Conditions: Nasopharyngeal Carcinoma
Keywords: PDR001 nasopharyngeal cancer moderately differentiated/undifferentiated locally advanced recurrent or metastatic NPC after first- line platinum-based therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 122
Healthy volunteers: no

Brief summary:
The purpose of this randomized controlled Phase II study is to assess the efficacy of PDR001 versus investigator's choice of chemotherapy in patients with advanced nasopharyngeal carcinoma (NPC).

By blocking the interaction between PD-1 and its ligands PD-L1 and PD-L2, PDR001 leads to the activation of a T-cell mediated antitumor immune response.

Detailed description:
This was an open-label, multi-center, randomized, and controlled Phase II study to evaluate the efficacy and safety of spartalizumab versus investigator's choice of treatment in subjects with moderately differentiated/undifferentiated locally advanced recurrent or metastatic NPC who progressed on or after first-line treatment.

Participants who met the inclusion/exclusion criteria were randomized in a 2:1 ratio to either investigational arm (spartalizumab) or control arm (commonly used chemotherapy as per investigator's choice). Participants treated with spartalizumab could continue treatment until confirmed progressive disease as per immune-related response criteria (irRC). Participants in the chemotherapy arm were allowed to crossover to spartalizumab if they had radiological progression as per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1) documented by an independent central review and the Investigator believed this was the best treatment option for the patient.

Arms:
arm 1: anti-PD1 humanized monoclonal antibody. Participants treated with spartalizumab who remained on spartalizumab arm 2: commonly used chemotherapy as per investigator's choice

Interventions: intervention 1: Spartalizumab intervention 2: Investigator choice of chemotherapy
Intervention descriptions: intervention 1: Spartalizumab was administered via intravenous infusion at a dose of 400 mg every 4 weeks (Q4W). Spartalizumab is a humanized anti-PD-1 IgG4 antibody which blocks the binding of PD1 to its ligands PD-L1 and PD-L2. intervention 2: Commonly used chemotherapy as per investigator's choice. The dose and route of administration was the one described in each drug's label.

Protocol document:
Prot_002.pdf: 
Clinical Development 
PDR001 
Protocol CPDR001X2201 / NCT02605967
A phase II, open-label, randomized controlled study of 
PDR001 in patients with moderately 
differentiated/undifferentiated locally advanced recurrent 
or metastatic nasopharyngeal carcinoma who progressed 
on standard treatment 
Document type 
Amended Protocol Version 
EUDRACT number 
2015-000454-38 
Version number 
06 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
24-Jun-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 7 
List of tables ........................................................................................................................ 7 
List of abbreviations ............................................................................................................ 9 
Glossary of terms ............................................................................................................... 11 
Protocol summary .............................................................................................................. 13 
Amendment 06 (24-Jun-2019) .......................................................................................... 15 
Amendment 05 (30-Aug-2018) ......................................................................................... 17 
Amendment 04 (07-Dec-2017) .......................................................................................... 19 
Amendment 03 (27-Jul-2016) ........................................................................................... 23 
Amendment 02 (21-Jan-2016) ........................................................................................... 26 
Amendment 01 (09-Nov-2015) ......................................................................................... 29 
1 
Background ........................................................................................................................ 31 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 31 
1.2 
Overview of conventional therapy in NPC ............................................................ 31 
1.3 
Introduction to investigational treatment and other study treatment(s) ................. 32 
1.3.1 
Overview of PD-1 and PDR001 ............................................................ 32 
2 
Rationale ............................................................................................................................ 34 
2.1 
Study rationale and purpose ................................................................................... 34 
2.2 
Rationale for the study design ............................................................................... 35 
2.3 
Rationale for dose and regimen selection .............................................................. 35 
2.4 
Rationale for choice of comparator drugs ............................................................. 35 
2.5 
Rationale for use of blood and tumor tissue biomarkers ....................................... 36 
3 
Objectives and endpoints ................................................................................................... 37 
4 
Study design ...................................................................................................................... 39 
4.1 
Description of study design ................................................................................... 39 
4.2 
Timing of interim analyses and design adaptations ............................................... 40 
4.3 
Definition of end of the study ................................................................................ 40 
4.4 
Early study termination .......................................................................................... 40 
5 
Population .......................................................................................................................... 41 
5.1 
Patient population .................................................................................................. 41 
5.2 
Inclusion criteria .................................................................................................... 41 
5.3 
Exclusion criteria ................................................................................................... 41 
6 
Treatment ........................................................................................................................... 44 
6.1 
Study treatment ...................................................................................................... 44 


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6.1.1 
Dosing regimen ..................................................................................... 44 
6.1.2 
Treatment duration ................................................................................ 44 
6.1.3 
Ancillary treatments (patients in PDR001 arm) .................................... 44 
6.1.4 
Chemotherapy treatments (patients in control arm only) ...................... 45 
6.2 
Safety and dose modifications (patients in PDR001 arm) ..................................... 45 
6.2.1 
Anticipated risks and safety concerns of the study drug (patients in 
PDR001 arm) ........................................................................................ 45 
6.2.2 
Immune-related adverse events (irAEs) ................................................ 45 
6.2.3 
Dose modifications and dose delay ....................................................... 45 
6.2.4 
Management of toxicities and immune related AEs (irAEs) ................ 46 
6.3 
Concomitant medications ...................................................................................... 51 
6.3.1 
Permitted concomitant therapy ............................................................. 51 
6.3.2 
Permitted concomitant therapy requiring caution and/or action 
(patients in PDR001 arm) ...................................................................... 51 
6.3.3 
Prohibited concomitant therapy (patients in PDR001 arm) .................. 51 
6.4 
Patient numbering, treatment assignment or randomization ................................. 52 
6.4.1 
Patient numbering ................................................................................. 52 
6.4.2 
Treatment assignment or randomization ............................................... 52 
6.5 
Study drug preparation and dispensation ............................................................... 53 
6.5.1 
Study drug packaging and labeling ....................................................... 53 
6.5.2 
Drug supply and storage ........................................................................ 53 
6.5.3 
Study drug compliance and accountability ........................................... 54 
6.5.4 
Disposal and destruction ....................................................................... 54 
7 
Visit schedule and assessments ......................................................................................... 54 
7.1 
Study flow and visit schedule ................................................................................ 54 
7.1.1 
Screening/baseline period ..................................................................... 62 
7.1.2 
Treatment period ................................................................................... 62 
7.1.3 
Discontinuation of study treatment ....................................................... 64 
7.1.4 
Withdrawal of consent .......................................................................... 65 
7.1.5 
Follow up for safety evaluations ........................................................... 65 
7.1.6 
Follow up for disease progression ......................................................... 66 
7.1.7 
Follow up for survival ........................................................................... 66 
7.1.8 
Lost to follow-up ................................................................................... 67 
7.2 
Assessment types ................................................................................................... 67 
7.2.1 
Efficacy assessments ............................................................................. 67 
7.2.2 
Safety and tolerability assessments ....................................................... 70 


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7.2.3 
Pharmacokinetics and immunogenicity assessments (patients in 
PDR001 arm) ........................................................................................ 73 
7.2.4 
Biomarkers (patients in PDR001 arm) .................................................. 75 
8 
Safety monitoring and reporting ........................................................................................ 78 
8.1 
Adverse events ....................................................................................................... 78 
8.1.1 
Definitions and reporting ...................................................................... 78 
8.1.2 
Laboratory test abnormalities ................................................................ 79 
8.2 
Serious adverse events ........................................................................................... 80 
8.2.1 
Definitions ............................................................................................. 80 
8.2.2 
Reporting ............................................................................................... 81 
8.3 
Pregnancies ............................................................................................................ 82 
8.4 
Warnings and precautions ...................................................................................... 82 
8.5 
Data Monitoring Committee .................................................................................. 83 
8.6 
Steering Committee ............................................................................................... 83 
9 
Data collection and management ....................................................................................... 83 
9.1 
Data confidentiality ............................................................................................... 83 
9.2 
Site monitoring ...................................................................................................... 84 
9.3 
Data collection ....................................................................................................... 84 
9.4 
Database management and quality control ............................................................ 85 
10 Statistical methods and data analysis ................................................................................ 85 
10.1 
Analysis sets .......................................................................................................... 86 
10.1.1 
Full Analysis Set ................................................................................... 86 
10.1.2 
Safety Set .............................................................................................. 86 
10.1.3 
Per-Protocol Set .................................................................................... 86 
10.1.4 
Pharmacokinetic analysis set ................................................................. 87 
10.2 
Patient demographics/other screening/baseline characteristics ............................. 87 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 87 
10.3.1 
Study treatment ..................................................................................... 87 
10.3.2 
Concomitant therapies ........................................................................... 87 
10.3.3 
Compliance ........................................................................................... 88 
10.4 
Primary objective ................................................................................................... 88 
10.4.1 
Variable ................................................................................................. 88 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 88 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 89 
10.4.4 
Supportive analyses ............................................................................... 89 
10.5 
Secondary objectives ............................................................................................. 89 


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10.5.1 
Key secondary objective(s) ................................................................... 89 
10.5.2 
Other secondary efficacy objectives ..................................................... 89 
10.5.3 
Safety objectives ................................................................................... 90 
10.5.4 
Pharmacokinetics (patients in PDR001 arm) ........................................ 92 
10.5.5 
Immunogenicity – exposure and/or adverse event relationship ............ 93 
10.5.6 
Biomarkers in plasma and in tumor (patients in PDR001 arm) ............ 93 
 
 94 
 
 94 
 
 94 
10.7 
Interim analysis ...................................................................................................... 94 
10.8 
Sample size calculation .......................................................................................... 94 
10.9 
Power for analysis of key secondary variables ...................................................... 95 
11 Ethical considerations and administrative procedures ...................................................... 95 
11.1 
Regulatory and ethical compliance ........................................................................ 95 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 95 
11.3 
Informed consent procedures ................................................................................. 95 
11.4 
Discontinuation of the study .................................................................................. 96 
11.5 
Publication of study protocol and results............................................................... 96 
11.6 
Study documentation, record keeping and retention of documents ....................... 97 
11.7 
Confidentiality of study documents and patient records ....................................... 98 
11.8 
Audits and inspections ........................................................................................... 98 
11.9 
Financial disclosures .............................................................................................. 98 
12 Protocol adherence ............................................................................................................ 98 
12.1 
Amendments to the protocol .................................................................................. 98 
13 References (available upon request) .................................................................................. 99 
14 Appendices ...................................................................................................................... 102 
14.1 
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival and Overall Survival (based on RECIST 1.1) . 102 
14.1.1 
Introduction ......................................................................................... 104 
14.1.2 
Efficacy assessments ........................................................................... 104 
14.1.3 
Efficacy definitions ............................................................................. 113 
14.1.4 
Data handling and programming rules ................................................ 121 
14.1.5 
References (available upon request) ................................................... 125 
14.2 
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using 
one-dimensional measurements (simulating RECIST 1.1) ................................. 126 
14.2.1 
Introduction ......................................................................................... 126 
14.2.2 
New lesions and non-target lesions ..................................................... 126 


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14.2.3 
Follow-up evaluation of target and non-target lesions ........................ 126 
14.2.4 
Definitions of response categories and evaluation of overall lesion 
response ............................................................................................... 127 
14.2.5 
References (available upon request) ................................................... 128 
14.3 
Appendix 3: Bayesian Cox proportional hazards model with meta-analytic-
predictive prior and operating characteristics of the design ................................ 129 
14.3.1 
Introduction ......................................................................................... 129 
14.3.2 
Operating characteristics ..................................................................... 136 
14.3.3 
References (available upon request) ................................................... 138 
14.4 
Appendix 4: Management algorithms ................................................................. 139 
14.4.1 
References (available upon request) ................................................... 146 


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List of appendices 
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, TTP, Progression-
Free Survival and Overall Survival (based on RECIST v1.1). 
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using one-dimensional 
measurements (simulating RECIST v1.1). 
Appendix 3: Bayesian Cox proportional hazards model with meta-analytic-predictive prior 
and operating characteristics of the design. 
Appendix 4: Management Algorithms 
 
List of figures 
Figure 4-1 
Study design .......................................................................................... 39 
Figure 14-1 
Prior distribution of corresponding progression free survival 
probabilities ......................................................................................... 135 
 
List of tables 
Table 1-1 
Second line treatment in metastatic or recurrent NPC .......................... 32 
Table 3-1 
Objectives and related endpoints .......................................................... 37 
Table 6-1 
Dose and treatment schedule ................................................................. 44 
Table 6-2 
Criteria for interruption, delay, re-initiation and discontinuation of 
PDR001 ................................................................................................. 47 
Table 7-1 
Visit evaluation schedule (patients in PDR001 arm) ............................ 55 
Table 7-2 
Visit evaluation schedule (patients in chemotherapy arm) ................... 58 
Table 7-3 
Visit evaluation schedule (crossover patients treated with PDR001) ... 60 
Table 7-4 
Disease assessment collection plan ....................................................... 68 
Table 7-5 
ECOG performance status ..................................................................... 71 
Table 7-6 
Local/central clinical laboratory parameters collection plan ................ 72 
Table 7-7 
12 lead ECG collection plan for central review (patients in 
PDR001 arm)*** .................................................................................. 73 
Table 7-8 
Pharmacokinetic blood collection log (patients in PDR001 arm) ......... 74 
Table 7-9 
Biomarker sample collection plan ......................................................... 76 
Table 10-1 
Noncompartmental pharmacokinetic parameters .................................. 92 
Table 14-1 
Response criteria for target lesions ..................................................... 109 
Table 14-2 
Response criteria for non-target lesions .............................................. 111 
Table 14-3 
Overall lesion response at each assessment ........................................ 112 
Table 14-4 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 119 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response ........ 120 


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Table 14-6 
Overall response at each assessment ................................................... 127 
Table 14-7 
Historical PFS data from 7 studies ...................................................... 131 
Table 14-8 
Prior distribution of daily long-hazards .............................................. 134 
Table 14-9 
Different scenarios of operating characteristics simulations .............. 136 
Table 14-10 
Operating characteristics for the six scenarios .................................... 137 
 


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List of abbreviations 
Abs 
Antibodies 
(m)OS 
(median) Overall Survival 
(m)PFS 
(median) Progression Free Survival 
(m)TTP 
(median) Time to Progression 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
APTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC 
Area Under the Curve 
BUN 
Blood Urea Nitrogen 
CMO&PS 
Chief Medical Office and Patient Safety 
CRO 
Contract Research Organization 
CRP 
c-Reactive protein 
CRS 
Cytokine Release Syndrome 
CRT 
Chemoradiotherapy 
CSF 
Colony Stimulating Growth Factor 
CSR 
Clinical Study report 
DC 
Dendritic Cell 
DOR 
Duration of Response 
EBV 
Epstein Barr Virus 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report/Record Form 
ELISA 
Enzyme Linked Immunosorbent Assay 
ESA 
Erythropoiesis Stimulating Agents 
eSAE 
Electronic Serious Adverse Event 
FAS 
Full Analysis Set 
Foxp3 
Forkhead box P3 
HAART 
Highly Active antiretroviral Therapy 
HbcAg 
Core Antigen to Hepatitis B 
HBsAg 
Surface Antigen of the Hepatitis B 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HNSCC 
Head and Neck Squamous Cell Carcinoma 
HR 
Hazard Ratio 
i.v. 
Intravenous(ly) 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IFN-γ 
Interferon-gamma 
IHC 
Immunohistochemistry 
IL-1 
Interleukin-1 
IL-6 
Interleukin-6 
INR 
International Normalized Ratio 
irAE(s) 
Immune-related Adverse Event(s) 
IRB 
Institutional Review Board 


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irPD 
Immuno-related Progressive Disease 
irPFS 
Immune-related Progression Free Survival 
irRC 
Immune-related Response Criteria 
IRT 
Interactive Response Technology 
LAG-3 
Lymphocyte Activation gene-3 
LLOQ 
Lower Limit Of Quantitation 
LMP1 
Latent Membrane Protein 1 
LMWH 
Low Molecular Weight Heparin 
mAb(s) 
Monoclonal Antibody(ies) 
MDSC 
Myeloid-derived Suppressor Cell 
MLR 
Mixed Lymphocyte Reaction 
MTD 
Maximum Tolerated Dose 
NKT cells 
Natural Killer T cells 
NPC 
Nasopharyngeal cancer 
NSCLC 
Non-Small Cell Lung Carcinoma 
ORR 
Overall Response Rate 
PAS 
Pharmacokinetic Analysis Set 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 
PD-L1 
Programmed Death-Ligand 1 
PD-L2 
Programmed Death-Ligand 2 
Per os 
Oral administration 
PK 
Pharmacokinetics 
PPOS 
Predictive Probability of Success 
PPS 
Per Protocol Set 
PR 
Partial Response 
PT 
Prothrombin time 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RF 
Rheumatoid factor 
RP2D 
Recommended phase II dose 
SAE(s) 
Serious Adverse Event(s) 
SEB 
Staphylococcal enterotoxin B 
SJS 
Stevens Johnson Syndrome 
TEN 
Lyell syndrome/toxic epidermal necrolysis 
TIL(s) 
Tumor Infiltrating Lymphocyte(s) 
TIM-3 
T-cell immunoglobulin domain and mucin domain-3 
TNF-α 
Tumor necrosis factor-alpha 
Tregs cells 
Regulatory T cells 
TSH 
Thyroid Stimulation Hormone 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study patient 
Control arm/Comparator 
drug 
A study treatment used as a comparator to reduce assessment bias, preserve 
blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g.: q28 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved indication/dosage 
Other study treatment 
Any drug administered to the patient as part of the required study procedures that 
was not included in the investigational treatment 
Patient Number (Patient 
No.) 
A unique identifying number assigned to each patient/ who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening/baseline, titration, washout, etc. 
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 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has spread 
from the original site to other parts of the body 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to the 
patient as part of the required study procedures, including placebo and active 
drug run-ins. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment in this case 
refers to the investigational and non-investigational treatments in combination 
Study treatment 
discontinuation 
Point/time when a patient permanently discontinues study treatment for any 
reason 
Supportive treatment 
(Concomitant 
medications) 
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 


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


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Protocol summary 
Protocol number 
CPDR001X2201 
Title 
A phase II, open-label, randomized controlled study of PDR001 in patients 
with moderately differentiated/undifferentiated locally advanced recurrent or 
metastatic nasopharyngeal carcinoma (NPC) who progressed on standard 
treatment. 
Brief title 
Phase II study of PDR001 in patients with nasopharyngeal carcinoma. 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose 
and 
rationale 
The purpose of this randomized controlled Phase II study is to assess the 
efficacy of PDR001 versus investigator’s choice of chemotherapy in patients 
with NPC. 
By blocking the interaction between PD-1 and its ligands, PD-L1, PDR001 
inhibits the PD-1 immune checkpoint, resulting in activation of an antitumor 
immune response by activating effector T-cells and inhibiting regulatory T-
cells. 
Primary 
Objective(s) 
Progression free survival (PFS) as per RECIST v1.1 
Secondary 
Objectives 
● 
Evaluate anti-tumor activity of PDR001 vs investigator’s choice of 
chemotherapy (OS, ORR, DOR, TTP, irPFS) 
● 
Characterize the safety and tolerability of PDR001 
● 
Characterize the pharmacokinetic profile of PDR001 
● 
Assess emergence of anti-PDR001 antibodies 
● 
Assess pharmacodynamic effect of PDR001 in peripheral blood 
Study design 
This is an open-label, multi-center, randomized, controlled phase II study to 
evaluate the efficacy and safety of PDR001 versus investigator’s choice of 
chemotherapy in patients with moderately differentiated/undifferentiated 
locally advanced recurrent or metastatic NPC who progressed on or after 
first-line platinum-based treatment. PDR001 will be administered every 4 
weeks until patient experiences unacceptable toxicity, progressive disease 
per immune related Response Criteria (irRC) and/or treatment is 
discontinued at the discretion of the investigator or the patient. A cycle is 
defined as 28 days. 
Population 
The study will be conducted in patients with moderately 
differentiated/undifferentiated locally advanced recurrent or metastatic NPC 
who progressed on or after first- line platinum-based therapy. 


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Inclusion criteria 
(selected) 
1. Histologically documented non-keratinizing locally advanced 
recurrent or metastatic NPC. 
2. Must be resistant to platinum-based chemotherapy (defined as 
progression on or after platinum-based chemotherapy given in the 
recurrent/metastatic setting). 
3. May have received at least 1 prior therapy for recurrent or 
metastatic disease, up to 2 prior systemic therapies. 
4. An archival tumor specimen or newly obtained tumor sample may 
be submitted at screening/baseline (a fresh tumor sample is 
preferred), unless agreed differently between Novartis and the 
Investigator. 
5. At least 1 measurable lesion (as per RECIST v1.1) progressing or 
new since last anti-tumor therapy. 
6. Prior treated brain or meningeal metastases must be without MRI 
evidence of progression for at least 8 weeks and off systemic 
steroids for at least 2 weeks prior to screening/baseline. 
7. Patient must be willing to undergo testing for human 
immunodeficiency virus (HIV) if not tested within the past 6 months. 
If HIV+ positive, patient will be eligible if: his/ her CD4+ count ≥ 
300/µL; his/her viral load is undetectable; he/she is currently 
receiving highly active antiretroviral therapy (HAART). 
Exclusion criteria 
(selected) 
1. 
History of severe hypersensitivity reactions to other mAbs 
2. 
Active autoimmune disease or a documented history of 
autoimmune disease, except vitiligo or resolved asthma/atopy that 
is treated with broncho-dilators. 
3. 
Active HBV or HCV infections requiring therapy. 
4. 
Prior PD-1- or PD-L1-directed therapy 
5. 
Patients receiving systemic treatment with any immunosuppressive 
medication. 
6. 
Use of any vaccines against infectious diseases (e.g. varicella, 
pneumococcus) or investigational therapeutic cancer vaccines 
within 4 weeks of initiation of study treatment. 
Investigational and 
reference therapy 
PDR001 
Investigator’s choice of chemotherapy 
Efficacy 
assessments 
Tumor assessment per RECIST v1.1 and per irRC 
Safety 
assessments 
Incidence and severity of AEs and SAEs, including changes in laboratory 
values, vital signs and ECGs 
Other 
assessments 
Serum PK parameters and Immunogenicity 
Pharmacodynamic assessment on pre- and post- treatment on tumor and 
blood samples 
Data analysis 
The primary analysis of PFS will be performed for the comparison of PDR001 
with the control arm (investigator’s choice of chemotherapy), after 
approximately 70 PFS events have occurred across both of the two arms 
combined. A final clinical data analysis will be performed once all patients have 
discontinued the study or at the end of the study (end of survival follow up 
period), whichever occurs first 
Key words 
Phase II, PDR001, Checkpoint inhibitor, PD-1, PD-L1, nasopharyngeal cancer 


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Amendment 06 (24-Jun-2019) 
 
Amendment rationale  
The main purpose of this protocol amendment is to revise the definition of end of study to 
include the option for patients still on study treatment and who in the opinion of the investigator 
are still deriving clinical benefit at the time of end of study, to transfer to another study or to an 
alternative treatment option to continue providing study treatment to these patients. 
In addition, the blood sample collection is removed for the assessment of serum cytokines used 
for retrospective analysis of a cytokine release syndrome adverse event. Blood samples for 
serum cytokines were included due to the unknown risk of CRS with IO agents alone and in 
combination, and to allow an assessment of any association between cytokines and clinical 
events. These samples have been drawn at baseline and at the time of a potential CRS event, 
stored, and analyzed retrospectively. Due to this, results are not intended to be used to support 
clinical decision-making for patients with possible CRS. There were no unexpected clinically 
assessed events of CRS observed across 19 studies including more than 2200 patients. The risk 
of CRS in the current study is deemed to be low, thus supporting the removal of this blood 
sample collection.  
Study status  
The study enrolment was completed with the last patient first dose on 03-Aug-2018.  In total 
122 patients have been randomized, including 82 patients randomized to the PDR001 arm. As 
of 21-May-2019, there are 12 ongoing patients, all of which are on PDR001 treatment. Among 
the 12 patients, 11 were randomized to PDR001 arm, and one was randomized to chemotherapy 
arm and then crossed over to receive PDR001 treatment.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
Section 4.3 Definition of end of the study: addition of language to account for patients who 
would transfer into another study or an alternative treatment option to continue provision of 
study treatment. 
Section 6.2.4 Management of toxicities and irAEs and Table 6-2 Criteria for interruption, delay, 
re-initiation and discontinuation of PDR001: removal of blood sample collection for 
retrospective central analysis of safety cytokines in case of suspected CRS. 
Table 7-1 and Table 7-3 Visit evaluation schedule (PDR001, Crossover): addition of footnotes 
to clarify the assessments within follow-up period are not applicable to patients who transfer to 
another study or an alternative treatment option to continue provision of study treatment. 
Table 7-1, Table 7-3 Visit evaluation schedule (PDR001, Crossover) and Table 7-6 Clinical lab 
parameters collection plan: addition of footnotes to clarify termination of safety cytokine 
sample collection upon implementation of Protocol amendment 06. 


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Section 7.1.3 Discontinuation of study treatment: addition of language to specify that patients 
who transfer to another study or an alternative treatment option to continue provision of study 
treatment will complete end of treatment procedures. 
Section 7.1.5, 7.1.6, 7.1.7 Follow up for safety evaluations, disease progression, survival: 
addition of language to specify that patients who transfer to another study or alternative 
treatment option to continue provision of study treatment will not complete safety, disease 
progression and/or survival follow up. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 
 


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Amendment 05 (30-Aug-2018)  
Amendment rationale  
 The primary purpose of this amendment is to incorporate health authority-requested 
language requiring study treatment discontinuation in the event of Stevens-Johnson 
syndrome (SJS)/ toxic epidermal necrolysis (TEN). After the occurrence of a case of 
Steven Johnson Syndrome in a study with PDR001 in combination with another 
investigational agent, the dose modification guidelines for protocols using PDR001 were 
updated to mandate permanent discontinuation of study treatment for patients who 
experience SJS or TEN. This change has already been implemented as part of an urgent 
safety measure released on 15 June 2018. This protocol amendment is now finalizing 
these changes in the dose modification section and corresponding table describing the 
criteria for dose reduction/interruption and re-initiation of treatment for adverse drug 
reactions (Table 6-2). Changes to other sections of the protocol have been made to align 
with the updated dose modification section. 
 The withdrawal of consent language was revised to differentiate sample use after a patient 
withdraws consent based on the different regulations/laws around the world. 
 The independent central review of imaging data will be terminated for the whole study 
when both criteria are met, 1) decisions are made based on central review results for all 
chemotherapy arm patients on whether to crossover; 2) all patient have reached a 
minimum of 12 months follow up after the first dose of study treatment (unless have been 
lost to follow-up). Because the purposes of applying the central review service will have 
been fulfilled.  
 Serology tests (Anti-DNA antibodies (Abs), Anti-nuclear abs, Anti-phospholipid abs, 
Anti-mitochondrial abs, c-Reactive protein (CRP), Rheumatoid factor (RF)) are no longer 
mandated. The available safety data from clinical studies indicate that PDR001 is 
generally well tolerated. 
 In this amendment, ECG will no longer be centrally reviewed. Sites will continue to 
perform local review of ECG following local practice or as clinically indicated. The 
reason is the data analyzed to date indicate PDR001 does not have a clinically relevant QT 
liability and support reduced ECG monitoring scheme for future clinical studies, as 
outlined in Section 7 of ICH E14 (PDR001 IB version 7.1).  
 PK and IG sample collection will be terminated after the Cycle 4 samples have been 
collected from all the PDR001 arm patients, as sufficient PK and IG samples have been 
collected for characterization of the PK and IG profile of PDR001 in NPC patients.  
 To simplify study conduct, all language related to CSR timing has been removed.   
 Additional editorial changes have been made to sections where previous language was 
deemed inaccurate or ambiguous. 
Study status 
The study enrolment was completed with the last patient first dose on 3 Aug 2018.  In total 122 
patients have been randomized, including 82 patients randomized to the PDR001 arm. As of 10 


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August 2018, there are 27 ongoing patients, among which 18 are on PDR001 treatment, 5 are 
on Chemotherapy, and 4 are crossover patients. 
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. 
List of abbreviations: Added SJS and TEN. 
Glossary of terms: Added term “Personal data” and updated term “Withdrawal of consent”. 
Table 6-2: Language has been added to mandate permanent study treatment discontinuation 
for SJS/TEN, as per the USM letter dated 15 June 2018. 
Section 7.1.3 and Section 7.1.4: Updated the withdrawal of consent language. 
Section 7.2.1: Specified the timing to terminate central imaging review. 
Section 7.2.2.5, Table 7-1, Table 7-2, Table 7-3 and Table 7-6: Specified the timing to 
terminate serology tests. 
Section 7.2.2.6, Table 7-1, Table 7-3 and Table 7-7: Specified the timing to terminate central 
ECG review, and that central ECG review of designated time points will be replaced by 
local ECG review of time points based on Investigator’s judgement. 
Section 7.2.3: Updated the timing to terminate PK and IG sample collection.  
Section 8.3: Follow-up of newborn has been extended from 3 months to 12 months.  
Section 10: Removed the timing of CSR. Section 4.3 is updated accordingly. 
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 in this amendment identified above as being related to the USM have already been 
implemented by a USM letter issued on 15 June 2018. These changes are required for patient 
safety (i.e. necessary to eliminate immediate hazards to the trial subjects ICH GCP 3.3.8). 
Therefore they were required to have been implemented prior to IRB/IEC approval of this 
amendment.  
All other changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 04 (07-Dec-2017) 
Amendment rationale 
This amendment introduces the addition of safety evaluations on 30 and 90 days to the 150-day 
safety follow-up visit, in order to ensure regular safety follow-up of patients after the last 
administration of PDR001. 
During the 150-day safety follow-up period, many patients will most likely start a new 
antineoplastic therapy. In such cases, only AEs and SAEs suspected to be related to PDR001 
will be collected in CRF, in order to focus on PDR001 related safety information; and 
concomitant medications will be recorded in CRF until the 30-day safety follow-up has been 
completed or the start of a new antineoplastic therapy, whichever occurs first. To ensure a 
consistent approach in the reporting of the safety profile of study treatment, the main data 
analysis will focus on the period from the first dose of study treatment to 30 days after the date 
of the last administration of study treatment. Data collected beyond this period (i.e. post-
treatment period) will be summarized separately. 
For prohibited concomitant therapy, the wording related to the use of systemic steroid therapy 
during the course of study is adjusted in order to provide more flexibility for patients who would 
need such therapy for treatment of acute conditions. 
The description of safety summaries is added to the safety data analysis to align with the 
program level approach. 
Immune-related adverse events (irAEs) have been included in the AEs part as secondary 
endpoints. To avoid redundant description and reporting, the irAEs are removed as standalone 
secondary endpoint but continue to be analyzed as part of the AEs analysis (secondary endpoint). 
Neurological Adverse Event Management Algorithm was inadvertently removed in the last 
protocol version 03, (dated 27-Jul-2016). Therefore this same algorithm is included back in the 
current amendment (protocol amendment 04). 
Although response rate (by RECIST 1.1) remains important, the meaningful benefit of 
immunotherapy has thus far been with the impressive durable clinical efficacy. PFS and OS 
benefits with immunotherapies have been demonstrated for those who do respond, as 
demonstrated by the 'long tail' on the Kaplan-Meier curve (Sharma and Allison, 2015). 
Therefore, in order to explore the durability of disease control by PDR001 in patients with NPC, 
the analysis of long term endpoints will be added to the primary CSR. This analysis will include 
all patients data up to the date when each patient has reached a minimum of 12 months of follow 
up after the first dose of study treatment or has been lost to follow-up. There are no changes to 
the pre-defined study endpoints. 
In order to better characterize PK through population approach, one more sample collection is 
added for PK and IG at the 150-day safety follow-up visit for PDR001 arm patients who come 
on site. 


