no response is observed, treatment 
guidelines recommend use of axicabtagene ciloleucel or tisagenelecleucel or another course of 
2 cycles of a new salvage therapy (i.e., 3rd salvage), or best supportive care. The possibility of 
being rescued after 3rd salvage chemotherapy is very low and most patients will die due to 
quickly progressing disease (NCCN V1 2019, Van den Neste et al 2017). For this reason, stable 
disease after 12 weeks (±1 week) from randomization (which corresponds to approximately 2 
rounds of different 2-cycle salvage therapy post randomization) will be considered as event (for 
both tisagenlecleucel and SOC arms). Patients enrolled in the SOC arm will be eligible to 
crossover to tisagenlecleucel after BIRC confirmation of PD or SD at or after the week 12 
assessment (±1 week) up until one year after HSCT, since the majority of relapses would occur 
within this 1 year timeframe. Additionally, patients with BIRC confirmation of PD or SD at the 
Week 6 assessment (±2 weeks) or patients with PR FDG+ disease by local assessment at the 
Week 12 assessment or after will be able to request a tisagenlecleucel manufacturing slot for 
potential crossover. Allowing crossover to tisagenlecleucel will confound the assessment of OS, 
but will ensure the access to a potentially effective therapy in these patients with poor prognosis. 
As the primary EFS endpoint will be evaluated by BIRC, crossover will only be allowed after 
PD or SD at or after the week 12 (±1 week) assessment is confirmed by BIRC in order to avoid 
informative censoring. 
In addition to the response assessment, three Patient Reported Outcome (PRO) tools, FACT-
Lym, SF-36 version 2 and EQ-5D-5L, are proposed for this study as they are considered 
adequate to support the establishment of clinical benefit for lymphoma patients. FACT-Lym 
tool will be used to assess disease-specific quality of life. SF-36 v2 will assess general 

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health/quality of life with EQ-5D to assess health utility for the purpose of economic evaluation. 
Both FACT-Lym and SF-36 v2 have been already used in previous tisagenlecleucel pivotal 
NHL studies. 
Safety will be monitored throughout the trial. Per Health Authority guidelines (FDA 2006, 
EMA 2009) for gene therapy products or advanced therapy medicinal products that utilize 
integrating vectors (e.g., lentiviral vectors), all patients treated with tisagenlecleucel must be 
monitored for specific toxicities for up to a total of 15 years following infusion, irrespective of 
their response to tisagenlecleucel. All patients who receive tisagenlecleucel will be monitored 
in this trial for 5 years, followed by semiannual and annual safety assessments in a separate 
long-term follow-up protocol (CCTL019A2205B) for an additional ten years to further define 
the long-term effects of tisagenlecleucel therapy. 
4.1.1 
Rationale for lymphodepletion 
Adoptive immunotherapy strategies may be able to capitalize on homeostatic T cell 
proliferation (Dummer et al 2002), a finding that naive T cells begin to proliferate and 
differentiate into memory-like T cells when the 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 potential mechanism of 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). Data indicates that the increased antitumor efficacy of adoptive transfer following host 
conditioning is more than simply “making room” because the quantitative recovery of 
adoptively transferred T cells in mice reveals that in vivo proliferation following adoptive 
transfer is identical in mice with or without previous irradiation (Palmer et al 2004). 
Fludarabine with cyclophosphamide has been the most commonly utilized lymohodepleting 
regimen with CD19 CAR-T cell therapies. It has been demonstrated that addition of fludarabine 
to cyclophosphamide  increases  CAR-T cell expansion and persistence and improves disease 
free survival rates in adult patients with r/r NHL (Turtle et al 2016). 
In previous and ongoing studies (CTL019C2201 and CTL019A2101J) with tisagenlecleucel 
most of the patients received lymphodepleting therapy with fludarabine and cyclophosphamide 
and around 20% of DLBCL patients received bendamustine. 
4.2 
Rationale for dose/regimen and duration of treatment 
The recommended tisagenlecleucel dose is a single intravenous (i.v.) infusion of 0.6 – 6.0 × 108 
CAR-positive viable T cells, based on available dose-response, dose-safety, and dose-cellular 
kinetics analyses performed using the data obtained from r/r DLBCL patients (data cut-off date: 
8-Mar-2017) in a Phase II study (CTL019C2201; JULIET).  This dose is the approved dose in 
DLBCL in 3rd or later line in the United States (US), European Union (EU), and several other 
countries.If bridging chemo therapy prior to tisagenlecleucel infusion is used, duration of 
treatment should follow local prescribing information. The allowed regimens are outlined in 

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Section 6.1.1 (control drugs). Lymphodepleting chemotherapy should be administered as per 
Section 6.1.4.2. 
Dose-response and dose-exposure: Across the dose range studied, dose and exposure were 
independent. Additionally, clinically meaningful responses were observed from 0.6 to 6.0×108 
CAR-positive viable T cells. 
Dose-safety: In patients with r/r DLBCL, the probability of any grade neurologic events and 
time to resolution of cytopenias were not impacted by dose. There was an increase in probability 
of any grade and grade 3/4 CRS with increasing dose; however, the probability of grade 3/4 
CRS was comparable across the dose range of 5.0 to 6.0×108 CAR-positive viable T cells. In 
addition, CRS is generally manageable in the study with the steps outlined in the CRS 
management algorithm (Section 6.6.2.1). 
Based on the totality of the dose-safety, dose-efficacy, dose-exposure and exposure-response, 
and considering the positive benefit risk observed across the full range of doses, the following 
dose specification will be utilized in this study: 0.6 - 6.0×108 CAR-positive viable T cells. 
For patients in the control arm, the duration of chemotherapy is determined by response to 
treatment, tolerability and the treating institution’s policies. Investigators should refer to the 
local label for each drug. 
4.3 
Rationale for choice of comparator drugs 
The ESMO and NCCN clinical treatment guidelines for patients with  r/r DLBCL recommend 
for patients with adequate performance status (defined by age and absence of major organ 
dysfunctions) a salvage regimen with rituximab and chemotherapy followed in responsive 
patients by high-dose chemotherapy and autologous HSCT (Tilly et al 2015, NCCN V1 2019). 
Without autologous HSCT, chemotherapy provides only short-term disease control in r/r 
DLBCL (Elmstrom et al 2010). For patients with r/r DLBCL failing first line treatment the 
established SOC treatment strategy is salvage therapy followed by autologous HSCT. 
In recent years, 4 regimens have been mainly used as salvage therapy in patients with r/r 
DLBCL eligible for autologous HSCT: R-DHAP, R- ICE, R-GDP (Tilly et al 2015), and R-
GemOx (Mounier 2013). In the present trial, all patients randomized to SOC therapy will 
receive one of the above-mentioned 4 regimens as per discretion of the treating physician. For 
patients randomized to the tisagenlecleucel treatment arm, investigators will have the option of 
using one of the four treatments as bridging chemotherapy while the patients’ tisagenlecleucel 
product is manufactured. The decision to use bridging chemotherapy is based on investigator 
decision in the best interest of the patient. The specific dosing regimens of each of the SOC 
regimens can be found in Section 6.1.1. 
Patients in the SOC arm who are unable to achieve a response to salvage therapy are not eligible 
to proceed to HSCT. Treatment options in this population include the following, with or without 
rituximab: bendamustine, GDP, GemOx, or lenalidomide. Additional treatment options are 
limited and include, ibrutinib (for non-GCB DLBCL), the anti-CD19 CAR-T therapies 
axicabtigene ciloleucel or tisagenlecleucel, and enrolment in clinical trials of new therapies 
(Tilly et al 2015, NCCN V1 2019). In the present trial, patients who do not achieve a response 
to the second line salvage therapy may switch to another salvage regimen in an attempt to 
achieve a response which may allow the patient to proceed to autologous HSCT. Only patients 

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who are deemed no longer eligible for HSCT (e.g. adverse event, poor tolerance to 
immunochemotherapy, 
worsening 
of 
performance 
status) 
after 
two 
cycles 
of 
immunochemotherapy may proceed to lenalidomide or ibrutinib treatment at investigator 
discretion. Patients who are still unable to achieve response at week 12 have the option to 
crossover to arm A to receive the anti-CD19 CAR-T therapy tisagenlecleucel. 
The use of such regimens and their similarities regarding efficacy in r/r DLBCL are supported 
by the 3 phase III trials discussed in the background section (i.e., CORAL, NCIC-CTG LY.12 
and ORCHARRD)(Refer to Section 1.1.1). 
4.4 
Purpose and timing of interim analyses 
Not applicable. 
4.5 
Risks and benefits 
Tisagenlecleucel administered to over 750 patients in clinical trials across the dose ranges tested 
has a well characterized safety profile in pediatric and young adult patients. Overall, it is 
anticipated that the study benefits of tisagenlecleucel therapy in this study will outweigh the 
risks. 
Appropriate eligibility criteria and specific dose-limiting toxicity definitions (as applicable) are 
included in this protocol. Recommended guidelines for prophylactic or supportive management 
of study-drug induced AEs are provided in Section 6.6.2. 
The risk to participants in this trial will be minimized by adherence to the eligibility criteria, 
close clinical monitoring, and adherence to the recommendations for the management of AEs 
known to be occur with tisagenlecleucel exposure, periodic review of the safety data by an 
independent Data Monitoring Committee (DMC), and guidance for the investigators in the 
[tisagenlecleucel Investigator’s Brochure]. 
Women of child bearing potential (WOCBP) and sexually active males must be informed that 
receiving the study treatment may pose unknown risks to the fetus if pregnancy were to occur 
during the study, and agree that in order to participate in the study they must adhere to the 
contraception requirements outlined in the exclusion criteria. If there is any question that the 
participant will not reliably comply, they should not be entered or continue in the study (Section 
4.5.3.1). 
Safety risks that have been identified with the use of tisagenlecleucel or are considered 
potentially associated with tisagenlecleucel are briefly outlined below. 
4.5.1 
Identified safety risks with the use of tisagenlecleucel 
Safety risks that have been identified with the use of tisagenlecleucel or are considered 
potentially associated with tisagenlecleucel are briefly outlined below. For more information, 
please refer to the [Tisagenlecleucel Investigator’s Brochure] 

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4.5.1.1 
Cytokine release syndrome (CRS) / macrophage activation syndrome 
(MAS) 
Cytokine release syndrome (CRS) is an on-target toxicity that is associated with 
tisagenlecleucel cell expansion, activation and tumor cell killing. It is a result of systemic 
inflammatory response caused when cytokines such as interferon gamma (IFNg), interleukin 6 
(IL-6) and tumor necrosis factor (TNF) are released by activated T cells or activated 
monocytes/macrophages. Cytokine release syndrome, including fatal or life-threatening events, 
has been frequently observed after tisagenlecleucel infusion, in particular if associated with 
concomitant infections. In almost all cases, development of cytokine release syndrome occurred 
between 1 to 10 days (median onset 3 days) after tisagenlecleucel infusion. The median time to 
resolution of cytokine release syndrome was 7 days. 
CRS shows a wide range of clinical signs and symptoms (Table 4-1) and is graded according 
to the Lee criteria (Table 4-2) (Lee et al 2014). In the setting of more severe CRS following 
CAR T cell therapy, AEs of macrophage activation syndrome (MAS) and hemophagocytic  
lymphohistiocytosis (HLH) have also been reported. Both HLH and MAS have similar clinical 
manifestations as CRS, irrespective of the underlying cause, and encompass a group of severe 
immunological disorders characterized by hyperactivation of macrophages and lymphocytes, 
proinflammatory cytokine production, lymphohistiocytic tissue infiltration, and immune-
mediated multiorgan failure (Neelapu et al 2018). Patients, who experienced severe CRS, 
showed a clinical phenotype that resembles MAS or HLH including high fever, multi-organ 
dysfunction or CNS disturbances that is further evidenced by similar laboratory findings of 
abnormal macrophage activation, high serum levels of ferritin, lactate dehydrogenase and 
soluble CD25, low fibrinogen, and cytokine profile. Thus, HLH/MAS might not only belong to 
a similar spectrum of hyperinflammatory disorders as CRS, but could be interpreted as 
manifestations of CRS of higher severity (Teachey et al 2018). 
The onset of CRS should be retrospectively defined as the date of the first sign or symptom 
consistent with CRS.  The resolution date of CRS should generally be declared resolved once 
fever, oxygen, and pressor requirements have resolved.  Patients that receive anti-cytokine 
therapy or antipyretics may quickly resolve fever, however CRS should be considered ongoing 
even in the absence of fever until improvement of hemodynamic status and/or hypoxia with 
resolution of pressor and/or oxygen requirements. Concurrent or subsequent neurotoxicity is 
considered as a separate event (See Section 4.5.1.2) and does not affect the grading or resolution 
of CRS.  For example, necessity of intubation  in those patients having a degree of neurotoxicity 
(e.g presence of seizure) where there is a concern for their ability to maintain a patent airway 
should not influence the grading or resolution of CRS (Lee et al 2019). 
Risk factors for severe CRS in pediatric and young adult B-ALL patients are high pre-infusion 
tumor burden, uncontrolled or accelerating tumor burden following lymphodepleting 
chemotherapy, active infection and early onset of fever or CRS following tisagenlecleucel 
infusion.  
In pediatric B-cell ALL and adult DLBCL patients, high tumor burden is a risk factor for 
developing severe CRS.  
In the ongoing clinical study B2202 in pediatric and young adult B-cell ALL (N=75), CRS was 
reported in 77% of patients (47% with Grade 3 or 4). Two deaths occurred within 30 days of 

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tisagenlecleucel infusion: one patient died with CRS and progressive leukaemia and the second 
patient had resolving CRS with abdominal compartment syndrome, coagulopathy and renal 
failure when death occurred due to an intracranial haemorrhage. In the ongoing DLBCL clinical 
study C2201 (N=111), CRS was reported in 58% of patients, (22% with Grade 3 or 4). 
Table 4-1 
Clinical signs and symptoms associated with CRS 
(Lee et al 2014) 
Organ system 
Symptoms 
Constitutional 
Fever ± rigors, malaise, fatigue, anorexia, myalgia, arthralgia, nausea, vomiting, 
headache 
Skin 
Rash 
Gastrointestinal 
Nausea, vomiting, diarrhea 
Respiratory 
Tachypnea, hypoxemia 
Cardiovascular 
Tachycardia, widened pulse pressure, hypotension, increased cardiac output (early), 
potentially diminished cardiac output (late) 
Coagulation 
Elevated D-dimer, hypofibrinogenemia ± bleeding 
Renal 
Azotemia 
Hepatic 
Transaminitis, hyperbilirubinemia 
 
 
Table 4-2 
Cytokine Release Syndrome Grading 
(Lee et al 2014) 
Grade 
Toxicity 
Grade 1 
Symptoms are not life threatening and require symptomatic treatment only, eg, fever, 
nausea, fatigue, headache, myalgias, malaise 
Grade 2 
Symptoms require and respond to moderate intervention 
Oxygen requirement <40% or 
Hypotension responsive to fluids or low dose* of one vasopressor or 
Grade 2 organ toxicity 
Grade 3 
Symptoms require and respond to aggressive intervention 
Oxygen requirement ≥40% or 
Hypotension requiring high dose* or multiple vasopressors or 
Grade 3 organ toxicity or grade 4 transaminitis 
Grade 4 
Life-threatening symptoms 
Requirement for ventilator support or 
Grade 4 organ toxicity (excluding transaminitis) 
Grade 5 
Death 
*Refer to Table 6-3 for definition of high dose vasopressors 
A therapeutic strategy for the management of CRS is provided in Section 6.6.2.1 that should be 
followed. 
4.5.1.2 
Neurological events 
Neurological events, indicative of  encephalopathy and delirium of non-infectious origin,  have 
been observed in patients following various types of T cell directed therapy including 
tisagenlecleucel and other CAR-T cell therapies of other institutions. The pathophysiology for 
neurotoxicity is not fully understood but thought to be related to generalized T cell mediated 

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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 preceeding 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 an attempt to standardize the assessment of these events, the CARTOX Working 
Group has suggested the name CAR T cell-related encephalopathy syndrome (CRES) (Neelapu 
et al 2018). This syndrome typically manifests as a toxic encephalopathy with a wide range of 
variable symptoms such as aphasia, confusion, delirium, tremors, occasionally seizures and 
rarely life-threatening cerebral edema. The manifestation of CRES is biphasic, with the first 
phase occurring concurrently with cytokine release syndrome (CRS) symptoms typically within 
the first 5 days after CAR T cell therapy, and the second phase after CRS subsides. Delayed 
neurological events with seizures or episodes of confusion 3-4 weeks following CAR T cell 
therapy have been reported to occur in approximately 10% of patients.  
Although encephalopathy is a dominant feature of neurotoxicity following treatment with CAR 
T cell therapy, there are other neurologic symptoms that should be taken into account. The 
American Society for Transplantation and Cellular Therapy (ASTCT) recently defined the term 
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) as “a disorder 
characterized by a pathologic process involving the central nervous system following any 
immune therapy that results in the activation or engagement of endogenous or infused T cells 
and/or other immune effector cells. Symptoms or signs can be progressive and may include 
aphasia, altered level of consciousness, impairment of cognitive skills, motor weakness, 
seizures, and cerebral edema” (Lee et al 2019). A grading system was developed in order to 
characterize this syndrome (Table 4-3) which incorporates key aspects of the mini-mental status 
exam via the Immune effector Cell-associated Encephalopathy (ICE) score (Table 4-4)  
In clinical trials, the majority of neurological events following tisagenlecleucel infusion were 
observed within 8 weeks, however, neurological events with later onset > 8 weeks and not in 
the context of CRS have also been reported. Most neurological events observed within 8 weeks 
were transient or self-limiting in nature. Frequently, encephalopathy, confusional state and 
delirium were observed. Other manifestations include a multifarious set of signs and symptoms 
including seizures, aphasia, speech disorder, and tremor. Some of the events are severe and may 
have a life-threatening outcome.  
Notably, the onset of neurological toxicity 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. In paediatric and young adult B-cell ALL patients, 
manifestations of encephalopathy and/or delirium occurred in 40% of patients (13% were Grade 
3; no grade 4 were observed ) within 8 weeks after tisagenlecleucel  infusion. In DLBCL 
patients, manifestations of encephalopathy and/or delirium occurred in 21% of patients (12% 
were Grade 3 or 4) within 8 weeks after tisagenlecleucel infusion. 

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The causality assessment of neurological events in patients treated with tisagenlecleucel can be 
confounded as CNS toxicity may be associated with chemotherapy used for lymphodepletion 
and the presence of comorbid conditions such as CRS, fever and infections. 
Table 4-3 
Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS) 
Grading  
(Lee et al 2019) 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE Score^ 
(Table 4-4) 
7-9 
3-6 
0-2 
0 (patient is unarousable and 
unable to perform ICE) 
Depressed level 
of 
consciousnessv 
Awakens 
spontaneously 
Awakens to 
voice 
Awakens only to 
tactile stimulus 
Patient is unarousable or 
requires vigorous or repetitive 
tactile stimuli to arouse. 
Stupor or coma 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves 
rapidly; or Non-
convulsive seizures 
on EEG that resolve 
with intervention 
Life-threatening prolonged 
seizure (>5 min); or 
Repetitive clinical or electrical 
seizures without return to 
baseline in between.  
Motor findings§ 
 
N/A  
N/A  
N/A 
Deep focal motor weakness 
such as hemiparesis or 
paraparesis 
Elevated ICP / 
Cerebral edema 
N/A 
N/A 
Focal/local edema 
on neuroimaging# 
Diffuse cerebral edema on 
neuroimaging; Decerebrate or 
decorticate posturing; or 
Cranial nerve VI palsy; or 
Papilledema; or Cushing's 
triad 
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, 
motor findings, raised ICP/cerebral edema) not attributable to any other cause. For example, a patient 
with an ICE score of 3 who has a generalized seizure is classified as having Grade 3 ICANS.  
^ A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake 
with global aphasia. But a patient with an ICE score of 0 may be classified as having Grade 4 ICANS if 
the patient is unarousable. 
v Depressed level of consciousness should be attributable to no other cause (e.g. no sedating 
medication) 
§ Tremors and myoclonus associated with immune effector cell therapies may be graded according to 
CTCAE v5.0 but they do not influence ICANS grading. 
# Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature 
and is excluded from ICANS grading. It may be graded according to CTCAE v5.0. 

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Table 4-4 
Immune effector Cell-associated Encephalopathy (ICE) score  
(Lee et al 2019) 
Category 
Test 
Scoring 
Orientation 
Orientation to year, month, city, hospital 
4 points total (1 point each) 
Naming 
Ability to name 3 objects (e.g. point to clock, 
pen, button) 
3 points total (1 point each) 
Following Commands 
Ability to follow simple commands (e.g. “Show 
me 2 fingers” or “Close your eyes and stick out 
your tongue”) 
1 point 
Writing 
Ability to write a standard sentence (e.g. “Our 
national bird is the bald eagle”) 
1 point 
Attention 
Ability to count backwards from 100 by 10 
1 point 
For the management of neurological events see Section 6.6.2.2. 
4.5.1.3 
Hypersensitivity including acute infusion reactions 
Since tisagenlecleucel is an autologous cellular product, hypersensitivity may occur due to the 
excipients (such as dimethyl sulfoxide (DMSO) or dextran 40) of the infused solution in which 
the cells are dispersed. In addition, host immune responses may result from presentation of 
CAR transgene expressed immunogenic epitopes including murine sequences in the scFv 
extracellular binding domain (derived from a murine monoclonal antibody) or novel epitopes 
arising at junctions between components of the CAR fusion polypeptide (Park et al 2007; 
Lamers et al 2006; Lamers et al 2007; Lamers et al 2011). 
Clinically, hypersensitivity reactions can be classified as 'immediate' or 'delayed' depending on 
their onset after drug administration (Corominas et al 2014; Limsuwan and Demoly 2010). In 
principle, immediate reactions including acute infusion reactions occur within less than 1 hour 
after drug administration and may present in a wide range of symptoms such as fever, chills, 
nausea, urticaria, angioedema, rhinitis, conjunctivitis, dyspnea, bronchospasm, tachycardia, 
hypotension, anaphylaxis or anaphylactic shock. Delayed hypersensitivity reactions appear 
after more than 1 hour and up to several days after drug exposure and could include variable 
cutaneous symptoms such as late-occurring urticaria, maculopapular eruptions, fixed drug 
eruptions, vasculitis, toxic epidermal necrolysis, Stevens- Johnson syndrome, or drug reaction 
with eosinophilia and systemic symptoms (DRESS) (Averbeck et al 2007; Descotes 2012; 
Corominas et al 2014). 
To date, the majority of events observed after tisagenlecleucel infusion were mild or moderate 
in severity, manageable and recovered. 
Patients will have typically received lymphodepleting chemotherapy that is completed several 
days prior to tisagenlecleucel infusion. Therefore it should be kept in mind that symptoms and 
findings at this time may also be the result of the onset of chemotherapy related toxicities. 
A therapeutic strategy for the management of hypersensitivity including acute infusion 
reactions is provided in Section 6.6.2.3. 
4.5.1.4 
Tumor lysis syndrome (TLS) 
Tumor lysis syndrome (TLS) is a potentially life-threatening metabolic disorder that occurs 
when tumor cells undergo rapid decomposition spontaneously or in response to cytoreductive 

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therapy. It tends to occur particularly with highly effective therapies and in patients with high 
tumor burden and cancers with a high potential for cell lysis include high-grade lymphomas, 
acute leukemias, and other rapidly proliferating tumors. 
Metabolic abnormalities characteristic of TLS include abnormally high serum uric acid levels 
(hyperuricemia) resulting from the breakdown of purine-containing nucleic acids and major 
electrolyte imbalances such as hyperkalemia, hyperphosphatemia, and hypocalcemia. Delayed 
recognition of the metabolic imbalances caused by the massive release of tumor cell contents 
may result in clinical complications such as acute kidney injury, seizures, and cardiac 
arrhythmias (Mughal et al 2010). 
Tumor lysis syndrome was clinically observed in a timely relation to tisagenlecleucel T cell 
expansion. In the clinical experience with tisagenlecleucel thus far, most cases of TLS had a 
grade 3 in Common Terminology Criteria for Adverse Events (CTCAE) severity, however, the 
risk has been moderate to low with appropriate monitoring after lymphodepleting chemotherapy, 
prophylaxis and treatment as needed. 
A therapeutic strategy for the management of TLS is provided in Section 6.6.2.4. 
4.5.1.5 
Infections 
There is an increased risk and severity of infections in patients with longer and more intense 
immunosuppression. Patients treated with tisagenlecleucel are at risk of infection for several 
reasons: 
• Underlying bone marrow disease or dysfunction increases the risk of infections.  
• Patient with prolonged and profound immunosuppression are at enhanced risk for more 
frequent and severe opportunistic infections. This may result from preceding anti-cancer 
treatment, such as radiation or chemotherapy, and lymphodepleting chemotherapy prior to 
treatment with tisagenlecleucel causing severe neutropenia and/or B-cell depletion from 
tisagenlecleucel. 
• B-cell depletion is known to be associated with hypo- or agammaglobulinemia that 
contributes to the risk. 
Serious infections were observed in patients after tisagenlecleucel infusion, some of which were 
life- threatening or fatal. 
A therapeutic strategy for the management of infections is provided in Section 6.6.2.5. 
4.5.1.5.1 Viral reactivation 
Patients with active hepatitis B or prior or active hepatitis C have been excluded from prior 
clinical studies with tisagenlecleucel, because of the potential risk of viral reactivation and the 
risk of fulminant hepatitis, hepatic failure and fatal outcome. Human immunodeficiency virus 
(HIV) positive patients have been also excluded, because of the possible effect on HIV viral 
suppression.  
In addition, there is currently no experience with manufacturing tisagenlecleucel for patients 
testing positive for active hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV. Patients 
are to be screened for any active HBV, HCV or HIV infection prior to leukapheresis.  

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Participants with confirmed active hepatitis B, hepatitis C or HIV will not be enrolled in the 
study; for detailed exclusion criteria see Section 5.2 for serology assessment see Section 16.1. 
4.5.1.6 
Febrile neutropenia 
Febrile neutropenia and associated events such as grade 3 or grade 4 decreased neutrophil 
counts with elevated temperature were reported in clinical studies with tisagenlecleucel. The 
use of chemotherapy is known to be associated with the risk of neutropenia and if severe, with 
febrile neutropenia. The risk of neutropenia depends on various factors such as type and dose 
of chemotherapy used, age, gender, performance status and baseline hematology lab data. As 
lymphodepleting therapy is used in all patients with a white blood cell (WBC) count >1000 
cells/μL, febrile neutropenia is seen in patients treated with tisagenlecleucel regimen. Also, as 
lymphodepleting therapy is given close to the infusion of tisagenlecleucel (within two weeks), 
therefore, overlapping toxicities can be expected. 
A therapeutic strategy for the management of febrile neutropenia is provided in Section 6.6.2.6. 
4.5.1.7 
Prolonged depletion of normal B cells and agammaglobulinemia 
Since normal B-cells express CD19, B-cell aplasia is an expected on-target toxicity of a 
successful CD19-directed CAR T cell therapy and a useful surrogate reflecting the persistence 
of CAR T cells and effectiveness of treatment. B-cell aplasia has been observed in all 
responding patients with B-ALL. The AEs observed after tisagenlecleucel infusion were 
managed well by treatment with immunoglobulins. 
Loss of B-cells can result in hypo- to a-gammaglobulinemia, potentially rendering the patients 
more susceptible to infections, especially with encapsulated organisms; and viral reactivation 
such as herpes viruses (Section 4.5.1.5.1). 
Given that a typical T-lymphocyte may have a lifespan of 40 years, tisagenlecleucel may 
potentially be detectable in a patient for a very prolonged period and prolonged depletion of 
B-cells may occur, in particular in the subset of patients who continue to demonstrate a tumor 
response. Long term data are currently not available. A therapeutic strategy for the management 
of B cell depletion with resulting hypogammaglobulinemia is provided in Section 6.6.2.7. 
4.5.1.8 
Hematopoietic cytopenias not resolved by day 28 post infusion 
Hematopoietic cytopenias are an on-target effect after tisagenlecleucel infusion and activity of 
tisagenlecleucel on normal B-cells. 
Patients treated with tisagenlecleucel may exhibit hematopoietic cytopenias for several weeks 
an on-target effect after tisagenlecleucel exposure and as sequelae of bridging and 
lymphodepleting chemotherapy. Prolonged neutropenia has been associated with increased risk 
of infection. Myeloid growth factors, particularly granulocyte-macrophage colony stimulating 
factor (GM-CSF), are not recommended during the first 3 weeks after tisagenlecleucel or until 
CRS has resolved. 
A therapeutic strategy for the management of hematopoietic cytopenias is provided in 
Section 6.6.2.8. 

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4.5.2 
Potential safety risks 
Thus far, an association with the potential safety risks briefly described below and 
tisagenlecleucel have not been confirmed. However, these topics are being closely monitored 
due to their clinical relevance. 
4.5.2.1 
Cerebral edema 
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. 
Following a retrospective exploratory analysis of these five cases, it is believed that these fatal 
cerebral edema cases emerged from fast and early CAR-T-cell expansion due to the specific 
CAR-T construct and subsequent sharp spike in cytokines (Gilbert 2017). 
No fatal cerebral edemas have been reported following tisagenlecleucel infusion in the clinical 
development program or the post-marketing setting to date that would resemble the clinical 
course reported for JCAR015. JCAR015 presents a different construct of an anti-CD19 CAR-
T-cell product compared to tisagenlecleucel. 
4.5.2.2 
Replication competent lentivirus (RCL) production 
Replication-competent lentivirus (RCL) may be generated during tisagenlecleucel 
manufacturing using a lentiviral vector to encode anti-CD19 CAR or subsequently after 
introduction of vector transduced viable T cells into the patient. 
However, generation of RCL resulting from manufacturing is highly unlikely since elements 
are incorporated in the design of the vector system that minimize the probability of 
recombination and generation of RCL. Furthermore, the vector used to transduce the T cells 
undergoes sensitive assays for detection of RCL Thus patients will only receive cell products 
that meet RCL release criteria considered sufficient to confirm the absence of RCL in 
tisagenlecleucel and the negligible probability of de novo generation of any RCL. 
Tisagenlecleucel uses third generation self-inactivating lentiviral vector to safeguard against 
the potential of generating RCL. No AEs related to generation of RCL were noted post-infusion 
in the tisagenlecleucel development program. However, generation of an RCL following 
tisagenlecleucel infusion remains a theoretical possibility. The development of RCL could pose 
a risk to both the patients and their close contact(s), and therefore, monitoring for RCL will be 
conducted during the course of the trial (see [Investigational Product Handling Manual] for a 
description of the assays).  
As per guidance for gene therapy medicinal products, patients exposed to tisagenlecleucel will 
be monitored for 15 years following last treatment for vectors persistence and RCL within the 
long-term follow-up study. 
The management of this potential risk is addressed in Section 6.6.2.9. 