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To align with the EMA standard term list, the PDR001 pharmaceutical form has been updated 
to “Powder for solution for infusion”. 
Additional editorial changes and clarifications have been made to sections where previous 
language was deemed inaccurate or ambiguous. 
Study status 
As of the cut-off date 16 October 2017, 114 patients have been randomized, including 76 
patients randomized to the PDR001 arm. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
Section 3 Objectives and endpoints 
 Removed irAEs from the Secondary endpoint because they are included in the AEs 
category. 
Section 4.1 Description of study design 
 Corrected the end of the 28-day screening period from randomization to C1D1 to be 
consistent throughout the protocol 
Section 4.3 Definition of end of the study 
 Added “primary CSR” to be consistent with Section 10. 
 Removed the details of data analysis, which have been described in Section 10. 
Section 6.1.1 Dosing regimen, Section 6.5 Study drug preparation and dispensation and Section 
6.5.1 Study drug packaging and labeling 
 Replaced “lyophilisate in vial” with the European Medicines Agency (EMA) standard 
term "powder for solution for Infusion" to describe the PDR001 pharmaceutical form. 
Section 6.3.3 Prohibited concomitant therapy (patients in PDR001 arm) 
 Added further information on the use of systemic steroid therapy: 
 For replacement-dose steroids in the setting of adrenal insufficiency, use is acceptable 
providing this is ≤ 10 mg/day prednisone or equivalent. 
 Use of systemic steroid therapy is authorized for transient exacerbations of other 
underlying diseases such as chronic obstructive pulmonary disease (COPD) requiring 
treatment for < 3 weeks. 
Section 7.1.5 Follow up for safety evaluations 
 Added safety follow-up phone call or visit at 30-, 90-, and 150-day for PDR001 arm and 
crossover patients. The schedule is also reflected in Table 7-1 and Table 7-3. 
 Added sampling for PK and IG at 150-day safety follow-up. It is also reflected in Table 7-
8 of section 7.2.3. 
 Specified data collection of Concomitant medications during safety follow-up period. It is 
also reflected in Table 7-1 and Table 7-3. 


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Section 7.2.2.5 Laboratory evaluations 
 Specified female patients of child-bearing potential should perform pregnancy tests every 
month during and at the end of the safety follow-up period. 
Section 8.1.1 Definitions and reporting 
 Specified AEs collection after initiation of a new post-treatment antineoplastic therapy 
during safety follow-up period. It is also reflected in Table 7-1 and Table 7-3. 
Section 8.2.2 Reporting 
 Removed “SAEs will only be reported if the event is suspected to be causally related to a 
study procedure as assessed by the investigator (e.g. an invasive procedure such as 
biopsy)” as it is not applicable to this study. 
 Specified SAEs collection after initiation of a new post-treatment antineoplastic therapy. 
Section 10 Statistical methods and data analysis 
 Specified the endpoints included in the primary analysis. 
 Added another analysis including all patients data up to the date when each patient has 
reached a minimum of 12 months follow up after the first dose of study treatment or has 
been lost to follow-up. 
 Specified that the primary CSR will include both analyses. 
Section 10.4.2 Statistical hypothesis, model, and method of analysis 
 Added log-rank test 
Section 10.5.3.1 Analysis set and grouping for the analyses 
 Updated the definition of “on-treatment period” and “post-treatment period” to ensure a 
consistent approach in the reporting of the safety profile of study treatment 
 Added description of the safety summaries in safety analysis. 
Section 10.5.3.2 Adverse events (AEs) 
 Removed irAEs because they are covered by AEs of special interest category in safety 
summaries. 
 Added description of the safety summaries in safety analysis. 
Section 11.5 Publication of study protocol and results 
 Updated to reflect latest procedures on the publication of study protocol and results. 
Section 14.4 Appendix 4: Management algorithms 
 Added Neurological Adverse Event Management Algorithm 


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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. 


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Amendment 03 (27-Jul-2016) 
Amendment rationale 
With the available PK data obtained from the single agent first-in-human study 
CPDR001X2101, an exploratory population PK (PopPK) analysis showed that the T1/2 of 
PDR001 in man is 20 [17, 23] days (mean [90% CI]). Using five times the upper limit of the 
half-life of 23 days and an added safety margin, the protocol is amended to increase the duration 
of contraception and safety follow-up period post PDR001 treatment from 90 days to 150 days. 
These changes are related to an Urgent Safety Measure communicated on 08-Jun-2016 to all 
investigators. 
This amendment also introduces the following changes. 
Clarification of Inclusion Criterion 8: specify that lesions in previously irradiated areas should 
not be considered measureable unless there is clear evidence of progression in such lesions 
since the radiotherapy. 
Modification of Exclusion Criterion 8: Patients who have previously received an investigational 
therapeutic cancer vaccine can be eligible. This change has been introduced considering the 
limited efficacy evidence available for cancer vaccines and the high unmet medical need in this 
patient population. 
Clarification of Exclusion Criterion 10: Patients who have previously received an 
investigational therapeutic cancer vaccine are eligible providing there is a minimum 4-week 
washout period between the last dose of the vaccine and the first dose of PDR001. 
The ECG monitoring plan is simplified to collection of ECGs at screening, Cycle 1 day 1, Cycle 
3 day 1 and as clinically indicated, because no signal of QT interval prolongation was observed 
in the first in human study (CPDR001X2101) (see PDR001 Investigator’s Brochure) or other 
currently approved anti-PD-1 antibodies (see KEYTRUDA® and OPDIVO® labels). 
 
There is a clerical error in the previous version of the protocol within the criteria for 
discontinuation language in Section 7.1.3 (Discontinuation of study treatment). Amendment 2 
equivocally indicated that patients must be discontinued from treatment upon observance of any 
of the events listed in the section. This section has been clarified by differentiating reasons that 
may cause treatment discontinuation from those that require mandatory treatment 
discontinuation. 
Clarification of Section 7.2.2.5: serum pregnancy test will be performed at screening/baseline 
and/or within ≤ 72 hours before first dose of study treatment, day 1 of each cycle and EOT. The 
change is to align with the latest Novartis guideline on prevention of pregnancies in participants 
in clinical trials. 
Clarification of Section 10.5.5 to immunogenicity data may be analyzed appropriately 
according to study demand. 
Minor changes have been made for consistency and to clarify operational details. 


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Study status 
As of the cut-off date 06-Jun-2016, 2 patients have been enrolled and 1 patient is treated with 
PDR001 at 400mg i.v. every 4 weeks. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
Section 4.1 Study Description of study design 
 The safety follow-up for patients receiving PDR001 treatment was extended from 90 to 
150 days. This change was applied throughout the protocol in Sections 5.3; 7.1.5; 8.1.1; 
8.2.2; 10.5.3.1.; Table 7-1 and Table 7-3. 
Section 5.2 Inclusion criteria 
 Revised criterion 8 to add that lesions in previously irradiated areas should not be 
considered measureable unless there is clear evidence of progression in such lesions since 
the radiotherapy. 
Section 5.3 Exclusion criteria 
 “Any therapeutic cancer vaccine” was removed from exclusion criterion 8. 
 Addition of a washout period for investigational therapeutic cancer vaccines in exclusion 
criterion 10. This specifies that use of investigational therapeutic cancer vaccines within 4 
weeks of initiation of study treatment is excluded. 
Section 7.1.3 Discontinuation of Study Treatment 
 The word “must” has been replaced by the word “may”. This sentence “Study treatment 
may be discontinued under the following circumstances” outlines the reasons that may 
require treatment discontinuation. 
 The criterion “confirmed Complete response as per RECISTv1.1” only requires patients 
treated with PDR001 to discontinue study treatment. 
Section 7.2.2.5 Laboratory evaluations 
 Table 7-6 “fasting” was added after “glucose” to clarify glucose tests shall be taken when 
patients are fasted. 
 The serum pregnancy test will be performed at screening/baseline and/or within ≤ 72 
hours before first dose of study treatment, day 1 of each cycle and EOT. 
Section 7.2.2.6.1 Electrocardiogram (ECG) 
 Cardiac assessments Electrocardiogram (ECG) collection has been removed on Cycle 1 
D1 pre-dose, Cycle 6 D1 and end of treatment. In addition, Table 7-7; Table 7-1 and Table 
7-3 have been updated accordingly. 
Section 10.5.5 Immunogenicity-exposure and/or adverse event relationship 
 Immunogenicity data may be analyzed appropriately according to study demand. “will” 
was replaced by “may” in the concentration/adverse event – immunogenicity relationship 
analysis. “may” was also used to replace “will” in other correlation analysis. 


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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 related to the urgent safety measure are to be implemented prior to IRB/IEC 
approval. All other changes described in this amended protocol require IRB/IEC approval prior 
to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 02 (21-Jan-2016) 
Amendment rationale 
The primary purpose of this amendment is to introduce the recommended phase II dose of 
PDR001 established in the phase I (first-in-human) study CPDR001X2101. Based on 
pharmacokinetic (PK) and safety data from study CPDR001X2101, the recommended Phase 2 
dose (RP2D) for PDR001 has been declared as a flat dose of 400mg i.v. every 4 weeks. 
Based on preliminary PK data from study CPDR001X2101 and the possibility of delayed 
appearance of immune-related adverse events, the safety follow-up period has been extended 
to 90 days after the last dose of PDR001 treatment. 
Patients who are HBV or HCV positive are eligible. As PD-1 blocking antibodies are not 
immunosuppressive, there is no specific contraindication to recruit patients who are HBV and 
HCV positive, provided their active disease is adequately controlled by antiviral therapy. 
Patients who have previously received CTLA-4-antagonists are eligible providing they don’t 
have hepatic, diarrhea/colitis or endocrine adverse events (AE)s Grade≥2, any other non-
laboratory immune-related AE≥3. Patients must have minimum 8 week washout period 
between the last dose of anti-CTLA4 and the first dose of PDR001. The 8 weeks washout period 
is needed to resolve the anti-CTLA4 induced irAE, which may have a delayed onset. 
To align this protocol with the latest Novartis guidelines for the prevention of pregnancies in 
participants in clinical trials and their partners, the exclusion criteria were updated to exclude 
sexually active male subjects who are not willing to use a condom during the study. 
For monitoring of thyroid function, the measurement of free T4 a more specific parameter as 
compared to total T4 is included, whereas total T4 is removed. 
The tumor assessment should include the head and neck if clinically relevant. 
This amendment also incorporates revision as requested by a regulatory authority to exclude 
patient with contraindications to the investigator’s choice of treatment for the control arm. 
Investigators must refer to the approved label of the product chosen in the control arm especially 
regarding contraindications, contraceptives regimens, dosage adjustment in case of toxicity, 
patient monitoring and prohibited drugs or drugs used with caution. 
As all SAEs information is collected and recorded within the Electronic Data Capture (EDC) 
system, this amendment introduces the electronic Serious Adverse Event (eSAE) reporting 
method. 
Minor changes have been made for consistency and to operations-related specifications. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Section 1.3.1.2 PDR001 clinical experience 
 Updated doses and regimens evaluated in the CPDR001X2101 study and the 
recommended phase II dose. 


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Section 2.3 Rationale for dose and regimen selection 
 Updated the RP2D which has been established in CPDR001X2101as a flat dose 400mg 
i.v. every 4 weeks. This change was applied in Section 2.2; 6.1.1.; 6.2.3; 6.5; 7.1.2. 
Section 4.1 Study Description of study design 
 The safety follow-up for patients receiving PDR001 treatment was extended from 30 to 90 
days. This change was applied throughout the protocol in Sections 7.1.5; 7.2.2.5; 8.1.1; 
8.2.2; 10.5.3.1. 
Section 5.3 Exclusion criteria: 
 Revised criterion 4 to allow patients who are HBV and HCV positive, providing their 
active disease is controlled by antiviral therapy(local guideline) 
 Addition of a washout period for CTLA-4 antagonists in criterion 7 
 Addition of total hysterectomy in the definition of female sterilization and update of the 
definition of highly effective contraception in exclusion criterion 17 
 Addition of exclusion criterion 18, which excludes sexually active male patients who do 
not wish to a condom during intercourse 
 Addition of exclusion criterion 19, which excludes patient with contraindications to the 
chosen treatment per investigator’s choice for the control arm 
Section 6.1.4 Chemotherapy treatment (patients in Control arm) 
 Addition section to indicate investigator must refer to the approved label of the product 
used in the control arm especially regarding pre-medication schemes, the 
contraindications, contraceptives regimens, dosage adjustment in case of toxicity, patient 
monitoring and the prohibited drugs or drugs used with caution. 
Table 7-1 and 7-3 Visit evaluation schedule: 
 Updated the safety follow-up from 30 days to 90 days after the last dose of PDR001 
treatment, as well as related assessments. 
 Visit schedule was incorporated to dose regimen every 4 weeks. 
Table 7-2 Visit evaluation schedule: 
 Addition of a footnote that investigators must refer to the approved label of the product 
used in the control arm. 
Section 7.1.5 Follow-up period: 
 Updated the safety follow-up from 30 day to 90 day follow-up and associated assessments 
for PDR001 treatment 
Section 7.2.1 Efficacy assessments: 
 Addition of wording to clarify the disease assessment at screening. 
Section 7.2.2.5 laboratory evaluations 
 Addition of wording to clarify serum pregnancy test at screening, sequential visits and 
safety follow-up visit. 
 Table 7-6 Free T4 has replaced Total T4. 


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 Table 7-8 PK sample time point was updated according to the dosing frequency of every 4 
weeks. 
Table 7-9 Biomarker sample collection-plan 
 Removal of the example of IFN-gamma being assessed in tumor biopsies, as this 
parameter might no longer be analyzed in this context, but only as soluble cytokine in 
plasma. 
Section 8.2.2.Reporting 
 Introduced the electronic Serious Adverse Event (eSAE) reporting method as all SAEs 
information would be collected and recorded within the Electronic Data Capture (EDC) 
system instead of paper SAE form. 
Section 8.3 Pregnancies 
 Addition of wording of pregnancy outcomes collection for the female partner of any male 
participant. 
Section 14.2 Appendix 2: Guidelines for immune-related Response Criteria (irRC) using one-
dimensional measurements (simulating RECIST 1.1) 
 The lesion diameter measurements under RECIST 1.1 and irRC are the long axis (or 
longest diameter) for non-nodal lesions and the short axis for the nodal lesions. Sections 
14.2.2, 14.2.3 and Table 14-6 were updated to clarify that assessments are not based only 
on longest diameters. 
IRB/IEC/HA 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 01 (09-Nov-2015) 
Amendment rationale 
This amendment addresses the following revision requested by regulatory authority: 
 To revise exclusion criteria to exclude patients receiving systemic corticosteroids at dose 
of >10mg/day prednisone 
 To specify in more detail guidelines and criteria about immune related and non- immune 
related AE management and study treatment recommendations 
 To clarify the criterion that patients beyond initial RECIST v1.1 defined disease 
progression are allowed to continue study treatment 
 To specify more frequent evaluations may be performed at investigator’s discretion or if 
recommended by drug product information. 
Minor changes have been made for consistency and to operations- related specifications. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Section 5.3 Exclusion criteria 
 Revised Exclusion criterion 9 to exclude patients who receive >10mg/per day prednisone 
Section 6.2 Dose modifications (patients in PDR001 arm) has been renamed as “Safety and 
Dose modifications (patients in PDR001 arm)” 
 Section 6.2.2.1 Anticipated risks and safety concerns of the study drug (patients in 
PDR001 arm) has been moved to Section 6.2.1 
 Section 6.2.2.2 Immune-related Adverse Events (irAEs) has been moved to Section 6.2.2 
 Section 6.2.1 Dose modifications and dose delay has been moved to Section 6.2.3 
 Section 6.2.2 Management of toxicities has been renamed as “Management of toxicities 
and immune related AEs (irAEs) ” and moved to Section 6.2.4 
 Updated Table 6-2 Criteria for interruption, delay and discontinuation of PDR001 
Section 7.1 Study flow and visit schedule 
 Table 7-2 Added footnote “More frequent evaluations may be performed at the 
investigator’s discretion if medically indicated or if recommended by drug product 
information.” 
 Table 7-1; 7-2; 7-3 modified to be consistent that first dose of C1D1 should be 
implemented within 72 hours after randomization. 
Section 7.1.2 Treatment Period 
 Defined the criteria for continuing treatment beyond initial RECISTv1.1, defined disease 
progression. 
Section 14.4 Appendix 4 Management Algorithms 


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 Added algorithms for managing the following groups of AEs: Gastrointestinal; Renal; 
Pulmonary; Hepatic; Endocrinopathy; Skin and Neurological. 
IRB/IEC/HA 
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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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Nasopharyngeal cancer (NPC) is a squamous carcinoma that usually develops around the 
ostium of the Eustachian tube in the lateral wall of the nasopharynx. Rare amongst whites, NPC 
is endemic (up to 50:100,000) in South East Asia, North Africa, Middle East and the Artic (Bray 
et al 2008). Chinese emigrants continue to have a high incidence of the disease, but the rate of 
NPC amongst ethnic Chinese born in North America is considerably lower (around 10:100,000) 
than those born in China. 
The etiology is complex and includes genetic, environmental and viral components. Epstein-
Barr Virus (EBV) has been associated with NPC as NPC tumor cells express EBV proteins such 
as EBNA-1 and LMP1 and 2 (Chien et al 2001). 
The World Health Organization (WHO) classifies NPC in 3 main subtypes. Type 1 is a well 
differentiated keratinizing squamous carcinoma. Type 2 is non-keratinizing moderately-
differentiated, and type 3 is non-keratinizing and undifferentiated, accounting for 90% of the 
tumors. Type 2 and 3 are Epstein - Barr Virus (EBV) associated, and this makes NPC unique 
from other cancers of the head and neck. 
More than 50% of the patients present at the time of diagnosis with locally advanced disease 
(stage III to IVB, according to the American Joint Committee of Cancer AJCC 13th Edition). 
NPC is characterized by an inherent chemosensitive and radiosensitive biology, and the 
spectrum of chemotherapeutics that can be used is fairly wide. The standard treatment for loco-
regionally advanced NPC is platinum-based chemoradiotherapy (CRT), which has shown to 
confer survival benefit, over radiotherapy alone in 8 randomized trials (Ma et al 2008, Kam et 
al 2007, Chan et al 2005). Despite the initial response rate as high as 65-70%, up to 40% of the 
patients relapse with distant metastases. The 5-year survival rates for locally advanced recurrent 
and metastatic disease are only 55% and 38%, respectively. The salvage therapy includes 
gemcitabine, capecitabine or taxanes, but none of these are approved for the treatment of NPC. 
The median progression free survival (mPFS) for patients who had at least one line of treatment 
ranges from 3.9 to 5.1 months and the median overall survival (mOS) is approximately 12-13 
months. 
Treatment of locally advanced recurrent and metastatic NPC remains an unmet need in the 
developing world. 
1.2 
Overview of conventional therapy in NPC 
Platinum combination regimens are commonly used in first-line for metastatic or recurrent NPC 
patients, since cisplatin represents the most effective drug. Patients who progress on a first-line 
treatment have a poor prognosis and are treated with palliative chemotherapy, as there are no 
standard regimens. Active agents used in second line (Table 1-1) include paclitaxel, docetaxel, 
gemcitabine, capecitabine, irinotecan, vinorelbine, ifosfamide, doxorubicin and oxaliplatin, 
which can be used as single agents or in combination. It has to be stressed, however, that 
whatever the treatment applied in second line, the prognosis remains poor, with a short median 


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time to progression (mTTP) and the median overall survival (mOS) usually does not exceed 13 
months (Table 1-1). 
Table 1-1 
Second line treatment in metastatic or recurrent NPC 
Source, 
n=sample size 
Regimen 
Median TTP 
(mo) 
Median OS 
(mo) 
Chua (2000), 
n=19 
Ifosfamide, 5-FU, leucovorin 
6.5 
NR 
Airoldi (2002), 
n=12 
Carboplatin-Paclitaxel 
- 
9.5 
Foo (2002), 
n=27 
Gemcitabine 
5.1 
7.2 
Chua (2003), 
n=17 
Capecitabine 
4.9 
7.6 
Poon (2005), 
n=28 
Irinotecan 
- 
11.4 
Wang (2006), 
n=39 
Gemcitabine-Vinorelbine 
- 
11.9 
Zhang (2008), 
n=32 
Gemcitabine 
5.1 
16 
Ngeow (2011), 
n=30 
Docetaxel (weekly) 
5.3 
12.8 
Zhang (2012), 
n=35 
Pemetrexed 
1.5 
13.3 
Yau (2012), 
n=15 
Cisplatin-Pemetrexed 
7.5 
Not reported 
Peng (2013), 
n=48 
Nedaplatin-Capecitabine 
5.8 
12.4 
Source: courtesy of Dr Brigette Ma, unpublished. 
1.3 
Introduction to investigational treatment and other study 
treatment(s) 
1.3.1 
Overview of PD-1 and PDR001 
PD-1 is a critical checkpoint receptor that is expressed by effector T cells upon activation 
(Okazaki et al 2013). It is also expressed by B cells, natural killer T (NKT) cells, CD4+ 
regulatory T (Tregs) cells, and some dendritic cell (DC) subsets upon activation (Francisco et 
al 2010). Its ligands, Programmed Death-Ligand 1 (PD-L1) and Programmed Death-Ligand 2 
(PD-L2) are expressed by dendritic cells, macrophages and monocytes, and can be induced on 
virus-infected cells and many types of tumors (Keir 2008). Engagement of PD-1 with its ligands 
PD-L1 and PD-L2 negatively regulates effector T cell signaling and function and protects the 
tumor cells from the induction of apoptosis by effector T cells. 
The PD-1/PD-L1 axis is exploited by many tumor types to avoid detection by the adaptive 
immune system (Murphy 2011). Blockade of the PD-1 pathway has been shown to lead to 
increased numbers of effector T cells through induction or expansion and improved cytolytic 
activity towards tumors. Additionally, PD-1 blockade is associated with accumulation of 
effector T cells and a reduced numbers of Tregs at the tumor site (Wang 2009, Mangsbo 2010, 
Mkrtichyan 2011, Rosenblatt 2011). 


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Both preclinical and clinical studies have demonstrated that anti-PD-1 blockade restores activity 
of “exhausted” effector T cells and results in robust anti-tumor response. Clinical data with 
other anti-PD-1 antibodies have demonstrated that PD-1 checkpoint inhibition results in 
clinically relevant anti-tumor activity in a variety of solid tumors, including melanoma, non-
small cell lung carcinoma (NSCLC), renal cell cancer (RCC) and head and neck squamous cell 
cancer (HNSCC) with an acceptable and manageable safety profile (Topalian 2012, Hamid 
2013, Topalian 2014, Lyford-Pike 2013). 
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody which blocks 
the binding of PD-L1 and PD-L2 to PD-1. This antibody does not induce antibody-dependent 
cell-mediated cytotoxicity (ADCC). 
1.3.1.1 
PDR001 non-clinical experience 
PDR001 binds specifically and with high affinity to human PD-1. 
PDR001 does not cross-react with rodent PD-1, and cannot be evaluated in murine tumor 
models. It does cross-react with cynomolgus monkey PD-1, and is functionally active, making 
cynomolgus monkey a relevant species for toxicology studies. 
Biacore binding studies for PDR001 have shown an equilibrium dissociation constant (KD) of 
0.827 ± 0.505 nM for Human PD-1 and 0.929 ± 0.150 nM for Cynomolgus monkey. 
PDR001 was able to inhibit the binding of PD-L1 and PD-L2 to PD-1 with an IC50 of 0.94 ± 
0.15 nM and 1.3 ± 0.25 nM, respectively. 
PDR001 shows functional activity in vitro/ex vivo. In ex vivo lymphocyte stimulation assays 
using human blood, PDR001 enhances IL-2 production by approximately 2 fold, in response to 
super antigen stimulation with Staphylococcal enterotoxin B (SEB). 
The activity of PDR001 was also tested in an in vitro Mixed Lymphocyte Reaction (MLR) assay 
based on the co-culture of PD-L1+ monocyte-derived DCs with allogeneic CD4+ T cells. Both 
cell proliferation and IFN- release were measured as readouts for this functional assay. 
Addition of PDR001 resulted in a less than 2-fold increase in proliferation over isotype control. 
However, PDR001 led to a dose dependent increase in IFN- release by an average factor of 8-
13 times the levels observed with an isotype control antibody at doses ranging between 5g/ml 
and 25g/ml. For further details, please refer to the [PDR001 Investigator’s Brochure]. 
1.3.1.2 
PDR001 clinical experience 
PDR001 is evaluated in a first-in-human, multi-center, open-label study [CPDR001X2101] 
starting with a phase I dose escalation part, followed by a phase II part. The CPDR001X2101 
study started enrollment on 27 April 2015 and is ongoing. As of 17 December 2015, a total of 
58 patients had been treated in the study at the dose levels of 1, 3 and 10 mg/kg Q2W and 3 and 
5 mg/kg Q4W. No patient experienced a DLT and the toxicity profile appears to be similar to 
that of marketed inhibitors of PD-1. The PK data obtained from the dose escalation, and 
modeling of the exposure data, support the use of flat dosing for PDR001 of 400 mg given every 
4 weeks for RP2D. The expected PDR001 Ctrough concentrations are in line with observed 
steady state mean Ctrough concentrations for pembrolizumab, which is approved with 
substantial efficacy in several cancer types. The data also support the use of 300 mg Q3W as 


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an alternative dose regimen if it is more convenient for scheduling purposes, for example in 
combination treatment regimens. 
The study is ongoing in Phase II part. For further details, please refer to the [PDR001 
Investigator’s Brochure]. 
2 
Rationale 
2.1 
Study rationale and purpose 
NPC is an inflammatory cancer associated with EBV infection (Chung et al 2013). A 
characteristic feature of NPC is the presence of immune infiltration in the primary tumor 
consisting of T cells, B cells, monocytes and dendritic cells. In NPC there is evidence for 
functional inactivation of NPC primary tumor infiltrating lymphocytes (TIL) as these, in 
contrast to peripheral T cells, have an “exhausted” phenotype and fail to produce IFN-γ upon 
stimulation (Li et al 2007, Ott et al 2013). Recently, PD-1 expression on CD8+ T cells from 
NPC tumors was found to be upregulated compared to CD8+ T cells from control 
nasopharyngeal tissues (Hsu et al 2010). Higher PD-1 expression was associated with shorter 
overall survival (OS), disease-free survival (DFS) and was also an independent risk factor for 
death and treatment failure. 
Preliminary data from the early clinical studies of anti PD-1 antibodies nivolumab and 
pembrolizumab, as well as the anti-PD-L1 antibodies MPDL3280A and MEDI4736, suggested 
that PD-L1 protein expression on tumor cells might associate with clinical response to these 
agents (Topalian 2012, Weber 2013, Taube 2014, Bellmunt 2014, Creelan 2014). More recent 
studies have confirmed that the association of tumor-infiltrating immune cell PD-L1 expression 
with treatment response appeared stronger than that with tumor cell PD-L1 expression (Herbst 
et al 2014). 
Furthermore, high levels of PD-L1 in tumor infiltrating immune cells may identify patients who 
respond to checkpoint inhibitors, as complete response following PD-1 blocking antibodies has 
also been observed in patients who were PD-L1 negative in tumor cells (Herbst et al 2014). 
We examined 115 primary NPC tumors for expression of PD-L1 and CD8, and found that the 
large majority (89.5%) expresses both high levels of PD-L1 and CD8, confirming both the target 
expression as well as a rich tumor immune infiltration [RDS-2015-00010]. 
Recent study also found that EBV-induced latent membrane protein 1 (LMP1) and IFN-γ 
pathways cooperate to regulate PD-L1 in NPC cell lines through STAT3, AP-1, and NF-κB 
pathways. PD-L1 overexpression in the tumor sample was associated with worse disease-free 
survival in NPC patients (Fang et al 2014, Zhang et al 2015). 
For these reasons, it is rational to hypothesize that treatment with a PD-1 blocking antibody 
may break tumor- induced immune suppression and produce clinical benefit in a proportion of 
NPC patients who have a worse prognosis. 


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2.2 
Rationale for the study design 
This is an open-label, multi-center, randomized and controlled phase II study of single-agent 
PDR001 in patients with moderately differentiated/undifferentiated, locally advanced recurrent 
or metastatic NPC, who have progressed on or after first-line platinum-based therapy. 
A randomized controlled study with PFS as primary endpoint is considered the appropriate 
study design to assess clinical activity of PDR001, given the high percentage of response to 
salvage chemotherapy, ranging up to 30%. This response is however of short duration, and TTP 
/PFS is around 5-6 months at best. It is therefore difficult to assess clinical activity of PDR001 
in NPC without a control arm, and response rate (RR) may be a misleading endpoint. 
Eligible patients who have progressed on platinum-based first-line therapy will be randomized 
2:1 to either PDR001 administered i.v. every 4 weeks (Q4W) or an investigator’s choice of 
chemotherapy. 
The primary endpoint will be progression free survival (PFS) as per RECIST v1.1, based on an 
independent central reader, to assess the efficacy of PDR001 versus investigator’s choice of 
chemotherapy. Disease progression will be evaluated according to investigator and independent 
central review. The local investigator’s assessment will be used for treatment decision making 
(study discontinuation due to progressive disease (PD) as per immune-related response criteria 
(irRC)). Secondary endpoints include immune-related Progression Free Survival (irPFS), 
duration of response (DOR), overall response rate (ORR), time to progression (TTP), overall 
survival (OS), and safety. A biomarker evaluation will also be performed (please refer to 
Section 2.5). 
If the study meets its primary endpoint, it will demonstrate the ability of PDR001 to elicit an 
anti-tumor response and improved treatment benefit versus commonly used chemotherapy 
agents in the second-line treatment of locally advanced recurrent or metastatic NPC patients 
who have progressed on or after first-line platinum-based therapy, establish a Phase II proof-
of-concept study, and open the path for a novel standard of care regimen for this patient 
population. 
2.3 
Rationale for dose and regimen selection 
The dose and regimen which will be used in this study is the recommended phase II dose (RP2D) 
established in the [CPDR001X2101] phase I (first-in-human) study. After completion of the 
dose escalation and review of the data, the RP2D was declared as 400 mg Q4W. 
2.4 
Rationale for choice of comparator drugs 
There is no gold standard for locally advanced recurrent or metastatic NPC patients who 
progress on or after the platinum-based first-line therapy. The choice of chemotherapy 
following progression on or after first-line therapy for metastatic NPC is not well defined and 
is based on several factors, including previous chemotherapy exposure, performance status, 
comorbidity conditions and tumor characteristics. None of the chemotherapeutic agents that are 
currently used as palliative treatment in these patients have been approved specifically for use 
in this setting. The rationale for giving the investigator a choice of active comparator regimen 


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is to allow the investigator to select the most suitable option for the patient, according to the 
institutional guidelines. 
2.5 
Rationale for use of blood and tumor tissue biomarkers 
Emerging data demonstrates a correlation between the presence of PD-L1 surface expression 
on tumor cells and tumor infiltrating immune cells and clinical efficacy of checkpoint inhibitors 
(anti-PD-1 /PD-L1 therapies) (Herbst et al 2014, Tumeh et al 2014 and Powles et al 2014). 
Similarly, the presence of pre-existing exhausted tumor infiltrating lymphocytes (TIL) is 
associated with response to anti PD-L1/PD-1 treatment whilst immunological ignorance is 
associated with absence of clinical response (Herbst et al 2014 and Tumeh et al 2014). 
In the periphery, circulating increases of CD8+, Ki67+, T cells, IFN-γ, IL-18 and CXCL11 
(IFN-γ induced CCK) suggest the rapid expansion of a pre-existing primed immune response, 
whilst the decrease of IL-6 is indicative of a reduction of Myeloid-derived Suppressor Cell 
(MDSC) (Herbst et al 2014, Tumeh et al 2014 and Powles et al 2014). 
Understanding the biology of the tumor microenvironment in tumor samples pre- and post- 
treatment is critical to evaluate the role of PDR001 in NPC patients. Furthermore, since PD-L1 
is not the only mechanism that allows tumor escape, it is important to assess the expression of 
other well identified checkpoint inhibitors such as LAG-3 and TIM-3 in tumor samples. 
Biomarkers in peripheral blood include immunophenotype and quantification of soluble 
proteins and expression of immune related genes. 


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3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4. 
To assess the efficacy of PDR001 versus investigator’s 
choice of chemotherapy in patients with moderately 
differentiated/undifferentiated locally advanced recurrent 
or metastatic NPC who progressed on or after first-line 
therapy 
Progression free survival (PFS) as per RECIST v1.1 
(Appendix 1) using central assessment 
 
Secondary 
 
Refer to Section 10.5. 
To evaluate the anti-tumor activity of PDR001 versus 
investigator ‘choice of chemotherapy in patients with 
moderately differentiated/undifferentiated locally 
advanced recurrent or metastatic NPC who progressed 
on or after first-line therapy 
Overall survival (OS), overall response rate (ORR), duration of 
response (DOR), time to progression (TTP) and immune 
related progression free survival (irPFS) as per irRC 
(Appendix 2) using central assessment 
 
To characterize the safety and tolerability of PDR001 
Safety: Incidence and severity of adverse events (AEs) and 
serious adverse events (SAEs), including changes in laboratory 
parameters, vital signs and electrocardiograms (ECGs) 
 
To characterize the pharmacokinetic profile of PDR001 
(patients in PDR001 arm) 
Serum PK parameters (e.g. AUC, Cmax, Tmax, half-life); 
Serum concentration vs. time profiles 
 
To assess emergence of anti-PDR001 antibodies 
following one or more intravenous (i.v.) infusions of 
PDR001(patients in PDR001 arm) 
Presence and/or concentration of anti-PDR001 antibodies 
 
To assess potential predictive markers of efficacy of 
PDR001 in tumor sample (patients in PDR001 arm) 
Assess potential associations between expression of PD-L1, 
CD8,Foxp3 and other immunological markers such as 
Lymphocyte activation gene-3 (LAG-3), T-cell immunoglobulin 
domain and mucin domain-3 (TIM-3), with anti-tumor activity 
 


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Objective 
Endpoint 
Analysis 
To assess the pharmacodynamic effect of PDR001 in 
tumor sample (patients in PDR001 arm) 
TIL counts and expression of immune-related genes 
(RNA/protein in tumor sample) 
 
To assess the pharmacodynamic effect of PDR001 in 
peripheral blood (patients in PDR001 arm) 
Assess peripheral, soluble ligands and cytokine levels 
(including but not limited to IFN-γ, TNF-α, IL-6) 
 


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4 
Study design 
4.1 
Description of study design 
This is an open-label, multi-center, randomized, controlled phase II study to evaluate the 
efficacy and safety of PDR001 versus investigator’s choice of treatment in patients with 
moderately differentiated/undifferentiated locally advanced recurrent or metastatic NPC who 
progressed on or after first-line treatment. The study design is summarized in Figure 4-1. 
Figure 4-1 
Study design 
 
*Patients treated with PDR001 will continue treatment until confirmed PD as per irRC. Please refer to 
Section 7.1.2 for further details. 
 
Approximately 114 patients will be recruited and randomized in the study in order to observe 
70 events of disease progression for the primary endpoint PFS analysis. The randomization will 
be stratified by disease status (locally advanced recurrent NPC vs. metastatic NPC). Please refer 
to Section 10 for details of analysis and reporting of data. 
Patients in the control arm will be allowed to crossover to PDR001 treatment if they have 
radiological progression (per RECIST v1.1) documented by an independent central review and 
the investigator believes this is the best treatment option for the patient. Each case must be first 
discussed with Novartis. Any patient enrolled in the control arm who does not meet the criteria 
of radiologically assessed disease progression will not be eligible for crossover to PDR001 arm. 
Please refer to Section 7.1.2.1 for further details. 


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This study will use an Interactive Response Technology (IRT) system for randomization and 
for study management of PDR001 study drug (see Section 6.4). Eligible patients should receive 
the first dose of study treatment within 28 days of signing the study informed consent. 
The study is comprised of 3 periods: Screening/Baseline, Treatment, Follow-up period (30-day 
Safety for Chemotherapy arm and 150-day Safety for PDR001 arm and crossover arm, Disease 
Progression and Survival). Please refer to Section 7 for detailed information on assessments to 
be performed during each period. 
4.2 
Timing of interim analyses and design adaptations 
No formal interim analyses are planned. 
4.3 
Definition of end of the study 
End of study will be defined as the time when:  
 the last randomized patient has died, has been lost to follow-up, withdrawn consent, or 
completed his/her final study visit,  
or 
 24 months survival follow-up after the first dose of the last randomized patient,  
or  
 the date when the study is terminated early,  
or  
 another clinical study becomes available that can continue to provide study treatment in 
this patient population, and all patients ongoing are transferred to that clinical study,  
whichever occurs first. Please refer to Section 7.1.3 for details. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative treatment option to patients who in the opinion of the 
investigator are still deriving clinical benefit. 
See Section 10 Statistical Methods and Data Analysis for details of timing of the primary 
analysis.  
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible for End of Treatment (EoT) visit and the 
assessments should be performed as described in Section 7.1.3 for a discontinued patient. The 
investigator may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests. The investigator will 
be responsible for informing Institutional Review Boards (IRBs) and/or independent ethics 
committees (IECs) of the early termination of the trial. 


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5 
Population 
5.1 
Patient population 
The study will be conducted in patients with moderately differentiated/undifferentiated locally 
advanced recurrent or metastatic NPC who progressed on or after first-line platinum-based 
therapy. 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Written informed consent must be obtained prior to any procedures. 
2. Age ≥ 18 years. 
3. Histologically documented non-keratinizing locally advanced recurrent or metastatic NPC. 
4. Must be resistant to platinum-based chemotherapy (defined as progression on or after 
platinum-based chemotherapy given in the recurrent/metastatic setting). 
5. May have received at least 1 prior therapy for recurrent or metastatic disease, up to 2 prior 
systemic therapies. 
6. ECOG Performance Status ≤ 2. 
7. An archival tumor specimen or newly obtained tumor sample may be submitted at 
screening/baseline (a new tumor sample is preferred), unless agreed differently between 
Novartis and the Investigator. 
8. At least 1 measurable lesion (as per RECIST v1.1) progressing or new since last anti-
tumor therapy. Lesions in previously irradiated areas should not be considered 
measureable unless there is clear evidence of progression in such lesions since the 
radiotherapy. 
9. Prior treated brain or meningeal metastases must be without MRI evidence of progression 
for at least 8 weeks and off systemic steroids for at least 2 weeks prior to 
screening/baseline. Lesions extending to the base of skull or abutting the temporal lobes 
are included. 
10. Must be willing to undergo testing for human immunodeficiency virus (HIV) if not tested 
within the past 6 months. If HIV+ positive, patient will be eligible for study provided that 
his/her CD4+ count ≥ 300/µL; his/her viral load is undetectable; he/she is currently 
receiving highly active antiretroviral therapy (HAART). 
11. Life expectancy > 12 weeks. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. History of severe hypersensitivity reactions to other monoclonal Antibodies (mAbs). 


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2. Having out of range laboratory values defined as: 
 Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 40 
mL/min 
 Total bilirubin > 1.5 x ULN, except for patients with Gilbert’s syndrome who are 
excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN 
 Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor 
involvement of the liver, who are excluded if ALT > 5 x ULN 
 Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor 
involvement of the liver, who are excluded if AST > 5 x ULN 
 Absolute neutrophil count (ANC) < 1.5 x 109/L 
 Platelet count < 75 x 109/L 
 Hemoglobin < 9 g/dL 
3. Active autoimmune disease or a documented history of autoimmune disease, or any 
condition that requires systemic steroids, except vitiligo or resolved asthma/atopy that is 
treated with broncho-dilators (e.g. albuterol). 
4. Active HBV and HCV infections requiring therapy. Patients on antiviral therapy may be 
allowed if disease is controlled according to local treatment standard. 
5. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers; any malignancy considered to be indolent and that has never required 
therapy; and completely resected carcinoma in situ of any type. 
6. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results. 
7. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment, unless 
agreed otherwise with Novartis. Any patient with the following reported drug-related 
adverse events on anti-CTLA4 will not be permitted on study: hepatic, diarrhea/colitis or 
endocrine adverse events (AE)s Grade ≥ 2, any other non-laboratory immune-related AE ≥ 
Grade 3. Patients must have minimum 8 week washout period between the last dose of 
anti-CTLA4 and the first dose of PDR001. 
8. Prior PD-1- or PD-L1-directed therapy. 
9. Receiving treatment with systemic steroid therapy or any immunosuppressive therapy, 
other than replacement-dose steroids<10mg/day prednisone in the setting of adrenal 
insufficiency. Topical, inhaled, nasal and ophthalmic steroids are not prohibited. 
10. Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) or 
investigational therapeutic cancer vaccines within 4 weeks of initiation of study treatment. 
11. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, 
insertion of a central venous access device, and insertion of a feeding tube are not 
considered major surgery). 
12. Radiotherapy within 2 weeks of the first dose of study treatment, except for palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful 
tumor mass. 


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13. Participation in an interventional, investigational study within 2 weeks of the first dose of 
study treatment, unless agreed otherwise with Novartis. 
14. Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy and 
ototoxicity, which are excluded if ≥ CTCAE grade 3) due to prior cancer therapy, unless 
agreed otherwise with Novartis. 
15. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) 
≤2 weeks prior to start of study drug. An erythroid stimulating agent is allowed as long as 
it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is 
on a stable dose. 
16. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test. 
17. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 150 days after the last dose of PDR001. Highly effective 
contraception methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient. 
 Use of oral, 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 have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 6 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. 
18. Sexually active males unless they use a condom during intercourse while taking drug and 
for 150 days after stopping study treatment and should not father a child in this period. A 
condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid. 
19. Patient with contraindications for the chosen treatment (control arm only) 


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6 
Treatment 
6.1 
Study treatment 
The study treatment in this study refers to: 
 Investigational drug: PDR001 
or 
 Chemotherapy: as per investigator’s choice (except for re-challenge with previously used 
drugs) 
6.1.1 
Dosing regimen 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form 
and route of 
administration 
Dose 
Frequency 
and/or 
Regimen 
PDR001 
 Powder for solution for 
infusion 
400mg 
Every 4 weeks 
(Q4W) 
Commonly used 
chemotherapy as 
per investigator’s 
choice 
As described in the 
drug label 
As described in the drug label 
As described in 
the drug label 
PDR001 will be administered via i.v. infusion over 30 minutes (up to 2 hours, if clinically 
indicated) once every 4 weeks. Next dose may be delayed by up to 7 days to recover from 
previous AEs. If the next dose cannot be administered within the above mentioned 7-days delay, 
then the dose should be skipped. Dosing will resume at the scheduled dose and assessment 
schedule will be shifted accordingly. 
6.1.2 
Treatment duration 
All patients treated with either PDR001 or chemotherapy (per Investigator’s choice) will begin 
treatment on Cycle 1 Day 1. Each cycle will have 28 days if treated with PDR001. Patients may 
be discontinued from study treatment earlier due to unacceptable toxicities, confirmed disease 
progression (per irRC only for patients treated with PDR001) and/or treatment is discontinued 
at the discretion of the investigator or the patient. Patients who discontinue study treatment 
should not be considered discontinued from the study (please refer to Section 7.1.3 and Section 
4.3 for further details). 
6.1.3 
Ancillary treatments (patients in PDR001 arm) 
All patients randomized into the PDR001 arm, should not receive pre-medication to prevent 
infusion reaction before the first infusion of PDR001, in order to determine if pre-medication 
is necessary. If a patient experiences an infusion reaction, he/she may receive pre-medication 
on subsequent dosing days. The pre-medication should be chosen per institutional standard of 
care, at the discretion of the treating physician. 
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 


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normal cardiopulmonary status. If a patient experiences a Grade 3 anaphylactic/anaphylactoid 
reaction, the patient may only continue on the study following discussion with Novartis. 
Patients should be treated in a facility equipped for cardiopulmonary resuscitation. Appropriate 
resuscitation equipment should be available at the bedside and a physician readily available. 
Guidelines on management of PDR001 infusion reactions are provided in Table 6-2. 
The CTCAE category of “Infusion related reaction” should be used to describe PDR001 
infusion reactions, unless the investigator considers another category, such as “Allergic 
reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation. 
6.1.4 
Chemotherapy treatments (patients in control arm only) 
For patients randomized into the control arm, investigators should follow local guidelines as 
per standard of care and approved product labels especially regarding pre-medication schemes, 
the contraindications, the contraceptive regimens, the dosage adjustment in case of toxicity, the 
patient monitoring and the prohibited or used with caution drug. 
6.2 
Safety and dose modifications (patients in PDR001 arm) 
6.2.1 
Anticipated risks and safety concerns of the study drug (patients in 
PDR001 arm) 
Appropriate eligibility criteria as well as specific dose modification and stopping rules are 
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for 
expected toxicities, including management of study-drug induced AEs, i.e. infusion reaction, 
pneumonitis, are provided in Table 6-2. Refer to preclinical toxicity data provided in the 
[PDR001 Investigator’s Brochure]. 
6.2.2 
Immune-related adverse events (irAEs) 
The emergence of immune related AE (irAE) may be anticipated based on general experience 
in clinical studies with similar class of compounds that block the negative immune regulators. 
An irAE is a clinically important AE of unknown etiology associated with the study drug 
exposure. irAEs are typically low grade and self-limited, often occurring after multiple doses, 
and most frequently involving the GI tract (diarrhea/colitis), skin (rashes), liver (hepatitis), and 
endocrine systems (a variety of endocrinopathies). Serologic, histologic (tumor sample) and 
immunological assessments should be performed to verify the immune related nature of the AE, 
and exclude the neoplastic, infectious or metabolic origin of the AE. 
6.2.3 
Dose modifications and dose delay 
There will be no dose modifications allowed for PDR001. 
All dose interruption, delay and discontinuation should be based on the worst preceding toxicity 
(CTCAE Version v4.03). If a patient experiences a Grade 3 PDR001-related AE, treatment with 
PDR001 should be interrupted unless otherwise specified in Table 6-2 Refer to Section 6.2 for 
Management of toxicities and immune related AEs. Following resolution of the toxicity to 


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Grade 1, patient may resume PDR001 treatment at the same dose level, if there is no evidence 
of disease progression. 
A decision to resume treatment with PDR001 following the occurrence of a Grade 3 AE is at 
the discretion of the Investigator. If the investigator considers it to be in the patient’s best 
interest to resume therapy before the toxicity has resolved to Grade 1, this may be permitted on 
a case by case basis, following discussion with Novartis. 
If a patient experiences any Grade 4 PDR001-related AE, the treatment should be discontinued 
unless otherwise specified in Table 6-2. 
In case the infusion cannot be administered at the scheduled visit, it has to be administered as 
soon as possible. If the delay is between 1 and 7 days the procedures at the original schedule 
visit should be performed. If the delay is longer than 7 days, the procedure of the following visit 
should be performed. 
Patients who missed 2 infusions plus 7 days should be discontinued from the study treatment 
and enter the Follow-up period. Exceptions may be made on a case by case basis after discussion 
between Novartis and the Investigator. 
Patients who discontinue the study for an AE or clinically significant abnormal laboratory value 
must be followed as described in Section 6.2. 
All changes in study drug administration must be recorded on the Dose Administration Record 
eCRF. 
6.2.4 
Management of toxicities and immune related AEs (irAEs) 
All the patients whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
In case of suspected irAEs, the relevant immunological assessments (e.g. rheumatoid factor, 
anti-DNA Ab, etc.) should be performed.  
Algorithms have been provided to assist investigators in assessing and managing the following 
groups of irAEs: Gastrointestinal; Renal; Pulmonary; Hepatic; Endocrinopathy; Skin; and 
Neurological. Management Algorithms can be found in the Appendix 4. 
For non- immune related AE as Grade 1 or 2, treatment with PDR001 maintains dose and 
schedule unless it specifies in the Table 6-2. 


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Table 6-2 
Criteria for interruption, delay, re-initiation and discontinuation of 
PDR001 
Worst toxicity CTCAE 
Grade (unless 
otherwise specified) 
Recommended dose interruption, delay and discontinuation for 
PDR001 during a cycle of treatment 
Infusion Reaction or Hypersensitivity reaction 
Grade 1 
Decrease infusion rate until recovery of the symptoms 
Grade 2 
Stop infusion immediately, and keep line open. Provide supplemental 
oxygen and fluids, as needed. 
Monitor vital signs (e.g. blood pressure, pulse, respiration, and 
temperature) every 15 ± 5 minutes until resolution. 
Administer medications for symptomatic relief as needed: 
● Urticaria: Diphenhydramine (25 to 100 mg i.v.) as needed every 4 to 6 
hours, or alternative as appropriate. 
● Fever: Acetaminophen/paracetamol (650-1000 mg by mouth) as 
needed every 4 to 6 hours, or alternative as appropriate. 
● Rigors: Meperidine 25 mg i.v. as needed every 6 hours or alternative as 
appropriate. Corticosteroids may be administered, as needed. 
Resume infusion once infusion reaction resolves (within 8 hours of initial 
start of infusion): 
Maintain dose level. Administer oral pre-medication (e.g.1000 mg of 
acetaminophen/paracetamol, 50-100 mg diphenhydramine hydrochloride or 
alternative antihistamine), within 60 minutes of restarting the infusion. 
Restart infusion at 50% of previous rate under continuous observation. 
Ensure that there is a minimum observation period of 1 hour prior to 
restarting the infusion. 
If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-
medication, then discontinue patient from study. 
Grade 3 or Grade 4 
Discontinue infusion immediately, and discontinue patient from study. 
Provide supplemental oxygen, fluids, and other resuscitative measures as 
needed. Monitor vital signs (e.g. blood pressure, pulse, respiration, and 
temperature) every 15 ± 5 minutes until resolution. 
Neutropenia (ANC) 
 
Grade 3 (ANC < 1000 - 
500/mm3) 
Dose delay for PDR001-related Grade 3 until resolved to ≤ Grade 1 
Grade 4 (ANC < 
500/mm3) 
Discontinue for PDR001-related Grade 4 > 7 days duration 
Thrombocytopenia 
 
Grade 3 (PLT < 50,000 - 
25,000/mm3) 
Dose delay for PDR001-related Grade 3 until resolved to ≤ Grade 1 
Discontinue for PDR001-related Grade 3 > 7 days or associated with 
bleeding 
Grade 4 (PLT < 
25,000/mm3) 
Discontinue for PDR001-related Grade 4 
Febrile neutropenia 
 
(ANC < 1.0 x 109/L, 
fever ≥ 38.5°C) 
Dose delay for PDR001-related Grade 3 until resolved to ≤ Grade 1 
Discontinue for PDR001-related Grade 4 


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Worst toxicity CTCAE 
Grade (unless 
otherwise specified) 
Recommended dose interruption, delay and discontinuation for 
PDR001 during a cycle of treatment 
Lymphopenia 
 
Grade 3 (<0.5-0.2 x 
109/L) 
Maintain dose and schedule for PDR001-related ≤ Grade 3 
Grade 4 (<0.2 x 109 /L) 
Dose delay for PDR001-related Grade 4 until resolved to ≤ Grade 3 
PDR001-related Grade 4 lymphopenia or leukopenia does not require 
discontinuation 
Renal 
See Appendix 4 “Renal Adverse Event Management Algorithm” for additional guidance on monitoring 
and management of any grade events 
Serum creatinine 
 
Grade 2 (> 1.5 - 3.0 x 
ULN) or 
Grade 3 (> 3.0 - 6.0 x 
ULN) 
Dose delay for PDR001-related ≥ Grade 2 until resolved to ≤ Grade 1 
Grade 4 (> 6.0 x ULN) 
Discontinue for PDR001-related Grade 4 
Liver 
See Appendix 4 “Hepatic Adverse Event Management Algorithm” for additional guidance on 
monitoring and management of any grade events 
AST or ALT 
 
Grade 2 (> 3.0 - 5.0 x 
ULN) 
Dose delay for PDR001-related ≥ Grade 2 until resolved to ≤ Grade 1 
Discontinue for concurrent AST or ALT >3x ULN and total bilirubin > 2x 
ULN 
Grade 3 (> 5.0 - 20.0 x 
ULN) or 
Grade 4 (> 20.0 x ULN) 
Discontinue for PDR001-related ≥ Grade 3 or Grade 4 
Bilirubin* 
Grade 2 (> 1.5 - 3.0 x 
ULN) 
Dose delay for PDR001-related ≥ Grade 2 until resolved to ≤ Grade 1 
Baseline total bilirubin is within normal limits, delay dosing for PDR001-
related Grade ≥ 2 toxicity 
Baseline AST/ALT or total bilirubin in the Grade 1 toxicity requiring dose 
delays for reasons other than a 2-Grade shift in AST/ALT or total bilirubin 
may resume treatment in the presence of Grade 2 AST/ALT or total 
bilirubin 
Grade 3 (> 3.0 - 10.0 x 
ULN) or Grade 4 (> 10.0 
x ULN) 
Discontinue for PDR001-related ≥ Grade 3 or Grade 4 
Asymptomatic amylase and/or lipase elevation** 
Grade 3 (> 2.0 - 5.0 x 
ULN) or 
Grade 4 (> 5.0 x ULN) 
Any Grade ≥3 PDR001-related isolated amylase or lipase abnormality that 
is not associated with symptoms or clinical manifestations of pancreatitis 
does not require dose delay or discontinuation. The Novartis Medical 
Monitor should be consulted for such amylase or lipase abnormalities 


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Worst toxicity CTCAE 
Grade (unless 
otherwise specified) 
Recommended dose interruption, delay and discontinuation for 
PDR001 during a cycle of treatment 
Cardiac general 
Grade 2 or Grade 3 
Dose delay for PDR001-related ≥ Grade 2 until resolved ≤ Grade 1 
Discontinue for PDR001-related Grade 3 lasting > 7 days 
Grade 4 
Discontinue for PDR001- related Grade 4 
Endocrine 
See Appendix 4 “Endocrinopathy Management Algorithm” for additional guidance on monitoring and 
management of any grade events 
Grade 2 or Grade 3 
Dose delay for any Grade ≥ 2 PDR001-related until resolved ≤ Grade 1 
Grade 3 PDR001-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not require discontinuation 
Grade 4 
Grade 4 PDR001-related endocrinopathies, such as adrenal insufficiency, 
ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, which 
resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and 
approval from the Novartis Medical Monitor. 
Skin Rash/photosensitivity 
See Appendix 4 “Skin Adverse Event Management Algorithm” for additional guidance on monitoring 
and management of any grade events. 
Grade 2 
In presence of Grade 2 PDR001-related skin toxicity, treatment may be 
resumed (even if patient experience before a Grade 3 PDR001-related 
toxicity) 
Grade 3 or Grade 4 
Dose delay for PDR001-related Grade 3 until resolved ≤ Grade 1 
Discontinue for PDR001-related Grade 3 lasting > 7 days, or PDR001-
related Grade 4 
Stevens-Johnson syndrome (SJS), or Lyell syndrome/toxic epidermal necrolysis (TEN) 
Any Grade 
Permanently discontinue study treatment. 
Gastrointestinal 
See Appendix 4 “GI Adverse Event Management Algorithm” for additional guidance on monitoring and 
management of any grade events 
Diarrhea*** 
 
Grade 2 
Dose delay for PDR001-related Grade ≥ 2 until resolved ≤ Grade 1 or 
baseline 
Grade 3 or Grade 4 
Discontinue for any PDR001-related Grade 3 lasting > 7 days, or PDR001- 
related Grade 4 
Fatigue/Asthenia Fatigue/ Asthenia (General disorders and administration site conditions) 
Grade 3 or Grade 4 
Dose delay for PDR001-related Grade 3 until resolved ≤ Grade 1 
Discontinue for PDR001-related Grade 3 lasting > 7 days, or PDR001-
related Grade 4 
Any Neurological toxicity 
See Appendix 4 “Neurological Adverse Event Management Algorithm” for additional guidance on 
monitoring and management of any grade events 
Grade 2 
Dose delay for PDR001-related Grade ≥ 2 until resolved ≤ Grade 1 


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Worst toxicity CTCAE 
Grade (unless 
otherwise specified) 
Recommended dose interruption, delay and discontinuation for 
PDR001 during a cycle of treatment 
Grade 3 or 4 
Discontinue for PDR001-related Grade 3 lasting > 7 days, or PDR001-
related G4 
Ocular (uveitis, eye pain, blurred vision) 
Grade 2 
Dose delay for PDR001-related Grade ≥ 2 until resolved ≤ Grade 1 
Discontinue for any Grade 2 PDR001-related uveitis, eye pain or blurred 
vision that does not respond to topical therapy and does not improve to 
Grade 1 severity within the re-treatment period OR requires systemic 
treatment 
Grade 3 or Grade 4 
Discontinue for Grade 3 PDR001-related uveitis of any duration 
Discontinue for PDR001-related Grade 3 lasting > 7 days, or PDR001- 
related Grade 4 
Pulmonary (pneumonitis, bronchospasm) 
See Appendix 4 “Pulmonary Adverse Event Management Algorithm” for additional guidance on 
monitoring and management of any grade events. 
Grade 1 
Patients with persistent Grade 1 pneumonitis after completion of a steroid 
taper over at least 1 month may be eligible for retreatment if discussed with 
and approved by Novartis Medical Monitor. 
Grade 2 
Dose delay for PDR001-related Grade ≥ 2 until resolved ≤ Grade 1 
Grade 3 or Grade 4 
Discontinuation for Grade 3 PDR001-related pneumonitis of any duration 
Discontinue for PDR001-related Grade 3 lasting > 7 days or PDR001- 
related Grade 4 
Cytokine Release Syndrome (CRS) 
Grade 2 or Grade 3 or 
Grade 4 
If CRS is suspected (very high fever and precipitous drops in blood 
pressure, myalgia, change in mental status) treat with corticosteroids. 
 