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4.5.2.3 
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 tisagenlecleucel therapy will need to take into account these additional 
confounding risk factors. 
Transduction of a patient’s T cells with the lentiviral vector could lead to insertional 
mutagenesis resulting in an uncontrolledT cell proliferation and an oncogenic effect that could 
result in 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 (Penn) / Children’s Hospital of Philadelphia with CTL019 as 
manufactured by Penn. The patient showed an initial response to treatment and relapsed 9 
months after infusion with CD19-negative leukemia cell that aberrantly expressed the anti-
CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during 
CAR-T cell manufacture at Penn and its product bound in cis to the CD19 epitope on the surface 
of leukemic cells, masking it from recognition by and conferring resistance to the CAR-T.  
The Novartis manufacturing process for tisagenlecleucel is designed to significantly reduce the 
probability of contaminating B cells in the T cell culture. Therefore, the risk of CAR 
transduction of B cells as observed at the early CTL019 study at Penn and described in the 
publication by Ruella et al can be considered low with the current Novartis manufacturing 
process. 
As described in Section 4.5.2.2, tisagenlecleucel uses third generation self-inactivating 
lentiviral vector to safeguard against the potential oncogenic effectsInsertional mutagenesis was 
evaluated in two lentivirus insertion site analysis (LISA) studies where 12 batches of 
manufactured patient product ready for infusion and two batches of product manufactured from 
healthy donor cells were analyzed. The results indicate that there was no preferential integration 
near genes of concern, no preferential sites of integration (hot spots), and no preferential 
outgrowth of cells harboring integration sites of concern.  
Tisagenlecleucel is based on autologous, fully differentiated T cells and therefore the 
carcinogenicity risk is considered to be low in comparison to genetic modification or repair 
such as HSC. In a recent review of CAR-T cell therapies, (Bonifant et al 2016) as well as 
(Mohanlal et al 2016) discussed that to date no cases of malignant transformation have been 
reported for genetic modification of T cells and that there currently is no evidence for vector-
induced immortalization, clonal expansion, or enrichment for integration sites near genes 
implicated in growth control or transformation. This is supported by the results of the lentivirus 
insertion site analysis (LISA) studies performed during the development of tisagenlecleucel. 
Theoretically, CAR-positive viable T cells could proliferate without control of normal 
homeostatic mechanisms. In pre-clinical studies (Milone et al 2009) and clinical experience to 
date (Porter et al 2011, Grupp et al 2013, Maude et al 2014), CAR-positive viable T cells have 
only proliferated in response to physiologic signals or upon exposure to CD19 antigen. In the 

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context of tisagenlecleucel therapy, it is expected that the T cells will proliferate in response to 
signals from the CD19 expressing malignant tumor and normal B cells. This could be either 
harmful depending on the extent of proliferation or beneficial, since clonal dominance of 
adoptively transferred T cells has been associated with tumor reduction in adoptive transfer 
trials (Dudley et al 2002, Dudley et al 2005). 
The management of this potential risk is addressed in Section 6.6.2.10. 
4.5.2.4 
New occurrence or exacerbation of an autoimmune disease 
An emerging number and variety of autoimmune diseases following after anti-cancer treatment 
including immunotherapy are reported, ranging from asymptomatic immunological alterations 
to life-threatening systemic autoimmune diseases (Pérez-De-Lis et al 2017). However, specific 
etiopathogenic mechanisms that could clearly link the induced autoimmune disorder with the 
immunological pathways altered by the anti-cancer treatments are not well understood. 
Persistent immune abnormalities after treatment with chemotherapy, development of auto-
antibodies and neoantigens are proposed to be crucial in the pathogenesis of autoimmune 
diseases post anti-cancer treatment (Descotes and Gouraud 2008, Chang and Gershwin 2010, 
Amos et al 2011). 
The risk of autoimmune reaction with tisagenlecleucel is low since CD19 is not present on most 
normal tissue other than normal B-cells. New occurence or exacerbation of an autoimmune 
disorder has not been observed with tisagenlecleucel thus far.  
No AEs associated with this potential were observed in tisagenlecleucel clinical trials. 
4.5.2.5 
Hematologic disorders (incl. aplastic anemia and bone marrow failure) 
There is potential risk of a hematologic disorder such as aplastic anemia or bone marrow failure, 
given that tisagenlecleucel is a genetically modified cell product that may have the potential to 
affect hematopoietic cell function, as could prior chemotherapy and radiation given for the 
underlying malignancy. 
4.5.2.6 
Transmission of infections agents 
Transmission of infections agents could lead to new infections and reactivation of pre-existing 
viral disease (e.g., HBV, HCV, or HIV), respectively, in close contacts including personnel 
involved in the tisagenlecleucel manufacturing process, health care providers involved in 
leukapheresis and administering tisagenlecleucel or the patients treated with tisagenlecleucel.  
Multiple steps are required to produce tisagenlecleucel CAR-T-cells, involving leukapheresis 
to obtain patient autologous starting material, enrichment and activation, gene transduction via 
lentiviral vector and expansion. Transmission of infectious material via product could 
potentially derive from the patient’s own leukapheresis material prepared from autologous 
blood, other material including the tisagenlecleucel viral vector required to manufacture 
tisagenlecleucel, through contamination during the manufacturing process or inadequate 
storage. Due to the nature of the product (i.e., cells), there is no possibility to introduce terminal 
sterilization or dedicated viral removal and inactivation steps. Stringent precautions to prevent 
introduction of viral adventitious agents and to ensure microbial safety of tisagenlecleucel are 

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in place in compliance with principles of good manufacturing practices and regulatory 
guidelines. 
The risk associated with tisagenlecleucel is considered low.  
4.5.2.7 
Decrease in cell viability due to inappropriate handling of the product 
Inappropriate handling of the manufactured product including transport, storage in addition to 
thawing and standing time prior to infusion may result in a decrease of viable cells. This may 
impact the efficacy and safety of tisagenlecleucel. Qualified center personnel must follow 
appropriate protocols for product handling to receive, thaw, and infuse the finished 
tisagenlecleucel product. Please refer to the 
 
 
4.5.3 
Other risks 
4.5.3.1 
Pregnancy, lactation, and effects on fertility 
No preclinical reproductive studies have been conducted with tisagenlecleucel to assess whether 
it can cause fetal harm when administered to a pregnant woman. The human placenta forms an 
incomplete barrier for blood cells, allowing bidirectional passage of nucleated blood cells. 
Circulating maternal cells transfer to the fetus during pregnancy, where they may integrate with 
the fetal immune and organ systems, creating a state of maternal microchimerism (MMc) 
(Loubiere et al 2006, Stevens 2016). Hence, there is a potential risk that immunologically active 
maternal tisagenlecleucel positive T cells may cross the placenta.  Currently, the potential 
impact on the offspring’s B cells such as inducing B-cell lymphocytopenia or other potential 
toxicities such as effects on the development of autoimmune disease is  not known.  
As it is also not known whether tisagenlecleucel can cause fetal harm when administered to a 
pregnant woman or can affect reproduction capacity, tisagenlecleucel should not be 
administered to pregnant women and care should be taken to avoid conceptions. 
Therefore, women of child bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, and sexually active males are excluded from clinical trials with 
tisagenlecleucel unless they use adequate contraception. No data are currently available to 
determine the duration of contraception after receiving tisagenlecleucel. 
WOCBP and sexually active males must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirements outlined 
in the exclusion criteria.  WOCBP and sexually active males who receive tisagenlecleucel must 
adhere to contraception requirements for at least 12 months following tisagenlecleucel infusion 
and until CAR T cells are no longer present by qPCR on two consecutive tests. The qPCR test 
results will be available upon request. For patients who move to long term additional follow-up 
after tisagenlecleucel infusion please refer to Table 8-12 for unscheduled qPCR collections for 
the purposes of determining when contraception requirements will end. In addition, male 
participants must not donate sperm and female patients must not donate oocytes. If there is any 
question that the participant will not reliably comply, they should not be entered or continue in 
the study. 

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There is no information regarding the presence of tisagenlecleucel in human milk, the effect on 
the breast-fed child or the effects of tisagenlecleucel on milk production. Nursing women are 
excluded from participation in this study. 
4.5.3.2 
Risks associated and with standard of care immunochemotherapy 
The toxicities of SOC treatment are widely described in Gisselbrecht et al (2010), Crump et al 
(2014), Tilly et al (2015), Van den Neste et al (2016), Van Imhoff et al (2017), Van den Neste et 
al (2017). Preventive measures, monitoring and management of toxicities should be managed 
as per local standard of care and the locally approved labels, including contraception 
requirements, contraindications, use of concomitant medication, special warnings and 
precautions. 
5 
Population 
The target population consists of adult participants with aggressive NHL who are refractory or 
relapsed within 365 days of their last dose of first line immunochemotherapy and eligible for 
stem cell transplant (SCT). Approximately 318 participants will be randomized for treatment. 
It is anticipated that the life expectancy of randomized patients is at least 12 weeks. 
The investigator or designee must ensure that only participants who meet all the following 
inclusion and none of the exclusion criteria at screening are offered treatment in the study. 
Central lab must be used to confirm eligibility of all lab parameters listed in Section 5.1 and 
Section 5.2. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Patients must be ≥18 years of age at the time of informed consent form (ICF) signature. 
3. Histologically confirmed (by local histopathological assessment), aggressive B-cell NHL 
at relapse/progression or PR after front line therapy.  For patients with 
relapse/progression, if biopsy after relapse/progression is not available or it is not 
clinically feasible to obtain a new biopsy, an archival tumor biopsy from the initial 
diagnosis may be submitted.  For patients in PR  after at least 6 cycles of first line 
treatment, a new biopsy must be submitted. (Refer to Section 8.5.3). Aggressive B-cell 
NHL is heretofore defined by the following list of subtypes (Swerdlow et al 2016): 
• DLBCL, NOS 
• FL grade 3B, 
• Primary mediastinal large B cell lymphoma (PMBCL), 
• T cell rich/histiocyte rich large B cell lymphoma (T/HRBCL), 
• DLBCL associated with chronic inflammation, 
• Intravascular large B-cell lymphoma, 
• ALK+ large B-cell lymphoma, 

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• B-cell lymphoma, unclassifiable, (with features intermediate between DLBCL and 
classical HL), 
• High grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, 
• High grade B-cell lymphoma, NOS 
• HHV8+ DLBCL, NOS 
• DLBCL transforming from follicular lymphoma 
• DLBCL transforming from marginal zone lymphoma 
• DLBCL, leg type 
4. Relapse or progression within 365 days from last dose of anti-CD20 antibody and 
anthracycline containing first line immunochemotherapy or refractory (have not achieved 
a CR). 
5. Patient is considered eligible for autologous HSCT as per local investigator assessment. 
Note: Intention to transplant and type of HDCT regimen will be documented in the IRT 
system  
6. Disease that is both active on PET scan (defined as Deauville score of 4 or 5) and 
measurable on CT scan, defined as: 
• Nodal lesions >15 mm in the long axis, regardless of the length of the short axis, 
and/or 
• Extranodal lesions (outside lymph node or nodal mass, but including liver and 
spleen) >10 mm in long AND short axis 
7. ECOG performance status 0 or 1 
8. Adequate organ function: 
a. Renal function defined as: 
• Serum creatinine of ≤1.5 x ULN, OR eGFR ≥ 60 mL/min/1.73 m2 
b. Hepatic function defined as: 
• ALT and AST ≤ 5 × ULN 
• Total Bilirubin ≤1.5 × ULN with the exception of patients with Gilbert syndrome 
who may be included if their total bilirubin is ≤3.0 × ULN and direct bilirubin 
≤1.5 × ULN 
c. Hematologic Function (regardless of transfusion) defined as: 
Absolute neutrophil count (ANC) >1000/mm3Only for patients with non-historical 
leukapheresis:  
• 
Absolute lymphocyte count (ALC) >300/mm3 or 
• 
Absolute number of CD3+ T cells >150/mm3 
• Platelets ≥50,000/mm3 
• Hemoglobin >8.0 g/dl 
d. Adequate pulmonary function defined as: 
• No or mild dyspnea (≤ Grade 1) 
• Oxygen saturation measured by pulse oximetry > 90% on room air 

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• Forced expiratory volume in 1 s (FEV1) ≥50% or carbon monoxide diffusion test 
(DLCO) ≥50% of predicted level 
9. Must have a leukapheresis material of non-mobilized cells available for manufacturing. 
Note: Please refer to Section 6.2.2, Section 8.1 (Leukapheresis) for prohibited 
concomitant medications and washout times to ensure adequate collection as well as the 
 for specific 
collection procedures. 
5.2 
Exclusion criteria 
1. Epstein Barr Virus positive (EBV+) DLBCL, NOS, Richter’s transformation, and Burkitt 
lymphoma, and primary DLBCL of CNS. 
2. Prior treatment with anti-CD19 therapy, adoptive T cell therapy, or any prior gene therapy 
product 
3. Treatment with any systemic lymphoma-directed second line anticancer therapy prior to 
randomization. Only steroids and local irradiation are permitted for disease control. 
4. Active CNS involvement by disease under study are excluded, except if the CNS 
involvement has been effectively treated  and local treatment was >4 weeks before 
randomization 
5. Prior allogeneic HSCT 
6. Investigational medicinal product (IMP) within the last 30 days prior to screening Note: 
IMPs should not be used at any time while on study until the first progression following 
tisagenlecleucel infusion 
7. Presence of active hepatitis B or hepatitis C  (in Section 16.1 Appendix 1). 
8. HIV positive patients. 
9. Clinically significant active infection confirmed by clinical evidence, imaging, or positive 
laboratory tests (e.g.,  blood cultures, PCR for DNA/RNA,  etc.) 
10. Any of the following cardiovascular conditions: 
a. Unstable angina, myocardial infarction, coronary artery bypass graft (CABG), or 
stroke within 6 months prior to screening, 
b. LVEF <45% as determined by ECHO or MRA or MUGA at screening. 
c. NYHA functional class III or IV (Chavey et al 2001), at screening or within the past 
12 months. 
d. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II) 
and third degree AV block, unless adequately controlled by pacemaker implantation. 
e. Resting QTcF ≥450 msec (male) or ≥460 msec (female) at screening or inability to 
determine the QTcF interval 
f. Risk factors for Torsades de Pointes (TdP), including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically significant/ 
symptomatic bradycardia, or any of the following: 
i. Long QT syndrome, family history of idiopathic sudden death or congenital long 
QT syndrome 

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11. Concomitant medication(s) with a “Known Risk of Torsades de Pointes” per 
crediblemeds.org that cannot be discontinued or replaced by safe alternative 
medicationPrevious or concurrent malignancy except for curatively treated non-melanoma 
skin cancers, in situ carcinoma (e.g. cervix, breast, bladder, prostate), and cancers in 
complete remission  for at least 3 years and without evidence of recurrence  
12. Hypersensitivity to the excipients of tisagenlecleucel or to any other drug product as 
advised for administration in the study protocol (e.g. lymphodepleting agents, 
tocilizumab) 
13. Active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré 
Syndrome (GBS), Amyotrophic Lateral Sclerosis (ALS)) and clinically significant active 
cerebrovascular disorders (e.g., cerebral edema, posterior reversible encephalopathy 
syndrome (PRES)) 
14. Pregnant or nursing (lactating) women 
 
Note: Women of child-bearing potential must have a negative serum pregnancy test 
performed within 24 hours before leukapeheresis 
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
starting from the time of informed consent form (ICF) signature and for: 
•  at least 12 months after the tisagenlecleucel infusion and until CART cells are no 
longer present by qPCR on two consecutive tests for patients in Arm A or patients 
who crossover.  
• a duration according to local label and physician recommendations for patients 
randomized to Arm B (SOC).  Furthermore, patients may need to also add barrier 
contraception methods if required by the local label.    
Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception. 
 
• In case of use of oral contraception women should have been stable on the same 
pill for a minimum of 3 months before taking study treatment. 
• Women are considered post-menopausal and not of child bearing potential if they 
havehad 12 months of natural (spontaneous) amenorrhea with an appropriate 

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clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy), total 
hysterectomy or bilateral tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child 
bearing potential. 
 
Note: If local regulations deviate from the contraception methods listed above to 
prevent pregnancy, local regulations apply and will be described in the ICF. 
In addition, participants must not donate oocytes.  
16. Sexually active males who do not use a condom during intercourse starting from the time 
of ICF signature and for:  
• at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no 
longer present by qPCR on two consecutive tests for patients in Arm A or patients 
who crossover.  
• a duration according to local label and physician recommendations for patients 
randomized to Arm B (SOC) 
A condom is required for all sexually active male participants to prevent them from fathering a 
child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
participants must not donate sperm. 
17. Patients who, in the investigator’s judgment and/or according to clinical standards, have a 
contradiction to any study procedure or have any other medical condition  that may put the 
patient at unacceptable risk.  
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible participants. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
Investigational Drug 
Bridging Therapy - For patients randomized to Arm A (tisagenlecleucel) who require optional 
bridging therapy, the investigator must choose one of the four regimens described under the 
control arm. Patients that crossover to arm A after failing treatment with SOC chemotherapy 
may use any type of bridging therapy at the investigator’s discretion and are not restricted to 
the four bridging therapies specified in the protocol in Section 3 and Section 6.1.1 Control Drug. 
Tisagenlecleucel - Tisagenlecleucel is an autologous cellular immunotherapy product that is 
comprised of CD3+ T cells that have undergone ex vivo T cell activation, gene modification, 
expansion and formulation in infusible cryomedia.   
For details please refer to the [Investigational Product Handling Manual and Investigational 
Product Transport Manual] and the current version of the [Tisagenlecleucel Investigator’s 
Brochure]. 

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Control Drug (Standard of Care) 
For patients randomized to Arm B (SOC therapy), investigators are to choose one of the 
following regimens.  Immunochemotherapy should start as soon as possible after randomization, 
and no later than 7 days after randomization.   
Rituximab (375 mg/m2 starting on the first day prior to chemotherapy on each cycle), 
• R-ICE: etoposide (100 mg/m2 per day) on days 1 through 3, ifosfamide (5,000 mg/m2) 
infused continuously for 24 hours on day 2 with mesna, carboplatin (area under the curve 
(AUC) = 5; maximum dose, 800 mg) on day 2 (Kewalramani et al 2004). Cycles repeated 
every 21 days. 
• R-DHAP: cisplatin (100 mg/m2) on day 1 via continuous 24-hour infusion, followed on 
day 2 by cytarabine (2 g/m2) in a 3-hour infusion repeated after 12 hours, dexamethasone 
(40 mg/d) for 4 consecutive days (Velasquez et al 1998). Cycles repeated every 21 days. 
• R-GDP: gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 75 mg/m2 on day 1, 
dexamethasone (40 mg/d) for 4 consecutive on days 1 through 4 (Baetz et al 2003). Cycles 
repeated every 21 days. 
• R-GemOx - gemcitabine and oxaliplatin at the doses of 1000 mg/m2 and 100 mg/m2, 
respectively, on day 2. (Mounier et al 2013). Cycles repeated every 15 days. 
For patients randomized to Arm B (SOC therapy), a change in immunochemotherapy is required 
if the patient achieves a response which is not sufficient to allow HSCT, and change in treatment 
is in the best interest of the patient. Investigators should choose one of the four regimens above 
in an effort to achieve a response that allows the patient to proceed to transplant.  Patients who 
are deemed no longer eligible for HSCT (e.g. adverse event, poor tolerance to 
immunochemotherapy, 
worsening 
of 
performance 
status) 
after 
two 
cycles 
of 
immunochemotherapy may proceed to treatment with ibrutinib or lenalidomide. 
For patients proceeding to autologous HSCT, mobilization of stem cells will be performed 
during cycle 2 and/or cycle 3 of salvage therapy according to local policy using granulocyte-
colony stimulating factor (G-CSF). In the case of a mobilization failure, additional attempts at 
mobilization or operative bone marrow harvest can be performed according to local policy. 
Leukapheresis and cryopreservation will be performed according to local procedures. 
Participants with CR or PR after the 2 cycles (SOC 1) of salvage therapy and adequate stem 
cell collection may receive an optional 3rd cycle of salvage therapy before transplant, or may 
proceed directly to transplant after 2 cycles.  At the investigator’s discretion, patients in PR may 
change to one of the other 4 regimens. Every effort should be attempted to have SOC patients 
proceed to transplant, if deemed in the best interest of the patient. Patients should receive high 
dose chemotherapy approximately 4-6 weeks after the last cycle of salvage therapy.   
In countries where the drugs are available, and can be used for this indication, the BEAM 
regimen is to be used. BEAM is recommended to be dosed as follows (days shown are relevant 
to HSCT): 
• Carmustine 300 mg/m2 i.v., Day -6, 
• Etoposide 200 mg/m2 i.v., Day -5, -4, -3, -2 
• Cytarabine 200 mg/m2 every 12 hours (q12hr, 2 doses) i.v., Day -5, -4, -3, -2, 

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• Melphalan 140 mg/m2 i.v., Day -1 
If BEAM is not used, the HDCT regimen will be in accordance with local policy. Before any 
participants are randomized, the HDCT regimen must be documented in the institutional 
treatment policy. The procedure for HSCT will be in accordance with local policy. Prophylaxis 
of CNS disease using intrathecal dosing of cytotoxic regimens is permitted and will be 
according to local policy. 
The date of HSCT will be recorded in IRT. 
6.1.2 
Tisagenlecleucel pre-infusion evaluation 
If any of the following criteria is met, tisagenlecleucel infusion must be delayed until resolution.   
If the period of delay is more than 4 weeks from completing lymphodepletion and there is no 
significant cytopenia (see Section 6.1.4.2) lymphodepletion should be repeated, and these 
criteria will need to be re-checked prior to tisagenlecleucel infusion.  In case of any doubt on 
fulfillment of pre-infusion evaluation criteria, the medical monitor may be contacted.   
The investigator will be required to sign the tisagenlecleucel pre-infusion checklist stating 
fulfillment of pre-infusion criteria within 24 hours prior to tisagenlecleucel infusion. Criteria 
must continue to be monitored after the form is signed until the time of infusion in case of any 
worsening of status which would preclude tisagenlecleucel infusion. 
The tisagenlecleucel pre-infusion criteria/checklist is found below: 
 
1. Rapidly progressing primary disease: Not limited to radiological evidence, but also 
including signs and symptoms of disease progression (i.e. significant rising LDH values) 
Particular attention must be placed on any significant rising of LDH value and on 
declining ECOG PS: e.g. patients with an ECOG PS of 3 must not be infused, while 
patients with ECOG PS of 2 must have their full clinical picture considered before 
proceeding to infusion 
2. Clinical evidence of CNS involvement by primary disease 
3. Laboratory abnormalities that, in the opinion of the investigator, may impact participant 
safety or the participants’ ability to receive tisagenlecleucel.  
4. Following clinical abnormalities: 
• Pulmonary: Requirement for supplemental oxygen to keep saturation greater than 
90% or presence of progressive radiographic abnormalities on chest x-ray 
• Cardiac arrhythmia not controlled with medical management 
• Hypotension requiring vasopressor support 
• Clinically significant active infection confirmed by clinical evidence, imaging, or 
positive laboratory tests (e.g.,  blood cultures, PCR for DNA/RNA, , etc.) 
Note: HBV, HCV, and HIV must be repeated, if the interval between testing prior to 
lymphodepletion and tisagenlecleucel infusion exceeds 8 weeks.   
5. A significant change in clinical status that would, in the opinion of the investigator, 
increase the risk of adverse events associated with tisagenlecleucel.  
6. Toxicities from chemotherapy (including lymphodepletion) 

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7. Prohibited concomitant medications as described in Section 6.2.2. 
8. Positive influenza test within 10 days prior to tisagenlecleucel infusion (please refer to 
Table 8-2). Note: If the participant 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 participant must complete their 10 day 
preventative treatment course prior to receiving tisagenlecleucel. The test does not need 
to be repeated prior to tisagenlecleucel infusion however if flu-like or respiratory signs 
and symptoms are present, tisagenlecleucel infusion should be delayed until the 
participant is asymptomatic. For participants residing in the northern hemisphere (e.g. 
United States, Canada, Europe and Japan), influenza testing is required during the months 
of October through May (inclusive). For participants residing in the southern hemisphere 
such as Australia, influenza testing is required during the months of April through 
November (inclusive). For participants with significant international travel, both calendar 
intervals above may need to be considered. 
9. Women of child-bearing potential must have a negative serum pregnancy test performed 
within 24 hours prior to tisagenlecleucel infusion.  
 
6.1.3 
Additional safety procedures prior to tisagenlecleucel infusion 
Tumor lysis syndrome (TLS) 
The risk of tumor lysis syndrome (TLS) is dependent on disease burden. Participants will be 
closely monitored both before and after lymphodepleting chemotherapy and the 
tisagenlecleucel infusion, including blood tests for potassium and uric acid. Participants with 
elevated uric acid or high tumor burden will receive prophylactic allopurinol, or a non-
allopurinol alternative (e.g. febuxostat). 
Infections 
Infection prophylaxis with regard to lymphodepletion and other additional treatments should 
follow local guideline. Prior to tisagenlecleucel infusion, infection prophylaxis should follow 
standard guidelines based on the degree of preceding immunosuppression. In patients with low 
immunoglobulin levels pre-emptive measures such as infection precautions, antibiotic and 
antifungal prophylaxis and immunoglobulin replacement should be taken according to age and 
standard guidelines. 
Cytokine Release Syndrome 
Prior to tisagenlecleucel infusion 2 doses of tocilizumab per participant (for the first 3 weeks 
after tisagenlecleucel infusion) must be confirmed as available by the local pharmacy and must 
be available for infusion within 2 hours of physician order for the management of CRS related 
adverse events (see Section 6.6.2.1 for details).  
Premedication 
Adverse effects from T cell infusions can include fever, chills and/or nausea. All participants 
should be pre-medicated with acetaminophen (paracetamol) and diphenhydramine or another 
H1 antihistamine approximately 30 to 60 minutes prior to infusion. These medications can be 

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repeated every 6 hours as needed. Non-steroidal anti- inflammatory medication may be 
prescribed if the participant continues to have fever not relieved with acetaminophen 
(paracetamol). Steroids should NOT be used for premedication. It is recommended that 
participants NOT receive systemic corticosteroids other than physiologic replacement, except 
for serious emergency, since this may have an adverse effect on tisagenlecleucel cell expansion 
and function. For more information on managing toxicities related to tisagenlecleucel treatment, 
please refer to Section 6.6.2. 
Supportive care 
Local guidelines will be followed for the supportive care of immunosuppressed and 
chemotherapy treated participants. All blood products administered should be irradiated. For 
details about prohibited concomitant medications and non-drug therapies please refer to Section 
6.2.2. 
6.1.4 
Additional study treatments 
6.1.4.1 
Optional bridging therapy 
For patients randomized to Arm A (tisagenlecleucel), there will be an estimated delay of 
treatment while tisagenlecleucel is manufactured and before it is available on-site. During this 
time, the treating physician will have the option to treat the patient according to local guidance, 
product label, and the medical condition of the patient. If bridging therapy is prescribed, the 
investigator should use one of the four prescribed regimens in Section 6.1.1.  During this 
optional bridging therapy period, all safety evaluations should follow the visit evaluation 
schedule and local standard of care guidelines and be captured in source documentation or 
database where denoted by Table 8-2. 
Patients that crossover to arm A after failing treatment with SOC chemotherapy may use any 
type of bridging therapy at the investigator’s discretion and are not restricted to the four bridging 
therapies specified in the protocol in Section 3 and Section 6.1.1. 
If optional bridging therapy is interrupted or delayed, the reason must be documented in source 
files and captured in the appropriate eCRF. 
The start of bridging chemotherapy visit start should be registered in IRT. 
6.1.4.2 
Lymphodepleting chemotherapy 
Prior to tisagenlecleucel infusion, each patient should undergo lymphodepletion, unless the 
patient has a significant cytopenia (e.g. WBC <1,000 cells/µL, absolute lymphocyte count 
<200/µL) or any condition that, in the investigator’s opinion, precludes lymphodepletion. 
If lymphodepleting chemotherapy is NOT required, a visit should still occur during this time 
window, and required assessments according to Table 8-2 should be completed. 
The lymphodepleting chemotherapy start date should be registered in IRT. 
Lymphodepletion should start within one week before tisagenlecleucel infusion, which means 
that tisagenlecleucel will be infused 2 to 6 days after lymphodepletion is completed depending 
on the lymphodepleting regimen.  The availability of tisagenlecleucel must be confirmed prior 
to starting the lymphodepleting chemotherapy. Lymphodepletion may be repeated in case 

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tisagenlecleucel has been delayed by more than 4 weeks (see Section 6.1.4.1). The preferred 
regimen is as follows: 
• Fludarabine (25 mg/m2 intravenously [i.v.] daily for 3 doses) 
• Cyclophosphamide (250 mg/m2 i.v. daily for 3 doses starting with the first dose of 
fludarabine) 
Note: Adverse effects of fludarabine can include severe nervous system events of seizure, 
agitation, blindness, coma and death. Instances of life-threatening and sometimes fatal 
autoimmune 
phenomena 
such 
as 
hemolytic 
anemia, 
autoimmune 
thrombocytopenia/thrombocytopenic purpura (ITP), Evans syndrome, and acquired hemophilia 
have been reported to occur after one or more cycles of treatment with fludarabine phosphate 
injection. It may also severely decrease bone marrow function (Fludarabine full prescribing 
information). 
Cyclophosphamide toxicities include cardiac dysfunction. Acute cardiac toxicity has been 
reported with doses as low as 2.4 g/m2 to as high as 26 g/m2, usually as a portion of an intensive 
antineoplastic multi-drug regimen or in conjunction with transplantation procedures. In a few 
instances with high doses of Cyclophosphamide, severe, and sometimes fatal, congestive heart 
failure has occurred after the first Cyclophosphamide dose. Severe marrow suppression is seen 
and occasional anaphylactic reactions have been reported. Hemorrhagic cystitis, pulmonary 
toxicity (pneumonitis, pulmonary fibrosis and pulmonary veno-occlusive disease leading to 
respiratory failure) and veno-occlusive liver disease may occur (Cyclophosphamide full 
prescribing information). 
If 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: Adverse effects of bendamustine include severely decreased bone marrow function, 
nausea, vomiting and diarrhea; jaundice may occur, including without other signs of hepatic 
dysfunction. 
Fatal 
and 
serious 
cases 
of 
liver 
injury 
have 
been 
reported 
(Bendamustine full prescribing information). 
No other regimen is allowed for lymphodepletion. 
Female patients of childbearing potential must have a negative serum pregnancy test within 24 
hours prior to the start of lymphodepleting therapy. If the patient does not require 
lymphodepleting therapy, she should still have a negative pregnancy test at the required visit 
that takes place within one week from tisagenlecleucel infusion. 
6.1.5 
Treatment arms 
Participants will be assigned at the randomization visit to one of the following 2 treatment 
arms/groups in a ratio of 1:1. 
• Arm A: A single dose of 0.6 to 6.0 × 108 of CAR positive viable autologous 
tisagenlecleucel transduced T cells administered via intravenous infusion. The patient may 
also have up to 3 days of lymphodepleting chemo prior to tisagenlecleucel infusion as 
described in Section 6.1.4.1. Optional platinum based bridging immunochemotherapy can 

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be given during the time period while tisagenlecleucel is being manufactured (after 
randomization and prior to lymphodepleting chemotherapy) as per investigator assessment 
as described in Section 6.1.4.2. 
• Arm B: SOC immunochemotherapy including, in suitable patients, autologous HSCT, as 
per local guidelines. Ibrutinib and lenalidomide are also allowed for patients who are 
deemed no longer eligible for HSCT (e.g. adverse event, poor tolerance to 
immunochemotherapy, worsening of performance status) after two cycles of 
immunochemotherapy . . 
6.1.6 
Treatment duration 
For patients randomized to Arm A, a single dose of tisagenlecleucel will be administered. Prior 
to tisagenlecleucel infusion, patients may receive optional bridging chemotherapy while 
tisagenlecleucel is manufactured, and then may receive lymphodepleting chemotherapy as 
outlined in Section 6.1.4.1. 
Patients randomized to Arm B will continue to receive immunochemotherapy as per local 
guidelines or until patients undergo autologous HSCT. 
Patients will continue treatment in Arm B until they experience any of the following: 
• Disease progression or continuous SD at or after the week 12 (± 1 week) assessment 
(confirmed by the BIRC). 
 
Note: All patients who have disease progression or continuous SD at or after the week 12 
(±1week) assessment determined by the local investigator will require an expedited tumor 
response review (within 5 business days) by the BIRC. SOC chemotherapy will continue 
until progressive disease or continuous SD at or after the week 12 (±1w) assessment has 
been confirmed by the BIRC if clinically acceptable. In cases of discordance (i.e., BIRC 
does not confirm the site’s assessment) for as long as it is clinically acceptable the patient 
should not be discontinued from study treatment. 
• Start of a new experimental (i.e., patient is enrolled in a clinical trial) anti-cancer therapy 
after the week 12 (±1 week) assessment 
• Pregnancy 
• Treatment is discontinued at the discretion of the investigator or patient 
• Lost to follow-up 
• Death 
• Study terminated by Sponsor 
Patients, that have discontinued early for reasons other than BIRC confirmed PD or continuous 
SD at or after the week 12 (± 1week) assessment, loss to follow-up, death, or study termination, 
will continue efficacy assessments as per protocol until BIRC confirmation of EFS event. 