Other Non-laboratory adverse events 
Grade 2 
Dose delay for PDR001-related Grade ≥ 2 until resolved ≤ Grade 1 
Grade 3 or Grade 4 
Discontinue for PDR001-related Grade 3 lasting > 7 days, or PDR001- 
related Grade 4 
Other laboratory adverse events 
Grade 3 or Grade 4 
Dose delay for PDR001-related ≥ Grade 3 until resolved to ≤ Grade 1 
Isolated Grade 4 electrolyte imbalances/abnormalities not associated with 
clinical sequelae and corrected with supplementation/appropriate 
management within 72hrs of their onset do not require discontinuation. 
*Note: If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and 
hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral 
blood smear and haptoglobin determination), then delay treatment until resolved ≤ Grade 1 and 
continue treatment at the discretion of the investigator. 
**Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be 
performed within 1 week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. If 
asymptomatic Grade 2 elevations of lipase and/or amylase occur for a second time, patients will be 
discontinued permanently from study treatment. 
***Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools 
or overt diarrhea. 


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6.3 
Concomitant medications 
6.3.1 
Permitted concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the patient are allowed. 
The patient must be told to notify the investigational site about any new medications, herbal 
remedies and dietary supplements he/she takes after the start of the study treatment. All 
medications (other than study treatment) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered during the study must 
be listed on the Prior and Concomitant Medications or the Surgical and Medical Procedures 
eCRF. Prior antineoplastic therapies including medications, radiotherapy, and surgery are to be 
recorded on the separate Prior Antineoplastic Therapy eCRF during screening/baseline. 
6.3.2 
Permitted concomitant therapy requiring caution and/or action 
(patients in PDR001 arm) 
Treatment with hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-
CSF) may not be taken during the study. If a patient is using erythropoiesis stimulating agents 
(ESAs) prior to enrollment (at least 2 weeks before start of study treatment), they may continue 
at the same dose. 
Anticoagulation is permitted if the patients are already at stable doses of warfarin or stable doses 
of low molecular weight heparin (LMWH) for >2 weeks at time of first dose and International 
Normalized Ratio (INR) should be monitored as clinically indicated per investigator’s 
discretion. However, ongoing anticoagulant therapy should be temporarily discontinued to 
allow tumor sample according to the institutional guidelines. 
Anti-hypertensives are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with PDR001. 
A brief (< 24 hours) course of steroids for prophylaxis against contrast dye allergy is permitted 
for patients undergoing tumor assessments with exposure to the allergen. 
6.3.3 
Prohibited concomitant therapy (patients in PDR001 arm) 
During the course of the study, patients may not receive other additional investigational drugs, 
agents, devices, chemotherapy, or any other therapies that may be active against cancer. 
Additionally, no other therapeutic monoclonal antibodies and no immunosuppressive 
medication may be administered while on this study. 
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed, with 
the only exclusion of steroids for the treatment of PDR001 infusion reaction, irAEs, 
replacement-dose steroids in the setting of adrenal insufficiency (providing this is ≤ 10 mg/day 
prednisone or equivalent), or transient exacerbations of other underlying diseases such as 
chronic obstructive pulmonary disease (COPD) requiring treatment for < 3 weeks. Systemic 
corticosteroids required for the control of infusion reactions or irAEs must be tapered and be at 
non-immunosuppresive doses (≤ 10 mg/day of prednisone or equivalent) before the next study 


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drug administration. If more than 10 mg/day prednisone is used, PDR001 treatment should be 
suspended (see Section 6.2.4). 
Topical, inhaled, nasal and ophthalmic steroids are not prohibited. The use of live vaccines is 
not allowed through the whole duration of the study. Other vaccines are excluded, except 
inactivated seasonal influenza vaccines. 
6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening/baseline and is retained as the primary identifier for 
the patient throughout his/her entire participation in the trial. The Patient No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
patient number suffixed to it, so that each patient is numbered uniquely across the entire 
database. Upon signing the informed consent form, the patient is assigned to the next sequential 
Patient No. available to the investigator through the Oracle Clinical RDC interface. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 
not be reused for any other Patient and the Patient No. for that individual must not be changed. 
If the patient is randomized but fails to start treatment for any reason, the reason will be entered 
into the End of Treatment phase Disposition eCRF and IRT must be notified within 2 days that 
the patient was not treated. 
6.4.2 
Treatment assignment or randomization 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased from patients and investigator staff. A patient randomization 
list will be produced by the IRT provider using a validated system that automates the random 
assignment of patient numbers to randomization numbers. These randomization numbers are 
linked to the different treatment arms, which in turn are linked to medication numbers. A 
separate medication randomization list will be produced by or under the responsibility of 
Novartis Drug Supply Management using a validated system that automates the random 
assignment of medication numbers to medication packs containing each of the study treatments. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms (Section 4.1 and Section 6.1) in a ratio of 2:1. Randomization 
will be stratified by patient’s baseline disease status: locally advanced recurrent NPC vs. 
metastatic NPC (Section 4.1). The investigator or his/her delegate will call or log on to the IRT 
and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
administered to the patient. The randomization number will not be communicated to the caller. 
For the patients crossing over to PDR001 arm, and only after agreement with Novartis, the 
investigator or his/her designee will call or log on to the IRT and confirm that the patient fulfills 


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the criteria to crossover. The IRT will assign a unique medication number for the study drug to 
be administered to the patient. 
6.5 
Study drug preparation and dispensation 
PDR001 
PDR001 (100 mg powder for solution for infusion) will be administered intravenously as a 30 
minute infusion (up to 2 hour, if clinically indicated). Further instructions for the preparation 
and dispensation of PDR001 are described in the [Pharmacy Manual]. 
Chemotherapy 
Commercially available chemotherapy will be sourced locally by each study site. Generic 
chemotherapy may be used for study treatment. 
All dosages for PDR001 and for the chemotherapy prescribed to the patient and all dose changes 
(except for PDR001 as no dose modifications) during the study must be recorded on the 
respective Dosage Administration Record eCRF. 
6.5.1 
Study drug packaging and labeling 
The study medication packaging has a 2-part label. A unique medication number is printed on 
each part of this label which corresponds to one of the treatment arms and a specific visit. 
Responsible site personnel will identify the study treatment package(s) to administer to the 
patient by using the IRT and obtaining the medication number(s). Site personnel will add the 
patient number on the label. Immediately before dispensing the package to the patient, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document (Drug Label Form) for that patient’s unique patient number. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and the medication number but no 
information about the patient. 
PDR001 (100 mg powder for solution for infusion) will be supplied by Novartis to Investigator 
as open label medication. 
6.5.2 
Drug supply and storage 
PDR001 
PDR001 must be received by designated personnel at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the investigator and designated site 
personnel have access. Upon receipt, PDR001 should be stored according to the instructions 
specified on the drug labels. 
Chemotherapy 
Chemotherapy should be stored and prepared according to the instructions on the package insert 
or summary of product characteristics of the commercial supply. The preparation and disposal 
of chemotherapy must be in accordance with local institutional guidelines. 


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6.5.3 
Study drug compliance and accountability 
6.5.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
6.5.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatments (PDR001 and chemotherapy) according to local institutional drug 
accountability processes. Drug accountability will be noted by the field monitor during site 
visits and at the completion of the study. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.5.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1, Table 7-2 and Table 7-3 list all of the assessments and indicate with an “X”, the visits 
when they are performed. All data obtained from these assessments must be supported in the 
patient’s source documentation. No eCRF will be used as a source document. 
Screening/Baseline evaluations must be performed ≤ 28 days of Cycle 1 Day 1 (except for the 
pregnancy test which has to be performed within 72 hours before first dose). Assessments 
performed as part of the screening/baseline evaluations and within 3 days prior to the first dose 
of study treatment, are not required to be repeated on Cycle 1 Day 1. Laboratory and 
radiological assessments performed as part of standard of care prior to signing informed consent 
may be used if performed within the screening/baseline time window. 
For the patients in the crossover, the first dose of PDR001 on Cycle 1 Day 1 should be 
administered ≤ 21 days from the radiological assessment performed as part of the End of 
Treatment (EoT1) visit. Assessments performed as part of the EoT1 visit and within 3 days 
prior to the first dose of PDR001, are not required to be repeated on Cycle 1 Day 1. 
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of +/- 7 days is allowed. If the infusion of PDR001 is delayed, the 
assessments will be shifted accordingly. On PK collection days the windows are provided in 
Section 7.2.3. 


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Table 7-1 
Visit evaluation schedule (patients in PDR001 arm) 
Visit name 
Category 
Protocol 
Section 
Screening/ 
Baseline 
Period 
Treatment Period 
Follow-up Period10 
Screening/ 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
EoT1 
150 -
Day 
Safety6 
Disease 
progression 
Survival 
Day of cycle 
 
 
-28 to -1 
1 
2 
8 
15 
1 
8 
15 
1 
2 
8 
15 
1 
 
 
 
 
Obtain Informed 
Consent 
D 
7.1.1. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IRT 
Registration 
D 
6.4. 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.1.2. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion 
criteria 
D 
5.2/5.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Newly obtained or 
archival tumor 
sample 
D 
7.2.4. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
D 
7.1.1.2. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent 
of cancer 
D 
7.1.1.2. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic 
therapy 
D 
6.3.1. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
D 
6.3.1. 
X 
Continuous 
 
 
Physical exam 
S 
7.2.2.1. 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X2 
X 
 
 
 
Vital signs 
D 
7.2.2.2. 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X2 
X 
 
 
 
Height 
D 
7.2.2.3. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3. 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X2 
X 
 
 
 
ECOG Performance 
status 
D 
7.2.2.4. 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X2 
X 
 
 
 
Hematology 
D 
7.2.2.5. 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X2 
X 
 
 
 


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Visit name 
Category 
Protocol 
Section 
Screening/ 
Baseline 
Period 
Treatment Period 
Follow-up Period10 
Screening/ 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
EoT1 
150 -
Day 
Safety6 
Disease 
progression 
Survival 
Day of cycle 
 
 
-28 to -1 
1 
2 
8 
15 
1 
8 
15 
1 
2 
8 
15 
1 
 
 
 
 
Chemistry 
D 
7.2.2.5. 
X 
X 
 
 
X 
X 
 
X 
X 
 
 
X 
X2 
X 
 
 
 
Coagulation 
D 
7.2.2.5. 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X2 
X 
 
 
 
Thyroid function 
D 
7.2.2.5. 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X2 
X 
 
 
 
Plasma EBV DNA 
level 
D 
7.2.2.5. 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X2 
X 
 
 
 
Serology exam8 
D 
7.2.2.5. 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X2 
X 
 
 
 
Pregnancy test 
(serum or urine) 
D 
7.2.2.5. 
X3 
 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
S 
X4 
Cytokines (IFN-γ, IL-
6, IL-1, TNF-α) for 
safety9 
D 
7.2.2.5. 
X 
When a suspected cytokine release syndrome, immediately after the AE, 
and one week after occurrence of the AE 
 
 
 
12-lead ECG8 
D 
7.2.2.6. 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Tumor evaluation as 
per RECIST/irRC 
D 
7.2.1. 
X 
 
 
During treatment: 8 weeks after Cycle 1 Day 1, and then every 8 
weeks until week 40. Then every 12 weeks until progression or 
patient withdrawal. 
Follow-up for progression: Every 8 weeks until week 40, then 
every 12 weeks until progression or lost to follow-up. 
 
Newly obtained 
tumor sample during 
treatment  
D 
7.2.4. 
 
 
 
 
 
 
 
 
Any time between C3D1 and End of 
treatment 
 
 
 
Blood sample for 
immunomonitoring 
D 
7.2.4. 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
Blood sample for 
cytokine analysis 
D 
7.2.4. 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
 
 
 
PDR001 infusion 
D 
6.1. 
 
i.v. every 4 weeks 
 
 
 
 
PK sampling 
D 
7.2.3. 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X5 
X 
X7 
 
 


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Visit name 
Category 
Protocol 
Section 
Screening/ 
Baseline 
Period 
Treatment Period 
Follow-up Period10 
Screening/ 
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
EoT1 
150 -
Day 
Safety6 
Disease 
progression 
Survival 
Day of cycle 
 
 
-28 to -1 
1 
2 
8 
15 
1 
8 
15 
1 
2 
8 
15 
1 
 
 
 
 
IG sampling 
D 
7.2.3. 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X5 
X 
X7 
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D 
7.1.5. 
7.1.6. 
7.1.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
AEs/irAEs 
D 
8. 
Continuous 
 
 
Survival contact 
(every 3 months) 
D 
7.1.7. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1IVRS/IRT must be contacted to randomize the patient before receiving first dose on Cycle 1 Day 1 (within 72 hours of first dose). 
2Every 12 weeks (cycles 3, 6, 9, 12, etc). 
3To be performed within 72 hours before first dose. 
4 To be performed monthly 
5 Cycles 4, 5 and 6 only. 
6 Safety evaluations for 150 days after last dose of PDR001 with contacts at 30-, 90-, and 150-day. After initiation of new antineoplastic therapy, only AEs/SAEs suspected 
to be related to PDR001 will be collected. Concomitant medications will be collected until the 30-day safety follow up has been completed or the start of a new 
antineoplastic therapy, whichever occurs first. 
7only for patients who come to site for 150-day safety follow up visit. 
8 To be terminated upon implementation of Protocol Amendment 05.  
9 To be terminated upon implementation of Protocol Amendment 06. 
10 Assessments within follow-up period are not applicable to patients who transfer to another clinical study or an alternative treatment option to continue provision of study 
treatment.  


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Table 7-2 
Visit evaluation schedule (patients in chemotherapy arm) 
Visit name 
Category 
Protocol 
Section 
Screening/.
Baseline 
Period 
Treatment Period 
Follow-up Period 
Screening/.
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
EoT1 
30-Day 
Safety 
Disease 
progression 
Survival 
Day of cycle 
 
 
-28 to -1 
1 
1 
1 
1 
 
 
 
 
Obtain Informed Consent 
D 
7.1.1. 
X 
 
 
 
 
 
 
 
 
IVRS/IRT Registration 
D 
6.4. 
X1 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.1.2. 
X 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
D 
5.2/5.3. 
X 
 
 
 
 
 
 
 
 
Newly obtained or archival 
tumor sample 
D 
7.2.4. 
X 
 
 
 
 
 
 
 
 
Medical History 
D 
7.1.1.2. 
X 
 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
D 
7.1.1.2. 
X 
 
 
 
 
 
 
 
 
Prior antineoplastic therapy 
D 
6.3.1. 
X 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
D 
6.3.1. 
X 
Continuous 
 
 
Physical exam 
S 
7.2.2.1. 
X 
X 
X 
X 
X2 
X 
 
 
 
Vital signs 
D 
7.2.2.2. 
X 
X 
X 
X 
X2 
X 
 
 
 
Height 
D 
7.2.2.3. 
X 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3. 
X 
X 
X 
X 
X2 
X 
 
 
 
ECOG Performance status 
D 
7.2.2.4. 
X 
X 
 
X 
X2 
X 
 
 
 
Hematology 
D 
7.2.2.5. 
X 
X 
X 
X 
X2 
X 
 
 
 
Chemistry 
D 
7.2.2.5. 
X 
X 
X 
X 
X2 
X 
 
 
 
Coagulation 
D 
7.2.2.5. 
X 
X 
X 
X 
X2 
X 
 
 
 
Thyroid function 
D 
7.2.2.5. 
X 
X 
X 
X 
X2 
X 
 
 
 
Plasma EBV DNA level 
D 
7.2.2.5. 
X 
X 
X 
X 
X2 
X 
 
 
 
Serology exam5 
D 
7.2.2.5. 
X 
X 
X 
X 
X2 
X 
 
 
 
Cytokines (IFN-γ, IL-6, IL-1, 
TNF-α) for safety 
D 
7.2.2.5. 
X 
 
 
 
 
 
 
 
 


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Visit name 
Category 
Protocol 
Section 
Screening/.
Baseline 
Period 
Treatment Period 
Follow-up Period 
Screening/.
Baseline 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
EoT1 
30-Day 
Safety 
Disease 
progression 
Survival 
Day of cycle 
 
 
-28 to -1 
1 
1 
1 
1 
 
 
 
 
Pregnancy test (serum or 
urine) 
D 
7.2.2.5. 
X3 
 
X4 
X4 
X4 
X 
 
 
 
S 
X4 
12-lead ECG 
D 
7.2.2.6. 
X 
 
 
 
 
 
 
 
 
Chemotherapy 
D 
6.1. 
 
as prescribed regimen4 
 
 
 
 
Tumor evaluation as per 
RECIST v1.1 
D 
7.2.1. 
X 
During treatment: 8 weeks after Cycle 1 Day 1, and then every 8 weeks until 
week 40. Then every 12 weeks until progression or patient withdrawal. 
Follow-up for progression: Every 8 weeks until week 40, then every 12 weeks 
until progression or lost to follow-up. 
 
Antineoplastic therapies since 
discontinuation of study 
treatment 
D 
7.1.5. 
7.1.6. 
7.1.7. 
 
 
 
 
 
 
X 
X 
X 
AEs 
D 
8. 
Continuous 
 
 
Survival contact (every 3 
months) 
D 
7.1.7. 
 
 
 
 
 
 
 
 
X 
1IVRS/IRT must be contacted to randomize the patient before receiving first dose on Cycle 1 Day 1 (within 72 hours of first dose). 
2Every 12 weeks (cycles 3, 6, 9, 12, etc). More frequent evaluations may be performed at the investigator’s discretion if medically indicated or if recommended by drug 
product information. 
3To be performed within 72 hours before first dose. 
4 Investigators must refer to the approved label of the product. 
5 To be terminated upon implementation of Protocol Amendment 05.  


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Table 7-3 
Visit evaluation schedule (crossover patients treated with PDR001) 
Visit name 
Category 
Protocol 
Section 
Treatment Period 
Follow-up Period8 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
EoT2 
150 -
Day 
Safety5 
Disease 
progression 
Survival 
Day of cycle 
 
 
1 
15 
1 
15 
1 
15 
1 
 
 
 
 
IVRS/IRT Registration 
S 
6.4. 
X1 
 
 
 
 
 
 
 
 
 
 
Prior/concomitantmedications 
D 
6.3.1. 
Continuous  
 
 
Physical exam 
S 
7.2.2.1. 
X 
X 
X 
X 
X 
X 
X3 
X 
 
 
 
Vital signs 
D 
7.2.2.2. 
X 
X 
X 
X 
X 
X 
X3 
X 
 
 
 
Weight 
D 
7.2.2.3. 
X 
 
X 
 
X 
 
X3 
X 
 
 
 
ECOG Performance status 
D 
7.2.2.4. 
X 
 
 
 
X 
 
X3 
X 
 
 
 
Hematology 
D 
7.2.2.5. 
X 
X 
X 
X 
X 
X 
X3 
X 
 
 
 
Chemistry 
D 
7.2.2.5. 
X 
X 
X 
X 
X 
X 
X3 
X 
 
 
 
Coagulation 
D 
7.2.2.5. 
X 
 
X 
 
X 
 
X3 
X 
 
 
 
Thyroid function 
D 
7.2.2.5. 
X 
 
X 
 
X 
 
X3 
X 
 
 
 
Plasma EBV DNA level 
D 
7.2.2.5. 
X 
 
X 
 
X 
 
X3 
X 
 
 
 
Serology exam6 
D 
7.2.2.5. 
X 
 
X 
 
X 
 
X3 
X 
 
 
 
Pregnancy test (serum or urine) 
D 
7.2.2.5. 
X2 
 
X 
 
X 
 
X 
X 
 
 
 
S 
X4 
Cytokines (IFN-γ, IL-6, IL-1, 
TNF-α) for safety7 
D 
7.2.2.5. 
When a suspected cytokine release syndrome, 
immediately after the AE, and one week after 
occurrence of the AE 
 
 
 
 
12-lead ECG6 
D 
7.2.2.6. 
X 
 
 
 
X 
 
 
 
 
 
 
Tumor evaluation as per 
RECIST/irRC 
D 
7.2.1. 
 
 
During treatment: 8 weeks after Cycle 1 Day 1, and then every 8 
weeks until week 40. Then every 12 weeks until progression or 
patient withdrawal. 
Follow-up for progression: Every 8 weeks until week 40, then 
every 12 weeks until progression or lost to follow-up. 
 
PDR001 infusion 
D 
6.1. 
i.v. every 4 weeks 
 
 
 
 
 


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Visit name 
Category 
Protocol 
Section 
Treatment Period 
Follow-up Period8 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
EoT2 
150 -
Day 
Safety5 
Disease 
progression 
Survival 
Day of cycle 
 
 
1 
15 
1 
15 
1 
15 
1 
 
 
 
 
Antineoplastic therapies since 
discontinuation of study 
treatment 
D 
7.1.5. 
7.1.6. 
7.1.7. 
 
 
 
 
 
 
 
 
X 
X 
X 
AEs/irAEs 
D 
8. 
Continuous  
 
 
Survival contact (every 3 
months) 
D 
7.1.7. 
 
 
 
 
 
 
 
 
 
 
X 
1IVRS/IRT must be contacted to receive medication number for the first package of PDR001 treatment before first dose on Cycle 1 Day 1 (within 72 hours of first dose). 
2To be performed within 72 hours before first dose. 
3Every 12 weeks (cycles 3, 6, 9, 12, etc).  
4To be performed monthly 
5 Safety evaluations for 150 days after last dose of PDR001 with contacts at 30-, 90-, and 150-day. After initiation of new antineoplastic therapy, only AEs/SAEs suspected 
to be related to PDR001 will be collected. Concomitant medications will be collected until the 30-day safety follow up has been completed or the start of a new 
antineoplastic therapy, whichever occurs first. 
6 To be terminated upon implementation of Protocol Amendment 05.  
7 To be terminated upon implementation of Protocol Amendment 06. 
8 Assessments within follow-up period are not applicable to patients who transfer to another clinical study or an alternative treatment option to continue provision of study 
treatment. 


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7.1.1 
Screening/baseline period 
The study IRC/IEC informed consent form must be signed and dated before any 
screening/baseline procedures are performed, except for evaluations performed as part of 
standard of care. 
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1, Table 7-2 and Table 7-3. Screening/Baseline 
assessments must be repeated if performed outside of the specified screening window 
(Section 7.1). The screening failure reason will be entered on the Screening Phase Disposition 
eCRF. 
Submission of a newly obtained tumor sample (formalin fixed, in ethanol) or an archival tumor 
sample (should a newly obtained tumor sample not be possible for medical reasons) are 
requested and will be collected, whenever possible, from all patients at screening/baseline. For 
details refer to Section 7.2.4. 
7.1.1.1 
Information to be collected on screening failures 
A patient who signed an Informed Consent Form but failed to be started on-treatment for any 
reason will be considered a screen failure. The screening failure reason will be entered on the 
Screening Phase Disposition eCRF. 
The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for Screen Failure patients. No other data will be entered into the clinical database 
for patients who are screen failures, unless the patient experienced a SAE during 
screening/baseline (see Section 8 for SAE reporting details) or died (Death eCRF should be 
completed) or withdrew consent (Withdrawal of consent eCRF should be completed). 
7.1.1.2 
Patient demographics and other screening/baseline characteristics 
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments, prior medication, procedures, significant non-drug therapies, Epstein–Barr virus 
(EBV) status and any other assessments that are done for the purpose of determining eligibility 
for inclusion in the study. 
7.1.2 
Treatment period 
Patients will be randomized according to a 2:1 ratio, to either the investigational arm or the 
control arm. An effort should be made to ensure patients start treatment at the latest within 72 
hours of randomization. 
 Investigational arm: PDR001 at the RP2D as established in the [CPDR001X2101] phase 
I (first-in-human) study (400mg i.v.Q4W). 
 Control arm: Commonly used chemotherapy as per investigator’s choice. 
For the purpose of scheduling and evaluations, a treatment cycle will consist of 28 days for 
patients treated with PDR001. Patients treated with PDR001 who meet the following criteria 
may continue treatment in additional cycles: 


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 Patients with a CR, PR or SD will continue to receive PDR001 until confirmed CR or 
until the patient experiences unacceptable toxicity. 
 Patients with PD according to the RECIST v1.1 that has been confirmed but is not 
worsening and in stable or improved clinical status. These patients should remain under 
treatment until there is a further progression or clinical deterioration. 
Note: Patients treated with PDR001 will not be discontinued from the study treatment due to 
progressive disease as per RECIST v1.1. 
Accumulating evidence indicates that objective responses to immunotherapy follows delayed 
kinetics of weeks or months, and can be preceded by initial apparent radiological progression 
or appearance of new lesions or some enlarging lesions while other target lesions are regressing 
(“mixed response”) (Wolchock et al 2009). It is therefore reasonable to allow for these 
possibilities and continue to treat the patient until progression is confirmed and found to be 
advancing at the next imaging assessment as per immune-related Response Criteria (irRC). An 
outline of the irRC is provided in Appendix 2. 
Example criteria for continuing treatment beyond progression are below: 
 Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
 No decline in ECOG performance status 
 Absence of rapid progression of disease 
 Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
These considerations should be balanced by clinical judgment as to whether the patient is 
clinically deteriorating and unlikely to receive any benefit from continued treatment. Such 
deterioration will be assessed to have occurred after a clinical event that, in the Investigator’s 
opinion, is attributable to disease progression, is unlikely to reverse with continued study 
treatment and therefore indicates that the patient is not benefiting from study treatment and 
cannot be managed by the addition of supportive care. 
The decision to continue or stop treatment should be discussed with the Novartis Medical 
Responsible and will be documented in the study files. 
Please refer to Table 7-1, Table 7-2 and Table 7-3 for details of the timing of required 
assessments and Section 7.1 for visit windows. 
7.1.2.1 
Crossover 
Patients in the control arm will be allowed to crossover to PDR001 treatment if they have 
radiological progression (as per RECIST v1.1) documented by an independent central review 
and the investigator believes this is the best treatment option for the patient. The End of 
Treatment (EoT1) visit assessments should be performed as described in Section 7.1.3 before a 
patient can receive PDR001 treatment. 
Patients should receive PDR001 within 21 days of the last radiological assessment, if they have 
no Grade 3/4 AEs and brain metastases. Each case must be first discussed with Novartis. No 
other antineoplastic therapies are allowed from the time of disease progression to the time of 


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crossover treatment initiation and throughout PDR001 treatment. Once transitioned to PDR001 
treatment, patients will attend the clinic for treatment and safety monitoring as described in 
Section 7.2.2. 
7.1.3 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision 
and record this information in the patient’s chart and on the appropriate eCRF. They may be 
considered discontinued if they state an intention to withdraw or fail to return for visits. 
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being. 
Study treatment may be discontinued under the following circumstances: 
 Adverse event 
 Lost to follow-up 
 Physician’s decision 
 Progressive disease as per irRC (not as per RECIST v1.1; patients treated with PDR001) 
 Progressive disease as per RECIST v1.1 (patients treated with chemotherapy) 
 Confirmed Complete response as per RECIST v1.1(patients treated with PDR001) 
 Study terminated by Novartis 
 Patient/guardian decision 
 Protocol deviation 
 Technical problems 
Study treatment must be discontinued if any of the following occur: 
 Death 
 Pregnancy 
Patients who discontinue study treatment should undergo as soon as possible and within 14 days 
of the last dose of study drug or within 14 days of the decision to discontinue study treatment, 
an End of Treatment (EoT1) visit and then be discontinued from the study treatment (please 
refer to Table 7-1 and Table 7-3 for list of assessments to be performed). 
Patients in the control arm, who switch to PDR001 treatment, should have an EoT visit (EoT2) 
once they are discontinued from PDR001 treatment (please refer to Table 7-3 for list of 
assessments to be performed). 
If the decision to discontinue the patient occurs at a regular scheduled visit, that visit may 
become the EoT visit rather than having the patient return for an additional visit. An End of 
Treatment Phase Disposition eCRF should be completed, giving the reason for stopping the 
study treatment. End of treatment/Premature withdrawal visit is not considered as the end of the 
study. The investigator must also contact IRT to register the patient’s discontinuation from 
study treatment. 


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Patients who discontinue study treatment should not be considered discontinued from the study. 
They should return for the assessments indicated in Section 7.1.5. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone calls, e-mail, letter) should be 
made to contact them as specified in Section 7.1.8. If a patient discontinues study treatment, but 
continues study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments. 
Patients who transfer into another study or an alternative treatment option to continue provision 
of study treatment will perform the EoT procedures, but not any further study assessments. 
7.1.4 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study any 
longer, and does not allow further collection of personal data. 
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone 
calls, e-mail, letter) to determine the primary reason for this decision 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 patient are not allowed unless safety findings require 
communication or follow up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.  
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. 
7.1.5 
Follow up for safety evaluations 
All patients in the PDR001 treatment arm must have safety evaluations for 150 days after the 
last dose of study treatment. Patient in the Chemotherapy arm must have safety evaluations for 
30 days after the last dose of study treatment. 
Patients in the control arm who crossover are not required to have a 30-day safety follow-up 
performed and can crossover as soon as the End of Treatment (EoT1) visit is complete. Once 
patients discontinue PDR001 crossover treatment, safety follow-up must be performed for 150 
days after the last dose of PDR001. 


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The evaluations can be done either by telephone call or visit for the 30-, 90-, and 150-day safety 
follow-up visits for the PDR001 arm and crossover patients. Concomitant medications will be 
collected until the 30- day safety follow-up has been completed or the start of a new 
antineoplastic therapy, whichever occurs first. A PK and immunogenicity sample should be 
collected at 150 days for PDR001 arm patients only, as described in Section 7.2.3. If the 150-
day safety evaluation is conducted by phone, samples do not need to be collected. 
Data collected during the Safety follow up period should be added to the Adverse Events eCRF, 
Concomitant Medications eCRF, Antineoplastic therapies since discontinuation of study drug 
eCRF (including tumor directed surgical procedures) and Unscheduled blood collection for PK 
and IG eCRFs. All AEs suspected to be related to study treatment should be followed weekly, 
or as clinically indicated, until resolution or stabilization. For female patients of child bearing 
potential, pregnancy tests will be performed as outlined in Section 7.2.2.5. 
The safety follow-up will not be performed for patients who transfer to another study or to an 
alternative treatment option to continue provision of study treatment. 
7.1.6 
Follow up for disease progression 
All patients who discontinue study treatment for any reason other than: 
 disease progression per irRC (for patients treated with PDR001) 
 disease progression per RECIST v1.1 (for patients treated with chemotherapy) 
 clinical deterioration, death, lost to follow up or consent withdrawal 
should return for tumor evaluation assessments (please refer to Table 7-4) until disease 
progression, death, discontinuation from the study for any other reason (e.g., loss to follow-up 
or withdrawal of consent), the initiation of a new antineoplastic treatment, or until the End of 
the Study whichever occurs first. 
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone, e-mail or letter, to determine if the 
patient had disease progression. Once the Follow up for Disease progression period ended, the 
End of Post treatment Phase disposition eCRF should be completed. 
Antineoplastic therapies or tumor directed surgical procedures initiated during the disease 
progression follow-up period must be recorded on the Antineoplastic therapies since 
discontinuation of study drug eCRF.  
The disease progression follow-up will not be performed for patients who transfer to another 
study or to an alternative treatment option to continue provision of study treatment. 
7.1.7 
Follow up for survival 
All patients will be followed for survival via a phone call, email or letter, every 12 weeks and 
up to one additional time per quarter if safety or regulatory needs, until any of the following 
(whichever occurs first): death, withdrawal of consent, loss to follow-up or at least 24 months 
from the first dose of study treatment. Antineoplastic therapies or tumor directed surgical 
procedures initiated during the survival follow-up period must be recorded on the 
Antineoplastic therapies since discontinuation of study drug eCRF. 


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The survival follow-up will not be performed for patients who transfer to another study or to an 
alternative treatment option to continue provision of study treatment.  
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient (e.g. dates of telephone calls, e-mail, 
letters). A patient should not be considered lost to follow-up until due diligence has been 
completed. Patients lost to follow up should be recorded as such on the appropriate Disposition 
eCRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be assessed locally and centrally according to the two following criteria 
1. RECIST v1.1 (Appendix 1, Eisenhauer et al 2009). 
2. irRC (Appendix 2, based on Wolchok et al 2009 and Nishino et al 2013). 
Imaging data will be centrally collected in blinded fashion 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 (study discontinuation due to PD as per 
irRC for patients treated with PDR001). Patients in PDR001 treatment will not be discontinued 
from the study treatment due to progressive disease as per RECIST v1.1. Similar to RECIST 
v1.1, irCR and irPR must be confirmed at a new assessment after at least 4 weeks. In addition, 
unlike RECIST v1.1, irPD also requires confirmation at a new assessment after at least 4 weeks. 
Please refer to Appendix 1 and Appendix 2 for further details. 
Patients in the control arm who progressed after chemotherapy are allowed to crossover to the 
PDR001 after their documented progression is confirmed as per RECIST v1.1 based on the 
independent central review. 
The independent central review of imaging data will be terminated for the whole study when 
both criteria are met, 1) decisions are made based on central review results for all chemotherapy 
arm patients on whether to crossover; 2) all patients have reached a minimum of 12 months 
follow up after the first dose of study treatment (unless have been lost to follow-up).  
The imaging assessment collection plan is presented in Table 7-4. Details of the central review 
process will be described in the independent review charter. 


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Table 7-4 
Disease assessment collection plan 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
CT or MRI 
with contrast 
enhancement 
(Chest, Abdomen, 
Pelvis) 
Mandated 
During treatment: 8 weeks after Cycle 1 Day 1, 
and then every 8 weeks until week 40. Then every 
12 weeks until progression or patient withdrawal. 
Follow-up for progression: Every 8 weeks until 
week 40, then every 12 weeks until progression or 
lost to follow-up. 
Brain CT or MRI with 
contrast 
Mandated 
If disease was detected at baseline, or if clinically 
indicated. 


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Screening/baseline assessments 
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1). 
Any imaging assessments already completed during the regular work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the screening/baseline images for this study. Any imaging assessments obtained 
after randomization cannot be considered screening/baseline images. At screening, all patients 
will undergo CT scan with i.v. contrast of the brain, chest, abdomen and pelvis. If there is 
clinical evidence of disease in the head and neck, a CT scan with i.v. contrast of the head and 
neck will also be performed. The assessments required at screening/baseline are indicated in 
Table 7-4. 
If a patient is known to have a contraindication to CT intravenous (i.v.) contrast media or 
develops a contraindication during the study, a non-contrast CT scan of the chest (MRI is 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. 
If brain metastases are suspected at screening/baseline, brain MRI or CT should be completed 
at the following assessments. Contrast enhanced brain MRI is preferred, however, if MRI 
contrast is contraindicated, then MRI without contrast or CT with/without contrast is acceptable. 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
Chest X-rays and ultrasound should not be used to measure tumor lesions. 
Post-screening/post-baseline imaging assessments 
Imaging assessments as described in Table 7-4 should be performed using the same imaging 
modality used at screening/baseline, irrespective of study treatment interruption or actual 
dosing. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a patient, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. 
Each lesion that is measured at screening/baseline must be measured by the same method (either 
same imaging method or by photography, including a metric ruler) and when possible, the same 
local radiologist/physician throughout the study so that the comparison is consistent. If an off-
schedule imaging assessment is performed because progression is suspected, subsequent 
imaging assessments should be performed in accordance with the original imaging schedule. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 


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Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
v1.1 (Appendix 1). 
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging CRO for analysis. 
Timepoints at which progression is determined locally 
All patients who have disease progression, determined by the local investigator require an 
expedited central review. Rapid image transmission to the imaging CRO may be accomplished 
by transferring the images electronically (e.g., via the Internet). In all instances, the process at 
the imaging CRO will ensure that the central reviewers remain blinded to the results of the local 
assessment and the expedited nature of the review. The investigator seeking an expedited review 
must indicate this request to the imaging CRO on a designated form or by alternative means. 
The imaging will undergo expedited central review (within 5 business days from the time of 
image receipt at the imaging CRO) and the results of the central review will be communicated 
to the site. While the investigator is awaiting the results of the central review, it is preferable 
that the patient continue on study treatment. However, during this time, the investigator should 
do whatever is medically necessary for the patient. 
Note: If an investigator would like to discuss the central review results, there will be an 
independent physician at the imaging CRO, who is not part of the central review pool for this 
study. This independent physician will be able to discuss the central review findings with the 
investigator. The central reviewers are completely excluded from such discussion. The contact 
at the imaging CRO can arrange such a discussion, as specified in the manual provided by the 
designated imaging CRO. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, thyroid function, pregnancy, ECG, as 
well as collecting of the AEs at every visit. For details on AE collection and reporting, refer to 
Section 8. 
7.2.2.1 
Physical examination 
Physical examination will be performed according to Table 7-1, Table 7-2 and Table 7-3. 
At Screening/Baseline and Cycle 1 Day 1, prior to PDR001 infusion or chemotherapy, a 
complete physical examination will be performed and will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities and neurological. If indicated based on medical history and/or 
symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
After Cycle 1 Day 1 and onwards, a short physical examination will be performed. A short 
physical exam will include the examination of general appearance, vital signs (blood pressure 
[BP] and pulse) and body sites as directed by symptoms. 


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Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History eCRF. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event eCRF. 
7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing 
(when the dose is taken/administered at the clinic) and as indicated in Table 7-1, Table 7-2 and 
Table 7-3 as per institutional standards. Vital signs should be assessed in the same position 
through the study. 
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator if medically 
indicated, and will be recorded as unscheduled assessment. 
7.2.2.3 
Height and weight 
Height and body weight will be measured as indicated in Table 7-1, Table 7-2 and Table 7-3 as 
per institutional standards. 
7.2.2.4 
Performance status 
ECOG performance status will be assessed according to Table 7-5 and as indicated in Table 7-1, 
Table 7-2 and Table 7-3. 
Table 7-5 
ECOG performance status 
Grade 
ECOG Status 
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 selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
Note: Grade 5 (death) was removed from this table. This information will be collected on a separate 
eCRF. 
7.2.2.5 
Laboratory evaluations 
All laboratory parameters assessed for safety purposes will be evaluated locally (except 
Cytokines, Serology and EBV test examinations that will be evaluated centrally). Refer to 
Table 7-6 for a summary of the parameters to be evaluated. 
More frequent evaluations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments. 
Novartis will be provided with a copy of the laboratory certification and tabulation of the normal 
ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, Novartis must be provided with a copy 
of the certification and a tabulation of the normal ranges for that laboratory. 


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All females of childbearing potential will have a serum pregnancy test at screening/baseline 
and/or within ≤ 72 hours before first dose of study treatment, day 1 of each cycle and at EOT 
visit. A urine or serum pregnancy test should be performed every month during and at the 
end of the safety follow-up period. If the patient is not coming to the clinic for the safety follow-
up visits, a urine or serum pregnancy test will be performed at home or at a local doctor’s office 
monthly and the results will be communicated to the site staff. The result will be recorded only 
in the source documentation, not in the CRF. A positive pregnancy test requires immediate 
discontinuation of study treatment. In addition, refer Section 8.3 for follow-up and reporting 
Pregnancies. 
Table 7-6 
Local/central clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells with Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Chemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, 
Calcium, Chloride, Sodium, Potassium, Creatinine, Glucose (fasting) 
Magnesium, Inorganic Phosphate, Total Bilirubin (also measure direct and 
indirect bilirubin if total bilirubin is > grade 1), Blood Urea Nitrogen (BUN) or 
Urea 
Coagulation 
Prothrombin time (PT) or International Normalized Ratio (INR), Activated 
partial thromboplastin time (APTT) 
Thyroid 
 Free T4, TSH (Thyroid Stimulation Hormone) 
Cytokines1, 2, 4 
Interferon-gamma (IFN-γ), Interleukin-6 (IL-6), Interleukin-1 (IL-1), Tumor 
necrosis factor-alpha (TNF-α) 
EBV2 
DNA levels in plasma 
Serology exam in 
serum2, 3 
Anti-DNA antibodies (Abs), Anti-nuclear abs, Anti-phospholipid abs, Anti-
mitochondrial abs, c-Reactive protein (CRP), Rheumatoid factor (RF) 
Pregnancy 
Serum and/or urine samples only for women of childbearing potential 
1To be performed at Screening/Baseline for all patients, and ad hoc (by ELISA), if cytokine release 
syndrome is suspected only for patients in PDR001 arm. 
2 To be performed by a Central laboratory. 
3 To be terminated upon implementation of Protocol Amendment 05. 
4 To be terminated upon implementation of Protocol Amendment 06. 
7.2.2.6 
Cardiac assessments (patients in PDR001 arm) 
7.2.2.6.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as per the assessment schedule in Table 7-1, 
Table 7-2, Table 7-3 and Table 7-7. Blood samples scheduled at the same time point should be 
taken after the ECGs are completed. The ECGs on Day 1 of Cycles 1 and 3 must be performed 
in triplicate. 


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Table 7-7 
12 lead ECG collection plan for central review (patients in PDR001 
arm)*** 
Cycle 
Day 
Time 
Screening/Baseline§ 
-28 to -1 
Anytime (all patients) 
1 
1 
*1h (±5 min) post-dose 
3 
1 
*Pre-dose 
3 
1 
*1h (±5 min) post-dose 
Unscheduled** 
- 
Anytime 
§ ECG at baseline should be performed for all patients. 
* ECGs performed in triplicate. 
** A PK sample should be collected just after an ECG performed due to an unexpected cardiac 
signal. 
** Unscheduled ECGs could be performed for safety reasons for all patients. 
*** This plan is only applicable to central ECG review, which is obsolete upon implementation of 
Protocol Amendment 05. 
All ECGs will be independently reviewed by a central laboratory. Instructions for the collection 
and transmission of ECGs to the central ECG laboratory will be provided in the ECG Manual. 
Upon implementation of Protocol Amendment 05, the ECG collection plan for central review 
as detailed in Table 7-1, 7-2, 7-3 and 7-7 is obsolete. Instead, ECGs are performed and reviewed 
locally, with the timing and frequency based on Investigator’s judgement. 
Clinically significant abnormalities present at screening/baseline should be reported on the 
Medical History eCRF. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the Adverse Events eCRF. All eligibility and patient 
management decisions should be made based on the local reading of the ECG. 
7.2.3 
Pharmacokinetics and immunogenicity assessments (patients in 
PDR001 arm) 
The following PK parameters may be determined for PDR001 using non-compartmental 
methods: Cmax, Tmax, AUC0-tlast (Cycle 1 and Cycle 3), time to last measurable 
concentration (Tlast), t1/2, and the accumulation ratio of PDR001. 
PK data will be collected from all patients in the PDR001 arm using a sparse sampling scheme 
as described in Table 7-8. Details on IG sample collections are also included in this table. 
If the dosing of Cycle 3 Day 1 is delayed, the PK sampling for the PK profile should be delayed 
accordingly to match the scheduled time points for Cycle 3 as outlined in Table 7-8. PK and IG 
samples will be collected also at the End of Treatment visit and in the event of a clinically 
significant AE (such as infusion reaction/anaphylaxis) or if IG is suspected. No additional PK 
and IG samples (including EoT and unscheduled samples) will be collected from any patient 
once Cycle 4 PK and IG samples have been collected from all the PDR001 arm patients.  
 
 
Note: PK or IG samples will not be collected for patients who crossover. 


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Table 7-8 
Pharmacokinetic blood collection log (patients in PDR001 arm) 
Cycle 
Day 
Scheduled Time Point (h)** 
Analytes 
PK 
Sample 
No 
IG 
Sample 
No* 
1 
1 
Pre-dose 
mAb and IG 
1 
401 
1 
1 
1h post-dose§ (± 5 min) 
mAb 
2 
1 
2 
24h post-dose§ (± 2h) 
mAb 
3 
1 
8 
168h post-dose§ (± 8h) 
mAb 
4 
1 
15 
336h post-dose§ (±24h) 
mAb 
5 
2 
1 
672h post-dose§ (±48h) /Pre-dose of cycle 
2 
mAb and IG 
6 
402 
2 
8 
168h post-dose§ (± 8h) 
mAb 
7 
2 
15 
336h post-dose§ (±24h) 
mAb 
8 
3 
1 
672h post-dose§ (±48h) /Pre-dose of cycle 
3 
mAb and IG 
9 
403 
3 
1 
1h post-dose§ (± 5 min) 
mAb 
10 
3 
2 
24h post-dose§ (± 2h) 
mAb 
11 
3 
8 
168h post-dose§ (± 8h) 
mAb 
12 
3 
15 
336h post-dose§ (± 24h) 
mAb 
13 
4 
1 
672h post-dose§ (±48h) / Pre-dose of 
cycle 4 
mAb and IG 
14 
404 
5 
1 
Pre-dose of cycle 5 
mAb and IG 
15 
405 
5 
1 
1h post-dose§ (± 5 min) 
mAb 
16 
6 
1 
Pre-dose of cycle 6 
mAb and IG 
17 
406 
6 
1 
1h post-dose§ (± 5 min) 
mAb 
18 
EoT 
mAb and IG 
5000 
6000 
Unscheduled (including 150-day safety follow-up visit)  
mAb and IG 
1001+ 
2001+ 
*IG samples are to be collected together with PK samples. 
§After completion of the infusion. 
**PK samples are to be collected from the arm opposite from infusion site, or alternatively, infusion 
site will need to be flushed with 10mL of saline. 
7.2.3.1 
Bioanalytics 
Bioanalysis for pharmacokinetic studies will employ 2 validated assays: 
1. The assay to quantify PDR001 will be a validated LCMS. The details of the assay will be 
documented in the [CPDR001X2201 Laboratory Manual]. 
2. The assay to quantify and assess the IG will be a validated homogeneous ELISA. The 
details of the assay will be documented in the [CPDR001X2201 Laboratory Manual]. 
7.2.3.2 
PK and immunogenicity sample handling, labeling, and shipping 
instructions 
A total of 4 mL of blood will be collected at each time point. For time points when PDR001 
(mAb) PK and IG are to be measured, a single blood sample will be collected for both IG and 
PDR001 PK. Blood samples should be collected from the arm opposite from the 


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investigational drug infusion, or from another site. After clotting, the resulting serum will 
be separated in aliquots and will be stored frozen until analysis. Please see the [CPDR001X2201 
Laboratory Manual] for detailed instructions about collection, handling and shipment of 
samples. 
The actual collection date and time of each sample will be entered on the 
Pharmacokinetics/Immunogenicity Blood Collection eCRF. 
7.2.4 
Biomarkers (patients in PDR001 arm) 
In this study biomarker analyses will be used to investigate the effect of the PDR001 at the 
molecular and cellular level as well as to determine how changes in the markers may relate to 
exposure and clinical outcomes. In addition, potential predictive markers of efficacy will also 
be explored. 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample collection and/or analysis may be omitted at the 
discretion of Novartis. 
The sample collection information must be entered on the appropriate sample collection log 
eCRF and requisition form(s). Detailed instructions for the collection, handling, and shipment 
of tumor samples are outlined in the [CPDR001X2201 Laboratory Manual]. 
Note: on-treatment tumor or blood samples for biomarker analysis will not be collected for 
patients who crossover. 


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Table 7-9 
Biomarker sample collection plan 
Sample Type 
Visit/ Time point 
Slides/Volume 
Marker* 
Purpose 
Tumor samples 
Newly obtained 
tumor sample or 
archival tumor 
block (if newly 
obtained tumor 
sample is not 
feasible) 
(all patients) 
Screening/Baseline 
Newly obtained 
formalin fixed 
tumor sample in 
ethanol (3-6 
passes) 
or 
archival FFPE 
tumor block or a 
minimum of 15 
freshly cut slides 
from archival 
paraffin tumor 
tissue 
RNA 
expression of 
immune-related 
genes 
IHC expression 
of markers 
such as: 
PD-L1 
LAG-3 
TIM-3 
CD8, Foxp3 TIL 
counts 
Protein 
expression of 
immune-related 
markers 
Assess 
expression status 
of potential 
predictors of 
efficacy 
Pharmacodynamic 
markers 
(Baseline) 
Newly obtained 
tumor sample 
(patients in 
PDR001 arm) 
Any time between 
C3D1 and End of 
Treatment 
Newly obtained 
formalin fixed 
tumor sample in 
ethanol (3-6 
passes) 
RNA 
expression of 
immune-related 
genes 
PD-L1, 
CD8, Foxp3 TIL 
counts 
Protein 
expression of 
immune-related 
markers 
Pharmacodynamic 
effect (on-
treatment) 
Blood samples 
Blood sample for 
plasma cytokine 
analysis 
(patients in 
PDR001 arm) 
C1D1 (pre-dose) 
C1D8 
C1D15 
C2D1 (pre-dose) 
C2D8 
C2D15 
End of Treatment 
Approximately 5 
mL 
Cytokine 
analysis (e.g., 
IFN-γ, TNF-α, 
IL-6) 
Pharmacodynamic 
effect (on-
treatment) 
Note: On days and time points when biomarker and pharmacokinetic blood samples are being 
collected, the PK sample must be drawn first (patients in PDR001 arm). 
*Markers are listed according to level of priority. 


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7.2.4.1 
Tumor collection 
7.2.4.1.1 Potential predictive markers 
The status of immune checkpoint targets and cell populations will be analyzed in newly 
obtained or archival tumor sample. Expression and localization of biomarkers including but not 
limited to PD-L1 and CD8+ TIL counts may be measured by immunohistochemistry (IHC) or 
using additional techniques deemed suitable. Other related biomarkers may also be analyzed 
from this sample, depending on sample availability, resources, and patient’s outcomes and as 
new scientific evidence becomes available. 
Submission of an archival specimen or newly obtained tumor sample (formalin fixed, in ethanol) 
will be requested at screening/baseline (a fresh tumor sample is preferred), unless agreed 
differently between Novartis and the Investigator. A corresponding pathology report should be 
included along with the archival samples. 
Archived tumor samples may be returned to the pathology laboratory at the end of the study, or 
at any time, at the request of the Investigator. 
7.2.4.1.2 Pharmacodynamic markers (patients in PDR001 arm) 
Pharmacodynamic assessments in tumor samples 
For pharmacodynamic assessments, collection of evaluable newly obtained on-treatment tumor 
samples between Cycle 3 Day 1 and End of Treatment is recommended, and if site of disease 
is accessible. Exceptions may be made on a case by case basis after discussion between Novartis 
and the Investigator. 
The pre- and on-treatment paired tumor samples will be used to assess PDR001 target 
modulation with established immunohistochemical methods and RNA expression analysis. 
Additional markers or methods may be utilized if indicated by new findings from the literature 
as well as from Novartis internal data. 
7.2.4.2 
Blood sample collection (patients in PDR001 arm) 
Blood samples will be collected as specified in Table 7-9 to characterize markers of activation 
in immune cells and circulating levels of cytokine in plasma. 
All blood samples will be collected and processed as described in the [CPDR001X2201 
Laboratory Manual]. 


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8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. For additional details about irAE, please refer to Section 6.2.2. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History of the patient’s eCRF. Adverse event monitoring should be 
continued for at least 30 days following the last dose of chemotherapy and 150 days following 
the last dose of PDR001 treatment. Adverse events (including lab abnormalities that constitute 
AEs) should be described using a diagnosis whenever possible, rather than individual 
underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or 
symptom should be reported as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study (but is collected as a seriousness 
criterion); rather, information about deaths will be collected through a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 


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6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1. 
and which seriousness criteria have been met. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per irRC or as per RECIST), should not be reported as a serious adverse 
event. 
Adverse events separate from the progression of malignancy (example, 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 drug. 
After initiation of new post-treatment antineoplastic therapy, only AEs suspected to be related 
to study treatment will be collected in the Adverse Events CRF. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 


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8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
 Is fatal or life-threatening 
 Results in persistent or significant disability/incapacity 
 Constitutes a congenital anomaly/birth defect 
 Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
 Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
 Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
 Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event. 
Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by RECIST or 
irRC. Hospitalization due solely to the progression of underlying malignancy should NOT be 
reported as a serious adverse event. 
Clinical symptoms of progression may be reported as adverse events if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study. 
Symptomatic deterioration may occur in some patients. In this situation, progression is evident 
in the patient’s clinical symptoms, but is not supported by the tumor measurements. Or, the 
disease progression is so evident that the investigator may elect not to perform further disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made 
to document the objective progression of underlying malignancy. 
If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE. 