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6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
Clinically significant prescription and nonprescription medication, excluding vitamins, and 
herbal and nutritional supplements, and procedure-related (inpatient or outpatient) medications 

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taken by the participant during the 30 days prior to screening will be recorded, as required by 
the modified reporting criteria in Section 16.3 Appendix 3. 
At every visit following the screening visit up to the end of the study, 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 Section 16.3 Appendix 3. 
Modified collection of concomitant medication information during these periods is designed to 
capture tisagenlecleucel -related toxicity, severity, interventions and response/resolution 
following intervention. Any additions, deletions, or changes of these medications will be 
documented. A safety follow-up visit should occur 8 weeks after last treatment administration 
or prior to starting new anticancer therapy, whichever occurs first. After this safety follow-up 
visit occurs, for patients who receive tisagenlecleucel concomitant medication collection will 
be modified as outlined in Section 16.3 Appendix 3 and CRF Completion Guidelines (CCGs). 
Patients who do not receive tisagenlecleucel do not require reporting of concomitant 
medications after the safety follow-up visit. Modified collection of concomitant medication 
information during these periods is designed to capture tisagenlecleucel -related toxicity, 
severity, interventions and response/resolution following intervention. Any additions, deletions, 
or changes of these medications will be documented. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
randomizing a participant or allowing a new medication to be started. If the participant is 
already enrolled, contact Novartis to determine if the participant should continue participation 
in the study. Drugs that cause QTc prolongation and/or “Torsades de Pointes” per 
crediblemeds.org should be used only if clinically indicated as per Investigator’s discretion. 
 
 

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6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is first enrolled for screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the trial. The Participant 
No. consists of the Center Number (Center No.) (as assigned by Novartis to the investigative 
site) with a sequential participant number suffixed to it, so that each participant is numbered 
uniquely across the entire database. Upon signing the informed consent form, the participant is 
assigned to the next sequential Participant No. available. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the participant to register them into the IRT. Once assigned, the Participant No. 
must not be reused for any other participant and the Participant No. for that individual must not 
be changed, even if the participant is re-screened. If the participant fails to start treatment for 
any reason, the reason will be entered into the appropriate CRF page. 
6.3.2 
Treatment assignment, randomization 
The following methods have been used to minimize bias in treatment assignment. The 
randomization numbers will be generated using the following procedure to ensure that treatment 
assignment is unbiased and concealed from participants and investigator staff. A participant 
randomization list will be produced by the IRT provider, or by a delegate under Novartis 
supervision, using a validated system that automates the random assignment of participant 
numbers to randomization numbers. These randomization numbers are linked to the different 
treatment arms. 

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Randomization will be stratified by remission duration (refractory or relapse <6 months from 
last dose of first line immunochemotherapy vs. relapsed 6 to 12 months from last dose of first 
line immunochemotherapy),IPI (<2 vs. ≥2), and region (North America vs. Rest of World). IPI 
will be assessed as follows as shown in Table 6-1. 
For the purposes of stratification, refractory is defined as subjects who did not achieve CR on 
first line immunochemotherapy to current lymphoma. Refractory patients include any patient 
with biopsy-proven PR after 6 cycles of first line immunochemotherapy.   
For the purposes of stratification, relapsed is defined as subjects who had CR on first line 
therapy to current lymphoma and relapsed prior to the study.  
Table 6-1 
Defined risk factors and risk groups of International Prognostic Index 
(IPI) 
Risk Factors 
• 
Age > 60 years 
• 
Performance Status 2 - 4 
• 
Tumor Stage III or IV 
• 
LDH > 1xULN 
• 
Extranodal lesions >1 
Number of Risk Factors 
Risk Group 
0-1 
1 – low 
2 
2 – low intermediate 
3 
3 – high intermediate 
4-5 
4 – high 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding 
Treatment will be open to participants, investigator staff, persons performing the assessments, 
and the CTT. 
6.5 
Dose modification 
Tisagenlecleucel is administered as a single dose and therefore dose modification is not 
applicable as participants will receive a single intravenous (i.v.) infusion of 0.6 – 6.0 x 108 
CAR-positive viable T cells. 
For patients randomized to SOC therapy or patients receiving optional bridging chemotherapy, 
modifications to the dose based on individual patient tolerability and institution’s policy are 
allowed.  Modifications/substitutions to the drug combinations of each regimen as per local 
clinical practice may be made only after discussion with the Novartis global medical 
representative (eg. substituting R-DHAOX for R-DHAP)). 
6.5.1 
Follow-up for toxicities 
For patients randomized to SOC the investigator should monitor any organ toxicities of SOC 
and take according measures as per local labeling and apply local standard of medical practice. 

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6.5.1.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential drug induced liver injury (DILI), and should be considered as clinically 
important events. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and TBIL 
value; participants meeting any of the following criteria will require further follow-up as 
outlined below: 
• For participants with normal ALT and AST and TBIL value at baseline: AST or ALT > 
3.0 x ULN combined with TBIL > 2.0 x ULN 
• For participants with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as alkaline phosphatase (ALP) elevation > 2.0 x ULN with R value < 2 in participants without 
bone metastasis, or elevation of ALP liver fraction 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 the absence of cholestasis, these participants should be immediately discontinued from study 
treatment, and repeat liver function test (LFT) as soon as possible, preferably within 48 hours 
from the awareness of the abnormal results. The evaluation should include laboratory tests, 
detailed history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/international normalized ratio (INR) 
and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain cellular kineticsample, as close as possible to last dose of study treatment 
5. Additional testing for other hepatotropic viral infection (cytomegalovirus (CMV), EBV or 
herpes simplex virus (HSV), autoimmune hepatitis or liver biopsy may be considered as 
clinically indicated or after consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of serious adverse event (SAE) and reported as SAE using 
the term “potential drug-induced liver injury”. All events should be followed up with the 
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6.6 
Additional treatment guidance 
6.6.2 
Recommended treatment for adverse events 
Participants infused with tisagenlecleucel are at risk of developing a number of severe and 
serious AEs that are related either to tisagenlecleucel itself, other therapies (e.g. 
immunochemotherapy) and conditions concurrent with the participant’s primary disease. 

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Following tisagenlecleucel infusion, participants can be discharged from the treating site only 
if, in the investigator’s opinion, they do not demonstrate any adverse events or worsening of 
underlying diseases. This chapter describes the management of such AEs. 
Drug and non-drug therapies used to treat AEs must be recorded on appropriate CRFs. 
6.6.2.1 
Cytokine Release Syndrome (CRS) 
Ensure that 2 doses of tocilizumab per patient are available on site prior to infusion of 
tisagenlecleucel. Hospitals should have timely access to additional doses of tocilizumab. 
Supportive care, tocilizumab, and corticosteroids have been used for effective management of 
CRS. Prompt responses to tocilizumab have been seen in most participants. See full local 
prescribing information to use tocilizumab.  
Identify CRS based on clinical presentation (see Section 4.5.1.1). Evaluate for and treat other 
causes of fever, hypoxia, and hypotension. Although signs and symptoms of CRS occur in most 
cases within 1-14 days after tisagenlecleucel infusion, monitor patients for signs or symptoms 
of CRS for at least 4 weeks after treatment with tisagenlecleucel. Counsel patients to seek 
immediate medical attention should signs or symptoms of CRS occur at any time. Participants 
will be required to remain proximal to the treating site for the first 4 weeks. 
At the first sign of CRS, immediately evaluate patient for hospitalization and institute treatment 
with supportive care, tocilizumab and/or corticosteroids as indicated. 
A detailed treatment algorithm for the management of CRS and definition of high dose 
vasopressors (Lee et al 2014) is presented below in Table 6-2 and Table 6-3 respectively. The 
CRS management algorithm is a guideline and the investigator may use discretion or modify 
the treatment approach as needed for an individual participant.   
Table 6-2 
CRS management 
CRS severity  
Symptomatic 
treatment 
Tocilizumab  
Corticosteroids 
Mild symptoms requiring 
symptomatic treatment 
only e.g. low fever, 
fatigue, anorexia, etc. 
Exclude other causes 
(e.g. infection) and treat 
specific symptoms with 
e.g. antipyretics, anti-
emetics, anti-
analgesics, etc.  
If neutropenic, 
administer antibiotics 
per local guidelines 
Not applicable 
Not applicable 
Symptoms requiring 
moderate intervention: 
- high fever 
- hypoxia 
- mild hypotension 
Antipyretics, oxygen, 
intravenous fluids 
and/or low dose 
vasopressors as 
needed. 
If no improvement after 
symptomatic treatment 
administer tocilizumab i.v. 
over 1 hour:    
- 8 mg/kg (max. 800 mg)     
   if body weight  ≥ 30 kg  
- 12 mg/kg if body weight     
   <30 kg   
If no improvement within 
12-18 hours of 
tocilizumab, administer 
a daily dose of 2 mg/kg 
i.v. methylprednisolone 
(or equivalent) until 
vasopressor and oxygen 
no longer need, then 
taper** 
Symptoms requiring 
aggressive intervention:  
Hypoxia requiring high-
flow oxygen 
supplementation or 
High-flow oxygen 
Intravenous fluids and 
high-dose* 
vasopressor/s 

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CRS severity  
Symptomatic 
treatment 
Tocilizumab  
Corticosteroids 
Hypotension requiring 
high-dose or multiple 
vasopressors 
Treat other organ 
toxicities as per local 
guidelines 
If no improvement,  repeat 
every 8 hours (max total of 4 
doses)** 
Life-threatening 
symptoms:               
− Hemodynamic                   
instability despite i.v. 
fluids and vasopressors 
− Worsening respiratory     
distress 
− Rapid clinical 
deterioration 
Mechanical ventilation 
Intravenous fluids and 
high-dose* 
vasopressor/s 
Treat other organ 
toxicities as per local 
guidelines 
*Refer to Table 6-3 for definition of high dose vasopressors 
** If no improvement after tocilizumab and steroids, consider other anti-cytokine and anti-T cell therapies. These 
therapies may include siltuximab (11 mg/kg i.v. over 1 hour), high doses of steroids (e.g. high dose 
methylprednisolone or equivalent steroid dose according to local ICU practice) cyclophosphamide, anti-thymocyte 
globulin (ATG) or alemtuzumab. 
Table 6-3 
Definition of high dose vasopressor use 
Vasopressor 
Dose to be given for ≥ 3 hours 
Norepinephrine monotherapy 
≥ 20 mcg/min 
Dopamine monotherapy 
≥ 10 mcg/kg/min 
Phenylephrine monotherapy 
≥ 200 mcg/min 
Epinephrine monotherapy 
≥ 10 mcg/min 
If on vasopressin 
Vasopressin + norepinephrine equivalent (NE) of ≥ 10 mcg/min* 
If on combination vasopressors (not 
vasopressin) 
NE of ≥ 20 mcg/min* 
 Vasopressin and Septic Shock Trial (VASST) Norepinephrine Equivalent Equation: 
NE dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + [epinephrine (mcg/min)] + [phenylephrine 
(mcg/min) ÷10] (Lee et al 2014) 
Any therapies given for CRS need to be captured in the appropriate CRF. 
The management of CRS is based solely upon clinical parameters as described in Section 
4.5.1.1. 
 
. Cases of transient left ventricular dysfunction, as assessed by 
ECHO, have been reported in some 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. 
6.6.2.2 
Neurologic adverse events 
Neurologic events, primarily reflective of encephalopathy and delirium, may occur after 
tisagenlecleucel infusion. These present clinically as signs and symptoms of varying severity 
including: confusion, disorientation, agitation, aphasia, somnolence and tremors. In severe 
cases seizures, motor weakness, incontinence, impaired consciousness, increased intracranial 
pressure, and cerebral edema may be concurrent to, following the resolution or in the absence 
of CRS. Patients should be monitored for neurologic events, diagnostically worked-up and 

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managed depending on the underlying pathophysiology and in accordance to local standard of 
care. 
Evaluation: 
Thorough neurological examination, with frequent monitoring and determination of CTCAE 
v5.0 grading, as well as ASTCT ICANS Consensus Grading (Table 4-4) 
• Diagnostic work up to evaluate potential secondary causes: 
• Brain imaging (CT scan and/or MRI): to exclude intracranial hemorrhage, disease 
relapse, evidence suggestive of infection or cerebral edema. 
• Lumbar puncture for CSF evaluation, if applicable. 
• Chemistry laboratory testing 
• Electroencephalography (EEG) 
Management: 
• If the neurological event is concurrent with CRS please refer to Table 6-2. CRS algorithm 
table for treatment recommendation. 
• Consider anti-seizure medications (e.g. Levetiracetam) for patient at high risk (prior 
history of seizure) or administer in the presence of seizure 
• For encephalopathy, delirium or associated events: appropriate treatment and supportive 
care should be implemented as per local standard of care. In worsening events, consider a 
short course of steroids (Neelapu et al 2018, Teachey et al 2018) 
6.6.2.3 
Hypersenstivity including acute infusion reactions 
Patients should be monitored for signs and symptoms of hypersensitivity following initiation of 
tisagenlecleucel infusion and treated appropriately. Tisagenlecleucel is contraindicated in 
patients with known hypersensitivity to tisagenlecleucel or to any component of the product 
formulation. 
As appropriate, prophylactic medications should be administered to minimize the risk of 
immediate hypersensitivity including acute infusion reactions. It is recommended to pre-
medicate all patients with acetaminophen (paracetamol) and diphenhydramine or another H1 
antihistamine within approximately 30-60 minutes prior to tisagenlecleucel infusion. These 
medications can be repeated every 6 hours as needed. Non-steroidal anti-inflammatory 
medication may be prescribed for fever not responding to acetaminophen. Steroids should not 
be used for premedication. Systemic corticosteroids should only be used for severe conditions. 
Should emergency treatment be required in the event of life-threatening hypersensitivity or 
other infusion-related reaction, supportive therapy such as oxygen and drug treatment should 
be given according to local institutional guidelines. Patients should be evaluated and carefully 
monitored until complete resolution of signs and symptoms. 
6.6.2.4 
Tumor lysis syndrome (TLS) 
Patients should be closely monitored for signs and symptoms of TLS both before and after 
lymphodepleting chemotherapy and tisagenlecleucel infusion including relevant laboratory 
tests. To minimize risk of TLS, patients with elevated uric acid or high tumor burden should 

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receive allopurinol, or an alternative prophylaxis, prior to tisagenlecleucel infusion. Events 
should be managed according to local guidelines. 
6.6.2.5 
Infections 
Patients with active, uncontrolled infection should not start tisagenlecleucel treatment until the 
infection is resolved. 
Patients should be monitored for signs and symptoms of infection and treated appropriately. As 
appropriate, prophylactic antibiotics should be administered and surveillance testing prior to 
and during treatment with tisagenlecleucel should be employed. 
Institutional guidelines for vaccination (e.g. pneumococcus) should be followed before starting 
tisagenlecleucel therapy. As the lack of effective B cells after infusion makes the likelihood of 
a systemic infection considerable, vaccination with live virus vaccines should not be given for 
at least 6 weeks prior to the start of lymphodepleting chemotherapy, during tisagenlecleucel and 
until immune recovery following treatment with tisagenlecleucel. 
Any suspected cases of viral hepatitis or HIV should be referred to a specialist. 
In patients with low immunoglobulin levels preventive measures such as immunoglobulin 
replacement and rapid attention to signs and symptoms of infection should be implemented as 
per age and local specific guidelines. 
6.6.2.6 
Febrile neutropenia 
Febrile neutropenia (significantly decreased neutrophil count with fever) may develop in the 
course of chemotherapy (including lymphodepletion) and may be concurrent with CRS. A 
febrile participant should be evaluated for infection (Section 4.5.1.5) and CRS (Section 4.5.1.1) 
and managed appropriately with fluids, antibiotics, and supportive care, if applicable. 
In the event that the patient develops sepsis or systemic bacteremia following tisagenlecleucel 
cell infusion, appropriate cultures and medical management should be initiated. If a 
contaminated tisagenlecleucel cell product is suspected, the product can be retested for sterility 
using archived samples that are stored at the manufacturing site. 
6.6.2.7 
B cell depletion and/ or hypogammaglobulinemia 
Monitor immunoglobulin levels after treatment with tisagenlecleucel, use infection precautions 
including antibiotic prophylaxis and immunoglobulin replacement as appropriate and per local 
standard of care. 
In case of new or worsening symptoms suggestive of PML, consultation with a neurologist 
should be considered. 
6.6.2.8 
Hematopoietic cytopenias not resolved by day 28 post infusion 
Since myeloid growth factors, particularly granulocyte macrophage colony stimulating factor 
(GM CSF), have the potential to worsen CRS (if it occurs), these are not recommended during 
the first 3 weeks after tisagenlecleucel infusion or until CRS has resolved. 

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Haematopoietic cytopenias should be managed with standard measures of observation, blood 
product support growth factors and/or antibiotics as indicated and per local standard of care. 
6.6.2.9 
Replication competent lentivirus (RCL) production 
The lentiviral vector has been designed to minimize the probability non-homologous 
recombination, thereby preventing the generation of a RCL, however, this remains a theoretical 
possibility. It will be detected by blood specimen, e.g., using Vesicular Stomatitis 
Virus/Glycoprotein (VSV-G) quantitative PCR. If a positive RCL assay result is obtained from 
a participant, the Investigator will be informed and the participant rescheduled for a retest of 
the DNA test.  
Currently, it is not known, how to manage a participant with confirmed RCL and, therefore, 
should be addressed on a case by case basis. Some considerations are: 
• Intensive follow-up of the participant in consultation with gene therapy experts, study 
investigators, and Health Authorities 
• Inform local and country specific public health officials 
• Identify sexual partners and provide appropriate counseling and intervention 
6.6.2.10 Secondary malignancies including vector insertion site 
oligo/monoclonality) 
All secondary malignancy should be managed/treated according to current medical practice and 
local standard of care.  
For the follow-up of secondary malignancy, refer to Section 10.2.6. 
6.6.3 
Emergency breaking of assigned treatment code 
Since this is an open label study, this is not applicable. 
6.7 
Preparation and dispensation 
 
SOC immunochemotherapy should be handled as per local institutional guidance. 
6.7.1 
Handling of study treatment and additional treatment 
 
 
 
 
 
 
 
 
 

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6.7.1.3 
Handling of Standard of Standard of Care Therapy, Optional Bridging 
Chemotherapy, and Lymphodepleting Chemotherapy 
SOC therapy, optional bridging chemotherapy, and lymphodepleting chemotherapy should be 
handled and stored according to local guidelines and locally approved labels. The investigator 
must maintain an accurate record of dispensing of study treatment in a drug accountability log. 
Monitoring of drug accountability will be performed by monitors during site visits or remotely 
and at the completion of the trial. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved informed consent. 
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council on Harmonization (ICH) GCP guidelines and 

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regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed consent form suggested by the investigator must be agreed by Novartis before 
submission to the IRB/IEC. 
Information about common adverse effects already known about the investigational drug can 
be found in the Investigator's Brochure (IB) and the core data sheet (CDS) for marketed drugs. 
This information will be included in the participant informed consent and should be discussed 
with the participant during the study as needed. Any new information regarding the safety 
profile of the investigational drug that is identified between IB updates will be communicated 
as appropriate, for example, via an investigator notification (IN) or an aggregate safety finding. 
New information might require an update to the informed consent and then must be discussed 
with the participant. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval. 
8 
Visit schedule and assessments 
Four tables will be used to manage assessments for the entire study duration 
• Visit evaluation schedule from pre-screening to randomization (Table 8-1) 
• Visit evaluation schedule for Arm A (Table 8-2) 
• Visit evaluation schedule for Arm B (Table 8-3) 
• Visit evaluation schedule for patient who cross over from Arm B to Arm A (Table 8-4) 
Participants should be seen for all visits/assessments as outlined in the assessment schedule or 
as close to the designated day/time as possible. 
During the 1st month following tisagenlecleucel infusion, patients will undergo assessments as 
per Table 8-2 or Table 8-4. If requested by HA or EC/IRB or based on local practice, more 
frequent monitoring assessments can be implemented by the physicians. Visits denoted with an 
asterisk (*) are timed based on a specific study treatment (chemotherapy cycles, 
tisagenlecleucel, or HSCT). All visits without an asterisk are timed based on the date of 
randomization.   
Missed or rescheduled visits should not lead to automatic discontinuation. Participants who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the Month 60/EOT visit will be 
performed. At this Month 60/EOT visit, all dispensed investigational product should be 
reconciled, and the adverse events and concomitant medications recorded on the CRF. 

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Patients who received tisagenlecleucel and who discontinue from the primary follow up due to 
BIRC-confirmed PD/SD prior to Month 60 will be followed every 3 months until month 12, 
then every 6 months until month 24, then yearly until month 60 in order to collect key safety 
data up to 5 years as part of long term additional follow-up. In cases where a patient discontinues 
without BIRC confirmed PD/SD, it may be possible for the patient to be followed for only key 
safety follow-up (without efficacy assessments) only after consultation and documented 
agreement with the Novartis medical monitor. 
All randomized patients should be followed-up for survival every 3 months until the end of 
study (defined as the last visit for the last patient randomized). 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. 
After 5 years, the patients who received tisagenlecleucel will continue to be followed for safety 
in a separate long-term follow-up (LTFU) study, [CCTL019A2205B]. 
In each table, required assessments are indicated with an “X” at the visits when they are 
performed. The letter (D) under the category column indicates the assessments that will have 
data entered into the clinical database and (S) is for assessments that will have data remain as 
source documentation. All data obtained from these assessments must be supported in the 
patient’s source documentation. 
No CRF will be used in the patient’s source documentation. 

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Table 8-1 
Visit evaluation schedule pre-screening to randomization 
Phase: 
Screening to Randomization 
Category 
Protocol 
Section 
Pre-Screening 
Screening 
Randomization 
Visit 
Study day 
 
D-14 to -1 (± 7d) 
Day 1 
Identify Patient 
S 
8.1. 
X 
 
 
Confirm Slot Availability 
S 
8.1. 
X 
 
 
Obtain Informed Consent 
D 
7. 
 
X 
 
IRT Registration 
S 
6.3.1. 
 
X 
X 
Randomization by IRT 
D 
6.3.2. 
 
 
X 
Stratification by IRT 
D 
6.3.2. 
 
 
X 
Demography 
D 
8.2. 
 
X 
 
Inclusion/exclusion criteria 
D 
5. 
 
X 
 
Medical history 
D 
8.2. 
 
X 
 
Diagnosis and Extent of Cancer 
D 
8.2. 
 
X 
 
Prior antineoplastic therapy 
D 
16.3. 
 
X 
 
Prior/concomitant medications 
D 
6.2.1. 
 
X 
X 
Physical examination 
S 
8.4. 
 
X 
 
Performance status 
D 
8.4. 
 
X 
 
Prognostic score (IPI) 
D 
6.3.2. 
 
X 
 
Height 
D 
8.4. 
 
X 
 
Weight 
D 
8.4. 
 
X 
 
Vital signs 
D 
8.4. 
 
X 
 
Pulse oximetry 
D 
8.4. 
 
X 
 
Spirometry 
S 
8.4.4. 
 
X(allowed up to 4 weeks 
prior to randomization) 
 

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Phase: 
Screening to Randomization 
Category 
Protocol 
Section 
Pre-Screening 
Screening 
Randomization 
Visit 
Study day 
 
D-14 to -1 (± 7d) 
Day 1 
ECHO/MRA/MUGA 
D 
8.4.2.1. 
 
X (allowed up to 4 weeks 
prior to randomization) 
 
Electrocardiogram (ECG) 
D 
8.4.2. 
 
X (allowed up to 4 weeks 
prior to randomization) 
 
Leukapheresis 
D 
8.1. 
 
X 
 
PET-CT with contrast enhanced diagnostic (Dx) 
CT – Neck, Chest, Abdomen, Pelvis, 
D 
8.3. 
 
X (allowed up to 4 weeks 
prior to randomization) 
 
CT/MRI – Neck, Chest, Abdomen, Pelvis 
D 
8.3. 
 
X If no Dx PET-CT 
 
Dedicated FDG-PET 
D 
8.3. 
 
X If no PET-CT 
 
CT/MRI Brain and/or CSF cytology by Lumbar 
Puncture 
D 
8.3. 
 
X (allowed up to 4 weeks 
prior to randomization) 
 
Response evaluation per Lugano classification 
2014 
D 
16.2. 
 
X 
 
Bone marrow biopsy and/ or aspirate 
D 
8.3. 
 
X (allowed up to 4 weeks 
prior to randomization) 
 
Adverse events 
D 
10.1.1 
 
X 
X 
Pregnancy Reporting 
S 
10.1.5  
 
X 
X4 
Fertility Assessment 
S 
8.4.3  
 
X 
 
Central Hematology 
D 
8.4.1 
 
X 
 
Central Chemistry 
D 
8.4.1. 
 
X 
 
Central Cardiac Enzymes 
D 
8.4.1. 
 
X 
 
Serum or Urine pregnancy test 
S 
8.4.1. 
 
X (Serum) pre-
leukapheresis 
 
Viral serology (EBV, HIV, HBsAg, HBsAb HBcAb, 
HCVab) 
D 
8.4.1. 
 
X 
 

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Phase: 
Screening to Randomization 
Category 
Protocol 
Section 
Pre-Screening 
Screening 
Randomization 
Visit 
Study day 
 
D-14 to -1 (± 7d) 
Day 1 
Central Coagulation (PT, aPTT, INR, fibrinogen, 
D-dimer) 
D 
8.4.1. 
 
X 
 
Central Serum immunoglobulin levels (IgG, IgA, 
IgM) 
D 
8.4.1. 
 
X 
 
Urine Dipstick 
D 
8.4.1. 
 
X 
 
Tisagenlecleucel cellular kinetics by qPCR (PB) 
D 
8.5.2. 
 
 
X4 
Humoral Immunogenicity (serum) 
D 
8.5.2. 
 
 
X4 
Cellular Immunogenicity (Peripheral Blood) 
D 
8.5.2. 
 
 
X4 
Peripheral blood (cell levels- central assessment)3 
D 
8.5.3. 
 
X 
X4 
RCL by VSV-g q-PCR 
D 
8.4.5. 
 
 
X4 
SF-36v2 (Acute Form) 
D 
8.5.1.1  
 
 
X4 
FACT-Lym 
D 
8.5.1.2  
 
 
X4 
EQ-5D-5L 
D 
8.5.1.3  
 
 
X4 
Disposition (End of Phase) 
D 
8.1.1. 
 
 
X 
 
 
  
3 
 
4 Assessments required at the time of randomization may be completed at any time during the screening period as long as they occur prior to the IRT randomization 
call.   

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Table 8-2 
Visit evaluation schedule for Arm A (patients randomized to tisagenlecleucel treatment strategy) 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
IRT Registration 
S  
X 
(only 
for 
first 
cycle) 
 
X 
X 
X 
 
X 
 
 
 
 
X 
 
 
 
Concomitant Treatments 
Concomitant medications 
D 16.3. 
Continuous until 8 weeks after last treatment administration or prior to start of 
new anticancer therapy, whichever comes first 
 
 
 
 
 
 
X 
 
 
Concomitant medications 
(modified captured) 
D 16.3. 
 
 
 
 
For patients that receive 
tisagenlecleucel, starting 8 
weeks after tisagenlecleucel or 
prior to start of new anticancer 
therapy, whichever comes first 
 
X 
 

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Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Post-treatment 
Antineoplastic therapies  
D 16.3. 
Continuous 
X X 
 
Physical Assessments 
Physical examination 
S 8.4. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
ICANS Consensus Grading 
& ICE score  
D 4.5.1.2  
 
 
 
X  
At the first sign or symptom of 
neurologic toxicity, the ICANS grade 
should be determined (as part of or 
outside the scheduled physical 
examination). If the patient 
experiences suspected worsening of 
the event, the grade should be 
reassessed and the worst grade 
should be recorded. 
 
 
 
 
 
 
 
 
 
Performance status 
D 8.4. 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Weight 
D 8.4. 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 

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Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Vital signs 
D 8.4. 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pulse oximetry 
D 8.4. 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG  
D 8.4.2. 
 As clinically indicated 
X 
As clinically indicated 
 
 
ECHO/MRA/MUGA 
D 8.4.2  
As clinically indicated 
 
 
Intervention 
Lymphodepleting 
chemotherapy 
D 6.1.4.2  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tisagenlecleucel 
preinfusion evaluation – 
mandatory signed form 
S 6.1.2. 
 
 
 
X 
 
 
 
 
 
 
Tisagenlecleucel infusion 
D 6.1.1. 
 
 
 
X 
 
 
 
 
 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Efficacy Assessments 
PET-CT with contrast 
enhanced diagnostic (Dx) 
CT – Neck, Chest, 
Abdomen, Pelvis 
D 8.3. 
 
 
X 
 
X 
 
X 
M6 
only 
 
 
 
 
 
 
CT/MRI – Neck, Chest, 
Abdomen, Pelvis (PET-CT 
with Dx CT is preferred for 
all image visits) 
D 8.3. 
 
 
X if 
no 
Dx 
PET-
CT 
 
X if 
no 
Dx 
PE
T-
CT 
 
X at 
M9, 
M12
(M6 
only 
if no 
Dx 
PET
-CT) 
X 
X 
X 
 
 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Dedicated FDG-PET 
D 8.3. 
 
 
X if 
no 
PET-
CT 
 
 
 
 
 
 
 
 
 
 
X if 
no 
PE
T-
CT 
 
M6 
only 
if no 
PET
-CT 
 
 
 
 
 
 
Response evaluation per 
Lugano classification 2014 
D 16.2. 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
 
 
Response (CR) 
confirmation by PET-CT or 
dedicated FDG-PET 
D 8.3. 
 
 
Only for new CR and not previously documented 
 
 
 
Bone marrow biopsy and/or 
aspirate for efficacy 
D 8.3. 
 
 
Only if prior history of BM involvement to confirm CR 
 
 
 
CT/MRI Brain and/or CSF 
cytology by lumbar 
puncture 
D 8.3. 
 
 
As clinically indicated 
 
 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Safety assessments 
Adverse events 
D 10.1. 
Continuous until 8 weeks after tisagenlecleucel or prior to start of new 
anticancer therapy, whichever comes first 
 
 
 
 
 
 
X 
 
 
Protocol defined AE and 
AESI, including new 
malignancies 
D 16.3 . 
 
 
 
 
Continuous starting 8 weeks 
after tisagenlecleucel or prior to 
start of new anticancer therapy, 
whichever comes first 
 
X 
X 
 
Pregnancy Reporting  
S 10.1.5 
Continuous 
X X 
 
Laboratory assessments 
Central Hematology 
D 8.4.1. 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Central Chemistry 
D 8.4.1. 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Central Cardiac Enzymes 
D 8.4.1. 
As clinically indicated 
 
 

Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Serum or Urine pregnancy 
test 
S 8.4.1. 
X 
serum  
  
 
X 
serum 
X 
serum 
 
X (monthly testing between 
visits for as long as 
contraception is required, See 
Section 5.2) 
X (serum) 
 
X 
(as 
per 
contr
acep
tion 
requi
reme
nts) 
 
Central Coagulation (PT, 
aPTT, INR, fibrinogen, D-
dimer) 
D 8.4.1. 
X 
 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
 
 
Central Serum 
immunoglobulin levels (IgG, 
IgA, IgM) 
D 8.4.1. 
 
 
 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
Rapid Influenza (A and B) 
Testing 
D 8.4.1. 
 
 
 
Within 10d to 
planned 
infusion 
 
 
 
 
 
 
 
 
 
 

Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Urine Dipstick 
D 8.4.1. 
X 
only 
first 
cycle 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tisagenlecleucel cellular kinetics,
 and safety assessments 
Humoral Immunogenicity 
(serum) 
D 8.5.2. 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
M4 
only 
M6 
and 
M12 
X 
M24 
only 
X 
 
X 
until 
M12 
 
Cellular Immunogenicity 
(Peripheral Blood) 
D 8.5.2. 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
M4 
only 
M6 
and 
M12 
X 
M24 
only 
X 
 
X 
until 
M12 
 

Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
CRS assessments in 
peripheral blood 
 
, 
 
, tisagenlecleucel 
cellular kinetics)5 
D 8.5.2. 
 