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8.2.2 
Reporting 
SAE collection will start upon signing the informed consent whether the patient is a screen 
failure or not. SAEs will be followed until resolution or until clinically relevant improvement 
or stabilization. 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
chemotherapy and 150 days after the patient has stopped PDR001 treatment must be reported 
to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days in Chemotherapy arm or 150 days in PDR001 
treatment period should only be reported to Novartis if the investigator suspects a causal 
relationship to the study treatment. If a patient starts a post treatment antineoplastic therapy, 
then only SAEs suspected to be related to study treatment will be reported. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
The follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or withdrew from study participation. 
Information about all SAEs (either initial or follow-up information) is collected and recorded 
within the Electronic Data Capture (EDC) system. Data are required to be entered in English 
by designated investigator site staff in the eSAE Case Report Form (CRF). The investigator 
must assess the relationship to each specific component of study treatment (if study treatment 
consists of several drugs). 
SAEs (initial and follow-up) that are recorded electronically in the EDC system should be 
entered and saved within 24 hours of awareness of the SAE. Data required for safety reporting 
will be transferred directly to the Novartis Chief Medical Office and Patient Safety (CMO&PS) 
Department. Follow-up information should be provided by updating the eSAE Case Report 
Form. 
Automatic validation procedures within the system check for data discrepancies during and 
after data entry and, by generating appropriate error messages, allow the data to be confirmed 
or corrected online by the designated investigator site staff. 
CMO&PS staff review the data entered into the eSAE CRFs for completeness and accuracy and 
instruct the site personnel to make any required corrections or additions. Queries are sent to the 
investigational site using an electronic data query. Designated investigator site staff is required 
to respond to the queries and confirm or correct the data. 
The Investigator must certify that the data entered into the electronic eSAE Report Forms are 
complete and accurate prior to database lock. After database lock, the investigator will receive 
copies of the eSAE data for archiving at the investigational site. 
The paper SAE Form may also be used in case of technical emergencies in order to report an 
SAE within 24 hours. As soon as the technical issues are overcome, the SAE should also be 


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entered via the eSAE CRF. The paper SAE Form may also be used for all new and follow up 
cases at the request of Novartis. 
If the SAE is not previously documented in the [PDR001 Investigator’s Brochure] or Package 
Insert (new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis 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 drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
8.3 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 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. After the mother has provided consent, the newborn will be 
followed-up for 12 months. 
When pregnancy occurs in a patient in the study, as general rule the study drug must be 
discontinued, though the patient may stay in the study and follow the assessments, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The patient may continue all other protocol assessments. In exceptional cases, such as a women 
responding to the lifesaving treatment, the study drug can be continued. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS Department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to the 
investigational treatment and any pregnancy outcome. Any SAE experienced during pregnancy 
must be reported on the SAE Report Form. 
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. 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 


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8.5 
Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will not be formed for this open-label 
phase II study. Individual patient data will be reviewed on an ongoing basis and aggregate safety 
data and the primary endpoint will be monitored quarterly by the study team across the duration 
of the trial based on the available data in the clinical database. 
The data will be discussed with investigators in teleconferences, if deemed needed by the 
Novartis team. In case of having sufficient evidence of lack of efficacy for the study drug, 
Novartis and the investigator parties must reach a consensus on whether to terminate further 
patient enrolment in the treatment group. 
8.6 
Steering Committee 
A Steering Committee constituted of members of the Translational Clinical Oncology 
Leadership Team will be formed for this study. If the monitoring of the study data requires a 
decision to be taken on the continuation of the study, then the relevant data (e.g., safety data or 
primary analysis and predictive probability of success (PPOS)) will be communicated to the 
Steering Committee for decision making purposes. 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
 What protected health information (PHI) will be collected from patients in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 


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place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, administered, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
PK and biomarker (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by a Novartis designated 
laboratory, contracted central laboratories, or local laboratories. ECG data collected during the 
study will be reviewed and processed centrally by a specialist CRO. During the course of the 
study, Novartis may decide to have a central review of the radiological assessments performed. 
In such case, the investigator’s staff will be instructed on how to send data from these 
radiological assessments to a Contract Research Organization (CRO) for central review when 
needed. Designated investigational site staff will enter the information required by the protocol 
into the appropriate eCRF and/or designated laboratory requisition forms. Field monitors will 
review the eCRFs and laboratory paper requisition forms for accuracy and completeness and 
instruct site personnel to make any required corrections or additions. One copy of the requisition 


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form will be forwarded to each analytical laboratory with the respective sample(s) by the field 
monitor or by the designated investigational site staff; and one copy will be retained at the 
investigational site. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff is 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
Data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to Novartis before publication or 
presentation. 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized with 
respect to demographic and screening/baseline characteristics, efficacy and safety observations 
and measurements and all relevant PK and PD measurements using descriptive statistics 
(quantitative data) and contingency tables (qualitative data). 
The primary analysis of PFS will be performed for the comparison of PDR001 with the control 
arm. The cutoff date for the primary analysis is after approximately 70 PFS events have 
occurred across both of the two arms combined (approximately 114 patients randomized). This 
analysis will include the primary and selected secondary endpoints of the study, as defined in 
the RAP.  
The following rules will be followed for reporting results unless stated otherwise: data will be 
summarized and listed by study arm. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented. 
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected, Section 7.1.1, will not be 
included in any analysis, but will be reported in the CSR as separate listings. 


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The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient. Other missing data will simply be noted as missing on 
appropriate tables/listings. 
Data analysis after crossover 
For patients who crossover to PDR001 after progression as per RECIST v1.1 to chemotherapy 
in the control arm, the data will be presented in listings separately from the randomized part of 
the study. If there are at least 10 patients crossing over, summary tables may be presented with 
frequency count and percentage for categorical data and descriptive statistics for continuous 
data. For these patients, the date of their first dose of PDR001 will be used as the starting date 
to define their safety and efficacy endpoints (such as ORR, irPFS and OS). Details will be 
provided in the RAP. 
10.1 
Analysis sets 
10.1.1 
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 FAS will be the primary population for all efficacy related data analyses. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study medication and have 
at least one valid post-screening/post-baseline safety assessment. Patients will be analyzed 
according to the study treatment (regimen) they actually received. The statement that a patient 
had no AEs (on the AE eCRF) constitutes a valid safety assessment. Patients will be classified 
according to treatment received, where treatment received is defined as: 
 The treatment assigned if it was received at least once, or 
 If the assigned treatment was never received, then the first treatment received when 
starting therapy with study treatment will be used for classification 
The safety set will be the primary population for all safety related endpoints. 
A precise definition of “actually received” will be added in the Reporting and Analysis Plan 
(RAP). 
10.1.3 
Per-Protocol Set 
The Per Protocol Set (PPS) consists of a subset of FAS patients who meet the following criteria: 
 Treatment according to the randomization scheme (see Section 6). 
 Presence of at least one measurable lesion at screening/baseline according to RECIST v1.1 
as per Appendix 1. 
 At least 2 post-screening/post-baseline tumor assessments (unless disease progression is 
observed before that time). 


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 Have not been previously treated with PD-1- or PD-L1-directed therapy or any therapeutic 
cancer vaccine. 
Patients will be classified according to treatment received. 
The PPS will define the patients used in the sensitivity analysis of the primary endpoint (see 
Section 10.4.4). If the PPS and the FAS are identical, then analyses described by the PPS below 
will not be performed. 
All protocol deviations leading to exclusion from the PPS will be detailed in the RAP. 
10.1.4 
Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one dose of 
PDR001 and have at least one evaluable concentration measurement of PDR001. The PAS will 
be used for all PK analyses. 
Note: Patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of analysis along with their reason for removal. 
10.2 
Patient demographics/other screening/baseline characteristics 
Demographic and other screening/baseline data including age, gender, height, weight, medical 
condition, and disease characteristics will be summarized descriptively by treatment arm on the 
FAS. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study treatment 
The actual dose and duration in days of PDR001 and as well as the dose intensity (computed as 
the ratio of actual dose received and actual duration) and the relative dose intensity (computed 
as the ratio of dose intensity and planned dose received/planned duration), will be listed and 
summarized by means of descriptive statistics. Categories for relative dose intensity of PDR001 
will be specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and 
proportion of patients falling in each category will be presented. The summary data will be 
presented for each treatment cycle individually, as well as for all study days as a single category 
using descriptive statistics (e.g. mean, median, and modal doses). Similar analysis will be 
performed for the patients included in the control arm. 
10.3.2 
Concomitant therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug treatment will be listed by patient and summarized by ATC (anatomical therapeutic 
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10.3.3 
Compliance 
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized by treatment group/study arm. Compliance to the study drug will be assessed by 
the number of dose reductions and dose interruptions, see Section 10.5. 
10.4 
Primary objective 
The primary objective of the Phase II study is to assess any improvement in the anti-tumor 
effects of the PDR001 versus investigator’s choice of treatment in patients with moderately 
differentiated/undifferentiated locally advanced recurrent or metastatic NPC who progressed on 
or after first-line therapy. 
10.4.1 
Variable 
The primary efficacy endpoint in this study is progression-free survival (PFS) based on central 
review of tumor scan, as defined per RECIST v1.1 (Appendix 1). 
PFS is the time from the date of randomization to the date of event defined as the first 
documented confirmed progression or death due to any cause. If a patient has not had an event, 
progression-free survival is censored at the date of last adequate tumor assessment. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
Patients are randomized in 2:1 ratio into either PDR001 arm or control arm. The primary 
efficacy endpoint, PFS as determined based on the central tumor assessment per RECIST v1.1, 
will be analyzed by study arm. Assuming proportional hazards for PFS, the following statistical 
hypothesis will be tested to address the primary efficacy objective: 
H01: θ1  ≥1   vs.   HA1: θ1 < 1 
where θ1 is the PFS hazard ratio (PDR001 arm vs control arm). The analysis to test this 
hypothesis will consist of a stratified log-rank test at an overall one-sided 10% level of 
significance. The stratification factor is disease status (locally advanced recurrent NPC vs. 
metastatic NPC). 
As a supportive analysis, a Bayesian Cox proportional hazard (PH) model (see Appendix 3) 
will be used to estimate the hazard ratio for PFS between the two treatment combination arms. 
The final analysis will be performed when 70 events (progressive disease or death due to any 
cause) are observed from the study. 
An evidence-based prior for the non-parametric, interval-specific hazards of the control arm in 
the Bayesian Cox PH model is derived using available historical PFS data from the list of the 
phase II studies (see Table 1-1 and Appendix 3), using the meta-analytic-predictive (MAP) 
approach (Neuenschwander et al 2010) with the assumption of moderate/large between-trial 
heterogeneity. For more details about the model specification including the prior derivation and 
its operating characteristics please refer to Appendix 3. 
Based on the historical studies, the median PFS for the patients in the control arm is assumed 
to be 5.5 months (165 days). 


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The dual-criterion for success based on Bayesian Cox PH model is defined to show a positive 
result if there is enough evidence that monotherapy PDR001 is superior to the control with 
respect to the primary PFS endpoint, such that: 
 Posterior probability (HR > 1) < 10%, and 
 Posterior median HR < 0.7 
The posterior median of the HRs along with the associated 95% two-sided credible intervals 
will be produced for the treatment comparison of PDR001 to the control. In addition, the 
posterior probability that the true HR lies in the following intervals will be produced: 
 Substantial efficacy: [0, 0.55) 
 Moderate efficacy: [0.55, 0.7) 
 Slight efficacy: [0.7, 1) 
 No efficacy: [1, ∞) 
Moreover, Kaplan-Meier plots will be provided in order to present PFS graphical outputs for 
the PDR001 and the control arm. KM estimates of the median and PFS rates at 2, 4, 6, 8, 10 
and 12 months will be given along with 95% confidence intervals. The FAS will be used for 
the primary analysis. A stratified Cox regression model will also be used to estimate the HR of 
PFS as supplementary analysis, 
10.4.3 
Handling of missing values/censoring/discontinuations 
If a patient has not had a PFS event at the time of analysis, he/she will be censored following 
the rules defined in RECIST v1.1 (please refer to Appendix 1). 
10.4.4 
Supportive analyses 
The PPS will be used in a supportive analysis of the primary endpoint. 
Additional 
 supportive analyses will be conducted if appropriate and defined in 
the RAP. 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
Not Applicable. 
10.5.2 
Other secondary efficacy objectives 
Efficacy endpoints ORR, BOR and TTP will be also assessed. irPFS will be derived using irRC 
(Appendix 2) based on central assessments. An immune related progression disease (irPD) is 
confirmed by 2 repeated scans at least 4 weeks apart from date of first documented irPD, and 
the date of 1st scan is defined as the date of irPD. 
Individual lesion measurements, overall lesion response, duration of response (DOR), BOR, 
irPFS and OS will be listed by patient. BOR and ORR will be summarized by treatment arm 
with accompanying 95% confidence intervals. OS and DOR will be presented descriptively 
using Kaplan Meier plots. Median OS and DOR will be estimated along with 95% confidence 


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intervals. The OS rates along with 95% CIs will be provided at 6, 12, 18 and 24 months for each 
treatment arm using the Kaplan Meier distribution. A stratified Cox regression model will be 
used to estimate the HR of PDR001 arm vs. the control arm in OS and irPFS, respectively, 
along with 95% CI for HR. 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study treatment 
3. post-treatment period: starting at day 31 after last dose of study treatment. 
Safety summaries will primarily be based on all data from the on-treatment period. Following 
last administration of study treatment, adverse events (including serious adverse events), and 
new antineoplastic therapies are collected for a period of 150 days for PDR001 treatment and 
for a period of 30 days for chemotherapy. Following start of new antineoplastic therapy, only 
study treatment related adverse events will be collected. Select summaries of related adverse 
events will be produced for the combined on-treatment and post-treatment periods 
(Section 10.5.3.2). 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from 
screening/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 by treatment group. 
Deaths reportable as SAEs, and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group. 
The following summaries will be produced for the combined on-treatment and post-treatment 
periods: AEs related to the study treatment by preferred term; SAEs related to the study 
treatment by preferred term; AEs of special interest related to the study treatment. 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by CTCAE version 4.03, the study’s biostatistical and reporting 
team will grade laboratory data accordingly. For laboratory tests covered by CTCAE, a Grade 
0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. 


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For laboratory tests where Grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
If the lower limits of normal ranges used in CTCAE definitions are missing, then they have to 
be replaced by a clinical meaningful limit. 
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests: 
 Frequency table for newly occurring on-treatment Grades 3 or 4. 
 Shift tables using CTCAE Grades to compare screening/baseline to the worst on-treatment 
value. 
 For laboratory tests where CTCAE Grades are not defined, shift tables using the 
low/normal/high/ (low and high) classification to compare screening/baseline to the worst 
on-treatment value. 
Listing of all laboratory data with values flagged to show the corresponding CTCAE Grades 
and the classifications relative to the laboratory normal ranges. 
 
 
 
10.5.3.4 Other safety data 
Any other safety information collected will be listed and notable values will be flagged. Any 
statistical tests performed to explore the data will be used only to highlight any interesting 
comparisons that may warrant further consideration. Additionally, the following outputs will 
be produced: 
ECG (patients in PDR001 arm) 
 Shift table screening/baseline to worst on-treatment result for overall assessments. 
 Listing of ECG evaluations for patients treated with PDR001 with at least one 
abnormality. 
Vital signs 
Definitions of notably abnormal results have to be part of the CDP, MAP, CSP and RAP. 
 shift table screening/baseline to worst on-treatment result. 
 table with descriptive statistics at screening/baseline, one or several post-
screening/post/baseline time points and change from screening/baseline to this/these post-
screening/post-baseline time points. 
10.5.3.5 Supportive analyses for secondary objectives 
Any supportive analyses that are considered appropriate for secondary variables will be 
described in the RAP prior to database lock. 


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10.5.3.6 Tolerability 
Tolerability of study treatment will be assessed by summarizing the number of treatment dose 
interruptions and dose reductions. Reasons for dose interruptions and dose reductions will be 
listed by patient and summarized. Cumulative dose, dose intensity and relative dose intensity 
of PDR001 will be listed by patient and summarized. 
10.5.4 
Pharmacokinetics (patients in PDR001 arm) 
The pharmacokinetic parameters that may be assessed are presented in Table 10-1. PK 
parameters will be determined for all PK-evaluable patients by non-compartmental method(s) 
using Phoenix (Pharsight, Mountain View, CA). PK parameters listed in Table 10-1 will be 
calculated and reported, when feasible for PDR001. Concentrations will be summarized by time 
and in each treatment arm. 
Table 10-1 
Noncompartmental pharmacokinetic parameters 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time 
x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives 
CL 
The total body clearance of drug from the plasma (volume x time-1) 
Vz 
The apparent volume of distribution during terminal phase (associated with z) 
(volume) 
PAS will be used in all pharmacokinetic data analysis and PK summary statistics, as appropriate. 
Pharmacokinetic variables: 
The following pharmacokinetic parameters may be determined by profile using non-
compartmental method(s) for PDR001: 
 AUCinf, AUC0-last, Cmax, Tmax, T1/2, CL and Vz. 
Biofluid concentrations will be expressed in mass per volume units. All concentrations below 
the lower limit of quantitation (LLOQ) or missing data will be reported as such in the 
concentration data listings. Concentrations below the limit of quantitation will be treated as zero 
in summary statistics. 
Descriptive statistics of all pharmacokinetic parameters may include arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will 
not be included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges may be given for this parameter. 


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Summary statistics will be presented for PDR001 serum concentrations at each scheduled time 
point. Descriptive graphical plots of individual serum concentration versus time profiles and 
mean concentration versus time profiles will be generated. 
Further analyses may be conducted using population PK approaches. In addition, a model based 
approach may be used to explore the potential relationship between efficacy, safety, and/or 
biomarker endpoints and PDR001 concentration and/or exposure metrics. Any analyses 
performed will be specified either in the RAP prior to clinical database lock or in a stand-alone 
analysis plan document. All analyses will be reported either in the CSR or a stand-alone report. 
10.5.4.1 Data handling principles 
Missing concentration values will be reported as is in data listings. Concentration values below 
LLOQ will be handled as zero in summary statistics, and reported as is in data listings. Any 
missing pharmacokinetic parameter data will not be imputed. 
10.5.5 
Immunogenicity – exposure and/or adverse event relationship 
Immunogenicity data may be analyzed for patients in PDR001 arm. Listing of immunogenicity 
evaluations will be provided. 
The concentration/adverse event – immunogenicity relationship may be explored graphically, 
tabulated and if appropriate, evaluated by a mixed effects model in order to characterize a 
relationship between the changes from screening/baseline immunogenicity presence and serum 
concentration of PDR001. 
In addition, the potential correlation between immunogenicity and other endpoints (major safety, 
efficacy and biomarker parameters) may be evaluated. This may be done in two steps. First, a 
descriptive analysis may be performed graphically between immunogenicity change from 
screening/baseline values and major safety, efficacy, and biomarker parameters (either as 
categories or continuous variables). 
 
 
 
 
 
 
 
 
10.5.6 
Biomarkers in plasma and in tumor (patients in PDR001 arm) 
PD markers in plasma 
Pharmacodynamic markers, including soluble ligands and cytokine levels (e.g. IFN-γ, TNF-α, 
IL-6) will be assessed using plasma samples on-treatment (between C1D1 and C2D15) and at 
End of Treatment. Assessments will be listed by patient and summarized (when sample size is 
sufficient) using descriptive statistics. Any association/correlation analyses with other 
endpoints (PK, early clinical activity) will be detailed in the RAP. 
PD markers in tumor 
Pharmacodynamic markers, including CD8, Foxp3, TIL counts, RNA expression of immune-
related genes, and protein expression of immune-related markers (e.g. IFN-γ) will be assessed 
using paired tumor samples at screening/baseline and on-treatment (between C3D1 and End of 
treatment). Assessments at screening/baseline and on-treatment and change from baseline will 
be listed by patient and summarized (when sample size is sufficient) using descriptive statistics. 


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Any association/correlation analyses with other endpoints (PK, early clinical activity) will be 
detailed in the RAP. 
PD-L1 and potential predictors of efficacy in tumor 
The expression levels of PD-L1, LAG-3 and TIM-3, at screening/baseline will be listed and 
summarized. The correlation between baseline PD-L1 expression and anti-tumor activity will 
be explored. Statistical analyses to assess the relationship between biomarker endpoints (PD-
L1, LAG-3, TIM-3) and clinical endpoints (e.g. ORR, PFS) will be described in the RAP. All 
other biomarker data will be listed or summarized as appropriate. 
10.7 
Interim analysis 
No formal interim analyses are planned. 
10.8 
Sample size calculation 
Assuming a 2:1 randomization ratio of PDR001 vs. Comparator, 70 events (PD or death) are to 
be observed in the randomized Phase II to provide 85% power to detect a 0.55 hazard ratio in 
terms of PFS (corresponding to a median PFS of 10 months in PDR001 group and 5.5 months 
in the Comparator group), using a log-rank test at a 1-sided significance level of 0.1. 
The final primary analysis of PFS will be done using a Bayesian proportional hazard model 
when there are at least 70 events observed. Based on the simulation results under different 
scenarios (see Appendix 3), 70 events provide reasonable operating characteristics in terms of 
the probability of obtaining a positive result (as defined in Section 10.4.2). Using the Bayesian 


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Cox PH model with mixture MAP prior for the yields reasonable 1-sided type I error (0.081) 
assuming no efficacy (HR=1) and power (0.92) assuming substantial efficacy (HR=0.55) when 
current data is in alignment with historical data. 
Considering a uniform recruitment time of about 14 months and a 15% drop out rate at 12 
months, approximately 114 patients need to be randomized in a 2:1 ratio to the two arms in 
order to observe 70 events after approximately 6 months follow up (approximately 20 months 
after FPFV): 
 76 patients to the PDR001 arm 
 38 patients to the control arm 
EAST® trial design software v5.4 is used to compute the sample size. 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form. 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 


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documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their eCRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 
 
 
 
 
 
 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 7.1.3 and 
Section 4.3. 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical trials involving 
pediatric patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 


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As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of Novartis and regulatory agencies to 
examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The electronic study case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
eCRF should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic eCRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper eCRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Novartis provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 


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


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13 
References (available upon request) 
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Herbst RS, Soria JC, Kowanetz M, et al (2014) Predictive correlates of response to the anti-
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Rosenblatt, J, Glotzbecker B, Mills H, et al (2011) PD-1 blockade by CT-011, anti-PD-1 
antibody, enhances ex vivo T-cell responses to autologous dendritic cell/myeloma fusion 
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Zhang L, Zhang Y, Huang PY, et al (2008) Phase II clinical study of gemcitabine in the 
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14 
Appendices 
14.1 
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival and Overall 
Survival (based on RECIST 1.1) 
Harmonization of Efficacy Analysis of Solid Tumor Studies 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.1: 
29-Nov-2011 
Version 3:0: 
19-Oct-2009 
Version 2:0: 
18-Jan-2007 
Version 1:0: 
13-Dec-2002 
Release date: 
29-Nov-2011 
 
List of Contributors 
Authors (Version 3.1): 
 
 
Authors (Version 3): 
 
 
Authors (Version 2): 
 
 
Authors (Version 1): 
 


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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
LPLV 
Last patient last visit 
MRI 
Magnetic resonance imaging 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PR 
Partial response 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
Stable disease 
SOD 
Sum of Diameter 
TTF 
Time to treatment failure 
TTP 
Time to progression 
UNK 
Unknown 


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14.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming. 
14.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247. 
14.1.2.1 Definitions 
14.1.2.1.1 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
 Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 14.1.3.2.8. 
Measurable lesions (both nodal and non-nodal) 
 Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
 Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability. 
 Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease. 


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 Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
 Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with  
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
14.1.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 14.1.3.2.8. 
14.1.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
 All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
 Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
 For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 


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 A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from 
the investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information. 
 FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
 No FDG-PET at baseline with a positive FDG-PET at follow-up: 
 If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
 If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan). 
 If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD. 
 Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
 Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination. 
 Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when tumor 
samples are obtained. 
 Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared. 


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 Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
 Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
14.1.2.3 Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
 Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
 Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.2.1.1. 
 Nodal target: See Section 14.1.2.1.1. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 
 Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 


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14.1.2.4 Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions. 
14.1.2.4.1 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number. 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated. 
Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 


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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination. 
14.1.2.4.2 
Determination of target lesion response 
Table 14-1 
Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any 
pathological lymph nodes assigned as target lesions must have a 
reduction in short axis to < 10 mm 1 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease 
(PD): 
At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline. In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm.2 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in 
lesions which would qualify for PD. 
Unknown (UNK) 
Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a different 
method than baseline.3 
1. SOD for CR may not be zero when nodal lesions are part of target lesions 
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present 
and all nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3. Methodology change See Section 14.1.2.2. 
Notes on target lesion response 
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following three 
possibilities: 
 The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease 
 The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will 
be determined if there is at least 20% increase in the sum of diameters of all measured 
target lesions, taking as reference the smallest sum of diameters of all target lesions 
recorded at or after baseline with at least 5 mm increase in the absolute sum of the 
diameters). Proper documentation should be available to support this decision. This 


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applies to patients who have not achieved target response of CR. For patients who have 
achieved CR, please refer to last bullet in this section. 
 For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
 Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
 Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes. 
 Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation. 
 Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
 The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
 Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared. 
 Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
 Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 


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14.1.2.4.3 
Determination of non-target lesion response 
Table 14-2 
Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes 
assigned a non-target lesions must be non-pathological in size (< 10 mm 
short axis) 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target 
lesions have not been assessed or have been assessed using a different 
method than baseline. 
1. Although a clear progression of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician does prevail and the progression status should be confirmed later on 
by the review panel (or study chair). 
Notes on non-target lesion response 
 The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e.  10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD). 
 Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 
14.1.2.4.4 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF. 


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 If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion 
 If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.2.5). 
 A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to  10 mm for the first time in the study plus 5 
mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.2.2. 
14.1.2.5 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in Table 14-3. 
Table 14-3 
Overall lesion response at each assessment 
Target lesions 
Non-target lesions 
New Lesions 
Overall 
lesion response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD3 
No 
PR 
CR, PR, SD 
UNK 
No 
UNK 
PR 
Non-PD and not UNK 
No 
PR1 
SD 
Non-PD and not UNK 
No 
SD1, 2 
UNK 
Non-PD or UNK 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1. This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2. Once confirmed PR was achieved, all these assessments are considered PR. 
3. As defined in Section 14.1.2.4. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR. 


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14.1.3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
14.1.3.1 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
 For non-randomized trials where response is the primary endpoint, confirmation is needed. 
 For trials intended to support accelerated approval, confirmation is needed 
 For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
 CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
 PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required 
 SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR). 
 PD = progression  12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD). 


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 UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks) 
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
 Investigator overall lesion response 
 Central Blinded Review overall lesion response 
 Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of investigator 
overall lesion responses. 
Based on the patients’ best overall response during the study, the following rates are then 
calculated: 
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications. 


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Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. 
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used: 
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment. 
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach). 
14.1.3.2 Time to event variables 
14.1.3.2.1 
Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
14.1.3.2.2 
Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
14.1.3.2.3 
Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 


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Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 
14.1.3.2.4 
Time to treatment failure 
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease. 
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment. 
14.1.3.2.5 
Duration of response 
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988). 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression. 


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The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen. 
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression. 
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression. 
14.1.3.2.6 
Time to response 
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed. 
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options. 
 at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
 at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
14.1.3.2.7 
Definition of start and end dates for time to event variables 
Assessment date 
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number. 


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Start dates 
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date. 
For the calculation of duration of response the following start date should be used: 
 Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed. 
End dates 
The end dates which are used to calculate ‘time to event’ variables are defined as follows: 
 Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page). 
 Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease. 
 Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. 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 tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
 Date of discontinuation is the date of the end of treatment visit. 
 Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
 Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
14.1.3.2.8 
Handling of patients with non-measurable disease only at baseline 
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations. 


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It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints. 
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4. 
Table 14-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 14.1.2.4. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
14.1.3.2.9 
Sensitivity analyses 
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed. 


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Based on definitions outlined in Section 14.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics-April 2005) 
as a reference, the following analyses can be considered: 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified 
differently in the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of 
treatment3 
Censored 
B 
Progression at or before next 
scheduled assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 
Progression or death after exactly 
one missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 
Progression or death after two or 
more missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
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 
Progressed 
F 
New anticancer therapy given 
(1) Date of last adequate assessment 
(2) Date of secondary anti-cancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) N/A 
Censored 
Censored 
Event 
Ignored 
G 
Deaths due to reason other than 
deterioration of ‘Study indication’ 
(1) Date of last adequate assessment 
Censored 
(only TTP 
and duration 
of response) 
1.=Definitions can be found in Section 14.1.3.2.7. 
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.1.3.2.7. 
3.=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 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. 


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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 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: 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 tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 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 tumor 
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 tumor 
assessment. 
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation. 
14.1.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
14.1.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 


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14.1.4.2 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
The end of treatment visit and its associated assessments should occur within 14 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons: 
 Adverse event(s) 
 Lost to follow-up 
 Physician decision 
 Pregnancy 
 Protocol deviation 
 Patient/guardian decision 
 Death 
 Progressive disease per irRC (not per RECIST) 
 Study terminated by Novartis 
14.1.4.3 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
 Adverse event 
 Lost to follow-up 
 Physician decision 
 Pregnancy 
 Protocol deviation 
 Technical problems 
 Patient/guardian decision 
 Death 
 New therapy for study indication 
 Progressive disease 
 Study terminated by Novartis 
14.1.4.4 Medical validation of programmed overall lesion response 
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 


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assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, data 
review reports will be available to identify assessments for which the investigators’ or central 
reader’s opinion does not match the programmed calculated response based on RECIST criteria. 
This may be queried for clarification. However, the investigator or central reader’s response 
assessment will never be overruled. 
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data. 
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation. 
14.1.4.5 Programming rules 
The following should be used for programming of efficacy results: 
14.1.4.5.1 
Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
14.1.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.3.2.7). 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. 
14.1.4.5.3 
Incomplete dates for last known date patient alive 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. 


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14.1.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
14.1.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
14.1.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
 Alive 
 Lost to follow-up 
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible: 
 Ongoing without event 
 Lost to follow-up 
 Withdrew consent 
 Adequate assessment no longer available* 
 Event documented after two or more missing tumor assessments (option 
 Death due al, see Table 14-5) to reason other than underlying cancer (only used for TTP 
and duration of response) 
 Initiation of new anti-cancer therapy 
*Adequate assessment is defined in Section 14.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 


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 This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Novartis decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
 The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
 This reason will also be used to censor in case of no baseline assessment. 
14.1.5 
References (available upon request) 
Dent S, et al (2001) Application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791. 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer; Vol.45: 228-47. 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465. 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007. 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18. 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16. 


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14.2 
Appendix 2: Guidelines for immune-related Response Criteria 
(irRC) using one-dimensional measurements (simulating RECIST 
1.1) 
14.2.1 
Introduction 
The currently used immune-related response criteria (irRC) uses unidimensional measurements 
to assess tumor response and it is an adaptation of the original irRC published by Wolchok 
(Wolchok et al 2009, Nishino 2013). 
The purpose of this document is to summarize the irRC guidelines in details focusing on 
differences in tumor response assessments between irRC and RECIST v1.1. 
The primary difference between irRC and RECIST 1.1 is the definition of progressive disease. 
The definitions of baseline target/non target lesions, number of lesions selected at baseline, the 
criteria for lesion measurement method of evaluation of response and definition of response are 
the same for irRC and RECIST 1.1 and are available in the RECIST 1.1 guidelines (Appendix 
1). 
14.2.2 
New lesions and non-target lesions 
In irRC a new lesion does not automatically indicate progressive disease. 
New measurable lesions are added to the sum of diameters of the previously existing target 
lesions, and the sum of diameters is followed at each subsequent tumor assessment. 
New measureable lesions are defined using the same criteria as for baseline target lesions in 
RECIST v1.1. New measurable lesions shall be prioritized according to size, and the largest 
lesions shall be selected as new measured lesions up to 10 lesions in total. 
Non-target lesions (baseline and new non-measurable lesions) are used primarily for 
determination of Complete Response (CR). The RECIST v1.1 definitions for the assessment of 
non-target lesions apply. A CR requires that all non-target lesions disappear (both those present 
at baseline and any new non-measurable lesions that have appeared during the study). If after 
worsening a non-target lesion becomes measurable, it should still be followed as a non-target 
lesion. Worsening of non-target lesions and new non-measurable lesions only indicate disease 
progression if there is unequivocal evidence of disease progression (Table 14-6). 
14.2.3 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions is calculated (at baseline 
and throughout the study). The diameters of any new measurable lesions are included in the 
sum of diameters at each assessment to provide the total tumor burden. At each assessment, 
percent change in the sum of diameters is calculated and compared to baseline or to nadir in 
order to evaluate the target lesion response (including new measurable lesions) (Section 14.2.4). 
This evaluation combined with the status of non-target lesions (baseline and new non-
measurable lesions) is then used to determinate the overall lesion response (Table 14-6). The 
thresholds for irPR and irPD assessment are the same as for RECIST v1.1. 


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14.2.4 
Definitions of response categories and evaluation of overall lesion 
response 
In irRC, the overall response is primarily based on target lesions (baseline and new measurable 
lesions). The non-target lesions only contribute to define irCR, and irPD in the case of 
unequivocal progression, as shown below in Table 14-6. 
Like in RECIST 1.1, irCR and irPR must be confirmed at a new assessment after at least 4 
weeks. Unlike RECIST 1.1, irPD also requires confirmation at a new assessment after at least 
4 weeks. 
The response categories are defined as follows: 
 Immune related Complete Response (irCR): Disappearance of all non-nodal target 
lesions and non-target lesions in two consecutive observations not less than 4 weeks apart. 
In addition, any pathological lymph nodes assigned as target lesions must have a reduction 
in short axis to < 10 mm. (Sum of diameters may be greater than zero at the time of CR, if 
nodal lesions are included as target lesions). 
 Immune related Partial Response (irPR): At least a 30% decrease in the sum of 
diameters of all target lesions including new measurable lesions in two consecutive 
observations not less than 4 weeks apart, taking as reference the baseline sum of 
diameters. 
 Immune related Progressive Disease (irPD): At least a 20% increase in the sum of 
diameters of all measured target lesions including new measurable lesions. The irPD must 
be confirmed in a second evaluation not less than 4 weeks later, taking as reference the 
smallest sum of diameter of all target lesions recorded at or after baseline (nadir). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. Worsening of non-target lesions (existing or new) only indicate 
PD when there is unequivocal evidence of progression, confirmed in a second evaluation 
not less than 4 weeks later. 
 Immune related Stable Disease (irSD): Neither a sufficient shrinkage to qualify for irPR 
or irCR, nor an increase in lesions which would qualify for irPD. 
 Unknown (UNK): Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a method significantly different from 
baseline that prevents reasonable comparison to the prior assessments. 
Table 14-6 
Overall response at each assessment 
Target and new measurable 
lesions (Tumor burden), * (%) 
Non-target lesions 
(both baseline and new non-measurable) 
Overall 
lesion response 
- 100 
Absent 
irCRa 
- 100 
Stable/not evaluated 
irPRa 
≤-30 
Absent/Stable/not evaluated 
irPRa 
>-30 and<+20 
Absent/Stable/not evaluated 
irSD 
≥+20 
Any 
irPDa 
Any 
Unequivocal progression 
irPDa 
*the diameter of new measurable lesions is included in the calculation of the sum of diameters. 
a To be confirmed after at least 4 weeks. 


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If the evaluation of any of the target lesions could not be made during follow-up, the overall 
status must be ‘unknown’ unless progression was documented. 
If the evaluation of any non-target lesions is not made, and all target lesions disappeared, irCR 
cannot be determined and overall response must be “irPR”. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the irCR. 
14.2.5 
References (available upon request) 
Nishino M, Giobbie-Hurder A, Gargano M, et al (2013) Developing a Common Language for 
Tumor Response to Immunotherapy: Immune-Related Response Criteria Using 
Unidimensional Measurements. Clin Cancer Res; 19:3936-3943. 
Wolchok JD, Hoos A, O'Day S, et al (2009) Guidelines for the Evaluation of Immune 
Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res; 
15:7412-20. 


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14.3 
Appendix 3: Bayesian Cox proportional hazards model with 
meta-analytic-predictive prior and operating characteristics of 
the design 
14.3.1 
Introduction 
In the following, the statistical model and prior distributions for the Bayesian Cox proportional 
hazard (PH) model will be described. We consider here the use of historical data of the same 
patient population (with moderately differentiated/undifferentiated, locally advanced recurrent 
or metastatic NPC) to enrich control arm. 
14.3.1.1 Model specification 
The primary analysis of progression free survival (PFS) will be based on a Bayesian Cox PH 
model. This model will be used to estimate the hazard ratio for PFS of PDR001 vs. SOC. This 
model assumes that the hazard function of individual in treatment group i (PDR001 or SOC) 
can be expressed as; 
 
Here λ0 (t) is the baseline hazard (or hazard for SOC), Xi indicates the treatment group 
membership (0 for SOC and 1 for PDR001) and  denotes the log hazard ratio (HR) between 
PDR001 group and the SOC group. Furthermore baseline or SOC group hazard function λ0 (t) 
is modeled via a piece-wise exponential model. This is a semi-parametric model which 
subdivides time into reasonably small K intervals and assumes that the baseline hazard is 
constant in each interval. i.e., 
 
Note that the λCk refer to hazard for unit time (per day). Sampling model (or likelihood) under 
this framework can be constructed using Binomial distribution. In this model for each of the K 
time intervals, the number of events in the SOC group (rCk) and PDR001 group (rTk) follow 
Binomial distributions with interval-specific hazards λCk. Under the proportional hazards 
assumption it follows that 
 
SOC data: 
rCk ~ Binomial(nCk, 
 
PDR001 data: 
rTk ~ Binomial(nTk, 
) 
where nCk and nTk are risk sets for event in the SOC and PDR001 groups, respectively, in 
interval (Ik-1, Ik] and Lk is the length of the k-th interval. 
The study plans to enroll approximately 114 patients to accrue 70 events for the primary 
analysis of PFS endpoint. This study will be considered successful if there is sufficient evidence 
that the monotherapy of PDR001 is superior to SOC in PFS based on the evaluation criteria, 
i.e.: 
 Posterior probability (HR>1) < 10%, and 
 Posterior mean HR<0.7. 


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14.3.1.2 Prior distribution 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
In this section we illustrated the specification of informative prior for interval specific hazards 
(λk‘s) using relevant data for SOC from publications and non-informative prior for log hazard 
ratio (β). 
14.3.1.2.1 
Prior for log hazard ratio (β) 
The prior distribution for the log hazard ratio  was assumed non-informative,  ~ N(mean=0, 
sd=10). 
14.3.1.2.2 
Prior derivation for interval specific hazard (λk ‘s) 
A robust mixture prior will be used for interval specific hazards (λk‘s). An evidence-based prior 
for the interval-specific hazards of the controls in the Bayesian Cox PH model is derived using 
a robust meta-analytic-predictive (MAP) approach (Neuenschwander et al 2010; Schmidli et al 
2014). The robust prior is a mixture prior with two components. The first component, derived 
from historical data, is a meta-analytic-predictive (MAP) prior (MAP component). The second 
component of the mixture prior (Weakly informative component) ensures further robustness 
against prior-data conflict to the control in the current trial. 
 MAP component: Obtained from the published Kaplan Meier (KM) curves of 7 published 
studies using the meta-analytic predictive (MAP) approach. 
 Weakly informative component: Reflecting the historical hazard rate for the controls but 
allowing for considerable prior uncertainty to handle possible prior-data conflict to the 
control arm in the current trial. 
Further details are provided below. 
MAP component 
PFS data for SOC from 7 published studies were used to derive prior for interval specific 
hazards using MAP approach (Neuenschwander et al 2010). Table 14-7 provides the historical 
data from the 7 studies of SOC treated in a total of 212 patients. These 7 trials were chosen from 
the 11 historical studies listed in Table 1-1 of the study protocol for deriving the MAP prior. 
The other 6 trials were not used since the KM plots (estimates) were not available as required 
by the MAP approach. 


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Table 14-7 
Historical PFS data from 7 studies 
Chua et al (2003). 
Time 
(days) 
Prob. of remaining 
progression free 
# patients at risk 
# patients censored 
# events 
0 
1 
17 
 
 
30 
0.76 
13 
0 
4 
60 
0.70 
12 
0 
1 
90 
0.64 
11 
0 
1 
120 
0.59 
10 
0 
1 
150 
0.47 
8 
0 
2. 
180 
0.35 
6 
0 
2 
240 
0.21 
4 
0 
2 
300 
0.21 
4 
0 
0 
360 
0.21 
4 
0 
0 
Foo et al (2002). 
Time 
(days) 
Prob. of remaining 
progression free 
# patients at risk 
# patients censored 
# events 
0 
1 
27 
 
 
30 
0.96 
26 
0 
1 
60 
0.88 
24 
0 
2 
90 
0.85 
23 
0 
1 
120 
0.77 
21 
0 
2 
150 
0.53 
14 
0 
7 
180 
0.39 
10 
0 
4 
240 
0.28 
8 
0 
2 
300 
0.12 
3 
1 
4 
360 
0.12 
3 
0 
0 
Ngeow et al (2011). 
Time 
(days) 
Prob. of remaining 
progression free 
# patients at risk 
# patients censored 
# events 
0 
1 
30 
 
 
30 
0.96 
29 
0 
1 
60 
0.67 
20 
0 
9 
90 
0.64 
19 
0 
1 
120 
0.53 
16 
0 
3 
150 
0.50 
15 
0 
1 
180 
0.40 
12 
0 
3 
240 
0.11 
3 
0 
9 
300 
0.07 
2 
0 
1 
360 
0 
0 
0 
2 


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Peng et al (2013). 
Time 
(days) 
Prob. of remaining 
progression free 
# patients at risk 
# patients censored 
# events 
0 
1 
48 
 
 
30 
1 
48 
0 
0 
60 
1 
48 
0 
0 
90 
0.98 
47 
0 
1 
120 
0.88 
42 
0 
5 
150 
0.77 
37 
0 
5 
180 
0.38 
18 
0 
19 
240 
0.03 
1 
0 
17 
300 
0.03 
1 
0 
0 
360 
0.03 
1 
0 
0 
Poon et al (2005). 
Time 
(days) 
Prob. of remaining 
progression free 
# patients at risk 
# patients censored 
# events 
0 
1 
28 
 
 
30 
1 
28 
0 
0 
60 
0.58 
16 
0 
12 
90 
0.53 
15 
0 
1 
120 
0.40 
11 
0 
4 
150 
0.26 
7 
0 
4 
180 
0.11 
3 
0 
4 
240 
0.11 
3 
0 
0 
300 
0.05 
2 
0 
1 
360 
0.003 
0 
1 
1 
Wang et al (2006). 
Time 
(days) 
Prob. of remaining 
progression free 
# patients at risk 
# patients censored 
# events 
0 
1 
39 
 
 
30 
0.95 
37 
0 
2 
60 
0.85 
33 
0 
4 
90 
0.80 
31 
0 
2 
120 
0.69 
27 
0 
4 
150 
0.56 
22 
0 
5 
180 
0.46 
18 
0 
4 
240 
0.38 
15 
0 
3 
300 
0.28 
11 
0 
4 
360 
0.18 
7 
0 
4 


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Zhang et al (2008). 
Time 
(days) 
Prob. of remaining 
progression free 
# patients at risk 
# patients censored 
# events 
0 
1 
32 
 
 
30 
0.99 
32 
0 
0 
60 
0.79 
25 
1 
6 
90 
0.66 
21 
0 
4 
120 
0.52 
17 
0 
4 
150 
0.52 
17 
0 
0 
180 
0.37 
12 
0 
5 
240 
0.15 
5 
0 
7 
300 
0.07 
2 
0 
3 
360 
0.01 
0 
0 
2 
In each of the 9 time intervals of the 7 historical trials, the number of events in the SOC group 
follows a Binomial distribution with interval-specific SOC hazards hCk h=1,2,…7 (as stated in 
previous section): 
Historical SOC data: rhCk ~ Binomial(nhCk, 
), 
The meta-analytic-predictive prior for the log-hazards log(*Ck) of the SOC arm in the current 
trial is obtained by analyzing the historical SOC data and using predictive distribution. The key 
assumption of this approach is similarity (not equality) of time-specific hazards in historical 
and current studies, hCk and *Ck, h= 1,..7 and k=1,…9. The degree of similarity is formally 
expressed via exchangeability (Spiegelhalter 2004) i.e. 
log(1Ck), ……, log(7Ck), log(*Ck) ~ Normal(k,2). 
with population mean μk and between-trial standard deviation  for the log-hazards for the k-th 
time interval in the SOC group. After considering the clinical context such that unrealistically 
large values of τ ( eg., > 1) have small probability (eg., 5%), it was decided to assume the degree 
of similarity as 
 
 ~ log-normal(mean=log(0.5), sd=0.354) 
This prior distribution has median 0.5, which amounts to moderate to large heterogeneity, and 
95% probability interval (0.25,1.00), which covers a range of moderate to large heterogeneity 
(Spiegelhalter et al 2003). 
Moreover in order to explore the related structure we modeled each k by relating to 
neighboring by a k-1 linear model. The model assumes the following functional form 
 
k ~ N(ƞκ, σ2κ) 
 
ƞk = ƞk-1 + ρk-1 
k= 2, 3,……..9 
Prior for ƞ1 is assumed to be N(mean=-1.386,sd=0.353) and ρk-1 ~ N(mean=0, sd=1), and 
σ2κ= ω*0.3532 with ω ~ Uniform(0,1). This uses similar formulation as Krams et al (2005). 
As mathematical closed form are not tractable statistical inference for the log-hazards of the 
SOC group in the new trial, log(*Ck), was obtained using WinBUGS. Note that for PFS times 


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that exceed 360 days (the maximum time in the historical data set), the prior for these log-
hazards is assumed equal mean to the prior from the last available log-hazard, i.e., *C9 but 
greater standard deviation. Table 14-8 displays the prior summaries of the log-hazards (per day). 
Table 14-8 
Prior distribution of daily long-hazards 
Time interval (days) 
Log-hazards 
 
Mean 
SD 
1-30 
-6.771 
0.560 
31-60 
-5.245 
0.484 
61-90 
-6.202 
0.538 
91-120 
-5.376 
0.501 
121-150 
-5.206 
0.494 
151-180 
-4.298 
0.479 
181-240 
-4.399 
0.480 
241-300 
-5.055 
0.531 
301-360 
-4.752 
0.571 
360-420 
-4.752 
1.151 
420-480 
-4.752 
2.080 
480-540 
-4.752 
3.054 


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Figure 14-1 shows the prior progression free survival probabilities and 95% credible interval 
(dotted line). This shows that the prior median in around 5.5 months. 
Figure 14-1 
Prior distribution of corresponding progression free survival 
probabilities 
 
Weakly informative component 
When considering the use of historical controls in the current trial, a careful selection of the 
historical trials is necessary to render the exchangeability assumption for the SOC parameters 
plausible. Nevertheless, one has to acknowledge the possibility of prior-data conflict. Hence, 
we consider a robust version of the MAP prior by assuming a weakly informative prior for 
log(Ck) as N(mean=-6.771, sd=3). This allows to take into account the additional uncertainties. 
Mixture prior 
To obtain the mixture prior, 50% weight will be assigned to the MAP component, and 50% 
weight will be assigned to the weakly informative component to be more on conservative side 
to handle possible prior data conflict. 


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14.3.2 
Operating characteristics 
The purpose of this section is to present the operating characteristics of the proposed design 
under various scenarios. The data for the SOC arm are simulated such that for some scenarios 
they are in alignment with the historical control data and for the others, they are not. Ddifferent 
magnitudes of efficacy are also considered, e.g, no efficacy, moderate efficacy and substantial 
efficacy under different scenarios. Type I error rate and power for this design under different 
scenarios will be investigated as mentioned in details in the next section. 
14.3.2.1 Scenarios investigated 
In order to investigate the operating characteristics, data are simulated under the scenarios as 
described in Table 14-9. 
Table 14-9 
Different scenarios of operating characteristics simulations 
Scenario# 
Current control 
aligned with 
prior? 
Efficacy 
Magnitude 
Median PFS, 
SOC arm 
(months) 
Median PFS, 
PDR001 arm 
(months) 
True 
Hazard Ratio 
1 
Yes 
No efficacy 
5.5 
5.5 
1 
2 
Yes 
Substantial 
5.5 
10.0 
0.55 
3 
Yes 
Moderate 
5.5 
8.2 
0.67 
4 
No 
No efficacy 
7.5 
7.5 
1 
5 
No 
Substantial 
7.5 
13.6 
0.55 
6 
No 
Moderate 
7.5 
12.9 
0.67 
As shown in the Table 14-9, SOC data are simulated to be aligned with the prior for scenarios 
1-3. Ddifferent magnitudes of efficacy will be tested in these three scenarios by varying the true 
hazard ratio. For scenario 1, hazard ratio 1 means that there is no efficacy. The simulation output 
in this case provides Type I error rate. For the other two scenarios, powers are obtained. 
Similarly for scenarios 4-6, controlled data not aligned with prior are simulated and scenario 4 
is the case with no efficacy where the simulation results provides Type I error rate. 
14.3.2.2 Simulation study description 
Each of the above described scenarios is investigated based on simulated data over 1000 trials. 
The following assumptions are made in order to run these simulations: 
1. The time to event (PD or death), censoring time and accrual time are all assumed to follow 
exponential distribution. For all the above scenarios the accrual is assumed to be 8 patients 
per month. 
2. The End of Study is assumed to be at the day of 70th event. 
Simulation is performed in the following steps: 
Step 1: 
Based on the assumed distributions of time to event and accrual time, PFS data are simulated 
for patients in the PDR001 arm and SOC arm (randomization ratio 2:1) sequentially until the 
required number of events (70 events) is reached. 


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Step 2: 
The simulated data is then transformed as the number of patients at risk and number of events 
in different time intervals for each treatment group similar to historical data. But the total 
number of interval in the simulation depends on maximum event/censored time. 
Step 3: 
As mathematical closed forms are not tractable, hence, posterior distributions for the log (HR) 
from Bayesian Cox PH model are computed via MCMC combining the mixture MAP prior 
obtained from the historical data together with the simulated transformed data. 
Step 4: 
Claim positive result for the Bayesian method if Posterior median HR < 0.7 and Prob (HR>1)< 
0.1. 
Step 5: 
Repeat step 1-4 for 1000 trials. Calculate the rate of positive results for both the Bayesian design 
and the frequentist approach. 
14.3.2.3 Simulation study results 
Table 14-10 shows the operating characteristics for the six scenarios. 
Results from Table 14-10 shows that the Bayesian Cox PH model using Mixture prior yields 
reasonable 1-sided type I error (0.081-0.191) and power (0.7-0.92) under different scenarios in 
alignment between current and historical data. 
Table 14-10 
Operating characteristics for the six scenarios 
Scenario 
Median PFS SOC Arm 
(months) 
Median PFS 
PDR001 Arm 
(months) 
HR 
Type I error/Power 
Estimated 
HR 
1 
5.5 
 5.5 
1 
0.081 
0.973 
2 
5.5 
10.0 
0.55 
0.922 
0.509 
3 
5.5 
 8.2 
0.67 
0.727 
0.629 
4 
7.5 
 7.5 
1 
0.191 
0.894 
5 
7.5 
13.6 
0.55 
0.911 
0.482 
6 
7.5 
12.9 
0.67 
0.728 
0.586 


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14.3.3 
References (available upon request) 
Chua DT, Sham JS, Au GK (2003) A phase II study of capecitabine in patients with recurrent 
and metastatic nasopharyngeal carcinoma pretreated with platinum-based chemotherapy. Oral 
Oncol; 39(4):361-6. 
Foo KF, Tan EH, Leong SS, et al (2002) Gemcitabine in metastatic nasopharyngeal 
carcinoma of the undifferentiated type. Ann Oncol.; 13(1):150-6. 
Krams M, Lees KR, Berry DA (2005) The past is the future: Innovative designs in acute 
stroke therapy trials, Stroke. 36(6):1341-7. 
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials; 7:5-18. 
Ngeow J, Lim WT, Leong SS, et al (2011) Docetaxel is effective in heavily pretreated patients 
with disseminated nasopharyngeal carcinoma. Ann Oncol.; 22(3):718-22. 
Peng PJ, Ou XQ, Chen ZB, et al (2013) Multicenter phase II study of capecitabine combined 
with nedaplatin for recurrent and metastatic nasopharyngeal carcinoma patients after failure of 
cisplatin-based chemotherapy. Cancer Chemother Pharmacol.; 72(2):323-8. 
Poon D, Chowbay B, Cheung YB, et al (2005) Phase II study of irinotecan (CPT-11) as 
salvage therapy for advanced nasopharyngeal carcinoma. Cancer; 103(3):576-81. 
Schmidli H, Gsteiger S, Roychoudhury S, et al (2014) Robust meta-analytic-predictive priors 
in clinical trials with historical control information. Biometrics.;70(4):1023-32. 
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation. Chichester: Wiley. 
Spiegelhalter DJ, Best NG (2003) Bayesian approaches to multiple sources of evidence and 
uncertainty in complex cost-effectiveness modelling. Stat Med.;22(23):3687-709. 
Wang CC, Chang JY, Liu TW, et al (2006) Phase II study of gemcitabine plus vinorelbine in 
the treatment of cisplatin-resistant nasopharyngeal carcinoma. Head Neck; 28(1):74-80. 
Zhang L, Zhang Y, Huang PY, et al (2008) Phase II clinical study of gemcitabine in the 
treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-
based chemotherapy. Cancer Chemother Pharmacol.; 61(1):33-8. 


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14.4 
Appendix 4: Management algorithms 
These general guidelines for management of toxicities (Postow 2015-supplementary appendix) 
constitute guidance to the Investigator and may be supplemented by discussions with the 
Medical Monitor representing the Sponsor. The guidance applies to all immuno-oncology (I-
O) agents and regimens. 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used. 


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14.4.1 
References (available upon request) 
Postow MA, Chesney J, Pavlick AC, et al (2015) Nivolumab and ipilimumab versus 
ipilimumab in untreated melanoma. N Engl J Med.;372(21):2006-17 (supplementary 
appendix). 

SAP_003.pdf: 
Clinical Development
PDR001/ Spartalizumab
CPDR001X2201 /  NCT02605967
A phase II, open-label, randomized controlled study of 
PDR001 in patients with moderately 
differentiated/undifferentiated locally advanced recurrent 
or metastatic nasopharyngeal carcinoma who progressed 
on standard treatment
Statistical Analysis Plan (SAP)
Author:
 Statistician
Document type:
SAP Documentation for final CSR
Document status:
Final 2.0
Release date:
23-Mar-2021
Number of pages:
33
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of SAP
Version
Date
Changes
1.0
16-Feb-2021
First version of the SAP for the final CSR
2.0
23-Mar-2021
Updates implemented for the final CSR


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CPDR001X2201
Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................5
1.1
Study design.............................................................................................................5
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical Methods ..............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General definitions..................................................................................8
2.2
Analysis sets ............................................................................................................9
2.2.1
Analysis set exclusion...........................................................................10
2.2.2
Withdrawal of Informed Consent..........................................................11
2.2.3
Subgroup of interest ..............................................................................11
2.3
Patient disposition, demographics and other baseline characteristics ...................12
2.3.1
Patient disposition.................................................................................12
2.3.2
Basic demographic and background data..............................................12
2.3.3
Medical History.....................................................................................12
2.3.4
Prior antineoplastic therapy...................................................................12
2.3.5
Diagnosis and extent of cancer .............................................................12
2.4
Protocol deviations ................................................................................................12
2.5
Treatments (study treatment, rescue medication, other concomitant therapies, 
compliance)............................................................................................................13
2.5.1
Study treatment .....................................................................................13
2.5.2
Concomitant therapies...........................................................................14
2.5.3
Compliance ...........................................................................................15
2.6
Analysis of the primary objective..........................................................................15
2.6.1
Primary endpoint...................................................................................15
2.6.2
Statistical hypothesis, model, and method of analysis..........................15
2.7
Analysis of the secondary efficacy variables.........................................................15
2.8
Safety analysis .......................................................................................................17
2.8.1
Adverse events ......................................................................................18
2.8.2
Laboratory data .....................................................................................20
2.8.3
Vital signs, weight and physical examinations .....................................22
2.8.4
Electrocardiograms ...............................................................................23
2.8.5
Tolerability............................................................................................23
2.9
Pharmacokinetic data.............................................................................................24
2.9.1
Data handling principles .......................................................................24


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2.9.2
Immunogenicity ....................................................................................24
2.10
Biomarkers.............................................................................................................26
2.10.1
Introduction...........................................................................................26
2.10.2
Outline of the data analysis...................................................................27
2.10.3
Biomarker objectives ............................................................................27
2.10.4
Biomarker analysis data ........................................................................27
2.10.5
Data analysis of biomarkers..................................................................28
2.11
Patient reported outcomes......................................................................................28
29
2.13
Interim analyses.....................................................................................................29
3
Sample size calculation .....................................................................................................29
4
Change to protocol specified analyses ..............................................................................29
4.1
Planned analyses due to COVID-19......................................................................29
5
Appendix ...........................................................................................................................29
5.1
Baseline..................................................................................................................29
5.2
Handling of missing and partial dates ...................................................................30
5.3
Construction of waterfall graphs ...........................................................................32
6
References .........................................................................................................................32


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CPDR001X2201 that will be presented in the final Clinical Study Report 
(CSR). The output shells (in-text and post-text) accompanying this document can be found in
the TFL shells document. The specifications for derived variable and datasets can be found in 
the Programming Datasets Specifications (PDS) document.
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend.
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., IB updates, abstracts, posters, presentations,
manuscripts and management updates. Data used for these analyses will have a status aligned 
to the database lock guidance.
1.1
Study design
This is an open-label, multi-center, randomized, controlled phase II study to evaluate the 
efficacy and safety of PDR001 versus investigator’s choice of treatment in patients with 
moderately differentiated/undifferentiated locally advanced recurrent or metastatic NPC who 
progressed on or after first-line treatment. Approximately 114 patients will be randomized with 
a 2:1 randomization ratio of investigational arm (PDR001) vs. control arm (chemotherapy). The 
randomization will be stratified by disease status (locally advanced recurrent NPC vs. metastatic 
NPC). Patients in the control arm will be allowed to crossover to PDR001 treatment if they have 
radiological progression (per RECIST v1.1) documented by an independent central review and 
discussed with Novartis. The study design is summarized in Figure 1-1.