 
 
 
 
As clinically indicated depending upon the presence and time- 
course of CRS and administration of anti-cytokine therapies: 
For tisagenlecleucel cellular kinetics, refer to Table 8-12. 
(qPCR in peripheral blood) and Table 8-13 (flow in peripheral 
blood). 
 
 
 
 
Tisagenlecleucel, 
, 
 
 assessments in PB 
in patients treated with 
tocilizumab5 
D 8.5.2. 
 
 
 
 
For qPCR cellular kinetics, please refer to Table 8-18
 
  
 
 
 
Tisagenlecleucel cellular 
kinetics by qPCR (PB) 
D 8.5.2. 
 
 
 
 
 
X 
pre-
infu
sion 
X 
X 
X 
X 
X 
X 
X 
X 
X 
M4 
only 
X 
X 
X 
X 
 
 
 

Novartis 
Confidential 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
Tisagenlecleucel cellular 
kinetics Bone Marrow 
(qPCR) 
D 8.5.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
As clinically indicated 
 
 
 
Tisagenlecleucel cellular 
kinetics – CSF (q-PCR)  
D 8.5.2. 
 
 
 
 
 
As clinically indicated 
 
 
 

Novartis 
Confidential 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
RCL by VSV-g q- PCR 
D 8.4.5. 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
 
X 
 
Electronic Patient Reported Outcomes 
SF-36v2 (Acute Form) 
D 8.5.1.1  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X7 
 
X7 
 
EQ-5D-5L 
D 8.5.1.3  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X7 
 
X7 
 

Novartis 
Confidential 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
FACT-Lym 
D 8.5.1.2  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X7 
 
X7 
 
Survival Follow-up 
D 8.5.5  
For all randomized patients, follow-up for survival every 3 months until the end of study (defined as the last visit for the last 
patient randomized). 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 
Disposition (End of Phase) 
D 9.1.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
1 For patients receiving R-GemOx bridging therapy, 14 day cycles will be used.  Day 1 assessments specified in the VES are to occur on Day 1 of odd-numbered 
cycles (i.e. C1D1, C3D1, C5D1, etc.), and Day 15 assessments specified in the VES are to occur on Day 1 of even-numbered cycles (i.e. C2D1, C4D1, C6D1, etc.). For 
patients receiving R-GDP Day 15 assessments may be performed on Day 8 on the day of gemcitabine dosing.   
2 The Week 6 visit should be scheduled after the completion of all planned bridging chemotherapy and as close as possible before lymphodepleting chemotherapy 
while staying within the visit window.  
3 The safety follow-up visit should occur 8 weeks after last treatment administration or prior to starting new anticancer therapy, whichever occurs first. After this safety 
visit occurs, adverse events and concomitant medications will follow a modified reporting criteria in patients that receive tisagenlecleucel (Section 16.3 Appendix 3). For 
ease of scheduling, the safety follow-up visit can occur as late as 9 weeks from their last treatment administration. 

Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm A 
 
 
Pre-tisagenlecleucel infusion  
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemotherapy  
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety 
follow-up visits (scheduled 
based on tisagenlecleucel 
infusion date) 
Safety and Efficacy 
Follow-up visits 
(scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up Visit3 
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each 
cycle1 
Week 6  ± 14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d*  
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3 
Post relapse4 
q3M 
D1 ±3d* 
D15  ±3d1* 
4 Patients that receive tisagenlecleucel and have BIRC-confirmed PD/SD prior to Month 60 will be followed to collect key safety data every 3 months until M12, then 
every 6 months until M24, then yearly until M60. All visits may occur ±14 days. 
 
 
7 Patients that experience BIRC-confirmed PD/SD prior to Month 60 should complete PROs at the end of treatment visit, 4 weeks after PD/SD ±7 days , 12 weeks after 
PD/SD ±14 days, and 6 months after PD/SD ±14 days.  If these timepoints align with scheduled long term additional follow-up visits they may be completed at the same 
time.   
* Visits denoted with an asterisk should be completed based on the timing of study treatment administration.  All other visits are completed based on the randomization 
date. 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Table 8-3 
Visit evaluation schedule for Arm B (patients randomized to SOC treatment strategy) 
Phase 
Arm B 
 
 
Treatment and Follow up  
 
 
 
 
Visit 
Category 
Protocol Section 
SOC 
Treatment 
visits – 
Repeat 
for each 
cycle 
HSCT visits  
(only required in 
patients that 
receive HSCT) 
SOC Safety and Efficacy Follow-up 
visits (scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Crossover 
Safety Follow-up Visit3 
Survival Follow-up 
Study day 
D1 ±3d* 
D15 ±3d1* 
Conditioning 
Therapy start* 
HSCT Day 1* 
Days 7,14,21,28 
post HSCT ±3d * 
Week 62 ±14d 
Week12 ±7d 
M4 M5 ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 
±14d 
M60 ±14d 
Week 12 ±7d 
onwards 
See footnote3 
q3M 
IRT Registration 
S 
 
X 
(only 
first 
cycle) 
 
 
X 
 
X 
X 
 
 
 
 
X 
X 
 
 
Concomitant Treatments 
Concomitant medications 
D 
16.3. 
Continuous until 8 weeks after the last dose of SOC study treatment or prior 
to start of other new anticancer therapy, whichever comes first 
 
X 
X 
 
Post-Treatment Antineoplastic therapies 
D 
16.3. 
Continuous 
X 
 
Physical Assessments 
Physical examination 
S 
8.4. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Performance status 
D 
8.4. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
D 
8.4. 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Vital signs 
D 
8.4. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
D 
8.4.2. 
As clinically indicated 
X 
 
 
ECHO/MRA/MUGA 
D 
8.4.2. 
As clinically indicated 
X 
 
 

Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm B 
 
 
Treatment and Follow up  
 
 
 
 
Visit 
Category 
Protocol Section 
SOC 
Treatment 
visits – 
Repeat 
for each 
cycle 
HSCT visits  
(only required in 
patients that 
receive HSCT) 
SOC Safety and Efficacy Follow-up 
visits (scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Crossover 
Safety Follow-up Visit3 
Survival Follow-up 
Study day 
D1 ±3d* 
D15 ±3d1* 
Conditioning 
Therapy start* 
HSCT Day 1* 
Days 7,14,21,28 
post HSCT ±3d * 
Week 62 ±14d 
Week12 ±7d 
M4 M5 ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 
±14d 
M60 ±14d 
Week 12 ±7d 
onwards 
See footnote3 
q3M 
Intervention 
Chemotherapy 
D 
6.1.1. 
SOC treatment at the investigator’s discretion 
 
confirm patient eligibility for crossover 
D 
8.3.3. 
 
 
 
 
 
X 
 
Efficacy Assessments 
PET-CT with contrast enhanced 
diagnostic (Dx) CT – Neck, Chest, 
Abdomen, Pelvis 
D 
8.3. 
 
 
 
 
X 
X 
 
X M6 
only 
 
 
 
 
 
CT/MRI – Neck, Chest, Abdomen, 
Pelvis 
D 
8.3. 
 
 
 
 
X if 
no 
Dx 
PE
T-
CT 
X if 
no 
Dx 
PET-
CT 
 
X at 
M9, 
M12( 
M6 
only if 
no Dx 
PET-
CT) 
X 
X 
X 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm B 
 
 
Treatment and Follow up  
 
 
 
 
Visit 
Category 
Protocol Section 
SOC 
Treatment 
visits – 
Repeat 
for each 
cycle 
HSCT visits  
(only required in 
patients that 
receive HSCT) 
SOC Safety and Efficacy Follow-up 
visits (scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Crossover 
Safety Follow-up Visit3 
Survival Follow-up 
Study day 
D1 ±3d* 
D15 ±3d1* 
Conditioning 
Therapy start* 
HSCT Day 1* 
Days 7,14,21,28 
post HSCT ±3d * 
Week 62 ±14d 
Week12 ±7d 
M4 M5 ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 
±14d 
M60 ±14d 
Week 12 ±7d 
onwards 
See footnote3 
q3M 
Dedicated PET 
D 
8.3. 
 
 
 
 
 
X if 
no 
PE
T-
CT 
X if 
no 
PET-
CT 
 
M6 
only if 
no 
PET-
CT 
 
 
 
 
 
 
Response evaluation per Lugano 
classification 2014 
D 
16.2. 
 
 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Response (CR) confirmation by PET-
CT or PET 
D 
8.3. 
 
Only for new CR and not previously documented 
 
 
CT/MRI Brain and/or CSF cytology by 
lumbar puncture 
S 
8.3. 
As clinically indicated 
 
 
Bone marrow biopsy and/or aspirate 
D 
8.3. 
 
 
 
 
 
Only if prior history of BM involvement to confirm 
CR on PET-CT or PET 
 
 
 
Safety Assessments 
Adverse events 
D 
10.1.1. 
Continuous until 8 weeks after the last dose of SOC study treatment or prior to start of 
other new anticancer therapy, whichever comes first 
X 
 
Pregnancy Reporting  
S 
10.1.5  
Continuous 
X 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm B 
 
 
Treatment and Follow up  
 
 
 
 
Visit 
Category 
Protocol Section 
SOC 
Treatment 
visits – 
Repeat 
for each 
cycle 
HSCT visits  
(only required in 
patients that 
receive HSCT) 
SOC Safety and Efficacy Follow-up 
visits (scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Crossover 
Safety Follow-up Visit3 
Survival Follow-up 
Study day 
D1 ±3d* 
D15 ±3d1* 
Conditioning 
Therapy start* 
HSCT Day 1* 
Days 7,14,21,28 
post HSCT ±3d * 
Week 62 ±14d 
Week12 ±7d 
M4 M5 ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 
±14d 
M60 ±14d 
Week 12 ±7d 
onwards 
See footnote3 
q3M 
Central Hematology 
D 
8.4.1. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Central Chemistry 
D 
8.4.1. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Central Cardiac Enzymes 
D 
8.4.1. 
As clinically indicated 
X 
 
 
Serum or Urine pregnancy test 
S 
8.4.1. 
X 
serum 
X 
serum 
 
 
X (monthly testing between visits for as 
long as contraception is required per 
local label, See Section 5.2) 
X 
serum 
 
Viral serology (EBV, HIV, HBsAg, 
HBsAb HBcAb, HCVab) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Coagulation (PT, aPTT, INR, fibrinogen, 
D-dimer) 
D 
8.4.1. 
X 
 
X 
 
 
 
X 
X 
 
 
 
 
 
X 
 
Serum immunoglobulin levels (IgG, IgA, 
IgM) 
D 
8.4.1. 
 
 
 
 
X 
X 
X 
 
Urine Dipstick 
D 
8.4.1. 
X 
only 
first 
cycle 
Repeat urinalysis following local labeling of SOC and local medical practice 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm B 
 
 
Treatment and Follow up  
 
 
 
 
Visit 
Category 
Protocol Section 
SOC 
Treatment 
visits – 
Repeat 
for each 
cycle 
HSCT visits  
(only required in 
patients that 
receive HSCT) 
SOC Safety and Efficacy Follow-up 
visits (scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Crossover 
Safety Follow-up Visit3 
Survival Follow-up 
Study day 
D1 ±3d* 
D15 ±3d1* 
Conditioning 
Therapy start* 
HSCT Day 1* 
Days 7,14,21,28 
post HSCT ±3d * 
Week 62 ±14d 
Week12 ±7d 
M4 M5 ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 
±14d 
M60 ±14d 
Week 12 ±7d 
onwards 
See footnote3 
q3M 
Electronic Patient Reported Outcomes 
SF-36v2 (Acute Form) 
D 
8.5.1.1 
 
 
 
 
X 
X 
X 
X 
X 
X5 
X 
 
EQ-5D-5L 
D 
8.5.1.3  
 
 
 
 
X 
X 
 
X 
X 
X 
X5 
X 
 
FACT-Lym 
D 
8.5.1.2. 
 
 
 
 
X 
X 
 
X 
X 
X 
X5 
X 
 
Survival follow-up 
D 
8.5.5. 
For all randomized patients, follow-up for survival every 3 months until the end of study (defined as the last 
visit for the last patient randomized). 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 
Disposition (End of Phase) 
D 
9.1.2. 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 

Novartis 
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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Arm B 
 
 
Treatment and Follow up  
 
 
 
 
Visit 
Category 
Protocol Section 
SOC 
Treatment 
visits – 
Repeat 
for each 
cycle 
HSCT visits  
(only required in 
patients that 
receive HSCT) 
SOC Safety and Efficacy Follow-up 
visits (scheduled based on 
randomization date) 
End of Treatment and 
Primary Follow- up 
Crossover 
Safety Follow-up Visit3 
Survival Follow-up 
Study day 
D1 ±3d* 
D15 ±3d1* 
Conditioning 
Therapy start* 
HSCT Day 1* 
Days 7,14,21,28 
post HSCT ±3d * 
Week 62 ±14d 
Week12 ±7d 
M4 M5 ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 
±14d 
M60 ±14d 
Week 12 ±7d 
onwards 
See footnote3 
q3M 
1 For patients receiving R-GemOx immunochemotherapy, 14 day cycles will be used.  Day 1 assessments specified in the VES are to occur on Day 1 of odd- 
numbered cycles (i.e. C1D1, C3D1, C5D1, etc.), and Day 15 assessments specified in the VES are to occur on Day 1 of even-numbered cycles (i.e. C2D1, C4D1, 
C6D1, etc.). For patients receiving R-GDP Day 15 assessments may be performed on Day 8 on the day of gemcitabine dosing.   
2. The Week 6 PET-CT should be scheduled no sooner than 14 days after the start of the second cycle of immunochemotherapy for R-DHAP, R-GDP, and R-ICE, or 7 
days after the third cycle of immunochemotherapy for R-GemOx 
3 The safety follow-up visit should occur 8 weeks after last treatment administration or prior to starting new anticancer therapy, whichever occurs first. If the patient 
received HSCT, this would occur 8 weeks after HSCT. After this safety visit occurs, no new adverse events or concomitant medications need to be reported. For ease 
of scheduling, the safety follow-up visit can occur as late as 9 weeks from their last treatment administration. 
 
 
   
*Visits denoted with an asterisk should be completed based on the timing of study treatment administrations. All other visits are completed based on the randomization 
date. 

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Protocol No. CCTL019H2301 
 
 
Table 8-4 
Visit evaluation schedule for patients who cross over from Arm B (SOC) to Arm A (tisagenlecleucel) 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
IRT Registration 
S  
X 
only 
first 
cycle 
 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
Concomitant Treatments 
Concomitant 
medications 
D 16.3. 
Continuous until 8 weeks after last treatment administration or prior to start of new 
anticancer therapy, whichever comes first 
 
 
 
 
 
 
X  
 
Concomitant 
medications 
(modified captured) 
D 16.3. 
 
 
 
 
For patients that receive 
tisagenlecleucel, starting 8 
weeks after tisagenlecleucel or 
prior to start of new anticancer 
therapy, whichever comes first 
 
X 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Post-treatment 
antineoplastic 
therapies  
D 16.3. 
 
 
 
Continuous 
X X 
 
Physical Assessments 
Physical 
examination 
S 8.4. 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
ICANS Consensus 
Grading & ICE 
score  
D 4.5.1.2   
 
 
 
X  
At the first sign or symptom of neurologic 
toxicity, the ICANS grade should be 
determined (as part of or outside the 
scheduled physical examination). If the patient 
experiences suspected worsening of the event, 
the grade should be reassessed and the worst 
grade should be recorded. 
 
 
 
 
 
 
 
 
 
Performance status D 8.4. 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Weight 
D 8.4. 
X 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 

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Protocol No. CCTL019H2301 
 
 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Vital signs 
D 8.4. 
X  
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pulse oximetry 
D 8.4. 
 
 
 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECG 
D 8.4.2. 
As clinically indicated 
X 
As clinically indicated 
 
 
ECHO/MRA/MUGA D 8.4.2. 
As clinically indicated 
 
 
Intervention 
Lymphodepleting 
chemotherapy 
D 6.1.4.2   
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tisagenlecleucel 
infusion 
prerequisite 
assessment – 
mandatory signed 
form 
S 6.1.2. 
 
 
 
X 
 
 
 
 
 
 
 
Tisagenlecleucel 
infusion 
D 6.1.1. 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol No. CCTL019H2301 
 
 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Efficacy Assessments 
Response 
evaluation per 
Lugano 
classification 2014 - 
Local 
D 16.2. 
 
 
X 
X 
 
X 
X 
X 
X 
 
 
 
Safety assessments 
Adverse events 
D 10.1. 
Continuous until 8 weeks after last treatment administration or prior to start of new 
anticancer therapy, whichever comes first 
 
 
 
 
 
 
X  
 
Protocol defined AE 
and AESI, including 
new malignancies 
D 16.3.  
 
 
 
 
 
For patients that receive 
tisagenlecleucel, starting 8 
weeks after tisagenlecleucel or 
prior to start of new anticancer 
therapy, whichever comes first 
 
X 
X 

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Protocol No. CCTL019H2301 
 
 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Pregnancy 
Reporting 
S 10.1.5  
Continuous 
X X 
 
Laboratory assessments 
Central Hematology D 8.4.1. 
X  
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X 
 
Central Chemistry 
D 8.4.1. 
X 
X 
X 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
 
Central Cardiac 
Enzymes 
D 8.4.1. 
As clinically indicated 
 
 
Serum or Urine 
pregnancy test 
S 8.4.1. 
X 
seru
m 
 
 
X serum X 
serum 
X (monthly testing between 
visits for as long as 
contraception is required, 
See Section 5.2) 
X (serum) 
 
X (as 
per 
contra-
ception 
require-
ments) 
 
Central Coagulation 
(PT, aPTT, INR, 
fibrinogen, D-dimer) 
D 8.4.1. 
X  
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X  
 

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Protocol No. CCTL019H2301 
 
 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Central Serum 
immunoglobulin 
levels (IgG, IgA, 
IgM) 
D 8.4.1. 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Rapid Influenza (A 
and B) Testing 
D 8.4.1. 
 
 
 
Within 10d to 
planned infusion 
 
 
 
 
 
 
 
 
 
 
Urine Dipstick 
D 8.4.1. 
X 
(only 
first 
cycle) 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tisagenlecleucel cellular kinetics, 
 and safety assessments 
Tisagenlecleucel 
cellular kinetics by 
qPCR (PB) 
D 8.5.2. 
 
 
 
 
 
 
 
X X 
X 
X 
X 
X 
X 
X 
M4 
only 
X 
X 
X 
X 
 
 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Tisagenlecleucel 
cellular kinetics 
Bone Marrow 
(qPCR) 
D 8.5.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
As clinically indicated 
 
 
 
Tisagenlecleucel 
cellular kinetics – 
CSF (q-PCR)  
D 8.5.2. 
 
 
 
 
 
As clinically indicated 
 
 
 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CCTL019H2301 
 
 
Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Humoral 
Immunogenicity 
(serum) 
D 8.5.2. 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
M4 
only 
M6 
and 
M12 
X 
M24 
only 
X 
 
X 
until 
M12 
 
Cellular 
Immunogenicity 
(Peripheral Blood) 
D 8.5.2. 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
M4 
only 
M6 
and 
M12 
X 
M24 
only 
X 
 
X 
until 
M12 
 
CRS assessments 
in peripheral blood 
(
, 
 
, 
tisagenlecleucel 
cellular kinetics)5 
D 8.5.2. 
 
 
 
 
 
 
 
As clinically indicated depending upon the presence and time- course of 
CRS and administration of anti-cytokine therapies: For tisagenlecleucel 
cellular kinetics, refer to Table 8-12 (qPCR in peripheral blood) and Table 
8-13 (flow in peripheral blood). 
 
 
 

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Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Tisagenlecleucel, 
 
 
 
assessments in PB 
in patients treated 
with tocilizumab5 
D 8.5.2. 
 
 
 
 
 
 
 
For qPCR cellular kinetics, please refer to Table 8-18
 
  
 
 
RCL by VSV-g q- 
PCR 
D 8.4.5. 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
X 
 

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Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
Electronic Patient Reported Outcomes (ePRO) 
SF-36v2 (Acute 
Form) 
D 8.5.1.1.  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X
7 
X7 
 

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Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
EQ-5D-5L 
D 8.5.1.3.  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X
7 
X7 
 
FACT-Lym 
D 8.5.1.2.  
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
X 
X
7 
X7 
 
Survival Follow-up 
D 9.2. 
For all patients who crossover, follow-up for survival every 3 months until the end of study (defined as the last visit for the last patient 
randomized). 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 
Disposition (End of 
Phase) 
D 9.1.2. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 

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Phase 
Crossover 
 
 
Pre-Tisagenlecleucel infusion 
Tisagenlecleucel Treatment and Follow up 
 
 
 
 
Visit 
Category 
Protocol Section 
Optional 
Bridging Chemo 
Post-bridging Evaluation 
Lymphodepleting 
Chemotherapy 
Pre-tisagenlecleucel 
Infusion 
Tisagenlecleucel 
Infusion 
Post-tisagenlecleucel safety follow-
up visits (timed based on 
tisagenlecleucel infusion date) 
Safety and Efficacy 
Follow-up visits 
(timed based on 
crossover visit date) 
End of Treatment and 
Primary Follow- up 
Safety Follow-up3
Long term additional 
Follow-up4 
Survival Follow-up 
Study day 
 
Repeat for 
each cycle 
Week 6  ±14d2 
Infusion -7d to 
Infusion -3d* 
Infusion-1d* 
Infusion* 
Infusion +1d* 
Infusion +3d ±1d* 
Infusion +6d ±1d* 
Infusion +10d ±3d* 
Infusion +13d ±3d* 
Infusion +21d ±3d* 
Infusion +28d ±7d* 
Week 12 ±7d 
M4 M5, ±14d 
M6 M9 M12 ±14d 
M18 ±14d 
M24 M36 M48 ±14d 
M60±14d 
See footnote3
Post relapse4 
q3M 
D1 ±3d* 
D15 ±3d1* 
1 For patients receiving R-GemOx bridging therapy, 14 day cycles will be used.  Day 1 assessments specified in the VES are to occur on Day 1 of odd-numbered cycles 
(i.e. C1D1, C3D1, C5D1, etc.), and Day 15 assessments specified in the VES are to occur on Day 1 of even-numbered cycles (i.e. C2D1, C4D1, C6D1, etc.). For 
patients receiving R-GDP Day 15 assessments may be performed on Day 8 on the day of gemcitabine dosing.   
2 In patients that crossover to Arm A, it is possible that the patient has tisagenlecleucel already available for infusion at the time of crossover due to an early 
manufacturing request.  In this case the patient may proceed to infusion with no bridging and the Week 6 visit would occur after infusion.  If tisagenlecleucel is not 
available at the time of crossover, the Week 6 assessment should occur after the completion of bridging chemotherapy as in Arm A. 
3 The safety follow-up visit should occur 8 weeks after last treatment administration or prior to starting new anticancer therapy, whichever occurs first. After this safety 
visit occurs, adverse events and concomitant medications will follow a modified reporting critera in patients that receive tisagenlecleucel (Section 16.3 Appendix 3). For 
ease of scheduling, the safety follow-up visit can occur as late as 9 weeks from their last treatment administration. 
4 Patients that receive tisagenlecleucel and have PD/SD prior to Month 60 will be followed to collect key safety data every 3 months until M12, then every 6 months until 
M24, then yearly until M60. All visits may occur ±14 days. 
 
 
7 Patients that experience PD/SD prior to Month 60 should complete PROs at the end of treatment visit, 4 weeks after PD/SD ±7 days , 12 weeks after PD/SD ±14 days, and 6 
months after PD/SD ±14 days.  If these timepoints align with scheduled long term additional follow-up visits they may be completed at the same time.   
* Visits denoted with an asterisk should be completed based on the timing of study treatment administrations. All other visits are completed based on the crossover visit date. 

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8.1 
Screening 
Patient identification 
Prior to signing ICF, when an investigator identifies a potential patient for CCTL019H2301, 
the site will contact the sponsor to inquire about tisagenlecleucel manufacturing slot availability 
within 3-6 weeks. If there is manufacturing slot availability and the patient is deemed a 
candidate to start second line treatment after randomization then the site should proceed to ICF 
signature within 48 hours of this contact. 
Screening 
Patients must sign the IRB/EC approved informed consent form (ICF) before any study specific 
screening procedures. Screening assessments to determine eligibility should be performed as 
per the visit evaluation schedule detailed in Table 8-1. Randomization should occur when all 
clinical eligibility has been completed. 
Patients who have signed an informed consent will be registered in the IRT system and undergo 
a routine lymphoma staging workup including all screening assessment outlined in Table 8-1. 
The assessments below do not need to be repeated if performed in the context of the 
leukapheresis procedure or if performed as part of clinical routine within 4 weeks of 
randomization: 
a. Disease assessments: Any imaging assessments, bone marrow biopsies, or lumbar 
punctures already completed during the regular care of the participant within 4 weeks 
prior to randomization, including before signing the main study ICF, can be considered as 
the screening disease assessments for this study. Any imaging or disease assessments 
obtained after randomization cannot be considered for screening. The patient should not 
receive any anticancer therapy between the screening disease assessments and 
randomization. 
b. Cardiac and lung function evaluation: Heart imaging assessment, ECG, and spirometry if 
already completed during the regular care of the participant within 4 weeks prior to 
randomization, including before signing the main study ICF, can be considered as the 
screening disease assessments for this study. 
If needed, laboratory parameters or other screening parameters may be retested within the 
screening period for an individual patient. In addition, rescreening (signing of a new ICF after 
initial screen failure) may be allowed under selected circumstances after discussion with the 
medical monitor. 
In the case where a safety laboratory assessment at screening outside of the range specified in 
the exclusion criteria, the assessment may be repeated once prior to randomization. If the repeat 
value remains outside of the specified ranges, the participant must be excluded from the study. 
In the case of a logistical error (e.g. temperature control breach during apheresis shipping, 
contamination of cell culture, etc) which compromises the manufacture of a patients 
tisagenlecleucel product, all screening procedures including collection of a new leukapheresis 
product can be repeated. In the event of a case that you feel qualifies as a logistical error, please 

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consult with the Novartis medical monitor prior to repeating screening procedures for the 
patient. 
8.1.1 
Eligibility screening 
Only following randomization will information on the patient’s leukapheresis product be 
transferred to the Novartis designated manufacturing facility. 
For sites performing the leukapheresis as part of this protocol leukapheresis can only be 
performed after patient consent has been obtained. At the time when manufacturing of 

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tisagenlecleucel is required (by randomization or crossover), a Novartis designated 
manufacturing facility will then evaluate the patient’s leukapheresis product for acceptance.  
The acceptance of the product will be registered in IRT by Novartis personnel.   
Randomization will occur at the point at which a patient meets all inclusion/exclusion criteria 
as per investigator judgement and registers the call in IRT. The patient is then randomized using 
the same Participant Number assigned at screening by the site investigator or designated staff. 
Once assigned, the Participant Number must not be reused for any other patient and the 
Participant Number for that individual must not be changed. If a screened patient is not 
randomized for any reason, the specific reason will be entered into the clinical database on a 
disposition CRF. 
At randomization, patients will be stratified by response to first line treatment (refractory or 
relapsed within 6 months from last dose of first line immunochemotherapy, and relapsed 6 to 
12 months from last dose of first line immunochemotherapy), IPI (<2 v ≥2) per local 
investigator assessment, and region (North America vs. Rest of World) and randomized in IRT. 
Novartis will supply a stratification form which must be signed and returned prior to 
randomization  to ensure adequate documentation of stratification factors. 
For detailed screening, and randomization procedures, related to the use of Interactive Response 
Technology (IRT), please refer to the [IRT User Manual]. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, leukapheresis collection information, and Inclusion/Exclusion pages must also be 
completed for screen failure participants. No other data will be entered into the clinical database 
for participants who are screen failures, unless the participant experienced a serious adverse 
event (see SAE section for reporting details) or an adverse event which leads to discontinuation 
during the screening phase. If the participant fails to be randomized, the IRT must be notified 
within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in error, 
will be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form. 
8.2 
Participant demographics/other baseline characteristics 
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
Participant demographic and baseline characteristic data are to be collected on all participants. 
Relevant medical history/current medical condition present before signing the informed consent 
will be recorded. Investigators will have the discretion to record abnormal test findings on the 
appropriate CRF whenever in their judgment, the test abnormality occurred prior to the 
informed consent signature. 

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8.3 
Efficacy 
Efficacy assessments will be performed as indicated in Table 8-1, Table 8-2, and Table 8-3, and 
as clinically indicated in all randomized patients (including those who may not receive study 
treatment) until BIRC-confirmed SD/PD at or after week 12, death, lost to follow up or 
withdrawal of consent.  Patients in Arm A that experience BIRC-confirmed SD/PD at or after 
the week 12 visit, but are still waiting to receive tisagenlecleucel (e.g. in case of 
remanufacturing attempt) should continue disease assessments as per local policy until SD/PD 
after tisagenlecleucel infusion (or until study discontinuation without infusion).  These 
assessments will be done locally with no central review.  For patients that initiate new anticancer 
therapy without BIRC confirmed SD/PD, efficacy assessment should be also performed just 
before initiation of new anticancer therapy and thereafter should continue to conduct efficacy 
assessments until BIRC confirmed SD/PD. For patients that are randomized to arm B and then 
crossover, efficacy will continue to be assessed by local investigator with no central review as 
per Table 8-4. The crossover visit would also mark the end of the treatment and primary follow-
up visit for patients in Arm B. 
Efficacy evaluation will be collected as described in Table 8-5 based on recommendations by 
the International Malignant Lymphomas Imaging Working Group (Cheson et al 2014; 
Barrington et al 2014) and detailed in Section 16.2 Appendix 2. 
A BIRC appointed by Novartis will review data related to disease response assessment 
according to the Novartis Guideline for Efficacy Evaluation in lymphoma studies, version 2. 
The BIRC will review all data related to disease response for all randomized patients. Sites 
should request expedited review of imaging files under the conditions described in Section 8.3.3. 
Patients who crossover to Arm A will not be assessed by BIRC. 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 BIRC. Clinical data such as, 
physical exam, bone marrow results, pathology/histology and cytology results; as well as, 
information regarding prior interventions, pre-existing radiographic findings that may mimic 
presence of disease at baseline/screening and on-study interventions will be transmitted to the 
imaging CRO for review by a medical oncologist/hematologist. At BIRC, during the overall 
review the available clinical data will be integrated with the pathological and radiological 
response data to provide the overall disease response: 
The presence of one (1) or more stable, but persistent clinical lesions will downgrade a 
radiology CR to an overall PR. 
The presence of one (1) or more new or worsening clinical lesions will result in Overall PD. 
If bone marrow biopsy is not negative, a radiographic timepoint response (TPR) of CR at that 
time point would be downgraded to an overall PR. 
A new lesion biopsy result indicating a malignancy would result in overall PD, if not already 
assessed as PD during the radiology review. 
For any given time point, any clinical listings that are within a +14 day window (+28 day 
window for bone marrow data) of the radiographic time point date can be used for the 
corresponding oncology time point assessments. Clinical listings that are +15 days after a 
radiographic time point will be grouped with the next radiographic time point. For example, if 

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the radiographic time point date is 01-Mar, and the non-bone marrow clinical evaluations on 
the listings occur on 10-Mar and 16-Mar, the listings from 10-Mar will be associated with the 
radiographic time point date of 01-Mar. The listings from 16-Mar will not be associated with 
the 01-Mar radiographic time point and will be grouped with the next radiographic time point. 
Any clinical listings that fall outside the allowable window will be evaluated with the next 
radiographic time point. 
For bone marrow data, the assessment window will be extended to +42 days if there are no 
subsequent radiographic time points. This +42 day window will only apply to overall 
assessments associated with the participant’s last radiographic time point. 
Further details regarding the BIRC assessment will be provided in the BIRC 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 BIRC. 
Disease characterization at baseline and evaluation of efficacy during study rely on the 
following: 
1. Pathology assessment 
2. Imaging 
3. Bone marrow biopsy or aspirate 
4. CNS Brain Imaging (CT/MRI) and/or diagnostic lumbar puncture with CSF cytology 
(mandatory at screening and at discretion of the Investigator to evaluate CNS disease 
thereafter) 
5. Lesions from physical exam findings 
6. Procedures performed on study 
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 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. 
Imaging assessments 
Imaging assessments will be performed at screening within D-14 to -1 of randomization. 
Screening/baseline imaging assessment should be done as close to randomization as possible. 
In the event more than one imaging assessment is performed after ICF and prior to 
randomization then only the assessment date closest to randomization should be captured in the 
clinical database and used as the screening/baseline assessment. 
Any imaging assessments, bone marrow biopsies, or lumbar punctures already completed 
during the regular care of the participant within 4 weeks prior to randomization, including 
before signing the main study ICF, can be considered as the screening disease assessments for 

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this study. Any imaging or disease assessments obtained after randomization cannot be 
considered for screening. The patient should not receive any anticancer therapy between the 
screening disease assessments and randomization. One of the following assessments are 
required at screening, Week 6, Week 12, and Month 6 and at other timepoints only for new CR 
on CT scan not previously documented to confirm response: 
1. PET-CT with diagnostic CT 
2. PET-CT with non-diagnostic CT + dedicated diagnostic CT 
3. Dedicated diagnostic CT + dedicated FDG PET 
In Arm A, the Week 6 PET-CT is required to be done after the completion of all planned 
bridging chemotherapy and as close as possible before lymphodepleting chemotherapy. 
In Arm B, the Week 6 PET-CT is required to be done no sooner than 14 days after the start of 
the second cycle of immunochemotherapy for R-DHAP, R-GDP, and R-ICE, or 7 days after the 
third cycle of immunochemotherapy for R-GemOx.   
In patients that crossover to Arm A, the most recent imaging assessment prior to crossover will 
be considered the new baseline images to be used in the crossover evaluations.  In most cases, 
this would be the imaging that was used to diagnose SD/PD.  If this imaging was a CT scan 
only, the investigator should obtain a PET scan within 14 days of the CT scan, at or prior to the 
crossover visit to serve as new baseline images for the crossover evaluations.    
In patients that crossover to Arm A, it is possible that the patient has tisagenlecleucel already 
available for infusion at the time of crossover due to an early manufacturing request.  In this 
case the patient may proceed to infusion with no bridging and Week 6 would occur after 
infusion.  If tisagenlecleucel is not available at the time of crossover, the Week 6 assessment 
should occur after the completion of bridging chemotherapy as in Arm A. 
PET imaging is always required in order to confirm the first documented complete response 
(CR). If the first documented radiological CR is seen on CT scan only, a confirmatory PET scan 
(either FDG PET or PET-CT) should be obtained within 14 days in order to confirm that 
timepoint’s response of CR. If the PET scan is not obtained within 14 days, the timepoint must 
be assessed as a PR, and the next scan should be done by one of the 3 methods above as soon 
as possible to confirm the CR. Once CR has been established by PET imaging, subsequent CR 
and/or PD may be followed by CT imaging only.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 with 
diagnostic 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 participant 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 at all imaging visits for any given patient. 
It is preferred to obtain a PET-CT with diagnostic CT at all protocol required imaging visits 
when possible. 
If a participant is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the neck and chest (MRI is 

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not recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed. 
Brain MRI or CT or CSF evaluation is mandatory to be completed at screening and only 
completed post-randomization if clinically indicated. Contrast enhanced brain MRI is preferred, 
however, if MRI contrast is contraindicated, then MRI without contrast or CT with/without 
contrast is acceptable. 
If skin lesions are identified as a result of a physical exam, these are to be documented via the 
Lugano classification 2014 assessment as a physical exam, skin lesion. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion for suspicion of PD or to support the efficacy evaluations for a 
participant, as necessary. If imaging is done for safety reasons only there should be no efficacy 
assessment and/or submission to the imaging CRO. (All imaging submitted to the imaging CRO 
are expected to have a corresponding local efficacy assessment). 
Any on protocol scheduled and/or unscheduled imaging assessments done within ± 14 day 
window are to be assessed under a single evaluation. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 

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Table 8-5 
Imaging or disease assessment collection plan 
Procedure 
Screening 
Treatment Assessment 
PET-CT with contrast 
enhanced diagnostic (Dx) 
CT - Neck, Chest, 
Abdomen, Pelvis 
Mandated 
Mandated at Week 6, Week 12, and at Month 6 
May be used within 14 days at any visit a new CR by CT 
needs to be confirmed, not seen previously 
Once CR is confirmed with PET, additional PET imaging is 
not required (CT only) 
Dedicated FDG PET 
Mandated, if no 
Dx PET-CT 
available 
Mandated at Week 6, Week 12, and Month 6, if no Dx PET-
CT is available 
May be used within 14 days at any visit a new CR by CT 
needs to be confirmed, not seen previously 
Once CR is confirmed with PET, additional PET imaging is 
not required (CT only). 
CT/MRI (Neck, Chest, 
Abdomen, Pelvis) 
Mandated, if no 
Dx PET-CT 
available 
Mandated at  months 9, 12, 18, 24, 36, 48 and 60/EOT and 
any time to confirm PD or response. 
Mandated at Week 6, Week 12, and Month 6, if no Dx PET-
CT available 
PET-CT with diagnostic CT is preferred at all imaging visits 
when possible. 
Response (CR) 
confirmation by PET-CT 
or dedicated FDG PET 
NA 
PET imaging is required ± 14 days within the same CT 
timepoint window when CR is seen by CT, only for new CR 
and not previously documented. Once CR has been 
confirmed PET imaging is no longer needed, however it is the 
preferred method when possible. 
CT/MRI brain and/or CSF 
cytology 
Mandated 
As clinically indicated 
Bone marrow aspirate 
and/or biopsy cells 
Mandated 
Mandated to confirm CR if bone marrow was involved by 
lymphoma prior infusion and as clinically indicated 
Tumor biopsy (FFPE)  
Mandated (used 
for pathology 
assessment and 
subtype 
determination; 
See Section 
8.5.3)* 
• 
Recommended if PET shows residual metabolically active 
tissue to rule out interference of tisagenlecleucel activity 
with PET results.   
 
 
 
 
  
8.3.1 
Transmission of efficacy data to BIRC 
All radiological assessments will be read locally and should be submitted promptly after 
acquisition to the imaging vendor designated by Novartis. Rapid image transmission to the 
central imaging vendor will be accomplished by transferring the images acquired by the 
investigator electronically in a secured website (e.g.: via the internet). In all instances, the 
process at the imaging vendor will ensure that the central reviewers remain blinded to the 
treatment arm, the results of the local assessment, and the expedited nature of the review. 
8.3.2 
Non-expedited review - timepoints without locally determined 
progression or stable disease 
All imaging time points without locally determined progression or stable disease per Lugano 
classification 2014 will be read on an ongoing non-expedited basis as detailed in the imaging 

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manual to be provided by the designated imaging vendor and independent review charter. 
Expedited review may be required if necessary. Results of these readings will not be 
communicated to the sites. 
8.3.3 
Expedited review - timepoints with locally determined progression or 
stable disease 
All imaging time points in Arm A or Arm B (not including crossover) with locally determined 
progression or stable disease per Lugano classification 2014 will require an expedited review 
by the BIRC.The investigator must seek an expedited review and indicate this request to the 
imaging vendor on a designated form or by alternative means identified by the imaging vendor. 
The imaging CRO will ensure that the BIRC reviewers are blinded to the results of the local 
assessments and the nature of the expedited review. 
Rapid image transmission to the imaging CRO may be accomplished by uploading all digital 
images acquired by the Investigator to the secure website provided by the imaging CRO (e.g., 
via the internet). The imaging will undergo expedited central review (within 5 business days 
from the time of the receipt of images at the imaging CRO and once all applicable image queries 
are resolved) and the results of the central review will be communicated to the site. While the 
investigator is awaiting the results of the BIRC from the imaging CRO confirming disease 
progression or stable disease, it is preferable that the patient continue on study treatment. 
However, during this time, the investigator should do whatever is medically necessary for 
his/her patient. 
If the central review does not determine disease progression or stable disease per Lugano 
classification 2014, the patient should continue to have imaging performed as per protocol and 
receiving the study treatment until the central review determines progressive disease or stable 
disease unless there is a medical need (i.e., clinical deterioration) for an immediate change in 
therapy per the investigator’s clinical judgment. 
If the central review confirms disease progression or stable disease, treatment may be continued 
beyond Lugano classification 2014 defined SD/PD if, in the judgment of the investigator, there 
is evidence of clinical benefit and the patient wishes to continue on the study treatment. 

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In patients randomized to Arm B: 
• If the central review confirms disease progression or stable disease at or after the week 6 
(±2w) assessment, then the physician may request a tisagenlecleucel manufacturing slot 
from the sponsor and change therapy as appropriate. 
• If the central review confirms disease progression or stable disease at or after the week 12 
(±1w) assessment, then the patient may cross over from SOC treatment to tisagenlecleucel 
treatment strategy.   
• Patients that proceed to transplant and do not experience SD/PD for 365 days after HSCT 
are no longer eligible for manufacturing request or crossover.    
8.4 
Safety 
For details on AE collection and reporting, refer to Section 10.1. 
ECOG Performance status grade will be used as described in the Table 8-6 
Table 8-6 
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 
Physical assessments are specified below in Table 8-7 , with the visit evaluation schedule 
detailing when each assessment is to be performed. 

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Table 8-7 
Physical assessments 
Assessment 
Specification 
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, vascular and neurological(including ICANS & ICE if applicable) 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 appropriate CRF page. Any lesions detected during a physical exam at any time-point 
that are not detectable by imaging should be recorded on the appropriate CRF page. Significant 
new findings, other than new lesions, that begins or worsens after informed consent must be 
recorded on the appropriate CRF page. 
Vital sign 
Vital signs include temperature, blood pressure, pulse rate, respiratory rate.Pulse oximetry is 
required as specified in the visit evaluation schedule. . 
For patients receiving tisagenlecleucel, vital signs (temperature, respiration rate, pulse rate, 
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. Fever is frequently the first symptom 
of CRS and must be monitored following infusion. 
For all patients, systolic and diastolic blood pressure should be measured after the patient has 
been sitting for five minutes, with back supported and both feet placed on the floor, using an 
automated validated device, with an appropriately sized cuff. In case the cuff sizes available are 
not large or small enough for the patient’s arm circumference, a sphygmomanometer with an 
appropriately sized cuff should be used. 
Height and 
weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured. 
8.4.1 
Laboratory evaluations 
Laboratory assessments are specified below in Table 8-8 and Table 8-9, with the visit evaluation 
schedule detailing when each assessment is to be performed. 
Regular sample collections for 
, tisagenlecleucel cellular kinetics, 
 
 are mandated during the first 28 days following 
tisagenlecleucel 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. 
 
(e.g. every day to several 
days) especially around the following clinical events: initial persistence of fevers, 
hemodynamic instability, initial and worsening of respiratory distress, rapid clinical 
deterioration, just prior to and daily for 2 days following tocilizumab administration, around 
other clinically significant events and upon the clinical resolution of CRS. 
Please note that results of 
 analyses are NOT to be used for clinical management 
decisions of CRS. A detailed treatment algorithm has been established with clear criteria for 
CRS management (see Table 6-2 and Table 6-3). 

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Table 8-8 
Laboratory assessments – Central Assessments 
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, Bands, Lymphoblasts, Plasma cells, Prolymphocytes, Myelocytes, 
Metamyelocytes, and Promyelocytes 
Chemistry 
Glucose (fasting), Blood Urea Nitrogen (BUN), Creatinine, eGFR, Sodium, Potassium, 
Calcium, Magnesium, Phosphorous, Total Cholesterol, Triglycerides, Total Protein, Albumin, 
Total Bilirubin, Direct Bilirubin, Indirect Bilirubin, Amylase, Alkaline phosphatase, ALT (SGPT), 
AST (SGOT), Lipase, LDH, 
, and Uric Acid 
Cardiac 
Enzymes 
Troponin I, NT-proBNP 
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 
Viral Serology 
Epstein-Barr Virus (EBV), Hepatitis C Virus (HCV) antibody, 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). Additionally HBV DNA and HCV RNA testing may 
be conducted as per the algorithm in Section 16.1 Appendix 1.  Viral serology testing must be 
within 8 weeks prior to lymphodepletion and  tisagenlecleucel infusion. 
Additional tests 
Serum immunoglobulin levels (IgG, IgA, IgM), RCL by VSV-g q- PCR 
Table 8-9 
Laboratory Assessments – Local Assessments 
Test Category 
Test Name 
Influenza 
Rapid Influenza A & B Test 
Pregnancy Test 
Serum testing, Urine tests (kits are supplied by central vendor) 
8.4.2 
Electrocardiogram (ECG) 
ECGs must be recorded after 10 minutes rest in the supine position to ensure stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood draws. The Fredericia QT correction formula (QTcF) 
should be used for clinical decisions. 

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Single 12- lead ECGs are to be collected. The original ECGs on a non-heat-sensitive paper or a 
certified copy on non-heat sensitive paper, appropriately signed, must be collected and archived 
at the study site. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. A monitoring or review process should be in place for clinically 
significant ECG findings throughout the study and especially at baseline before administration 
of study treatment. 
Any identifier details must be redacted, e.g. participant initials, date of birth. 
In the event that a clinically significant ECG abnormality is identified at the site (e.g. severe 
arrhythmia, conduction abnormality of QTcF ≥ 450 ms for males and QTcF ≥ 460 ms for 
females), the ECG is to be repeated to confirm the diagnosis. If the participant is 
hemodynamically compromised, the investigator or a medically qualified person must initiate 
appropriate safety procedures without delay (for example cardioversion). 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate 
A standard 12-lead ECG will be performed 
• at screening prior to randomization (any ECG already completed during the regular care of 
the participant within 4 weeks prior to randomization, including before signing the main 
study ICF, can be considered as the screening assessments for this study) 
• on the day of but prior to tisagenlecleucel infusion for patients randomized to Arm A or 
crossover patients 
• as clinically indicated and at crossover for patients randomized to Arm B 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate CRF. Each ECG tracing should be labeled with the study number, participant 
initials (where regulations permit), participant number, date, and kept in the source documents 
at the study site. Clinically significant abnormalities present at screening should be reported on 
the appropriate CRF. Clinically significant findings must be discussed with Novartis prior to 
enrolling the participant in the study and reported on the appropriate CRF. New or worsened 
clinically significant findings occurring after informed consent must be recorded as adverse 
events. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
8.4.2.1 
Cardiac imaging 
An ECHO/MRA/MUGA test is required to be completed at screening and crossover. Any 
ECHO/MRA/MUGA test already completed during the regular care of the participant within 4 
weeks prior to randomization, including before signing the main study ICF, can be considered 
as the screening assessments for this study.Clinically significant abnormalities present when 
the patient signed the informed consent should be reported on the appropriate eCRF page. 

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Clinically significant findings must be discussed with the Novartis Medical Monitor 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. 
8.4.2.2 
Cardiac enzymes 
Cardiac enzymes should be performed if clinically indicated as per the visit evaluation schedule.  
8.4.3 
Pregnancy and fertility 
All WOCBP will have pregnancy testing. Additional pregnancy testing might be performed if 
requested by local requirements. For the frequency of pregnancy testing please refer to Table 
8-2, Table 8-3, and Table 8-4. For all pregnancy tests performed at home, the site personnel 
will follow-up with the participant via telephone call to collect the date and the test results and 
document the information in the participant’s source documents. 
For pregnancy reporting requirements and follow-up of the pregnancy outcome including the 
newborn refer to Section 10.1.5. 
The assessment of fertility done at screening should include discussion regarding the menstrual 
cycle and onset of the menopause, respectively. 
For more information about the effects of tisagenlecleucel on reproduction please refer to the 
recent [Tisagenlecleucel Investigator’s Brochure]. 
8.4.4 
Spirometry 
In order to assess, HSCT eligibility, a FEV1 or DLCO test should be performed at screening 
according to local institutional practice. Any spriometry test already completed during the 
regular care of the participant within 4 weeks prior to randomization, including before signing 
the main study ICF, can be considered as the screening assessments for this study. 
8.4.5 
Other safety evaluations 
Humoral immunogenicity to tisagenlecleucel and detectable RCL will be assessed as described 
Table 8-2 and Table 8-4. 
8.4.6 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
Patient reported outcomes (PRO) 
Three questionnaires will be used in this study to capture electronic patient reported outcomes 
(ePROs): the Short Form (36) Health Survey (SF-36 v2), the Functional Assessment of Cancer 
Therapy—Lymphoma (FACT-Lym version 4), and the EuroQol 5D (EQ-5D-5L) questionnaire. 
Patient reported outcome data will be assessed during the study as indicated in Table 8-1, Table 
8-2, Table 8-3, and Table 8-4. Descriptive statistics (e.g. mean, median and frequency) and 

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change from baseline of the summary scores for each post baseline time-point/window of 
assessment will be provided by treatment arm. FAS will be used for all analysis. 
Each of the questionnaires mentioned above is designed for patient self-administration. Method 
of activating and operating the data capture device is provided in a separate user guide. 
The patient should be given the tablet to complete the questionnaire(s) at the scheduled visit 
prior to any testing, treatment, or discussion with the physician or clinical personnel. Patient 
refusal to complete all or any part of a PRO measure should be documented in the study data 
capture systems and should not be captured as a protocol deviation. The questions should be 
completed in the language the respondent is most familiar with, at the scheduled visit before 
the patient sees the investigator for clinical assessments. The patient should be given sufficient 
space and time to complete the PRO measures. 
The responsible site personnel should check the patients’ responses for completeness and 
encourage the patient to complete any missing responses.  The responses stored electronically 
in the database will be considered the source file.Detailed instructions relating to the 
administrative procedures of the questionnaires will be provided to the sites.  
The completed ePRO data and any unsolicited comments made by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs, 
including SAEs, before any clinical study examinations. This assessment should be documented 
in study source records. If AEs or SAEs are confirmed, study investigators should not encourage 
the patient to change responses reported in the completed ePRO data. 
Patients that crossover to the tisagenlecleucel arm will still need to complete the SF-36v2, 
FACT-Lym, and EQ-5D-5L at the same time points specified above and in Table 8-4. The SF-
36v2, FACT-Lym, and EQ-5D-5L should be collected at the EOT visit in patients that 
experience BIRC-confirmed PD/SD in Arm A (or patients that crossover from Arm B to Arm 
A), and in patients that experience BIRC-confirmed PD/SD in Arm B, but do not plan to 
crossover.  Whenever possible, this collection should occur prior to initiation of new anticancer 
therapy. These patients should also complete the SF-36v2, FACT-Lym, and EQ-5D-5L at 4 
weeks after PD/SD, 12 weeks after PD/SD, and 6 months after PD/SD. 
Study investigators must follow reporting instructions outlined in Section 10.1. 
8.5.1.1 
SF-36 v2 (acute form) 
The 36-item short form (SF-36v2) is a generic quality of life measure used widely in clinical 
practice and research, general population surveys and health policy evaluations 
(Ware and Sherbourne 1992). The SF-36 v2 comprises 36 questions, which are summarized in 
eight health domain scores: Physical Functioning, Role-Physical, Bodily Pain, General Health, 
Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall component 
summary scores, the Physical Component Summary (PCS) and the Mental Component 
Summary (MCS), also can be computed. Domain and component summary scores can be 
converted to norm-based scores. A higher SF-36 score denotes better HRQoL. 
The SF-36 has proven useful in monitoring general and specific populations, comparing the 
relative burden of different disease, differentiating the health benefits produced by different 
treatments, and in screening individual patients. Although a generic HRQoL measure, the SF-

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36 is sensitive to variations in specific health states (known groups validity). For example, a 
study documenting the long term effects of NHL and its treatment found that those with 
comorbid health conditions had lower SF-36 physical functioning scores than those without 
such conditions (Mols et al. 2007). 
8.5.1.2 
FACT-Lym version 4 
The Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) is a questionnaire to 
assess the quality of life in patients with Lymphoma. The FACT-Lym questionnaire is 
composed of the FACT-General (FACT-G) – a 27-item compilation of general questions scored 
on a 5 point scale ranging from 0 = “not at all” to 4 = “very much” - and an additional 15 items 
that assess patient concerns relating to lymphoma: FACT-Lym lymphoma-specific subscale 
(FACT-LymS; range, 0-60). 
FACT-G items are divided into four primary HRQoL domains: PWB (Physical Well-Being; 
seven items, range 0-28), SWB (Social/Family Well-Being; seven items, range 0-28), EWB 
(Emotional Well-Being, six items, range 0-24), and FWB (Functional Well-Being and 
Additional Concerns; seven items range, 0-28). 
The FACT-LymS consists of common lymphoma disease and/or treatment-related symptoms 
(e.g., pain, fever, swelling, night sweats, insomnia, itching, weight loss, fatigue, and loss of 
appetite). Two summary scales: FACT-Lym trial outcomes index (FACT-Lym TOI; range: 0-
116; composed of the PWB, FWB, and FACT-Lym LYMS scales); FACT-Lym total score 
(FACT-Lym TS, range, 0-168; composed of all of the scales) can also be calculated. Negatively 
worded items are reverse scored prior to summing so that higher scores are reflective of better 
HRQoL. 
This scale is designed for patient self-administration. Patients should be instructed to read the 
brief. After the patient's correct understanding has been confirmed they should be encouraged 
to complete every item in order without skipping any. Some patients may feel that a given 
question is not applicable to them and therefore will skip the item altogether. Patients should 
be encouraged to check the response most applicable. 
8.5.1.3 
EQ-5D-5L 
The EQ-5D-5L is a widely used, self-administered questionnaire designed to assess health 
status in adults. The measure is divided into two distinct sections. The first section includes one 
item addressing each of five dimensions (mobility, self-care, usual activity, pain/discomfort, 
and anxiety/depression). Patients report each of these items from “no problem”, “slight 
problem”, “moderate problem”, “severe problem”, or “extreme problem.” A composite health 
index is then defined by combining the levels for each dimension. The second section of the 
questionnaire (EQ-VAS) measures self-rated (global) health status utilizing a vertically oriented 
visual analogue scale where 100 represents the “best possible health state” and 0 represents the 
“worst possible health state.” Respondents are asked to rate their current health by placing a 
mark along this continuum. The recall period is “today,” and the questionnaire requires 5 to 10 
minutes to complete. 

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8.5.2 
Pharmacokinetics/ Cellular Kinetics 
Cellular kinetic samples will be collected in all participants at the visits defined in the 
assessment schedule. Follow instructions outlined in the [CCTL019H2301 Laboratory Manual] 
regarding sample collection, numbering, processing and shipment. See the potential use of 
residual samples for more information. 
In order to better define the kinetic profile, the timing of the kinetic sample collection may be 
altered based on emergent data. 
The number of samples/blood draws and total blood volume collected will not exceed those 
stated in the protocol. 
Tisagenlecleucel transgene 
 measurement 
Tisagenlecleucel concentrations in peripheral blood (and bone marrow, CSF, and other tissues 
if available) will be listed, graphed and summarized by time points as assessed by the following: 
• Tisagenlecleucel transgene levels as measured by q-PCR 
 

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Descriptive statistics of cellular kinetics parameters (arithmetic and geometric means, standard 
deviation, CV%, CV% geometric mean, minimum, median and maximum) will be summarized 
by best overall response for all patients who receive tisagenlecleucel in arm A or after crossover. 
For Tmax only minimum, median and maximum will be presented. 
The linear trapezoidal linear interpolation rule will be used for AUC calculation. Regression 
analysis of the terminal plasma elimination phase for the determination of T1/2 will include at 
least 3 data points after Cmax. If the adjusted R2 value of the regression analysis of the terminal 
phase will be less than 0.6, no values will be reported for T1/2. 
Table 8-10 
Non compartmental cellular kinetics parameters 
Parameter 
Definition 
AUC 0 - 28d and/or 
AUC0-84d 
The AUC from time zero to day 28 and/or day 84 and or other disease assessment 
days, in peripheral blood (days*copies/ µg) 
Cmax 
The maximum (peak) observed in peripheral blood or other body fluid drug 
concentration after single dose administration (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 (copies/ug) 
Tlast 
The time of last observed quantifiable concentration in peripheral blood (days) 
 
 
 

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Table 8-11 
Validated analytical methods and limit of quantification associated 
with the cellular kinetic analytes and immunogenicity assessments 
Analyte 
Analytical 
method 
Units 
Lower limit of 
quantification 
(LLOQ) 
Type of 
biological 
sample 
Dataset 
tisagenlecleucel 
transgene 
Quantitative 
polymerase 
chain reaction 
(qPCR) 
copies/µg and/or 
copies/ µL 
10 copies/reaction 
equivalent to approx. 
50 copies/ug of 
genomic DNA 
Peripheral 
blood 
PAS 

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8.5.2.1 
Cellular kinetic blood collection and handling 
Sample(s) will be collected at the time point(s) defined in the assessment schedules below. 
 

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Table 8-12 
Tisagenlecleucel cellular kinetics by qPCR in peripheral blood collection log for patients in screening to 
randomization, Arm A, and in patients that cross over from Arm B to Arm A. 
 
 
 
Screening to Randomization Arm A 
Cross over from Arm B to 
Arm A 
 
Cycle 
Day** 
Scheduled Time 
Point relative to 
dosing* 
Dose 
Reference ID 
PK1 
Sample No 
Dose 
Reference ID 
PK1 
Sample No 
Dose 
Reference ID*** 
PK1 
Sample No 
Sample 
Volume (ml) 
1 
D1 Randomization 
Pre-dose 
- 
101 
- 
- 
- 
- 
3 
1 
Unscheduled cellular 
kinetic samplesa 
Pre-dose 
- 
10101 
- 
- 
- 
- 
3 
1 
Infusion (immediately prior 
to infusion) 
D1 (Pre-dose) 
- 
- 
1 
102 
- 
- 
3 
1 
Infusion +1d 
D2 
- 
- 
1 
103 
- 
- 
3 
1 
Infusion +3d ±1d 
D4 
- 
- 
1 
104 
2 
201 
3 
1 
Infusion +6d ±1d 
D7 
- 
- 
1 
105 
2 
202 
3 
1 
Infusion +10d ±3d 
D11 
- 
- 
1 
106 
2 
203 
3 
1 
Infusion +13d ±3d 
D14 
- 
- 
1 
107 
2 
204 
3 
1 
Infusion + 21d ±3d 
D22 
- 
- 
1 
108 
2 
205 
3 
1 
Infusion + 28d ±7d 
D29 
- 
- 
1 
109 
2 
206 
3 
1 
Week 12 ±7d 
Week 12 – RTI* 
- 
- 
1 
110 
2 
207 
3 
1 
M4±14d 
M4 – RTI* 
- 
- 
1 
111 
2 
208 
3 
1 
M6±14d 
M6 – RTI* 
- 
- 
1 
112 
2 
209 
3 
1 
M9±14d 
M9 – RTI* 
- 
- 
1 
113 
2 
210 
3 
1 
M12±14d 
M12 – RTI* 
- 
- 
1 
114 
2 
211 
3 
1 
M18±14d 
M18 – RTI* 
- 
- 
1 
115 
2 
212 
3 
1 
M24±14d 
M24 – RTI* 
- 
- 
1 
116 
2 
213 
3 
1 
M36±14d 
M36 –RTI* 
- 
- 
1 
117 
2 
214 
3 
1 
M48±14d 
M48 – RTI* 
- 
- 
1 
118 
2 
215 
3 
1 
M60±14d 
M60 – RTI* 
- 
- 
1 
119 
2 
216 
3 

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Screening to Randomization Arm A 
Cross over from Arm B to 
Arm A 
 
Cycle 
Day** 
Scheduled Time 
Point relative to 
dosing* 
Dose 
Reference ID 
PK1 
Sample No 
Dose 
Reference ID 
PK1 
Sample No 
Dose 
Reference ID*** 
PK1 
Sample No 
Sample 
Volume (ml) 
1 
Unscheduled cellular 
kinetic samples related to 
CRSb 
 
- 
- 
1 
10131 
2 
10201 
3 
1 
Unscheduled ( cellular 
kinetic samples related to 
non-CRS safety events)c 
 
- 
- 
1 
10151 
2 
10251 
3 
1 
Unscheduled ( cellular 
kinetic samples at 
relapse)d 
 
- 
- 
1 
10175 
2 
10275 
3 
*RTI refers to the time period between randomization (or the crossover visit) to infusion.  Since the time between randomization (or crossover visit) and infusion will be 
variable between patients, samples collected from Week 12 onward will have a variable time from the date of infusion, represented by the difference between the visit time 
and the RTI time.   
**Additional unscheduled samples may be collected as needed dependent upon individual patient differences in the clinical time-course of CRS, if clinically feasible.  
***The DRID of 2 refers to the first dose received for patients in the crossover arm and patients will not receive more than one dose of tisagenlecleucel, this distinguishes 
the dose reference ID from patients originally randomized to Arm A. 
a. Unscheduled  cellular kinetic samples for Screening to Randomizaton arm are uniquely, sequentially numbered as 10101, 10102 etc, 
b. Unscheduled  cellular kinetic samples related to a CRS events whereby tocilizumab is not administered are uniquely, sequentially numbered as 10131, 10132 etc.for 
Arm A; and 10201, 10202 etc, for Crossover Arm. See Table 8-18 for tisagenlecleucel kinetic collections (qPCR) when tocilizumab is administered during CRS. 
c. Unscheduled anytime cellular kinetic qPCRsamples related to other non-CRS safety events will be uniquely, sequentially numbered 10151, 10152 etc. for Arm A and 
10251, 10252 etc for Crossover Arm. Samples collected in this category also include additional qPCR samples collected to monitor the need for contraception during the 
long-term additional follow-up (after BIRC-confirmed SD/PD). 
d. In the event patient relapses, an unscheduled  cellular kinetic sample should be collected along with corresponding immunogenicity sample (refer to Table 8-16 and 
Table 8-17), and will be uniquely, sequentially numbered 10175, 10176 etc for Arm A and 10275, 10276 for Cross-over Arm. 

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Table 8-14 
Tisagenlecleucel cellular kinetics by q-PCR in bone marrow aspirate collection log for patients in screening to 
randomization, Arm A, and for patients that cross over from Arm B to Arm A. 
 
 
 
Screening to Randomization 
Arm A 
Crossover from Arm B to Arm 
A 
 
Cycle 
Day 
Scheduled 
time point 
relative to 
dosing* 
PK DRID 
(CTL019) 
PK3 Sample 
No. (CTL019) 
PK DRID 
(CTL019) 
PK3 Sample 
No. 
(CTL019)** 
PK DRID 
(CTL019)*** 
PK3 Sample 
No. (CTL019)** 
Sample 
Volume 
(mL) 
1 
Week 12±7d 
Week 12 – RTI* - 
- 
1 
501 
2 
601 
3 
1 
Unscheduled (e.g. at 
time of radiological 
CR, related to 
relapse)1 
 
- 
- 
1 
10551 
2 
10601 
3 
* RTI refers to the time period between randomization (or the crossover visit) to infusion.  Since the time between randomization (or the crossover visit) and infusion will 
be variable between patients, samples collected from Week 12 onward will have a variable time from the date of infusion, represented by the difference between the visit 
time and the RTI time.   
** Bone Marrow to be collected at or after Week 12 only if prior history of BM involvement, as clinically indicated in case of radiological CR. 
***The DRID of 2 refers to the first dose received for patients in the crossover arm and patients will not receive more than one dose of tisagenlecleucel, this 
distinguishes the dose reference ID from patients originally randomized to Arm A. 
1 Unscheduled cellular kinetic samples will be uniquely, sequentially numbered 10551, 10552 etc. for patient in Arm A and10601, 10602 etc. for patient in Crossover 
Arm 
Table 8-15 
Tisagenlecleucel cellular kinetics by q-PCR in CSF  
To be completed only if CSF collection performed. 
 
Arm A 
Crossover from Arm B 
to Arm A 
 
Day/ Scheduled Time Point 
PK5 Sample No. 
(CTL019) 
PK5 Sample No. 
(CTL019) 
Sample Volume 
Unscheduled (e.g. related to 
adverse event/relapse)1 
10801 
10901 
4-8 mL 
1Unscheduled cellular kinetic samples for Arm A will be uniquely, sequentially numbered 10801, 10802  etc., while 
for crossover arm, the samples will be numbered 10901, 10902 etc., respectively. 

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Table 8-16 
Humoral Immunogenicity serum sample collection for patients in screening to randomization, and Arm A, and in 
patients that cross over from Arm B to Arm A. 
 
Screening to 
Randomization 
Arm A 
Cross over from Arm B 
to Arm A 
Sample 
volume (mL) 
Day/ Scheduled Time Point 
Scheduled time point 
relative to dosing* 
IG1 Immunogenicity 
Sample Number 
IG1 Immunogenicity 
Sample Number 
IG1 Immunogenicity 
Sample Number 
 
D1 Randomization 
Pre-dose 
1101 
- 
- 
3 
Unscheduled samples1 
Pre-dose 
11151 
- 
- 
3 
Infusion -1d (pre-infusion) 
D-1 (Pre-dose) 
- 
2101 
3101 
3 
Infusion +13d ±3d 
D14 
- 
2102 
3102 
3 
Infusion +28d ±7d 
D29 
- 
2103 
3103 
3 
M4±14d 
M4- RTI* 
- 
2104 
3104 
3 
M6±14d 
M6- RTI* 
- 
2105 
3105 
3 
M12±14d 
M12- RTI* 
- 
2106 
3106 
3 
M18±14d 
M18- RTI* 
- 
2107 
3107 
3 
M24±14d 
M24- RTI* 
- 
2108 
3108 
3 
M60 ±14d /EOT 
M60- RTI* 
- 
2109 
3109 
3 
Unscheduled (at relapse)**,2 
 
- 
12151 
13151 
3 
Unscheduled (e.g. related to 
safety events)3 
 
- 
12175 
13175 
3 
* RTI refers to the time period between randomization (or the crossover visit) to infusion.  Since the time between randomization (or the crossover visit) and infusion will 
be variable between patients, samples collected from Week 12 onward will have a variable time from the date of infusion, represented by the difference between the 
visit time and the RTI time  
** In the event patient relapses, an unscheduled humoral immunogenicity sample should be collected along with corresponding cellular kinetic sample (refer to Table 8-
12, Table 8-13, Table 8-14, and Table 8-15) 
1Unscheduled humoral immunogenicity samples are uniquely, sequentially numbered 11151, 11152 etc. for Screening to Randomization Arm. 
2Unscheduled humoral immunogenicity samples related to a relapse are uniquely, sequentially numbered 12151, 12152 etc.for Arm A and 13151, 13152 etc. for 
Crossover arm. 
3Unscheduled humoral immunogenicity samples related to safety events will be uniquely, sequentially numbered 12175, 12176 etc. for Arm A and 13175, 13176 etc. 
for Crossover Arm. 
Note: Long-term additional follow-up collection after SD/PD confirmed by BIRC as per Table 8-2 and Table 8-4 are collected with the same sample numbers as at 
Month 6 and 12 above.  Month 9 can be collected as unscheduled visit. 

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Table 8-17 
Cellular Immunogenicity peripheral blood sample collection log for patients in screening to randomization, and 
Arm A, and in patients that cross over from Arm B to Arm A. 
Scheduled time point 
relative to dosing* 
Screening to 
Randomization 
Arm A 
Cross over from Arm B 
to Arm A 
Sample 
volume (mL) 
Day/ Scheduled Time Point 
 
IG2 Immunogenicity 
Sample Number 
IG2 Immunogenicity 
Sample Number 
IG2 Immunogenicity 
Sample Number 
 
D1 Randomization 
Pre-dose 
4101 
- 
- 
6 
Unscheduled samples1 
Pre-dose 
14151 
- 
- 
6 
Infusion-1d (pre-infusion) 
D-1 Pre-dose 
- 
5101 
6101 
6 
Infusion + 13d ±3d 
D14 
- 
5102 
6102 
6 
Infusion + 28d ±7d 
D29 
- 
5103 
6103 
6 
M4±14d 
M4- RTI* 
- 
5104 
6104 
6 
M6±14d 
M6- RTI* 
- 
5105 
6105 
6 
M12±14d 
M12- RTI* 
- 
5106 
6106 
6 
M18±14d 
M18- RTI* 
- 
5107 
6107 
6 
M24±14d 
M24- RTI* 
- 
5108 
6108 
6 
M60 ±14d /EOT 
M60- RTI* 
- 
5109 
6109 
6 
Unscheduled (at relapse)**,2 
 
- 
15151 
16151 
6 
Unscheduled (e.g. related to 
safety events)3 
 
- 
15175 
16175 
6 
* RTI refers to the time period between randomization (or the crossover visit) to infusion.  Since the time between randomization (or the crossover visit) and infusion will 
be variable between patients, samples collected from Week 12 onward will have a variable time from the date of infusion, represented by the difference between the 
visit time and the RTI time  
** In the event patient relapses, an unscheduled cellular immunogenicity sample should be collected along with corresponding cellular kinetic sample (refer to Table 8-
12, Table 8-13, Table 8-14, and Table 8-15) 
1Unscheduled cellular immunogenicity samples are uniquely, sequentially numbered 14151, 14152 etc. for Screening to Randomization Arm. 
2Unscheduled cellular immunogenicity samples related to a relapse are uniquely, sequentially numbered 15151,15152 etc.for Arm A and 16151, 16152 etc. for 
Crossover arm. 
3Unscheduled cellular immunogenicity samples related to safety events will be uniquely, sequentially numbered 15175, 15176 etc. for Arm A and 16175, 16176 etc. for 
Crossover Arm. 
Note: Long-term additional follow-up collection after SD/PD confirmed by BIRC as per Table 8-2 and Table 8-4 are collected with the same sample numbers as at 
Month 6 and 12 above. .  Month 9 can be collected as unscheduled visit. 

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Table 8-18 
Tisagenlecleucel cellular kinetics by qPCR in tocilizumab treated patients during CRS in Arm A and in patients 
that crossover from Arm B to Arm A 
Day/ Scheduled Time Point*/** 
Toci Dose Reference 
ID 
tisagenlecleucel Dose 
Reference ID§ 
tisagenlecleucel cellular 
kinetics by qPCR Sample 
Number^ 
Sample Volume 
(whole blood) 
D1 1h ± 15 min post infusion 
101 
1/2 
251 
2 mL 
D2 ± 2h 
101 
1/2 
252 
2 mL 
D3 ± 4h 
101 
1/2 
253 
2 mL 
D7 ± 1d 
101 
1/2 
254 
2 mL 
D1 (pre-dose; second infusion) 
101 
1/2 
255 
2 mL 
D2 ± 2h from second infusion 
102 
1/2 
256 
2 mL 
D3 ± 4 hours (post second infusion) 
102 
1/2 
257 
2 mL 
D7±1d (post second infusion) 
102 
1/2 
258 
2 mL 
D1 (5-15 minutes pre-dose; additional infusion) 
102 
1/2 
259 
2 mL 
D2 ± 2 hours 
103 
1/2 
260 
2 mL 
D3 ± 4 hours 
103 
1/2 
261 
2 mL 
D7 ± 1d 
103 
1/2 
262 
2 mL 
Unscheduled*** 
104,105 
1/2 
10263, 10264, 10265, 
10266 
2 mL 
* Scheduled timepoints are relative to date of tocilizumab infusion 
**Samples may be collected as needed dependent upon administration of tocilizumab, if clinically feasible. 
§ For patients in Arm A, the tisagenlecleucel dose reference ID will be 1, while for patients in Crossover Arm, the tisagenlecleucel dose reference ID will be 2. Patients 
in either arm will not receive more than one dose of tisagenlecleucel. 
Unscheduled tisagenlecleucel cellular kinetics sample collections related to CRS as specified in Table 8-12 will cease once cellular kinetic sample collections related to 
tocilizumab administration commence according to Table 8-18, if applicable. 
^ Cellular kinetic collections for CTL019 measured by qPCR will be numbered starting with 251, 252 etc. series  
*** Unscheduled cellular kinetic samples collected in the event more than 2 tocilizumab doses are administered should follow additional cellular kinetic collection and 
numbering schedule (eg. 10263, 10264, etc). 

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8.5.2.2 
Analytical method 
All the cellular kinetic analytes along with the analytical methods and the associated limit of 
quantification are summarized in Table 8-11. 

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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
A single tisagenlecleucel infusion may be discontinued if, in the investigator’s opinion, its 
continuation would be detrimental to the patient's safety. 
For patients randomized to Arm B (SOC) arm or patients who never receive tisagenlecleucel in 
Arm A, study treatment includes multiple lines of salvage immunochemotherapy as per local 
practice. Discontinuation of study treatment for a patient occurs when this study treatment is 
stopped earlier than the planned duration according to local guidelines and the approved drug 
label, and can be initiated by either the patient or the investigator. 

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Regardless of treatment arm, patients should NOT be considered withdrawn from treatment and 
primary follow-up, before they return for the safety follow-up visit,  and the Month 60/EOT 
assessments indicated in Section 9.2. If they fail to return for these assessments, every effort 
(e.g. telephone, email, letter) should be made to contact them. 
Study treatment must be discontinued under the following circumstances 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which study participation might result in a safety risk to the participant 
• Any AEs that in the judgment of the investigator, prevents the patient from continuing 
study treatment” 
• Any laboratory abnormalities that in the judgment of the investigator, prevents the patient 
from continuing study treatment 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the participant/pre-designated contact as specified in the lost to follow-up Section 
9.1.4. This contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• new / concomitant treatments 
• adverse events/serious adverse events 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be 
performed as per the visit evaluation schedule until documented disease progression per BIRC, 
death, lost to follow-up, or withdrawal of consent. 
9.1.2 
Criteria for premature patient discontinuation from the study 
Patients must be followed according to the visit schedule to ensure adequate data are collected 
for the proper assessment of study primary and secondary objectives. 

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All patients should be kept on study until the Month 60 visit whenever possible. It is anticipated 
that patients who received tisagenlecleucel treatment may discontinue from the primary follow-
up (efficacy portion of the study) due to BIRC-confirmed disease PD/SD and only require the 
collection of key safety data in the long term additional follow-up. In cases where a patient 
discontinues without BIRC confirmed PD/SD, it may be possible for the patient to be followed 
for only key safety follow-up (without efficacy assessment) only after consultation and 
documented agreement with the Novartis medical monitor. 
After 5 years of long term follow-up, patients who receive tisagenlecleucel will be asked to join 
the separate long term follow-up study (CCTL019A2205B). If patients move to the long term 
follow-up study, survival status should still be collected in this study until the end of study, 
defined as the last visit for the last patient randomized. The appropriate disposition eCRF should 
be recorded when the patient moves into the separate long term additional follow-up study and 
if the patient withdraws from the study prematurely. 
Patients may voluntarily withdraw from the study or be withdrawn from the study at the 
discretion of the investigator at any time. Patients may also request to only be followed for 
survival at any time. 
Patients may be withdrawn from the study if any of the following occur: 
• The patient is lost to follow-up 
• Patient noncompliance with study therapy and/or clinic appointments 
• Voluntary withdrawal; a patient may remove himself/herself from the study at any time 
without prejudice. 
• Termination of the study by the sponsor or the health authorities 
9.1.3 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: · 
• Does not want to participate in the study anymore, and · 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. Study treatment must be discontinued and no further assessments 
conducted, and the data that would have been collected at subsequent visits will be considered 
missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. All efforts should be made to complete the assessments prior to 
study withdrawal. A final evaluation at the time of the participant’s study withdrawal should be 
made as detailed in the assessment table based on which phase of the study the patient is 
currently in (Primary Follow Up, Long term follow up, or Survival follow up). 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a participant’s samples until their time of withdrawal) according to 
applicable law. 

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For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
9.1.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.1.5 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time.  
Reasons for early termination may include: 
• Unexpected, significant or unacceptable safety risk(s) to patients enrolled in the study,  
• Decision based on recommendation from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development  
In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible 
(provide instruction for contacting the participant, when the participant should stop taking drug, 
when the participant should come for a final visit) and the same assessments should be 
performed as described in Section 8 for a discontinued or withdrawn participant. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the participant’s interests. For participants 
who have received a tisagenlecleucel infusion, a long term post-study follow-up for lentiviral 
vector safety will still continue under a separate destination protocol for 15 years post infusion 
per health authority guidelines.  
The investigator or sponsor depending on the local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial. 
9.1.6 
Criteria for stopping or pausing the study 
The study will be paused, and health authorities notified if: 
• Any participant develops detectable replication competent lentivirus (RCL) during the 
study 
• The Sponsor, DMC (if applicable), or any regulatory body decides for any reason that 
participant safety may be compromised by continuing the study 

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• The Sponsor decides to discontinue the development of the intervention to be used in this 
study 
The study may be paused pending notification of the health authorities and the DMC for 
investigation and possible protocol amendment if any participant experiences any of the 
following events within three weeks of the tisagenlecleucel cell infusion and re-infusion: 
• Life-threatening (grade 4) toxicity attributable to protocol therapy that is unmanageable, 
unexpected and unrelated to chemotherapy and attributable to protocol therapy. High 
fevers, hypotension, hypoxia, disseminated intravascular coagulation, encephalopathy 
(e.g. lethargy, confusion, aphasia, seizure), ICU admission, dialysis and mechanical 
ventilation are expected. The expected adverse effects can also result in grade 4 liver 
toxicity, nephrotoxicity and cardiac dysfunction. 
• Death suspected to be related to tisagenlecleucel therapy 
9.2 
Study completion and post-study treatment 
All randomized patients should have a safety follow-up visit conducted 8 weeks after their last 
treatment administration or prior to starting another anticancer therapy, whichever occurs first. 
For ease of scheduling, the safety follow-up visit can occur as late as 9 weeks from their last 
treatment administration. The information collected is kept as source documentation. All SAEs 
reported during this time period must be reported as described in Section 10.1.3. Patients should 
continue to be followed under the current protocol for key safety and survival, as per the 
survival follow-up in Table 8-2, Table 8-3, and Table 8-4 and the long term additional follow-
up schedule in Table 8-2 and Table 8-4. Survival assessments can be conducted via a form or 
telephone contact until last patient last visit (LPLV)as defined above. 
The end of study is the when all participants have completed Month 60/EOT evaluation or were 
withdrawn prematurely, and any repeat assessments associated with this visit have been 
documented and followed-up appropriately by the Investigator, or in the event of an early study 
termination decision, the date of that decision. Participants who have completed their Month 
60/EOT visit before the end of the study (defined as the last visit for the last patient randomized) 
will be followed every 3 months (q3m) until the end of the study for survival information, and 
will also be asked to join the separate LTFU study (CCTL019A2205B). 
The primary analysis will occur when approximately 200 of EFS events is reached. At this time, 
the primary clinical study report (CSR) will be produced. After the primary analysis of EFS, 
the study will remain open provided the EFS demonstrates treatment benefit. If the primary 
analysis of EFS does not demonstrate treatment benefit, the follow-up for OS will end. 
Participants still being followed on the study after the primary analysis time point will continue 
as per the schedule of assessments. The study will end once the final OS analysis is performed 
when statistical significance is reached for OS analysis, see the statistical model, hypothesis, 
and method of analysis section) and the final analysis of study data is conducted. All available 
data from all participants up to this cutoff date will be analyzed.  
At the time of the end of this study (defined as the last visit for the last patient randomized), 
participants continuing to derive benefit from the comparator treatment in the opinion of the 
Investigator may continue such treatment at the investigators discretion according to local 
clinical practice. 

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In addition, semiannual and annual evaluations will be performed for up to 15 years from the 
date of tisagenlecleucel infusion on all participants. Patients should be followed for the first 5 
years on this protocol and an additional 10 years  under a separate long term follow-up (LTFU) 
protocol as recommended by health authority guidance for participants treated with gene 
therapies. Patients who receive tisagenlecleucel will be asked to join a separate long term follow 
up study [CCTL019A2205B]. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant 
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
infusion of tisagenlecleucel. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. Adverse events also may be detected when they are volunteered by the 
participant during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event. 
Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. the grade according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0, with the exception of CRS, which will follow Table 4-2. If CTCAE grading 
does not exist for an AE, the severity of mild, moderate, severe, life-threatening and fatal, 
corresponding to Grades 1 - 5, will be used. 
2. its relationship to the study treatment and other investigational treatment If the event is 
due to lack of efficacy or progression of underlying illness (i.e. progression of the study 
indication) the assessment of causality will usually be ‘Not suspected’. The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 

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both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single participant. 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. whether it constitutes a serious adverse events (SAE) (see Section 10.1.2 for definition of 
SAE) and which seriousness criteria have been met. 
5. action taken regarding with study treatment. 
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• Dose not changed 
• Dose reduced/increased 
• Drug interrupted/withdrawn 
6. its outcome, i.e., its recovery status or whether it was fatal. 
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For AEs grade 3 and 4 only, if improvement to a lower 
grade is determined, a new entry for this event should be reported in the eCRF noting the start 
date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history eCRF. 
Adverse events (including laboratory abnormalities that constitute AEs) should be described 
using a diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for the duration as specified in Section 10.1.1. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g., continuing at the end of the study), and assessment should be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the study treatment, the interventions required to treat it, and the outcome. Non-fatal disease 
progression should not be reported as AE 
Adverse events separate from the progression of malignancy (e.g., deep vein thrombosis at the 
time of progression or hemoptysis concurrent with finding of disease progression) will be 
reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the treatment. 
Information about adverse drug reactions for tisagenlecleucel  can be found in the 
[Tisagenlecleucel Investigator's Brochure], for drugs used for optional bridging chemotherapy, 
lymphodepleting chemotherapy and standard of care refer to the local label. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 

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Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participants 
with the underlying disease. 
From the time of signing the ICF to the safety follow-up visit, all new or worsening AEs 
(including laboratory or test abnormalities deemed clinically significant by the investigator), 
regardless of causality will be recorded in the Adverse Events eCRF. Any AE, which started 
prior to the safety follow-up visit and is ongoing at the time of the visit, should continue to be 
followed until resolution. The primary safety analysis will occur using only those events which 
occur during this time period for both arms. 
The safety follow-up visit should occur 8 weeks (56 days) after last treatment administration or 
prior to starting new anticancer therapy, whichever occurs first. After the safety follow-up visit, 
the collection of certain adverse events (Section 16.3 Appendix 3) through 5 years is required 
for all patients treated with tisagenlecleucel, while AEs are no longer reportable for patients 
who did not receive tisagenlecleucel.  Patients in arm B who have the safety follow-up visit 
(indicating the end of AE collection), and then crossover to Arm A, should report from the time 
of the crossover visit to the next safety follow-up visit all new or worsening AEs (including 
laboratory or test abnormalities deemed clinically significant by the investigator), regardless of 
causality. After this next safety follow-up visit (as per Table 8-4), the collection of certain 
adverse events (Section 16.3 Appendix 3) through 5 years is required for all patients treated 
with tisagenlecleucel. 
After 5 years (end of this study), patients who received tisagenlecleucel should be offered 
enrollment into long-term follow-up study CCTL019A2205B to monitor patients up to 15 years 
post tisagenlecleucel. 
Detailed guidance on the reporting requirements for non-serious and serious AEs, in addition 
to  concomitant medication and laboratory results during the relevant study period are provided 
in Section 16.3 Appendix 3. 
Detailed information regarding CRS adverse events (e.g. oxygen requirements, vasopressor 
usage) will be collected to allow for assessment using alternative CRS grading scales (e.g. 
ASTCT consensus grading). 
10.1.2 
Serious adverse events 
An SAE is defined as any AE (appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 

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• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Progression of malignancy with fatal outcome must be reported as an SAE within 24 hours of 
awareness, if the following criteria are met: 
• Death within 30 days after tisagenlecleucel infusion, irrespective of causality to 
tisagenlecleucel  
• Death beyond 30 days after tisagenlecleucel infusion, if there is at least a possible 
causality to tisagenlecleucel  
Non-fatal disease progression should not be reported as SAE 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent to Novartis safety within 24 hours of learning of its occurrence. 
The duration of this SAE reporting requirement is outlined in Section 10.1.1. Detailed 
instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 

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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety (CMO&PS) Department associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
SAEs will be followed until resolution or until clinically relevant improvement or stabilization.. 
10.1.4 
Adverse events of special reporting requirements 
If specifically requested by a local Health Authority, expedited reporting of pre-specified AEs 
will occur. 
10.1.5 
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant 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. In case of live birth, the 
newborn should be followed up until 12 months of age to detect any developmental issue or 
abnormality that would not be seen at birth. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to tisagenlecleucel infusion 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
10.1.6 
Reporting of study treatment errors 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (European Medicines Agency (EMA) definition). 

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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing CRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated 
with an SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional safety monitoring 
10.2.1 
Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
tisagenlecleucel, a standardized process for identification, monitoring and evaluation of liver 
events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE): 
• Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter 
• Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs 
Please refer to Table 16-7 in Section 16.4 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver event defined in Table 16-7 should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case 
of liver events are outlined in Table 16-8. Repeat liver chemistry tests (ALT, AST, TBILI, 
PT/INR, ALP and gamma glutanyl transferase (GGT)) to confirm elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a 
local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate CRF 
If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 

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• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
Section 9.1.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event, which can include based on investigator’s 
discretion: 
• Serology tests, imaging (e.g., such as abdominal ultrasound (US), CT or MRI, as 
appropriate) and pathology assessments, gastroenterologist’s or hepatologist’s 
consultancy; obtaining more detailed history of symptoms and prior or concurrent 
diseases, history of concomitant drug use, exclusion of underlying liver disease, 
obtaining a history of exposure to environmental chemical agents. 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. 
10.2.2 
Renal safety monitoring 
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study: 
• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
• Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR new onset dipstick 
proteinuria ≥ 3+ OR new onset dipstick hematuria ≥ 3+ (after excluding menstruation, 
urinary tract infection, extreme exercise, or trauma) 
Renal event findings must be confirmed 24-48 hours after the first assessment (select as 
applicable: for Phase 1 and early Phase 2) OR 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 as defined in Table 16-9 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Table 16-9. 
10.2.3 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
and safety data of the clinical trial, and recommend to the sponsor whether to continue, modify 
or terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between the sponsor and the DMC. 
10.2.4 
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 

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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. 
10.2.5 
Blinded independent review committee (BIRC) 
A BIRC will be established to review data related to disease response assessments during the 
study, before randomization and determine response and relapse for the primary analysis. A 
BIRC charter will detail the BIRC data flow and review process in alignment with the response 
definitions in Section 16.2 Appendix 2. Patient management will be based upon local 
investigator assessments except for the eligibility crossover. The designation of response and 
relapse for the primary analysis and other related secondary efficacy endpoints will be based on 
the evaluations made by the BIRC. Details regarding the constitution of the BIRC and its 
specific roles will be documented in the BIRC charter and agreed upon between Novartis and 
the BIRC before initiation of any BIRC review. 
10.2.6 
Follow up of secondary malignancy 
For patients treated with tisagenlecleucel, treating physician/ healthcare providers should 
contact Novartis if the patient develops a secondary malignancy. Upon clinical confirmation 
secondary malignancy, blood samples should be collected for cellular kinetic analysis by 
qPCR 
. Two tubes of blood are requested: 10 ml sample of peripheral 
blood mononuclear cells (PBMCs) in a sodium heparin collection tube and 6 ml of blood in 
ethylenediaminetetraacetic acid (EDTA) tube. 
 
. 
 
  
Additional details for sample handling and shipping are outlined in the [CCTL019H2301 
Laboratory Manual]. 
11 
Data collection and database management 
11.1 
Data collection 
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 electronic data capture (EDC) system until they have been trained. 
Automatic validation programs check for data discrepancies in the eCRFs, allow modification 
and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 

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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical (ATC) 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Randomization codes will be tracked using an Interactive Response Technology (IRT). The 
system will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis/ CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 

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adherence to PRO assessment, documentation of SAEs, and of data that will be used for all 
primary variables. Additional checks of the consistency of the source data with the CRFs are 
performed according to the study-specific monitoring plan. No information in source 
documents about the identity of the participants will be disclosed. 
12 
Data analysis and statistical methods 
It is planned that the data from all centers participating in the trial will be combined, so that an 
adequate number of patients are available for analysis. Novartis and/or a designated CRO will 
perform the final EFS analyses. Any data analyses performed independently by any investigator 
should be submitted to Novartis before publication or presentation. 
The primary efficacy and safety analyses will be performed after observing approximately 200 
EFS events have been documented by BIRC. Following the primary analysis for EFS, the study 
will remain open. Patients still being followed on the study will continue as per the schedule of 
assessments. 
The study will end once the final OS analysis is performed at approximately 5 years from the 
1st patient randomized to the study, or earlier, if statistical significance is reached at the interim 
analysis for OS at the time of the primary analysis of EFS, at which point the final CSR will be 
published. All available OS and safety data from all patients up to this cutoff date will be 
analyzed. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The analysis sets to be used are defined below.  
12.1.1 
Screened Set 
The Screened Set comprises all patients who have signed informed consent and were screened 
in the study. 
12.1.2 
Infused Set 
The Infused set comprises all participants who received infusion of tisagenlecleucel. The 
Infused set will be used for efficacy and safety summaries of participants infused with 
tisagenlecleucel.  
12.1.3 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
The Full Analysis Set (FAS) will be used as the main analysis set for efficacy, demographics 
and other baseline characteristics. 

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12.1.4 
Safety Set 
The Safety Set includes all patients to whom study treatment has been assigned by 
randomization. The Safety set will be used for all randomized safety comparisons. Please note 
in this study, the Safety set is the same as the FAS.  
12.1.5 
Per-Protocol Set 
The Per-Protocol Set (PPS) consists of a subset of patients in the FAS who are compliant with 
requirements of the clinical study protocol (CSP). 
Protocol deviations leading to exclusion from the PPS include: 
• Diagnosis of disease other than histologically confirmed, aggressive B-cell NHL at relapse 
/progression or PR after front line therapy (inclusion criterion #3); 
The detailed exclusion criteria of PPS will be determined and documented in the study 
Statistical Analysis Plan (SAP). 
12.1.6 
Cellular Kinetic Analysis Set 
The tisagenlecleucel cellular kinetic analysis set (CKAS) consists of patients in the FAS who 
have received one dose of tisagenlecleucel and have at least one evaluable cellular kinetic 
parameter. The CKAS will be used for summaries (tables and figures) of cellular kinetic data. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data will be listed and summarized descriptively by treatment 
arm for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, 
summary statistics will be presented (i.e., including mean, standard deviation, median, 
minimum, and maximum). For selected parameters, 25th and 75th percentiles will also be 
presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment arm. Number and percentage of patients 
who received prior anti-neoplastic medications/therapies will be summarized. Patients will be 
classified by their prior treatment response. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
For patients who received tisagenlecleucel infusion, the total cells infused (cells) and total 
tisagenlecleucel transduced viable T cells infused (cells) will be listed and summarized using 
descriptive statistics. Patients will be categorized as below, within or above the prescribed dose 
range. 
For patients who received standard of care therapy, the medication name, length of therapy and 
total dose will be listed and summarized using descriptive statistics. 

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Concomitant medications and significant non-drug therapies prior to and after the start of 
tisagenlecleucel infusion or SOC treatment(s) will be listed by patient and summarized by the 
Anatomical Therapeutic Chemical (ATC) term classification system, by treatment arm. 
Lymphodepleting chemotherapies will be listed and summarized. Transfusion during the study 
will be listed. In addition, anti-cytokine medications for the management of CRS will be 
summarized. 
12.4 
Analysis of the primary endpoint 
The primary aim of the study is to compare two second line treatment strategies in adult patients 
with aggressive B-cell non-Hodgkin lymphoma who are refractory to or relapsed after frontline 
standard of care and are eligible for stem cell transplantation. The treatment strategies will be 
compared based on their effect on delaying the composite event of disease progression / stable 
disease at or after the week 12  assessment or death at any time. These two treatment strategies 
will be compared based on all randomized patients, irrespective of whether the patient received 
all or some of the components of the randomized treatment. Intercurrent events preventing 
compliance with these strategies such as initiation of alternative cancer therapies prior to the 
composite event of interest, will be handled accordingly. A Cox regression model stratified by 
randomization stratification factors will be used to estimate the hazard ratio (HR) of EFS. 
12.4.1 
Definition of primary endpoint 
The primary endpoint of the study is event-free survival (EFS), defined as the time from the 
date of randomization to the date of the first documented disease progression or stable disease 
at or after the week 12 assessment, as assessed by BIRC per Lugano criteria (see Section 16.2 
Appendix 2 for further details), or death due to any cause, at any time. Censoring conventions 
are provided in Section 12.4.3. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The following statistical hypothesis will be tested to address the primary efficacy objective: 
H01: θ1 ≥ 1 vs. HA1: θ1 < 1where θ1 is the hazard ratio (tisagenlecleucel arm vs. SOC arm) of 
EFS . The primary efficacy analysis to test this hypothesis will be conducted using a stratified 
log-rank test at the one-sided 2.5% level of significance. The stratification will be based on the 
randomization stratification factors, i.e., remission duration (refractory to front line therapy or 
relapsed <6 months vs. relapsed at 6 - 12 months),IPI score (<2 vs. ≥2) (The International Non-
Hodgkin's Lymphoma Prognostic Factors Project 1993; Moskowitz 1999), and region (North 
America vs. Rest of World). 
The analysis of EFS will be based on the FAS according to the randomized treatment arm and 
strata assigned at randomization. The distribution of EFS will be estimated using the Kaplan-
Meier method. Kaplan-Meier curves, medians and 95% confidence intervals of the medians 
will be presented for each treatment arm. The hazard ratio for EFS will be calculated, along 
with its 95% confidence interval, from a stratified Cox model using the same stratification 
factors as for the log-rank test. 
There will be no interim analysis for EFS. The analysis for EFS in the FAS will be performed 
after approximately 200 EFS events have been documented by the BIRC.  

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12.4.3 
Handling of missing values/censoring/discontinuations 
If no EFS event is observed prior to the earliest censoring event, EFS will be censored at the 
date of the last adequate assessment prior to the earliest censoring event. The censoring events 
include lost to follow-up, withdrew consent, analysis cut-off, and initiation of new cancer 
therapy. 
The following scenarios after randomization will be considered as initiation of new cancer 
therapy and EFS will be censored: 
In tisagenlecleucel arm, 
• start any anti-CD19 or gene therapy other than tisagenlecleucel, 
• start conditioning therapy with intention of HSCT 
• start any anti-neoplastic therapy at any time after tisagenlecleucel infusion 
• start any anti-neoplastic therapy other than optional bridging therapy or lymphodepleting 
chemotherapy prior to tisagenlecleucel infusion (including for patients who do not go on 
to receive tisagenlecleucel) 
In the SOC arm, 
• start anti-CD19 or gene therapy including tisagenlecleucel 
• start any anti-neoplastic therapy other than protocol allowed SOC treatment options prior 
to HSCT (including for patients who do not go to HSCT) 
• start of any anti-neoplastic therapy at any time after HSCT 
12.4.4 
Sensitivity and supportive analyses 
Due to the  delay between randomization and tisagenlecleucel infusion, a weighted log rank test 
may be used as a sensitivity analysis. For example a piecewise weighted log-rank test (e.g., 
assigning weights of 0 to event times in the delayed period and weights of 1 thereafter), or 
Fleming-Harrington (FH) weighted log-rank test (e.g. FH (0,1) to assign more weight to later 
events) etc. The exact weights to be used will be defined in the statistical analysis plan 
The hazard ratio and 95% confidence interval for EFS per BIRC assessment based on: 
• An unstratified and covariate unadjusted Cox model. 
• A stratified and covariate adjusted Cox model including as covariates the following: (age, 
race, gender, etc.) 
EFS as per investigator assessment will be analyzed using a stratified Cox model, with the same 
analysis conventions as the primary efficacy analysis, and the treatment effect will be 
summarized by the hazard ratio with its 95% confidence interval. Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians will be presented for each treatment 
group. 
The following two supportive analyses will also be performed: 
• EFS per BIRC irrespective of new anti-cancer therapy for lymphoma, i.e., EFS events will 
be counted even if occurring after start of a new anti-cancer therapy. This corresponds to a 
fully intention-to-treat approach for both treatment strategies. 

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• EFS per BIRC considering new anti-cancer therapy for lymphoma at any time as an EFS 
event.  
Depending on the amount of missing assessments, further sensitivity analyses may be 
considered, for example, if an EFS event is observed after two or more missing or non-adequate 
tumor assessments, then EFS will be censored at the last adequate assessment before the EFS 
event. 
These analyses will include Kaplan-Meier medians with their 95% confidence intervals, and 
summarized by hazard ratio with its 95% confidence interval. 
EFS per BIRC review will be analyzed based on the Per Protocol Set, using the same analysis 
conventions as in the primary efficacy analysis (with the exception of the log-rank test, which 
will not be performed). 
If the primary analysis is statistically significant, subgroup analyses to assess the homogeneity 
of the treatment effect across demographic and baseline disease characteristics will be 
performed based on the following: 
• Remission duration (refractory to front line therapy or relapsed <6 months vs. relapsed 6 - 
12 months)  
• IPI score (<2 vs. ≥2)  
• Region (North America vs. Rest of World) 
• Age: <65 years, ≥ 65 years 
• Gender: Male, Female 
• Race: Asian, Black, Caucasian, Other, 
• Ethnicity: Hispanic or Latino, Chinese, Indian, Japanese, Mixed ethnicity, Other 
• Prior response status: Primary refractory, relapsed 
• Histology: e.g. DLBCL, NOS, FL3B, Other 
• Disease stage at study entry: I/II vs III/IV 
• DLBCL cell of origin subtype: GCB, ABC, Other 
• Rearrangements in MYC/BCL2/BCL6 genes: Double/Triple hits, Other 
The analyses will include Kaplan-Meier summaries and hazard ratios (together with associated 
95% CI) from stratified Cox models. Subgroup analyses will only be performed if adequate 
number of events are observed. 
The number of participants censored and reasons for censoring will be summarized by treatment 
group using descriptive statistics, presented separately for local review and BIRC. 
12.5 
Analysis of secondary endpoints 
The secondary objectives in this study are to compare the two treatment groups with respect to 
overall survival (OS), and to evaluate the overall response rate (ORR), duration of response 
(DOR), time to response (TTR), PRO, and safety. 
There are no key secondary endpoints in this study. 

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Overall survival (OS), defined as time from the date of randomization to date of death due to 
any cause, will only be formally tested between the two treatment arms, if the primary endpoint 
(EFS by BIRC) is significant. 
Testing of the null hypothesis, that the survival functions for OS in the two arms are identical, 
will be conducted by stratified log-rank tests in the FAS as part of a group sequential design 
with two looks. The interim analysis of OS will be at the time of the primary analysis for EFS, 
and the final analysis will be 5 years after randomization of the first patient if OS is not 
significant at the time of primary analysis. A Haybittle-Peto boundary will be used, where the 
one-sided significance level is 0.05% at the interim analysis and 2.5% at the final analysis. The 
stratification will be based on the randomization stratification factors, i.e., remission duration 
(refractory to front line therapy or relapsed <6 months vs. relapsed 6 - 12 months), IPI score 
(<2 vs. ≥2) and region (North America vs. Rest of World). 
Patients in SOC arm are eligible to cross over to tisagenlecleucel treatment, after BIRC-
confirmed progression of disease or continuation of stable disease at or after the week 12  
assessment up until one year after HSCT. The primary analysis of OS will be based on the 
intent-to-treat (ITT) population, i.e., patients randomized to SOC arm who cross over to 
tisagenlecleucel arm will be considered to be in the SOC arm for OS analysis. As a sensitivity 
analysis, methods of analysis of OS accounting for crossover (for example,
 
 will be considered. 
If death has not been observed by the date of analysis cutoff, OS will be censored at the date of 
last contact. 
Distribution of OS will be estimated using the Kaplan-Meier method. The median OS and the 
proportion of patients alive at 6, 12 weeks, 6, 12, 18, 24, 36, 48 and 60 months with 95% 
confidence intervals will be presented by treatment arms. The hazard ratio (HR) of OS will be 
summarized along with 95% confidence interval. 
 
12.5.1 
Efficacy and/or pharmacodynamic endpoints 
BIRC assessment as well as investigator assessment will be used for the analysis of secondary 
endpoints that involve disease response. Specifications below are described for BIRC, and the 
same analyses will be repeated for investigator, unless specified otherwise. 
12.5.1.1 Overall response rate (ORR) 
Overall response rate (ORR) is defined as the proportion of participants with best overall 
response (BOR) of complete response (CR) or partial response (PR) on or after the Week 12 
assessment, as per BIRC and according to the Lugano criteria (see Section 16.2 Appendix 2 for 
details). 
ORR and its 95% confidence interval will be presented by treatment arm in the FAS. As a 
sensitivity analysis, ORR as per investigator assessment will be presented by treatment group, 
along with 95% confidence intervals. A further sensitivity analysis for ORR will be performed 
in the tisagenlecleucel arm using evidence of disease at the Week 6 assessment (i.e., after the 

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end of bridging chemotherapy). A descriptive summary of patients’ disease response status at 
the Week 6 assessment will also be provided.  
12.5.1.2 Duration of response (DOR) 
Duration of response (DOR) only applies to patients whose best overall response is complete 
response (CR) or partial response (PR) according to Lugano criteria based on disease response 
data per BIRC. It is defined as the time from the date of first documented response of CR or PR 
to the date of first documented progression (SD or PD at or after the week 10 will be considered 
progression) or death due to aggressive B-cell NHL. 
In case a patient does not have progression or death due to aggressive B-cell NHL 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 same censoring reasons and censoring date options used in the 
primary EFS analysis will be used for DOR, with the addition of death due to reason other than 
aggressive B-cell NHL. 
The distribution of DOR will be estimated using the Kaplan-Meier method. Kaplan-Meier 
curves, medians and 95% confidence intervals of the medians will be presented for each 
treatment arm. The hazard ratio for DOR will be calculated, along with its 95% confidence 
interval, from a stratified Cox model using the randomization stratification factors. 
As a sensitivity analysis, distribution of DOR will also be estimated using the Kaplan-Meier 
method in which death due to reason other than aggressive B-cell NHL will be included as an 
event. 
12.5.1.3 Time to response (TTR) 
Time to overall disease response (CR or PR) is defined as time from the date of randomization 
to the date of first documented overall disease response of PR or CR according to Lugano 
criteria based on disease response data per BIRC on or after the Week 12 assessment. 
The TTR analysis will be based on the ITT population, i.e., patients randomized to SOC arm 
who cross over to tisagenlecleucel arm will be considered to be in the SOC arm. 
 
TTR will be censored for patients who did not achieve a PR or CR: 
• At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who died 
due to any cause, progressed on or after the week 12 assessment, or initiated new 
anticancer therapy (as defined in Section 12.4.3), 
• At the date of the last adequate assessment otherwise. 
TTR will be estimated using the Kaplan-Meier method and the median time to response will be 
presented along with a 95% confidence interval. As a sensitivity analysis, TTR as per 
investigator assessment will be presented by treatment group, along with 95% confidence 
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12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used, unless otherwise specified. All listings and 
tables will be presented by treatment arms. 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before 
randomization. 
2. Safety comparison period: from day of randomization to the earlier of: 
• 56 days after last dose of study treatment 
• Start date of new cancer therapy other than assigned treatment 
3. Post-safety comparison period: after end of safety comparison period until end of study 
Primary safety summaries (tables, figures) by treatment arms include only data from the safety 
comparison period with the exception of baseline data which will also be summarized where 
appropriate (e.g. change from baseline summaries). All safety data will be summarized and 
listed by treatment period. 
Please note that patients crossed over from arm B to arm A will be considered as having started 
new cancer therapy other than assigned treatment and therefore will not be included in the 
primary safety summaries.  
In addition, safety data after tisagenlecleucel infusion will be separately summarized (including 
patients received tisagenlecleucel infusion in either arm A or patients crossed-over from arm B) 
for the post-infusion period, defined as from day of tisagenlecleucel infusion until end of study. 
Adverse events 
For randomized safety comparison, all information obtained on adverse events will be displayed 
by treatment arm and patient. 
The number (and percentage) of patients with treatment emergent adverse events will be 
summarized in the following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
Summary tables for adverse events will be provided for AEs that started or worsened during the 
safety comparison period. All safety data will be listed by reporting period. 
The incidence of adverse events during the safety comparison period will be summarized by 
primary system organ class (SOC), preferred term, severity (based on CTCAE grades), and 
relation to study treatment by treatment arm. The frequency of Common Toxicity Criteria (CTC) 
grade 3 and 4 AEs will be summarized separately. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation. 
The number (and proportion) of patients with adverse events of special interest (AESI) will be 
summarized by treatment. 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 

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criteria of AESI will be updated prior to reporting. AESI that occur within 8 weeks of the 
tisagenlecleucel infusion will be summarized by group term and preferred term. 
A patient with multiple adverse events within a primary system organ class is only counted once 
towards the total of the primary system organ class. 
Adverse events which will be counted for a specific treatment period are those which are 
treatment-emergent. These events are those with an onset after the start of the treatment period, 
or which were present prior to the start of the treatment period but increased in severity, changed 
from being not suspected to being suspected of study drug relationship, or developed into SAEs 
after the start of the treatment period. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the safety comparison period will be tabulated. 
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be summarized and listed and those collected during the pre-treatment and post-
safety comparison period will be flagged. 
In addition, safety data after tisagenlecleucel infusion will be separately summarized. The AE 
summaries will include all AEs that started or worsened during the post-infusion period, i.e. the 
tisagenlecleucel-treatment-emergent AEs. 
 
 
 
  
Vital signs 
All vital signs data will be listed by treatment group, patient, and visit and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by treatment. 
12-lead ECG 
12-lead ECGs including PR, QRS, QT, QTcF intervals and heart rate (HR) will be obtained for 
each patient during the study. ECG data will be read and interpreted locally. 
Categorical Analysis of QT/QTc interval data based on the number of patients meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these patients will be produced by treatment arm. 
All ECG data will be listed by treatment arm, participant and visit, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit. 
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5. The calculation of CTCAE 

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grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE 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 v5, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests 
by treatment arm: 
For laboratory tests where grades are defined by CTCAE v5 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v5 grades to compare baseline to the worst value during safety 
comparison period for SOC and to compare baseline to the worst post-infusion value for 
tisagenlecleucel arm 
For laboratory tests where grades are not defined by CTCAE v5, 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst value during safety comparison period. 
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5 grades 
if applicable and the classifications relative to the laboratory normal ranges. 
 
 
Other safety evaluations 
Presence of detectable RCL will be tested by VSV-G at scheduled assessments. All safety data 
will be listed. 
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 of age, gender, race, ethnicity, histology, and DLBCL cell of 
origin subtype subgroups. 
Summary tables will only be performed if at least 5 patients are present in each subgroup. Some 
grouping of classes will be considered. 
Immunogenicity 
The humoral immunogenicity assay measures the antibody titers specific to the tisagenlecleucel 
molecule prior to and following infusion. Data will be further fractionated to determine 
proportion of participants who make transient versus sustained antibody responses. The cellular 
immunogenicity assay assesses the presence of T lymphocytes activated by the tisagenlecleucel 

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protein. Data will be reported as summary statistics of pre and post-dose levels of activated T 
lymphocytes. Cellular kinetic parameters, efficacy and concentration time profiles will be 
summarized according to pre-existing and treatment-induced immunogenicity categories in 
Arm A and patients who have crossed over to tisagenlecleucel. 
12.5.3 
Patient reported outcomes 
PRO data from FACT-Lym, EQ-5D-5L and the SF-36 v2 (Acute form) will be assessed during 
the study as indicated in Table 8-1, Table 8-2, Table 8-3, and Table 8-4. Summary scores will 
be generated by summing the item responses on the questions for each domain in accordance 
with the respective scoring manual provided by the developers. Descriptive statistics (e.g. mean, 
median and frequency) and change from baseline of the summary scores for each post baseline 
time-point/window of assessment will be provided by treatment arm (tisagenlecleucel and SOC) 
and crossover, respectively. FAS will be used for all analysis. 
For each treatment group and at each time point, the number and percentage of patients who 
complete the SF-36 v2, FACT-Lym, and EQ5D will be summarized in a table. 
12.5.3.1 SF-36 v2 
The SF-36 comprises 36 questions, which can be summarized in eight health domain scores and 
further combined into a physical component summary (PCS) and a mental component summary 
(MCS) score. Domain and component summary scores will be converted to norm-based scores 
based on the general population. A higher SF-36 score denotes better quality of life. 

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Summary statistics will be reported for each of domains and components over time by treatment 
arm. Repeated measures mixed-effects model will be carried to compare the two groups with 
respect to the change from baseline. 
Time to definitive deterioration for PCS and MCS will be summarized using Kaplan-Meier 
methods. Time to definitive deterioration is defined as the time from randomization to the 
earliest time when the patient’s score shows at least 3 points or higher decrease from baseline 
(with no later change below this threshold). Time to definitive deterioration in each of the eight 
health domain will also be analyzed. The log-rank test will be used to compare the time to 
definitive deterioration between the two treatment groups. Rates of improvement for PCS and 
MCS will be evaluated from baseline to each time point and will be compared between the two 
treatment groups using chi-square test. Improvement is defined as increase of at least 3 points 
for PCS and MCS (Swigris et al 2010; Oerlemans et al 2011; Mehta et al 2017). 
12.5.3.2 FACT-Lym 
Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) is an extension of the 
FACT-General (FACT-G) standardized assessment of patients that includes the lymphoma 
subscale (FACT-LymS). The FACT-G is divided into 4 domains: physical, social/family, 
emotional, and functional well-being. The FACT-LymS is an additional 15 questions meant to 
evaluate response to treatment and symptoms associated with lymphoma. The FACT-Lym also 
includes the trial outcome index (FACT-Lym TOI) and the total score (FACT-Lym TS). 
Summary statistics will be reported for each of scales over time by treatment arm. Repeated 
measures mixed-effects model will be carried to compare the two groups with respect to the 
change from baseline for FACT-G total score, FACT-LymS, FACT-Lym TOI and FACT-Lym 
TS. 
Time to definitive deterioration for FACT-G total score (≥3 decrease), FACT-LymS (≥2.9 
decrease), FACT-Lym TOI (≥5.5 decrease) and FACT-Lym TS (≥6.5 decrease) will be 
summarized using Kaplan-Meier methods. Time to definitive deterioration is defined as the 
time from randomization to the earliest time when the patient’s score shows the above decrease 
from baseline (with no later change below this threshold). The log-rank test will be used to 
compare the time to first deterioration between the two treatment groups. 
Rates of improvement for these four scores will be evaluated from baseline to each time point 
and will be compared between the two treatment groups using chi-square test. Improvement is 
defined as increase of at least 3 points, 2.9 points, 5.5 points, and 6.5 points for FACT-G total 
score, FACT-LymS, FACT-Lym TOI, and FACT-Lym TS respectively (Webster et al 2003; 
Carter et al 2008). 
12.5.3.3 EQ-5D-5L 
The EQ-5D-5L questionnaire consists of the EQ-5D descriptive system and a visual analogue 
scale (the EQ-VAS). The EQ-5D descriptive system measures a patient’s health state on 5 
dimensions which include: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. The respondent’s self-rated health is assessed on a scale from 0 (worst 
imaginable health state) to 100 (best imaginable health state) by the EQ-VAS. 

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Summary statistics will be reported for EQ-VAS over time by treatment arm. Repeated 
measures mixed-effects model will be carried to compare the two groups with respect to the 
change from baseline. 
Time to definitive deterioration for EQ-VAS is defined as the time from randomization to the 
earliest time when the patient’s score shows at least 7 points or higher decrease from baseline 
(with no later change below this threshold). The log-rank test will be used to compare the time 
to first deterioration between the two treatment groups. 
Rates of improvement for EQ-VAS will be evaluated from baseline to each time point and will 
be compared between the two treatment groups using chi-square test. Improvement is defined 
as increase of at least 7 points (Kantarjian et al 2016) 
For the EQ-5D health state profiles, the proportions of patients reported having “no”, “slight”, 
“moderate”, “severe”, or “extreme” problems at each time point will be reported for each of the 
5 dimensions. 
12.5.4 
Cellular kinetics 
Tisagenlecleucel concentrations in peripheral blood (and bone marrow and CSF if available) 
will be listed, graphed and summarized (arithmetic and geometric means, standard deviation, 
CV%, CV% geometric mean, minimum, median and maximum) by time points and Month 3 
response as assessed by the following: 
• Tisagenlecleucel transgene levels as measured by q-PCR 
 
 
 
 
 
The non-quantifiable 
concentrations will be imputed to zero for concentration summaries, and will not be included 
for estimation of cellular kinetics parameters. Results reported but deemed unreliable will be 
flagged and excluded from the summaries and cellular kinetics parameter derivations. 
Descriptive statistics of cellular kinetics parameters (arithmetic and geometric means, standard 
deviation, CV%, CV% geometric mean, minimum, median and maximum) will be summarized 
by Month 3 response for Arm A as well as for patients who crossover and receive 
tisagenlecleucel. For Tmax and Tlast only minimum, median and maximum will be presented. 
The relationship between tisagenlecleucel cellular kinetics and dose and response will be 
explored using appropriate logistic regression and cox regression models if sufficient data is 
available for Arm A and for patients who crossover and receive tisagenlecleucel. Further details 
will be provided in the SAP. 

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12.5.5.6 Genomic and/or Next Generation Sequencing (NGS) analysis 
Genomic and/or NGS analysis in relation with clinical endpoints will be performed and 
documented in separate reports. 
Potential analysis exploring relationship of efficacy/safety endpoints with tumor cells mutation 
and/or gene expression could be also conducted. Analysis of leukocyte transcriptome changes 
pre and post tisagenlecleucel administration and the correlations between apheresis/cell product 
and clinical responses (efficacy, safety and cellular kinetic parameters) will be summarized in 
a separate report. 
12.5.5.8 Molecular characteristics of tisagenlecleucel apheresis product /final 
product 
Apheresis product and/or final product molecular read-outs (e.g. immune cell subsets, T cell 
differentiation and exhaustion markers, gene expression) will be assessed, listed and 
summarized by clinical response and/or relevant adverse events for Arm A and crossover 
patients and summarized in a separate report. 

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12.5.6 
Efficacy in sub-populations 
Clinical outcomes (ORR, DOR, EFS and OS) will be summarized descriptively by the 
following sub-populations: 
• Immunogenicity to tisagenlecleucel: 
• prevalence of immunogenicity against tisagenlecleucel (pre-existing), both humoral and 
cellular 
• incidence of immunogenicity against tisagenlecleucel, both humoral and cellular 
 
 
12.7 
Interim analyses 
No interim analysis is planned for this trial for the primary endpoint of EFS. A hierarchical 
testing procedure will be adopted and the statistical test for OS will be performed only if the 
primary efficacy endpoint, EFS is statistically significant. 
A maximum of two analyses are planned for OS: 1) an interim analysis at the time of the primary 
analysis for EFS (provided EFS is significant, as outlined in Section 12.5) in FAS and 2) a final 
analysis for OS at approximately 5 years from the first patient randomized. Haybittle–Peto 
boundary will be used for testing OS. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoints 
Based on the data from the ORCHARRD study (Novartis unpublished analyses), EFS time for 
patients who were randomized to receive salvage chemotherapy (DHAP plus Rituximab or 
DHAP plus Ofatumumab), who never reached CR before or relapsed within 12 months from 
response to previous therapy, or had a response of PR, SD or PD to previous therapy was 
considered as a reference for SOC. In ORCHARRD study, for these patients, who continue to 
be in SD status at the end of cycle 2/3 (which is earlier than the 12 week assessment, each cycle: 
21 days) or had progressed earlier than the 12 week assessment, based on the definition of EFS 
endpoint used in BELINDA (where patients with documented SD/PD at the 12 week assessment 

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(+/-1 week) is considered an EFS event), EFS event time was adjusted to 12 weeks, to account 
for these earlier events. 
The 9 month EFS rate is estimated to be 22.32% in SOC arm and is assumed to be 40% in 
tisagenlecleucel arm. Due to delayed tisagenlecleucel infusion of 6 weeks and ignoring SD/PD 
at week 6, we assume piecewise hazard rate in both treatment arms. The hazard ratio between 
two arms during the first 6 weeks is assumed to be 1 and 0.61 after 6 weeks. Given those 
assumptions, a total of 200 EFS events are required to have 92% power at an one-sided 2.5% 
level of significance to reject the null hypothesis (i.e. the survival functions for EFS in the two 
arms are identical), using a stratified log-rank test with equal weights. The sample size 
calculation was conducted via simulation with software package East 6.4. 
Based on a recruitment period of approximately 21 months using staggered enrollment rates of 
2, 10, and 16 patients in the 1st 3 months followed by 17 patients thereafter, and assuming 15% 
drop out rate, a total of approximately 318 patients will need to be randomized to the two 
treatment arms in a 1:1 ratio. Given the above assumptions, it is estimated that the 200th EFS 
event will be observed at approximately 23 months from the date of first patient randomized. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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 Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc). 

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For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality control and quality assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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15 
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Biffi A, Montini E, Lorioli L, et al (2013) Lentiviral hematopoietic stem cell gene therapy 
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16 
Appendices 
16.1 
Appendix 1:  Assessment algorithms for hepatitis B and C status 
at screening 
Hepatitis B 
1. Test for HBsAg, HBcAb, HBsAb. 
2. If all these three tests are negative, the patient is eligible. 
3. If HBsAb only is positive  
a. the patient is eligible in absence of signs of hepatitis (e.g. increase of ALT/AST) 
b. test for HBV DNA, in presence of signs of hepatitis (e.g. increase of ALT/AST) 
4. If HBsAg is positive, the patient is NOT eligible. 
5. If HBsAg is negative but either HBcAb or both HBcAb and HBsAb are positive, test for 
HBV DNA. 
a. If HBV DNA is positive, the patient is NOT eligible. 
b. If HBV DNA is negative, the patient is eligible 
Hepatitis C 
1. Test for HCV Ab 
2. If HCV Ab is negative, the patient is eligible. 
3. If HCV Ab is positive, test for HCV RNA. 
a. If HCV RNA is negative, the patient is eligible. 
b. If HCV RNA is positive, the patient is NOT eligible. 
Patients with a history of hepatitis B or C should be managed according to the current guidance 
by American Society of Clinical Oncology (Hwang et al, 2018) and HCV Guidance from the 
American Association for the Study of Liver Disease-Infectious Disease Society of America 
guidelines (2014-2017) 

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16.2 
Appendix 2: Guidelines for efficacy evaluation in non-Hodgkin-
Lymphoma studies 
16.2.1 
Introduction 
The purpose of this document is to provide working definitions and rules to evaluate efficacy 
in non-Hodgkin lymphoma (NHL) studies conducted by Novartis. This document is based on 
the International Working Group response criteria (Cheson et al 1999), the International 
Harmonization Project revised response criteria (Cheson et al 2007), and the revised Consensus 
of the International Conference on Malignant Imaging Working Group and the Lugano 
Classification (Barrington et al 2014; Cheson et al 2014), and it is intended for studies of 
radiographically measurable disease. For studies without measurable disease, e.g., studies of 
consolidation of complete response, maintenance treatment, or autologous stem cell 
transplantation, see Appendix A. 
16.2.2 
Methodologies 
16.2.2.1 Computed tomography (CT) 
The same method of assessment and technique should be used to characterize each identified 
and reported lesion throughout the study. Contrast-enhanced CT of neck, chest, abdomen and 
pelvis, from skull base through lesser trochanters ensuring complete coverage of the pelvis and 
inguinal areas, should be performed using a ≤ 5 mm slice thickness with a contiguous 
reconstruction algorithm. If a patient has a CT contrast allergy or develops it during the trial, 
non-contrast CT of the chest plus contrast-enhanced MRI of abdomen and pelvis are acceptable 
for a follow up. Chest MRI is not recommended due to respiratory artifacts. 
16.2.2.2 Positron emission tomography (PET) 
Studies of FDG-avid histologies require PET using the radiotracer 18F-fluorodeoxyglucose 
(FDG) to confirm any new CR determined by CT. PET will not be required to confirm 
progression or relapse. 
PET scans should cover the whole body from base of skull to mid-thigh. Examinations should 
be consistent across all time points including amount of tracer, location of injection, arm 
location, and scan delay. Information of height, weight, gender, administered dose, time 
between dose administration and imaging, and glucose level are required for each time point. 
PET images should be converted to standardized uptake value (SUV) maps to support 
comparison across time points and to standardize viewing conditions. 
16.2.2.3 PET-CT 
Hybrid PET-CT may be used to acquire PET and CT images if CT images produced by the 
scanner are of diagnostic quality and include intravenous contrast. Non-diagnostic CT images 
acquired for attenuation purposes during PET-CT are NOT acceptable as the only images for 
the time point. 
If diagnostic CT and PET are to be acquired on the same day, PET must be performed prior to 
CT with IV contrast to avoid compromising PET results. 

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Thus, any of the three following imaging methodologies are possible in a lymphoma study: 
• PET-CT with diagnostic CT 
• PET-CT with non-diagnostic CT and dedicated diagnostic CT 
• Dedicated diagnostic CT and dedicated FDG PET 
16.2.2.4 Magnetic resonance imaging (MRI) and PET-MRI 
MRI or PET-MRI is an acceptable method of imaging if CT is contraindicated e.g., due to CT 
contrast allergy. If at baseline a patient is known to be allergic to CT contrast or develops allergy 
during the trial, the following change in imaging modality will be accepted for follow up: a 
non-contrast CT of the chest plus contrast-enhanced MRI of abdomen and pelvis (MRI of the 
chest is not recommended due to respiratory artifacts). 
16.2.2.5 Five point scale (5PS) 
To standardize PET interpretation, a simple reproducible scoring method called the five point 
scale (5PS) or the Deauville criteria has been implemented for initial staging and assessment of 
interim and end of treatment responses (Barrington et al 2014). The 5PS assesses the most 
intense uptake in a site of disease (Table 16-1). 
Table 16-1 
Five Point Scale (5PS) 
Score 
Findings 
Score 1 
No uptake above background 
Score 2 
Uptake ≤ mediastinum 
Score 3* 
Uptake > mediastinum, but ≤ liver 
Score 4** 
Uptake moderately > liver 
Score 5** 
Uptake markedly higher than liver and/or new lesions 
* 
The protocol will need to define the significance of a score 3, depending on the studied disease, patient 
characteristics and goal of therapy. 
• 
Score 3 will be considered PET negative unless otherwise specified in the protocol (e.g. de-escalation 
studies, in which case CMR will be based on 5PS of 1 or 2 only, and PMR/NMR/PMD will be based on 5PS 
of 3,4 or 5) 
** 
Score 4 should be applied to uptake greater than the maximum standard uptake value (SUV) in a large 
region \ of normal liver and score 5 to uptake 2 times greater than the maximum SUV in the liver. PET images 
should be converted to SUV maps to support comparison across time points and to standardize viewing 
conditions. 
(New) areas of uptake unlikely to be related to lymphoma will be marked as “X” (Barrington et al. 2014). 
16.2.3 
Definitions 
16.2.3.1 Disease stage 
Extent and involvement by lymphoma is described by the disease stage and is an important 
prognostic factor. Stage can also influence treatment decisions. 

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16.2.3.2 Baseline 
Baseline examination should be as close as possible to the randomization/start of treatment (e.g., 
within 4 weeks prior to randomization/start of treatment). Longer periods may be allowed 
depending on the disease studied and the study design. 
16.2.3.3 Nodal vs. extranodal lesion 
A lesion can be categorized as: 
• Nodal lesion (a lymph node or a nodal mass) 
• Extranodal lesion (a lesion located in other organs, including spleen and liver) 
16.2.3.4 Measurable disease 
All anatomic measurements should be taken in two perpendicular dimensions and recorded in 
metric notation, using a ruler or calipers. 
Throughout this document, a lesion will be called measurable if: 
• It can be measured accurately in two perpendicular dimensions: longest diameter (LDi) 
(also known as transverse diameter), and shortest diameter (SDi), which is the longest 
diameter perpendicular to LDi (also known as perpendicular diameter). The LDi and SDi 
must be measured on the same slice. 
• For a nodal lesion, LDi is greater than 15 mm, regardless of SDi 
• For an extranodal lesion, if both LDi and SDi are greater than 10 mm 
A lymph node not meeting the measurability criteria but with LDi greater than 15 mm (e.g. SDi 
cannot be measured accurately) will constitute a non-measurable nodal lesion if FDG-avid (for 
FDG-avid histologies). 
A lymph node not meeting the measurability criteria but with LDi ranging from 11 mm to 15 
mm and with SDi greater than 10 mm will be checked for relationship to disease as follows: 
• If it is related to lymphoma, it will constitute a non-measurable nodal lesion (referred to as 
“involved node” in Cheson et al (2007)) 
• If not related to lymphoma and not FDG-avid, it will constitute an abnormal lymph node 
but not a nodal lesion for FDG-avid histologies 
All lesions visible on PET but not on CT/MRI will be treated as non-measurable. 
Bulky disease 
Bulky disease is captured by means of the longest measurement by CT scan. The definition of 
bulky disease (a minimum size) should be included in the study protocol. 
16.2.3.5 Assessable disease 
Assessable disease refers to disease presentations that are consistent with lymphoma but are not 
suitable for measurement, e.g., pleural effusion, ascites, etc. Assessable disease will be followed 
qualitatively. 

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16.2.3.6 Index lesion 
• Up to 6 of the largest nodes, nodal masses or other lymphomatous lesions, including 
extranodal lesions, measurable in two diameters (LDi and SDi) 
• Should represent overall disease burden and include mediastinal and retroperitoneal 
disease, if involved 
16.2.3.7 Non-index lesion 
• All other lesions which are not selected as index lesions but are consistent with lymphoma 
• Abnormal nodes and extranodal lesions, both measurable and non-measurable, such as 
cutaneous, gastrointestinal, and bone lesions, pleural or pericardial effusions, and ascites 
16.2.3.8 New lesions 
• Regrowth of previously resolved lesions 
• A new nodal lesion > 15 mm in any axis 
• A new extranodal lesion > 10 mm in any axis 
• A new extranodal lesion ≤ 10 mm in any axis that is unequivocal and attributable to 
lymphoma 
• A new assessable lesion attributable to lymphoma (e.g., ascites, pleural effusion) 
16.2.4 
Efficacy assessments 
16.2.4.1 Eligibility 
In general, patients should have at least one measurable nodal lesion (greater than 15 mm in the 
long axis) or at least one measurable extranodal lesion (with both LDi and SDi greater than 10 
mm). 
16.2.4.2 Methods of disease assessment 
16.2.4.2.1 
PET combined with diagnostic CT 
The integration of PET into more frequently acquired CT evaluation does present a challenge 
to the way response is assessed in a clinical trial. The study protocol must clearly define the 
imaging intervals and imaging methods to be used at each imaging visit. PET scans should be 
performed at pre-specified times for example at randomization before treatment and at clearly 
defined times during and/or after the end of treatment. PET may also be acquired to confirm 
CT results. 
The same CT imaging modality should be used at baseline and all post-baseline assessments in 
order to reduce the risk of false responses or progressions based on measurement error. A 
change in modality can be either a change in contrast use (i.e., with contrast versus without 
contrast) or a change in technique (e.g. from CT to MRI). Response assessments made after a 
change in imaging modality should be queried, and if the investigator or blinded central 
reviewer can provide sufficient justification, then the response can be accepted. 
In order to calculate the sum of the product of the perpendicular diameters (PPD) of all index 
lesions, their size must be recorded throughout the study. Actual lesion measurements should 

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be entered on the corresponding CRFs. If, during the course of the study, either of the 
perpendicular diameters of a lesion cannot be reliably measured because of its small size, it is 
recommended to enter the minimum limit of detection as the diameter size (e.g., 5 mm for spiral 
CT). In other cases when, during the course of the study, the diameter cannot be reliably 
measured for reasons other than its size (i.e., borders of the lesion are confounded by 
neighboring anatomical structures), no measurement should be entered and the lesion cannot be 
evaluated. 
If lesions become confluent over time, it is recommended to measure them as one lesion, report 
the overall diameters to one of the lesions and assign 0 mm × 0 mm to each of the other 
previously measured lesions. The PPD of the current confluent mass should be used to measure 
response, with more than 50% increase in the PPD of the confluent mass compared with nadir 
of the sum of individual nodes necessary to indicate progressive disease. 
If a lesion splits into several discrete lesions, the individual product of the perpendicular 
diameters (PPDs) of each lesion should be summed together to represent the PPD of the split 
lesion; this PPD is added to the sum of the PPDs of the remaining lesions to measure response. 
If subsequent growth of any or all of these discrete nodes occurs, the nadir of each individual 
node is used to determine progression (as if each individual node was selected as an index lesion 
at baseline). 
16.2.4.2.2 
Bone marrow assessment 
Bone marrow should be evaluated by biopsy or aspirate in all patients at baseline. If lymphoma 
involvement in bone marrow is observed at baseline, then biopsy or aspirate should be 
performed post-baseline to confirm radiological CR. Any deviation from this approach should 
be justified in the study protocol. 
16.2.4.2.3 
Physical examination 
Skin lesions must be histologically confirmed for lymphoma involvement (the investigational 
site must document the histological confirmation (yes or no) on the corresponding CRF) and 
photographed including a ruler (color photography using digital camera). Response assessment 
of skin lesions will be performed and results will be recorded on the corresponding CRF at 
baseline and at the time of each radiological assessment. 
16.2.4.3 Documentation of disease 
For the evaluation of disease at baseline and throughout the study, the following will be 
recorded. 
16.2.4.3.1 
FGD uptake 
FDG uptake in a nodal or extranodal site that is suggestive of lymphoma will be assessed using 
5PS. 
16.2.4.3.2 
Index lesions 
A minimum of one measurable index lesion and a maximum of six of the largest dominant 
nodal and extranodal lesions must be documented at baseline and assessed throughout the study 

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in two dimensions. The lesions should come from different body regions representative of the 
patient’s overall disease burden and should include mediastinal and retroperitoneal disease, if 
involved. Two perpendicular dimensions (LDi, SDi) must be recorded on the corresponding 
CRF at each assessment of a measurable lesion selected to be an index lesion. 
Index nodal lesions 
Index nodal lesions are selected from the measurable nodal lesions and should be documented 
at baseline and assessed throughout the study. Index nodal lesions should be from disparate 
regions of the body including mediastinal and retroperitoneal areas of disease whenever these 
sites are involved. 
Index extranodal lesions 
Other organs such as breast and lung can be occasionally involved by lymphoma. Such 
extranodal lesions (e.g. hepatic nodules) may be included (if measurable) in the six index lesions 
to be assessed throughout the study. In some cases histological examination may be necessary 
to confirm that these lesions represent lymphoma involvement (e.g. skin lesions). 
16.2.4.3.3 
Non-index lesions 
Non-index nodal lesions 
Nodal lesions not selected as index lesions (both measurable and non-measurable) are 
considered as non-index lesions. Non-index lesions should be documented at baseline and 
assessed throughout the study. Measurements of these lesions are not required to be documented 
on the CRF. 
Non-index extranodal lesions 
Measurable extranodal lesions not selected as index lesions and all non-measurable extranodal 
lesions (including non-measurable but assessable disease e.g. pleural effusion) will be 
documented at baseline and assessed throughout the study as non-index lesions. Measurements 
of these lesions are not required to be documented on the CRF. 
16.2.4.3.4 
Spleen involvement 
Splenic involvement is determined by imaging: vertical (cranial to caudal) length > 13 cm is 
considered as involved, and spleen length must be assessed at each imaging time point. 
Intrasplenic lesions should be followed as index, non-index and new extranodal lesions. 
16.2.4.3.5 
Liver involvement 
Given variability in physical habitus and the impact of numerous medical conditions, 
assessment of liver size is not considered a reliable measure of hepatic involvement and 
therefore liver assessment is not included in the Lugano 2014 classification. Intrahepatic lesions 
should be followed as index, non-index and new extranodal lesions. 
16.2.4.3.6 
Bone marrow involvement 
Lymphoma involvement in bone marrow should be documented in the CRF as “Yes” or “No” 
at each bone marrow biopsy and/or aspiration. 

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16.2.4.4 Response evaluation 
The efficacy variables in the statistical analysis are based on overall disease response, which 
is a combined evaluation of response based on both radiological and clinical findings, and is 
determined at each post-baseline assessment. The radiological response is first obtained from 
CT and PET studies according to the Lugano criteria (Table 16-1) and overall disease response 
is then determined by taking into account results of bone marrow biopsies and other clinical 
information (Table 16-2). 
16.2.4.4.1 
Radiological response 
There are three separate components to radiological response, all of which should be collected 
on the CRF at each post-baseline assessment: 
1. CT response based on anatomical measurements of index/non-index/new lesions and 
spleen length. The possible response outcomes are complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD) as defined in Table 16-2. 
2. PET response based on 5PS, changes in intensity or extent of standard uptake values 
(SUVs) and bone marrow assessments directly from the PET scan. The possible outcomes 
for PET response are complete metabolic response (CMR), partial metabolic response 
(PMR), no metabolic response (NMR), or progressive metabolic disease (PMD) as defined 
in Table 16-2. 
3. Overall radiological response combines CT response with PET response. The outcomes 
include CR, PR, SD, and PD. For time points when both CT and PET are available, PET 
response overrules CT response. Overall radiological response at a time point with CT 
only may also be affected by PET response obtained at a different time point. 
Example 
A CT response of PR at the same assessment as a PET response of CMR will constitute an 
overall radiological response of CR, and (i) a subsequent time point with CT only and CT 
response of PR will still constitute an overall radiological response of CR, (ii) a previous time 
point with CT only and CT response of PR may be upgraded to CR at the discretion of the 
investigator or blinded central reviewer. 
Table 16-2 
Radiological response assessment 
 
 
PET-based response 
CT-based response 
 
 
Complete Metabolic Response 
(CMR) 
(All of the following) 
Complete Response (CR) 
(All of the following) 
Complete 
Response 
Index 
5PS† of 1, 2, or 3* with or without 
residual mass on 5PS 
Nodal lesion: ≤ 15 mm in LDi 
Extranodal lesion: Absent (0 mm x 
0 mm) 
Non-index 
Absent 
Spleen 
Return to normal (≤ 13 cm) 
New lesions 
None 
None 
Bone 
marrow 
No FDG-avid disease 
Not applicable 
 
 
Partial Metabolic Response (PMR) 
(all of the following) 
Partial Response (PR) 
(all of the following) 

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PET-based response 
CT-based response 
Partial 
Response 
Index 
5PS of 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 across all index lesions 
Non-index 
No increase 
Spleen 
≥ 50% decrease from baseline in 
enlarged portion of spleen 
Example: If 16 cm, then enlarged 
portion is 3 cm. A decrease by 2 cm 
gives a 66.6% decrease 
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 
 
 
No Metabolic Response (NMR) 
(all of the following) 
Stable Disease (SD) 
(all of the following) 
Stable 
Disease 
Index 
5PS of 4 or 5 with no significant 
change in FDG uptake from baseline 
• 
<50% decrease from baseline 
in SPD across all index lesions 
• 
No criteria for PD are met 
Non-index 
No progression 
Spleen 
No progression 
New lesions 
None 
None 
Bone 
marrow 
No change in FDG uptake from 
baseline 
Not applicable 
 
 
Progressive Metabolic Disease 
(PMD 
(At least one of the following) 
Progressive Disease (PD) 
(At least one of the following) 
Progressive 
Disease 
Index 
5PS of 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 > 15 mm AND 
• 
Increase by >= 50% from PPD 
nadir AND 
• 
An increase in LDi or SDi from 
nadir: 
• 
≥ 5 mm for lesions with LDi ≤ 
20 mm at current assessment 
• 
≥ 10 mm for lesions with LDi > 
20 mm at current assessment 
Non-index 
Unequivocal Progression 

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PET-based response 
CT-based response 
Spleen 
• 
Progression (increase from 
baseline by >50% in enlarged 
portion). Example: If 15 cm at 
baseline then enlarged portion 
is 2 cm and an increase by >1 
cm would be progression 
• 
New splenomegaly (> 13 cm 
and increase by > 2 cm from 
normal at baseline) 
• 
Recurrent splenomegaly 
(normalization followed by 
increase by > 2 cm from nadir 
reaching > 13 cm) 
New lesions 
• 
Regrowth of previously 
resolved lesions 
• 
New node > 15 mm in any axis 
• 
New extranodal site > 10 mm 
in any axis 
• 
New extranodal site ≤ 10 mm 
in LDi, unequivocal and 
attributable to lymphoma 
• 
Assessable disease of any size 
Unequivocally attributable to 
Lymphoma 
Bone 
marrow 
New/recurrent FDG-avid foci 
Not applicable 
Abbreviations: LDi Longest diameter; SDi Shortest diameter; PPD Product of perpendicular diameters; SPD 
Sum of the product of the perpendicular diameters. 
* 
Score 3 will be considered PET negative unless otherwise specified in the protocol (e.g. de-escalation 
studies, in which case CMR will be based on 5PS of 1 or 2 only, and PMR/NMR/PMD will be based on 
5PS of 3, 4 or 5) 
# 
In the context of an agent associated with a flare reaction, caution must be exercised not to confuse the 
possible tumor flare with progressive disease. It is recommended that either a biopsy be performed or the 
lesion be reassessed in at least 2 weeks, and if there is continued evidence of tumor progression, the date 
of progressive disease is the previous evaluation. 
† 
PET 5PS 1: no uptake > background; 2: uptake ≤ mediastinum; 3: uptake > mediastinum but ≤ liver; 4: 
uptake moderately > liver; 5: uptake markedly > liver and/or new lesions; X: new areas of uptake unlikely 
to be related to lymphoma. 
16.2.4.4.2 
Overall disease response 
Overall disease response is determined by assessing whether the combined radiological 
responses at each time point are appropriate, based on bone marrow biopsies and other clinical 
findings that may be available, such as cytology results, physical examination results of 
palpable lesions or skin lesions, and biopsies of lymph nodes or extra-nodal lesions (Table 16-
3). The possible outcomes for overall disease response are CR, PR, SD, and PD. 
For example, suppose there was lymphoma involvement in the baseline bone marrow biopsy, 
and the month 3 combined radiological response was CR (implying that PET-based bone 
marrow involvement at month 3 was negative). In that case, overall disease response could only 
be CR if there was a negative bone marrow biopsy otherwise overall disease response would be 
downgraded to PR. This is a case where the bone marrow biopsy results overrule the bone 

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marrow findings on PET. Another example is when the combined radiological response is SD, 
but cytology results of a pleural effusion show lymphoma involvement: this could lead to an 
overall disease response of PD. 
Overall disease response at each post-baseline assessment should be captured on the CRF, along 
with the date of response. In addition, the source of any clinical data that affected the overall 
disease response should be documented. 
Table 16-3 
Overall disease response 
Overall radiological 
response 
Bone marrow 
biopsy/aspirate 
Clinical findings 
Overall disease 
response 
CR/PR/SD 
Negative at baseline or 
negative ± 28 days from 
assessment 
Any except new or 
recurrent lymphoma 
involvement 
CR/PR/SD 
CR 
Positive at baseline and 
either positive (without 
new or recurrent 
involvement) or not done 
± 28 days from 
assessment 
Any except new or 
recurrent lymphoma 
involvement 
PR 
PR/SD 
Positive at baseline and 
either positive (without 
new or recurrent 
involvement) or not done 
± 28 days from 
assessment 
Any except new or 
recurrent lymphoma 
involvement 
PR/SD 
PD 
Any 
Any 
PD 
Any 
New or recurrent 
involvement 
Any 
PD 
Any 
Any 
New or recurrent 
lymphoma involvement 
PD 
16.2.4.5 Efficacy analysis definitions 
16.2.4.5.1 
Best overall response 
The best overall response (BOR) is the best overall disease response recorded from 
randomization/start of treatment until progressive disease or start of new anticancer therapy, 
whichever comes first. The definition of new anticancer therapy may need to be defined in the 
study protocol (e.g., high-dose chemotherapy with autologous stem cell transplantation). 
A patient will have a best overall response of CR if they have CR as overall disease response 
for at least one of the assessments. 
A patient will have a best overall response of PR if at least one overall disease response of PR 
is available (and the patient does not qualify for CR). 
A best overall response of SD will be declared when at least one overall disease response of SD 
is available at least 6 weeks after randomization/start of treatment (and the patient does not 
qualify for CR or PR). If SD is observed before this minimum follow-up period, and the patient 
does not qualify for CR, PR or PD, then the best overall response would be unknown (UNK). 

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If a different minimum follow-up period for SD is more appropriate (e.g., if first post-baseline 
visit is at 28 days) then this must be specified in the Study Protocol. 
A patient will have a best overall response of PD if overall disease response is PD between 
randomization/start of treatment and the second scheduled post-baseline assessment (and the 
patient does not qualify for CR, PR or SD). 
For example, assuming 12 weeks between assessments and a permitted variation in visit timing 
of ± 1 week, this would mean during the first 25 weeks after randomization/start of treatment. 
If PD is observed after this maximum follow-up period, and the patient does not qualify for CR, 
PR or SD, then the best overall response would be UNK. If a different maximum follow-up 
period for PD is more appropriate then this must be specified in the Study Protocol. 
A patient will have a best overall response of UNK if the patient does not qualify for CR, PR, 
SD or PD. 
Overall disease response at a given assessment may be provided from different sources: 
• Per Investigator: overall disease response based on local radiological assessments, using 
investigator choice of index lesions, measurements and assessments of lesion status and 
5PS along with clinical findings 
• Per Central Blinded Review, with or without blinded adjudication: based on central review 
of local radiological assessments, using central reviewer choice of index lesions, 
measurements and assessments of lesion status and 5PS, along with clinical findings 
In studies that include a central blinded review, the Study Protocol should state which source 
will be used for the primary analysis. 
Best overall response is summarized by calculating the overall response rate (ORR), which is 
defined as the proportion of patients with a best overall response of CR or PR. 
Similarly, the complete response rate is the proportion of patients with a best overall response 
of CR. 
16.2.4.5.2 
Time to event variables 
Most of the time to event variables are defined in this section according to the revised 
International Working Group response criteria (Cheson et al 2007). Further details on dates and 
censoring rules are provided respectively in Section 16.2.4.5.3 and Section 16.2.4.5.4. 
Overall survival 
Overall survival (OS) is defined as the time from the date of randomization/start of treatment 
to the date of death due to any cause. If a patient is not known to have died, OS will be censored 
at the date of last contact. 
Progression-free survival 
Progression-free survival (PFS) is defined as the time from the date of randomization/start of 
treatment to the date of event defined as the first documented progression (overall disease 
response = PD) or death due to any cause. If a patient has not had an event, PFS is censored at 
the date of the last adequate assessment as defined in Section 16.2.4.5.3. 

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Time to progression 
Time to progression (TTP) is defined as the time from the date of randomization/start of 
treatment to the date of first documented progression (overall disease response = PD) or death 
due to lymphoma. If a patient has not had an event, TTP is censored at the date of the last 
adequate assessment. 
Duration of response 
Duration of response (DOR) applies only to patients with best overall disease response of CR 
or PR. It is defined as the time from the date of the first documented overall disease response 
of CR or PR to the date of first documented progression or death due to lymphoma. If a patient 
has not had an event, DOR is censored at the date of the last adequate assessment. It should be 
stated that this analysis might introduce a bias as it includes only responders. 
Duration of complete response applies only to patients with best overall disease response of CR. 
It is defined as the time from the date of the first documented overall disease response of CR to 
the date of first documented progression or death due to lymphoma. If a patient has not had an 
event, duration of CR is censored at the date of the last adequate assessment. Duration of CR 
might be calculated in addition for studies in which a reasonable number of complete responders 
are seen. 
The analysis of DOR should only be used as a descriptive analysis. If used as an inferential 
comparison between treatments, clear justification must be given in the study protocol. 
Time to response 
Time to response (TTR) is defined as the time from the date of randomization/start of treatment 
to the date of first documented overall disease response of PR or CR. Depending on the study 
design, this analysis could be based on all patients only, or on responders only, or both of these 
analysis populations may be used. The choice of analysis population for TTR should be stated 
in the study protocol. 
For analysis using all patients, TTR will be censored for patients who did not achieve a PR or 
CR: 
• At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. either progressed or died due to any cause) 
• At the date of the last adequate assessment otherwise 
Time to complete response (TTCR) is defined similarly to TTR except using CR only instead 
of either PR or CR, and with this difference, the above rules and definitions for TTR also apply 
to TTCR. 
Lymphoma specific survival 
Lymphoma specific survival (LSS) is defined as the time from the date of randomization/start 
of treatment to the date of death documented as a result of lymphoma. If a patient has not had 
an event, LSS will be censored: 
• at the date of last contact if the patient is not known to have died 
• at the date of death if the patient died for reason other than lymphoma 

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Event-free survival 
Event-free survival (EFS) may be appropriate in studies of advanced disease where early 
discontinuation is typically related to intolerance of the study drug. In some protocols, EFS may 
be considered as a sensitivity analysis for TTP. If a patient has not had an event, EFS is censored 
at the date of the last adequate assessment as defined in Section 16.2.4.5.3. The definition of 
event needs to be defined in the Study Protocol according to study design. 
16.2.4.5.3 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment, the assessment date is calculated as: 
• the latest date of all radiological measurements (e.g. PET-CT, CT, or MRI), excluding 
bone marrow biopsy, if overall disease response at that assessment is CR/PR/SD/UNK 
• the earliest date of all measurements (e.g. PET-CT, CT, or MRI), including bone marrow 
biopsy if overall disease response at that assessment is PD 
Start date 
For all “time to event” variables other than the duration of response variables, the date of 
randomization/start of treatment will be used as the start date. 
For the calculation of duration of response variables the following start date should be used: 
• Date of first documented response is the assessment date of the first overall disease 
response of CR for duration of complete response or CR/PR for duration of response 
End date 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
• Date of death as reported on the disposition CRF 
• Date of last contact is defined as the last date the patient was known to be alive as derived 
from different CRF pages (see details in Section 16.2.5.2) 
• Date of progression is the first assessment date at which the overall disease response was 
recorded as PD 
• Date of last adequate assessment is the date of the last assessment with overall disease 
response of CR, PR or SD which was made before an event or a censoring reason 
occurred. If no post-baseline assessments are available (before an event or a censoring 
reason occurred) the date of randomization/start of treatment is used. 
• Date of next scheduled assessment is the date of the last adequate assessment plus the 
protocol specified time interval between assessments. This date may be used if back-
dating is considered when the event occurred beyond the acceptable time window for the 
next radiological assessment as per protocol. 
Example (if protocol defined schedule of assessments is 3 months): response assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of treatment discontinuation is the last known date subject took study drug (to be 
used, if applicable) 

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• Date of new anti-cancer therapy is defined as the start date of first new antineoplastic 
therapy (including medication, radiotherapy, surgery or HSCT) 
16.2.4.5.4 
Censoring and sensitivity analyses 
Censoring reasons 
This section outlines the possible censoring reasons for each time to event variables. In order 
to summarize the various reasons for censoring, the following categories (Table 16-4) will be 
calculated for each time to event variable based on the information reported. 
Table 16-4 
Censoring reasons 
Time to event variables 
Possible censoring reasons 
OS 
• 
Alive 
• 
Lost to follow-up 
PFS, EFS, TTP and DOR 
• 
Ongoing without event 
• 
Lost to follow-up 
• 
Withdrew consent 
• 
Death due to reason other than lymphoma (only used for TTP and DOR) 
• 
New anti-cancer therapy added  
• 
Event documented after two or more missing response assessments 
(optional, see Table 16-5) 
• 
Adequate assessment no longer available1 
LSS 
• 
Alive 
• 
Lost to follow-up 
• 
Death due to reason other than lymphoma 
1 Adequate assessment is defined in Section 16.2.4.5.3. This reason corresponds to any censoring reasons 
after two or more missing response assessments. This reason will also be used for censor in case of no 
baseline assessment 
Event date, censoring date and sensitivity analyses 
This section outlines the possible event and censoring dates for progression (Table 16-5), as 
well as addressing the issues of missing response assessments during the study. It is important 
that the protocol and analysis plan specify the primary analysis in detail with respect to the 
definition of event and censoring dates and also include a description of one or more sensitivity 
analyses to be performed. 
Based on definitions outlined in Section 16.2.4.5.2, and using the draft FDA guideline on 
endpoints (FDA 2007) as a reference, the following analyses can be considered: 

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Table 16-5 
Options for event dates used in PFS, EFS, TTP, DOR 
Situation 
Options for end-date (progression)1 
(1) = default unless specified differently in 
the protocol or analysis plan 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment2 
Censor 
B 
Progression at or before next 
scheduled assessment 
(1) Date of progression 
(2) Date of next scheduled assessment1 
Event 
Event 
C1 
Progression or death due to any 
reason after exactly one missing 
assessments 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment1 
Event 
Event 
C2 
Progression or death due to any 
reason after two or more missing 
assessments 
(1) Date of last adequate assessment1 
(2) Date of next scheduled assessment1 
(3) Date of progression (or death) 
Censor 
Event 
Event 
D 
No progression 
(1) Date of last adequate assessment 
Censor 
E 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim 
(1) N/A 
(2) Date of discontinuation (visit date at which 
clinical progression was determined) 
Ignored 
Event 
F 
New anticancer therapy given  
(1) Date of last adequate assessment 
(2) Date of new anticancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) N/A 
Censor 
Censor 
Event 
Ignored 
G 
Death due to reason other than 
lymphoma 
(1) Date of last adequate assessment 
Censor 
(only TTP and 
DOR) 
1 = Definitions can be found in Section 16.2.4.5.3. 
2 = The rare exception to this is if the patient dies no later than the time of the second scheduled assessment 
as defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the Study Protocol. 
Clearly define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: 
The primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing 
assessment 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments 
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 

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of response assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the response due to clinical deterioration. 
Situation F: New cancer therapy given (except for EFS): the handling of this situation must 
be specified in detail in the protocol. However, option (1), i.e. censoring at last adequate 
assessment may be used as a default in this case. 
Additional suggestions for sensitivity analyses 
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for response assessments, e.g.: 
• By assigning the dates for censoring and events only at scheduled visit dates. The latter 
could be handled by replacing in Table 16-5 the “Date of last adequate assessment” by the 
“Date of previous scheduled assessment (from baseline)”, with the following definition: 
Date of previous scheduled assessment (from baseline) is the date when a response assessment 
would have taken place, if the protocol assessment scheme was strictly followed from baseline, 
immediately before or on the date of the last adequate assessment. 
The need for these types of sensitivity analyses will depend on the requirements for a specific 
study and disease area and have to be specified in the Study Protocol or RAP documentation. 
16.2.5 
Data handling and programming conventions 
The following rules should be used and specified in the RAP documentation: 
16.2.5.1 Calculation of ‘time to event’ variables 
Time to event = enddate - startdate + 1 (in days) 
When no post-baseline assessments are available, the date of randomization/start of treatment 
will be used as enddate (duration = 1 day) when time is to be censored at last assessment, i.e. 
time to event variables can never be negative. 
16.2.5.2 Date of last contact 
The date of last contact will be derived for patients alive using the latest complete date among 
the following: 
• Assessment dates (e.g., vital signs assessment, performance status assessment, efficacy 
assessment, laboratory, pharmacokinetics assessment) 
• Medication dates including study medication and antineoplastic therapies administered 
after study treatment discontinuation 
• Adverse events dates 
• Last known date subject alive collected on the ‘Survival information’ eCRF 
• Randomization date 

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16.2.5.3 Date of new anti-cancer therapy 
The date of new anti-cancer therapy is the date of the first antineoplastic therapy (including 
medicine, radiotherapy and surgery) reported on the post-treatment antineoplastic therapy CRF 
or from other sources (e.g., HSCT CRF). 
16.2.5.4 Incomplete assessment dates 
All investigation dates (e.g., PET-CT scan) must be completed with day, month and year. If one 
or more investigation dates are incomplete but other investigation dates are available, this/these 
incomplete date(s) are not considered for calculation of the assessment date (and assessment 
date is calculated as outlined in Section 16.2.4.5.3). If all measurement dates have no day 
recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.2.5.5 Incomplete dates for last contact or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
16.2.6 
Appendices 
Appendix A: Adaptation for use in maintenance/adjuvant settings 
For study populations without measurable disease at baseline (e.g., maintenance), the event of 
interest is no longer progression but relapse, and the main endpoint is no longer progression-
free survival but disease-free survival (see below). 
Relapsed disease 
Any of the following meets the definition of relapsed disease (RD): 
• Any new nodal lesion > 15 mm in any axis (i.e. previously normal lymph node 
becoming >1.5 cm in any axis) on CT (or MRI) after baseline 
• Any discrete extranodal lesion (including liver or spleen) reliably appearing on CT (or 
MRI) after baseline 
• ≥ 50% increase in long axis from baseline of any residual lymph node or mass. A residual 
lymph node or mass is defined as a previously lymphoma-involved lymph node or mass 
(>10 mm in short axis (without any upper limit)) that was PET negative at baseline and 
only reliably detected by baseline CT (or MRI). Note: If a residual lymph node or mass at 
baseline decreases in size during treatment and becomes normal (i.e. complete 
disappearance of extranodal mass or ≤ 10 mm in short axis and ≤ 15 mm long axis for 
nodal mass), then reappearance of an extranodal lesion at the same site or increase of the 
same nodal mass to > 15 mm in the long axis, will be considered RD and will be recorded 
as a new lesion. 
• Any new bone marrow involvement 

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• Any new malignant effusion 
Disease-free survival 
Disease-free survival (DFS) is the time from date of randomization / start of treatment to the 
date of event defined as the first documented relapse of the disease or death due to any cause. 
If a patient has not had an event, DFS is censored at the date of the last adequate assessment. 
Similar censoring rules and reasons as the ones used for PFS can be applied. 

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16.3 
Appendix 3:  Modified data reporting by study period 
Table 16-6 
Data reporting adverse events, concomitant medications, and 
laboratory values 
 
From ICF 
signature (or 
crossover 
visit) to 
safety follow-
up visit1 
Only patients who receive tisagenlecleucel 
From safety follow-up visit2 until Month 60 or early discontinuation from 
study 
AE and SAE 
All, including 
all laboratory 
abnormalities 
deemed 
clinically 
significant by 
the 
investigator 
• 
Any non-serious AEs ≥ Grade 3 and any SAEs irrespective of Grade with 
at least a possible causal relationship to tisagenlecleucel 
• 
The following AEs (i.e., non-serious AE and SAEs, if not otherwise 
specified) should be reported to Novartis regardless of causality: 
• 
AEs with fatal outcome 
• 
Events related to a study procedure 
• 
Serious neurologic disorder 
• 
Serious or opportunistic infections that fulfill any of the following 
criteria: 
• 
Require anti-infective treatment  
• 
Lead to significant disability or hospitalization  
• 
Need for surgical or other intervention 
• 
Hepatitis B reactivation 
• 
Progressive multifocal leucoencephalopathy (PML) 
• 
Prolonged depletion of normal B cells/ Agammaglobulinemia 
• 
New occurrence or exacerbation of an autoimmune disorder 
• 
Hematological disorders (incl. aplastic anemia and bone marrow 
failure) 
• 
Positive RCL test result 
• 
New secondary T cell or non T cell malignancy other than the primary 
underlying malignancy 
• 
Vector insertion site sequencing result with a mono-or oligoclonality 
pattern or in a location near a known human oncogene  
Concomitant 
medication 
All 
• 
Treatment related to an AE or SAE from the above mentioned list 
• 
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 
Laboratory 
data 
All 
• 
Record all scheduled labs (per Visit Evaluation Schedule, Table 8-2) 
• 
Record abnormal lab values that is in the opinion of the investigator 
related to the list of AEs and SAEs provided above. 
1 Patients in arm B who have the safety follow-up visit (indicating the end of AE collection), and then crossover 
to Arm A should restart AE reporting as described in this table starting at the time of the crossover visit.   
2 The safety follow-up visit will take place 8 weeks after last treatment administration or prior to starting a new 
anti-cancer therapy, whichever occurs first. 

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16.4 
Appendix 4: Liver event and laboratory trigger definitions and 
follow-up requirements 
Table 16-7 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
LIVER LABORATORY TRIGGERS 
3 x ULN ALT / AST ≤ 5 x ULN 
1.5 x ULN < TBL ≤ 2 x ULN 
LIVER EVENTS 
ALT or AST > 5 × ULN 
 
ALP > 2 × ULN (in the absence of known bone pathology) 
 
TBL > 2 × ULN (in the absence of known Gilbert syndrome) 
 
ALT or AST > 3 × ULN and INR > 1.5 
 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and 
TBL > 2 × ULN [mainly conjugated fraction] without notable increase 
in ALP to > 2 × ULN) 
 
Any clinical event of jaundice (or equivalent term) 
 
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia 
 
Any adverse event potentially indicative of a liver toxicity* 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms TBL: total 
bilirubin; ULN: upper limit of normal 
Table 16-8 
Follow up requirements for liver events and laboratory triggers 
Criteria 
Actions required 
Follow-up monitoring 
Potential Hy’s Law casea 
Discontinue the study treatment 
immediately (if applicable) 
Hospitalize, if clinically appropriate 
Establish causality 
Record the AE and contributing factors 
(e.g., concomitant medication, medical 
history, lab) in the appropriate CRF 
ALT, AST, TBL, indirect and direct 
bilirubin, albumin, Alb, PT/INR, ALP and 
GGT, until resolution (frequency at 
investigator discretion) 
ALT or AST 
> 8 × ULN 
Discontinue the study treatment 
immediately (if applicable) 
Hospitalize if clinically appropriate 
Establish causality 
Record the AE and contributing factors 
(e.g., concomitant medication, medical 
history, lab) in the appropriate CRF 
ALT, AST, TBL, indirect and direct 
bilirubin, albumin, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion) 
> 3 × ULN and INR > 1.5 
Discontinue the study treatment 
immediately (if applicable) 
Hospitalize, if clinically appropriate 
Establish causality 
Record the AE and contributing factors 
(e.g., concomitant medication, medical 
history, lab) in the appropriate CRF 
ALT, AST, TBL, indirect and direct 
bilirubin, albumin, Alb, PT/INR, ALP and 
GGT until resolutionc (frequency at 
investigator discretion) 

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

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Criteria 
Actions required 
Follow-up monitoring 
a Elevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN b 
(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia c Resolution is 
defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at three 
subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 months, 
(4) liver transplantation, and (5) death. 
Based on investigator’s discretion investigation(s) for contributing factors for the liver event can include: 
serology tests, imaging and pathology assessments, hepatologist’s consultancy; obtaining more detailed 
history of symptoms and prior or concurrent diseases, history of concomitant drug use, history of exposure to 
environmental chemical agents, exclusion of underlying liver disease. 

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16.5 
Appendix 5: Specific renal alert criteria and actions and event 
follow-up 
Table 16-9 
Specific renal alert criteria and actions 
Renal Event 
Actions 
Confirmed serum creatinine increase 25 – 49% 
Consider causes and possible interventions 
Follow up within 2-5 days 
Serum creatinine increase ≥50 % + 
OR if <18 years old, eGFR ≤35 mL/min/1.73 m2 
Consider causes and possible interventions 
Repeat assessment within 24-48 hours if possible 
Consider drug interruption or discontinuation unless other 
causes are diagnosed and corrected 
Consider patient hospitalization and specialized treatment 
New onset dipstick proteinuria ≥ 3+ OR 
(Spot) urinary protein-creatinine ratio (PCR) ≥ 1g/g 
(or mg/ mmoL equivalent as converted by the 
measuring laboratory) 
Consider causes and possible interventions 
Assess serum albumin & serum total protein 
Repeat assessment to confirm 
Consider drug interruption or discontinuation unless other 
causes are diagnosed and corrected 
New onset hematuria ≥3+ on urine dipstick 
Assess & document 
• 
Repeat assessment to confirm 
• 
Distinguish hemoglobinuria from hematuria 
• 
Urine sediment microscopy 
• 
Assess serum creatinine 
• 
Exclude infection, trauma, bleeding from the distal 
urinary tract/bladder, menstruation 
• 
Consider bleeding disorder 
+Corresponds to KDIGO criteria for Acute Kidney Injury 
Table 16-10 
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