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Figure 1-1
Study Design
*Patients treated with PDR001 will continue treatment until confirmed PD as per irRC. 
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To assess the efficacy of PDR001
versus investigator’s choice of 
chemotherapy in patients with 
moderately 
differentiated/undifferentiated locally 
advanced recurrent or metastatic NPC 
who progressed on or after first-line 
therapy
Progression free survival (PFS) as per RECIST 
v1.1 using central assessment
Section 2.6
Secondary
To evaluate the anti-tumor activity of 
PDR001 versus investigator ‘choice of 
chemotherapy in patients with 
moderately 
differentiated/undifferentiated locally 
advanced recurrent or metastatic NPC 
who progressed on or after first-line 
therapy
Overall survival (OS), overall response rate 
(ORR), duration of response (DOR), time to 
progression (TTP) and immune related 
progression free survival (irPFS) as per irRC 
using central assessment
Section 2.7
To characterize the safety and 
tolerability of PDR001
Safety: Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), 
including changes in laboratory parameters, vital 
signs and electrocardiograms (ECGs)
Section 2.8


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Objective
Endpoint
Analysis
To characterize the pharmacokinetic 
profile of PDR001 (patients in PDR001 
arm)
Serum PK parameters (e.g. AUC, Cmax, Tmax, 
half-life); Serum concentration vs. time profiles
Section 2.9
To assess emergence of anti-PDR001 
antibodies following one or more 
intravenous (i.v.) infusions of PDR001
(patients in PDR001 arm)
Presence and/or concentration of anti-PDR001 
antibodies
Section 2.10
To assess potential predictive markers 
of efficacy of PDR001 in tumor sample 
(patients in PDR001 arm)
Assess potential associations between 
expression of PD-L1, CD8, Foxp3 and other 
immunological markers such as Lymphocyte 
activation gene-3 (LAG-3), T-cell immunoglobulin 
domain and mucin domain-3 (TIM-3), with anti-
tumor activity
Section 2.10
To assess the pharmacodynamic effect 
of PDR001 in tumor sample (patients in 
PDR001 arm)
TIL counts and expression of immune-related 
genes (RNA/protein in tumor sample)
Section 2.10
To assess the pharmacodynamic effect 
of PDR001 in peripheral blood (patients 
in PDR001 arm)
Assess peripheral, soluble ligands and cytokine 
levels (including but not limited to IFN-γ, TNF-α, 
IL-6)
Section 2.10
2
Statistical Methods
2.1
Data analysis general information
The data will be analyzed by Novartis personnel and/or designated CRO(s) using the most 
updated version of SAS, R and JAGS. PK parameters will be calculated using non-
compartmental methods available in most updated version of Phoenix WinNonlin.
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) and pharmacodynamics (PD) measurements using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) for quantitative data and 
contingency tables (frequencies and percentages) for qualitative data.
Data will be summarized and listed by study arms or by study treatment groups. Details are 
specified in each of the subsections. 
Study arms refer to

PDR001

Chemotherapy
Study treatment groups refer to


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
PDR001

Chemotherapy

Crossover
Crossover treatment group consists of the patients in the chemotherapy arm who crossover to 
PDR001 and treated with PDR001 after progression to chemotherapy. The clinical data 
collected before the crossover will be summarized in the chemotherapy treatment group; the 
clinical data collected after the crossover will be summarized or listed as appropriate in 
crossover treatment group.
2.1.1
General definitions
Study drug and study treatment
Study drug refers to PDR001. Study treatment refers to both PDR001 and Chemotherapy.
Chemotherapy used in control arm may differ across centers.
Date of first/last administration of study drug and study treatment
The date of first (last) administration of study treatment is derived as the first (last) date when 
a non-zero dose of study treatment was administered and recorded on the Dosage 
Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment.
Study day
For PDR001 and Chemotherapy treatment group:
The study day for safety assessments/events will be calculated using the start date of study 
treatment as reference. The study day for efficacy assessments/events will be calculated using 
the date of randomization as reference. 
For safety assessments/events occurring on or after the start date of study treatment, study day 
will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1
Therefore, the first day of study treatment is study day 1.
For safety assessment/events occurring prior to the start of the study treatment, study day will 
be negative and will be calculated as:
Study day (days) = Event date – Start date of study treatment
For efficacy assessments/events occurring on or after randomization, study day will be 
calculated as: 
Study day (days) = Event date – Date of randomization + 1
For efficacy assessment/events occurring prior to randomization, study day will be negative and 
will be calculated as:
Study day (days) = Event date – Date of randomization


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Study day will be displayed in the data listings.
For Crossover treatment group:
The study day for safety and efficacy assessments/events will be calculated using the start date 
of PDR001 treatment as reference.
For assessments/events occurring on or after the start date of PDR001 treatment, study day will 
be calculated as:
Study day (days) = Event date – Start date of PDR001 treatment + 1
Therefore, the first day of PDR001 treatment is study day 1.
For assessment/events occurring prior to the start of the PDR001 treatment, study day will be 
negative and will be calculated as:
Study day (days) = Event date – Start date of PDR001 treatment
On-treatment assessment/event
For PDR001 arm, an on-treatment assessment/event is defined as any assessment/event 
obtained in the time interval from the start date of study treatment until the minimum date of 
(last date of study treatment + 30 days).
For crossover treatment group, an on-treatment assessment/event is defined as any 
assessment/event obtained in the time interval from the start date of PDR001 treatment until the 
minimum date of (last date of study treatment + 30 days).
For chemotherapy arm, an on-treatment assessment/event is defined as any assessment/event 
obtained in the time interval from the start date of study treatment until the minimum date of 
(the last date of study treatment + 30 days inclusive, start of crossover PDR treatment if 
crossovered).
2.2
Analysis sets 
The number (%) of patients in each of the defined analysis set will be summarized using the 
FAS.
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 FAS will be the primary population for all efficacy related data analyses.
Safety Set
The Safety Set includes all patients who received at least one dose of study medication and have 
at least one valid post-screening/post-baseline safety assessment. Patients will be analyzed 
according to the study treatment (regimen) they received.


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The statement that a patient had no AEs (on the AE eCRF) constitutes a valid safety assessment. 
Patients will be classified according to treatment received, where treatment received is defined 
as:

The treatment assigned if it was received at least once, or

If the assigned treatment was never received, then the first treatment received when 
starting therapy with study treatment will be used for classification
The safety set will be the primary population for all safety related endpoints.
Per-protocol Set
The Per Protocol Set (PPS) consists of a subset of FAS patients who meet the following criteria:

Treatment according to the randomization scheme (see CPDR01X2201-Protocol-Section 
6).

Presence of at least one measurable lesion at screening/baseline according to RECIST v1.1 
as per CPDR01X2201-Protocol-Appendix 1.

At least 2 post-screening/post-baseline tumor assessments (unless disease progression is 
observed before that time).

Have not been previously treated with PD-1- or PD-L1-directed therapy or any therapeutic 
cancer vaccine.
Patients will be classified according to treatment received.
In the final CRS no sensitivity analysis with PPS will be conducted. 
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one dose of 
PDR001 and have at least one evaluable concentration measurement of PDR001. The PAS will 
be used for all PK analyses.
Note: Patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of analysis along with their reason for removal.
Immunogenicity (IG) analysis set
The Immunogenicity prevalence set includes all subjects in the Safety analysis set with a 
determinant baseline IG sample or at least one determinant post-baseline IG sample.
The Immunogenicity incidence set includes all subjects in the Immunogenicity prevalence set 
with a determinant baseline IG sample and at least one determinant post-baseline IG sample.   
See Section 2.9.2 for the definition of determinant.
2.2.1
Analysis set exclusion
Patients will be excluded from the analysis sets based on the protocol deviations and specific 
non-protocol deviations entered in the database. All protocol deviations and non-protocol 


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deviations leading to exclusion from specific analysis sets will be identified before database 
lock. Details in Table 2-1.
Table 2-1 Protocol deviation and non-protocol deviation leading to exclusion from 
analysis set definitions
Analysis set
PDs leading to exclusion (ID)
Non-PDs leading to exclusion
FAS
No written inform consent (INCL01).
Safety set
No written inform consent (INCL01).
No administration of study drug.
No valid post-baseline safety assessment.
PPS
No written inform consent (INCL01).
Receive study treatment not 
according to the randomization 
scheme (i.e., randomize to PDR but 
receive Chemotherapy, vice versa) 
(TRT01, TRT02)
Patient has no measurable lesion as 
determined by RECIST 1.1 at 
baseline (INCL09)
Have been previously treated with 
PD-1- or PD-L1-directed therapy or
any therapeutic cancer vaccine. 
(INCL14)
No administration of study drug.
Less than 2 post-screening/post-baseline 
tumor assessments (unless disease 
progression is observed before that time).
PAS
No written inform consent (INCL01).
No administration of study drug.
No evaluable PK data.
Immunogenicity 
prevalence set
No written inform consent (INCL01).
No administration of study drug.
No determinant IG sample at both baseline 
and post-baseline
Immunogenicity 
incidence set
No written inform consent (INCL01).
No administration of study drug
No determinant IG sample at baseline or 
post-baseline or both
2.2.2
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF. 
Additional data for which there is a separate informed consent, e.g. PK, biomarker etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion.
2.2.3
Subgroup of interest
No subgroup analysis will be conducted in the final CSR as the primary efficacy analysis 
reported in the interim CSR was not statistically significant.


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2.3
Patient disposition, demographics and other baseline
characteristics
Summaries and listings described in this section will be done by study arms based on the FAS.
2.3.1
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The following
will be tabulated:

Number (%) of patients who are still on-treatment (based on non-completion of the ‘End 
of Treatment’ page),

Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment’ page with discontinuation date and reason entered),

Primary reasons for study treatment discontinuation (based on discontinuation reason
entered in the ‘End of Treatment’ page),

Number (%) of patients who discontinued from study (based on completion of the ‘End of 
Post Treatment Phase Disposition’ page with discontinuation date and reason entered),

Primary reasons for study evaluation completion (based on discontinuation reason entered 
in the ‘End of Post Treatment Phase Disposition’ page).
2.3.2
Basic demographic and background data
Demographic data including age, sex, race, ethnicity, height, and baseline weight and 
ECOG(WHO) performance status will be listed and summarized. In addition, body mass index 
(BMI) and child bearing potential will be listed, and age (18-<65, 65-<85, ≥85 years) categories 
will be summarized.
BMI is calculated using the following formulas:

BMI [kg/m2] = weight[kg] / (height[m]**2)
2.3.3
Medical History
Medical history and current (ongoing) medical conditions will not be reported in the final CSR.
2.3.4
Prior antineoplastic therapy
Prior anti-neoplastic therapy will will not be reported in the final CSR.
2.3.5
Diagnosis and extent of cancer
Diagnosis and extent of cancer (disease history) will not be reported in the final CSR.
2.4
Protocol deviations
Summaries and listings described in this section will be done by study arms based on the FAS.
The number (%) of patients with any protocol deviation will be tabulated by the deviation 
category (selection criteria not met; study treatment deviation; not discontinued after meeting 


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withdrawal criteria; use of prohibited concomitant medication; other deviation). The full list of 
protocol deviations are documented in the Study Specification Document (SSD). COVID-19 
specific protocol deviations will be listed. Details about COVID-19 impact are provided in 
Section 4.1.
2.5
Treatments (study treatment, rescue medication, other 
concomitant therapies, compliance)
Summaries and listings described in this section will be done by study treatment groups based 
on the Safety set. Exceptions are specified in each subsection.
2.5.1
Study treatment
Study treatment refers to:

PDR001

Chemotherapy: as per investigator’s choice
Below summaries will be done for PDR001 treatment group. For chemotherapy, Duration of 
exposure (days) and Duration of dose interruptions (days) will be summarized, dosage 
administration records will be listed by patient and by each chemotherapy per investigator’s 
choice. For patients in Chemotherapy arm who crossover to PDR001 after progression to 
chemotherapy, below summaries will be done as well for PDR001 treatment if there are more 
than 10 crossover patients.
Duration of exposure to PDR001 = (last date of exposure to PDR001) – (date of first 
administration of PDR001) + 1.
The last date of exposure to PDR001 is defined as: minimum date of (date of last administration 
of a non-zero dose of the PDR001 + 27 days, data cutoff date, death date);
Duration of exposure to Chemotherapy = (last date of exposure to Chemotherapy) – (date of 
first administration of Chemotherapy) + 1
The last date of exposure to Chemotherapy is defined in Table 2-2.
Table 2-2
Definition of last date of exposure to chemotherapy
Regimen
Definition of last date of exposure*
Daily administration of the study 
treatment, i.e., BID, QD and 
EVERY OTHER DAY
Date of last administration of a non-zero dose 
study treatment with a cyclic 
administration:
- WEEKLY (EVERY 7 DAYS)
- 1 WEEK ON 3 WEEKS OFF
- 21 DAYS ON 7 DAYS OFF
- 2 WEEKS ON 1 WEEK OFF
- 2 WEEKS ON 2 WEEKS OFF
The planned end date of the last cycle in which the last 
non-zero dose of the study treatment was administered: 
the date of first administration of study treatment in the 
last cycle + cycle length - 1
i.e., for 1 WEEK ON 3 WEEKS OFF, the cycle length 
is 28 days, last date of exposure = the date of first 


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- 2 WEEKS ON 3 WEEKS OFF
- EVERY 2 WEEKS
- EVERY 3 WEEKS
- EVERY 4 WEEKS
administration of study treatment in the last cycle + 27
days;
For EVERY 2 WEEKS, the cycle length is 14 days, last 
date of exposure = the date of first administration of 
study treatment in the last cycle + 13 days;
* If the derived last date of exposure goes beyond the data cutoff date, death date, then it should 
be truncated to the date of the minimum of (data cutoff date, death date).
Definitions of cumulative dose, actual dose intensity (DI), planned dose intensity (PDI), relative 
dose intensity (RDI), percentage of cycles dosed, percentage of cycles at the prescribed dose 
was received, as well as intermediate calculations, are as follows:

Duration of dose interruptions (days): Sum of all dose delays. See definition of dose 
delay/interruption below.

Cumulative dose (mg): sum of all doses of study drug taken by a patient

Cumulative prescribed dose (mg): sum of all doses of study drug that was intended to have 
been taken during the treated period by a patient

DI (mg/cycle): cumulative dose (mg) ⁄ number of doses scheduled per protocol during 
treatment period

PDI (mg/cycle): cumulative prescribed dose (mg) ⁄ number of doses scheduled per 
protocol during treatment period

RDI (%): 100 × DI (mg/cycle) ⁄ PDI (mg/cycle)
The duration of exposure to study treatment (including categories: <=4 weeks, 4-<=12 weeks, 
12-<=16 weeks, 16-<=24 weeks and >24 weeks) will be summarized. In addition, the
cumulative dose, DI, and RDI (including categories: <0.5, ≥0.5-<0.75, ≥0.75-<0.9, ≥0.9-<1.1, 
≥1.1) will be summarized. The number (%) of patients who have dose interruptions and dose 
reductions, and the corresponding reasons, will be provided. The number of dose interruptions 
and dose reductions per patient and the duration of interruptions and dose reductions will be 
summarized.
All doses of the study treatment along with reasons for any dose change will be listed.
Dose interruption: ‘Dose interrupted’ field from the Dosage Administration CRF pages (DAR) 
will be used to determine the dose interruptions. For patients in Chemotherapy arm taking 
doublet or triplet chemotherapies, if ‘Dose interrupted’ field is ticked for all of the combo/triple 
components on the same day, then only count the dose interruption once.
2.5.2
Concomitant therapies
Concomitant therapies will not be reported in the final CSR.


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2.5.3
Compliance
Compliance to the protocol will be assessed by the number and percentage of patients with 
protocol deviations. Details are provided in Section 2.4.
Compliance to the study treatment PDR001 will be assessed by the percentage of patients who 
took a predefined percentage (RDI categories: <0.5, 0.5-<0.75, 0.75- <0.9, 0.9-<1.1, ≥1.1) of 
the number of prescribed doses of study treatment. Details are provided in Section 2.5.1.
2.6
Analysis of the primary objective
2.6.1
Primary endpoint
The primary efficacy endpoint is progression-free survival (PFS) based on central review of 
tumor scan, as defined per RECIST v1.1 (CPDR01X2201-Protocol-Appendix 1).
PFS is the time from the date of randomization to the date of event defined as the first 
documented confirmed progression or death due to any cause. If a patient has not had an event, 
progression-free survival is censored at the date of last adequate tumor assessment.
2.6.2
Statistical hypothesis, model, and method of analysis
Patients are randomized in 2:1 ratio into either PDR001 arm or control arm. The primary 
efficacy endpoint, PFS as determined based on the central tumor assessment per RECIST v1.1, 
will be analyzed by study arm.
Kaplan-Meier plots will be provided in order to present PFS graphical outputs for the PDR001 
and the control arm. KM estimates of the median and PFS rates at 2, 4, 6, 8 and 12 months will 
be given along with 95% confidence intervals. The FAS will be used for the primary analysis.
In addition to the primary PFS analysis by study arm the KM estimates will be analyzed by PD-
L1 and CD8 expression.
2.7
Analysis of the secondary efficacy variables
Evaluation of anti-tumor activity will be based on central review of overall lesion response 
according to
RECIST v1.1 (see CPDR01X2201-Protocol-Appendix
1)
and irRC 
(CPDR01X2201-Protocol-Appendix 2). The variables used to evaluate anti-tumor activity are 
OS, ORR, BOR, DOR, TTP as per RECIST v1.1 and irPFS as per irRC. Summaries and listings 
described in this section will be done by study arms based on the FAS.
Individual lesion measurements, overall lesion response, OS, DOR, and irPFS will be listed by 
patient. OS, ORR, BOR, DOR, TTP and irPFS will be summarized as per specification in Table 
2-3. A waterfall plot of best percentage change from baseline in sum of longest diameters of 
target lesions per RECIST 1.1 and total measured tumor burden (TMTB) per irRC
(CPDR01X2201-Protocol-Appendix 2) will be presented for each study treatment group. 
Table 2-3
Analysis of the secondary efficacy variables
Endpoint
Definition
Analysis


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OS
Time from the date of randomization to
date of death due to any cause. If a patient 
is not known to have died, survival will be
censored at the date of last known date 
patient alive.
A Kaplan-Meier plot for OS will be 
presented. Median OS (in months) with 
corresponding 95% CI, 25th and 75th 
percentiles (Brookmeyer and Crowley 
1982, Klein and Moeschberger 1997) 
and Kaplan-Meier estimated 
probabilities (OS rate) with 
corresponding 95% CIs (Greenwood’s 
formula, Kalbfleisch and Prentice 1980) 
at several time points (6, 12, 18 and 24 
months) will be presented. The number 
(%) of deaths and patients censored 
will also be summarized.
irPFS (per 
irRC)
Time from the date of randomization to the 
date of the first documented disease 
progression (irPD) (CPDR01X2201-
Protocol-Appendix 2), or death due to any 
cause. 
Median irPFS (in months) with 
corresponding 95% CI, 25th and 75th 
percentiles (Brookmeyer and Crowley 
1982, Klein and Moeschberger 1997) 
and Kaplan-Meier estimated 
probabilities (irPFS rate) with 
corresponding 95% CIs (Greenwood’s 
formula, Kalbfleisch and Prentice 1980) 
at several time points (2, 4, 6, 8and 12
months) will be presented. The number 
(%) of progressions, deaths and 
patients censored will also be 
summarized.
The analysis of irPFS will be done for 
PDR001 arm and crossover patients if 
there are more than 10 crossover 
patients.
TTP (per 
RECIST 1.1)
Time from date of randomization to the
date of event defined as the first 
documented progression or death due to 
underlying cancer. If a patient has not had 
an event, time to progression is censored 
at the date of last adequate tumor 
assessment.
Median TTP (in months) with 
corresponding 95% CI, 25th and 75th 
percentiles (Brookmeyer and Crowley 
1982, Klein and Moeschberger 1997) 
and Kaplan-Meier estimated 
probabilities (TTP rate) with 
corresponding 95% CIs (Greenwood’s 
formula, Kalbfleisch and Prentice 1980) 
at several time points (2, 4, 6, 8 and 12
months) will be presented. The number 
(%) of progressions, deaths and 
patients censored will also be 
summarized.


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BOR (per 
RECIST 1.1)
The best overall response (BOR) is the 
best response recorded from the start of 
the treatment until disease 
progression/recurrence.
BOR will be summarized as observed 
proportion in each category, and 
corresponding 95% confidence 
intervals (CIs) based on the exact 
binomial distribution will be presented.
Tumor volume best change from 
baseline of solid tumors will be 
presented graphically (waterfall 
graphs).
Tumor assessments performed more 
than 30 days after the last study 
treatment (and before any new anti-
neoplastic therapy) have to be 
considered in derivation of the BOR.
ORR (per 
RECIST 1.1)
Proportion of patients with a best overall 
response of confirmed CR or confirmed 
PR.
ORR and corresponding 95% 
confidence intervals (CIs) based on the 
exact binomial distribution will be 
presented.
DOR (per 
RECIST 1.1)
Time from  the date of first documented 
response (confirmed CR or confirmed PR) 
to the date of the first documented disease 
progression or death due to underlying 
cancer.
Summaries of DOR will be provided if 
at least 10 patients responded to study 
treatment. Present DOR rate at 6, 10, 
12, 18, 24 months.
2.8
Safety analysis
Summaries and listings described in this section will be done by study treatment groups based 
on the Safety set:

PDR001

Chemotherapy

Crossover
For crossover treatment group, summaries will be done if there are more than 10 crossover 
patients.
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE) grading limits or normal ranges as appropriate). 
Other safety data include electrocardiogram and vital signs.
The overall observation period will be divided into three mutually exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study treatment,

On-treatment period: from day of first dose of study treatment to the end of safety follow 
up, i.e., for PDR001, to 30 days after last dose of PDR001; For chemotherapy, to 30 days 
after last dose of chemotherapy.


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
Post-treatment period: starting at Day 31 after last dose of PDR001 for PDR001 treatment 
group; Starting at Day 31 after last dose of chemotherapy for chemotherapy treatment 
group.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period.
Safety summaries will primarily be based on all data from the on-treatment period.  Following 
last administration of PDR001, adverse events (including serious adverse events), and new 
antineoplastic therapies are collected for a period of 150 days.  Following start of new 
antineoplastic therapy only treatment related adverse events will be collected.  Select summaries 
of related adverse events will be produced for the combined on-treatment and post-treatment 
periods (Section 2.8.1).
2.8.1
Adverse events
AEs will be coded and graded using the latest version of MedDRA and CTCAE, respectively,
available at the time of reporting. If CTCAE grading does not exist for an AE, grades 1, 2, 3, or 
4 corresponding to the severity of mild, moderate, severe, and life-threatening, respectively, 
will be used. CTCAE grade 5 (death) will not be used in this study. Death information will be 
collected on the ‘End of Treatment’, ‘Survival Information’ and ‘Death’ eCRF pages.
AE Summaries (CSR outputs)
Primary AE summaries will include all AEs occurring during the on-treatment period. 
Additional select summaries will be produced using all treatment related AEs starting or 
worsening during the on-treatment or post-treatment period.
All AEs collected in the AE (e)CRF page will be listed along with the information collected on 
those AEs e.g. AE relationship to study drug, AE outcome etc. AEs starting during the pre- or 
post-treatment periods will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables. 
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the PDR001 treatment group
The following AE summaries will be produced for AEs starting or worsening during the on-
treatment period:

Overview of adverse events and deaths (number and % of subjects who died, with any AE, 
any SAE, any dose reductions/interruptions, AE leading to discontinuation)

AEs by SOC and/or PT, summarized by relationship (all AEs and AEs related to study 
treatment);


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
Seriousness (SAEs, and non-SAEs);

Leading to treatment discontinuation;

Leading to dose interruption/adjustment; 

Requiring additional therapy;

Leading to fatal outcome;
The following AE summaries will be produced for PDR001 for all AEs starting or worsening 
during the on-treatment or post-treatment periods: 

AEs suspected to be study treatment related;

SAEs related to study treatment
The following listings will be produced:

All adverse events (safety set) 
Deaths (CSR Outputs)
Separate summaries for on-treatment and all deaths (including post-treatment deaths) will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed for the safety set, deaths occurring after the treatment period will be 
flagged. 
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment-
emergent adverse events which are not serious adverse events with an incidence greater than 5% 
and on treatment emergent SAEs and SAEs suspected to be related to study treatment will be 
provided by SOC and PT on the safety set population.  These summaries will include any events 
starting or worsening in the on-treatment period.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by PT.
Adverse events of special interests / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound PDR001. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 


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level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) 
may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. 
For each specified AESI, number and percentage of subjects with at least one event of the AESI 
occurring during on-treatment period will be summarized. 
Summaries of these AESIs will be provided for treatment group PDR001 and Crossover. A 
listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
Summarize adverse events in Crossover treatment group
Patients from randomized to Chemotherapy treatment group are allowed to crossover to 
PDR001 group after confirmation of PD to chemotherapy. Below diagram specifies how to 
summarize the AEs for crossover treatment group.
2.8.2
Laboratory data
Laboratory data will be converted into SI units and classified (by Novartis statistical 
programming) into CTC grades according to CTCAE. Grade 5 will not be used.
A Grade 0 CTC grade will be set when laboratory value is:

Within LLN and ULN and grading in both direction,

Below ULN and grading in hyper direction,

Above LLN and grading in hypo direction.
Laboratory data for which a CTC grading does not exist will be classified into low, normal, or 
high based on local laboratory normal ranges as applicable. For the laboratory parameters where 
the CTC grades depend on the normal ranges, when normal ranges are captured as 0 and 
888888.xxx or above then the normal ranges and normal ranges indicator should not be present 
and the corresponding CTC grade should not be derived.


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The following summaries will be produced for hematology and biochemistry parameters:

For parameters with CTC grades: Shifts from baseline to the worst post-baseline CTC  
grade,

For parameters with no CTC grades defined: Shifts from baseline to the worst post-
baseline using low/normal/high classifications,
The following listings will be produced:

Listing of patients with laboratory abnormalities of CTC grade 3 and 4
Table 2-4 and Table 2-5 list all laboratory parameters with CTCAE or normal ranges that have 
been collected in the study. The laboratory parameters that will be summarized in the CSR will 
be mentioned in the TLF shells document. Other labpratory parameters without confirmed 
normal ranges include:
EBV test, DNA levels in plasma: ‘Copies/mL’ will be reported units. EBV conversion factor: 
Copies/mL = 10^ log IU/mL / 0.369.
Serology exam of Anti-DNA antibodies (Abs), Anti-nuclear abs, Anti-phospholipid abs, Anti-
mitochondrial abs.
Table 2-4
Laboratory parameters for which CTCAE grades are defined
Hematology and coagulation
Biochemistry
White Blood Cells (WBC)
↑↓
Creatinine
↑
Hemoglobin
↓
Sodium
↑↓
Platelets counts
↓
Potassium 
↑↓
Absolute Neutrophils
↓
Corrected Calcium
↑↓
Absolute Lymphocytes
↑↓
Magnesium 
↑↓
APTT
↑
Albumin
↓
INR
↑
AST (SGOT)
↑
ALT (SGPT)
↑
Total Bilirubin
↑
Inorganic Phosphate
↓
Glucose (fasting)
↑↓
Glucose, plasma 
(fasting)
↑↓
Alkaline Phosphatase
↑
↑ Indicates that CTC grade increases as the parameter increases.
↓ Indicates that CTC grade increases as the parameter decreases.


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Table 2-5
Laboratory parameters (without CTCAE grades) for which lab
reference ranges are defined
Hematology and coagulation
Biochemistry
Serology 
Prothrombin time (PT)
Blood urea nitrogen (BUN)
c-Reactive protein (CRP)
Absolute Basophils
Urea*
Rheumatoid factor (RF)
Absolute Eosinophils
TSH
Absolute Monocytes
Total T4
Direct bilirubin                      
Indirect bilirubin    
Calcium     
Chloride  
Bicarbonate
*Urea will be converted to BUN and reported as BUN
Imputation rules
CTC grading for blood differentials is based on absolute values. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100)
Corrected calcium can be derived using the reported total calcium value and albumin at the 
same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium are as defined in the previous section.
2.8.3
Vital signs, weight and physical examinations
Vital sign parameters collected are systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), body temperature (°C), and weight (kg). Vital sign values considered 
notably abnormal are defined in Table 2-6.
Table 2-6
Criteria for notable vital sign values
Vital sign
Criteria for clinically notable vital sign values
Systolic blood pressure 
[mmHg]
≥180 mmHg/≤90 mmHg with increase/decrease from baseline of 
≥20 mmHg


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Diastolic blood pressure 
[mmHg]
≥105 mmHg/≤50 mmHg with increase/decrease from baseline of 
≥15 mmHg
Pulse rate [bpm]
≥100 bpm/≤50 bpm with increase/decrease from baseline of >25%
Body temperature [°C]
39.1
Weight [kg]
≥10% decrease/increase from baseline
The number and percentage of patients with notable vital sign valyes (high/low) will be 
presented by treatment group.
Patients with any clinically notable vital sign value will be listed.
2.8.4
Electrocardiograms
Baseline for ECG analysis is defined as the average of all available ECG measurements
associated with the baseline assessment. Scheduled study day 1 pre-dose ECGs will be
considered to have been obtained prior to study drug administration if dosing time is missing.
If a patient has more than one post-baseline measurement at a specific time point, the average 
of all available measurements associated with the nominal time point will be used for analyses 
(not when flagging abnormalities).
The following summaries will be provided for each applicable ECG parameter:

Number (%) of patients having notable ECG values according to Table 2-7.
Table 2-7
Criteria for notable ECG values
ECG parameter
Criteria for notable ECG values
QT, QTcF
New absolute values >450 ms, >480 ms and >500 ms
Change from baseline >30 ms and >60 ms
HR (bpm)
Increase from baseline >25% and value >100 bpm
Decrease from baseline >25% and value <50 bpm
PR (ms)
Increase from baseline >25% and value >200 ms
New PR >200 ms
QRS (ms)
Increase from baseline >25% and value >120 ms
New QRS >120 ms
Patients with any notable change from baseline for each QT/QTc interval will be listed.
2.8.5
Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions by study treatment. Reasons for dose interruption will be listed by patient and 
study treatment and summarized by study treatment. Cumulative dose, dose intensity and 
relative dose intensity of study treatment (see Section 2.5.1) will be also be used to assess 
tolerability.


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2.9
Pharmacokinetic data
All PK analyses will be performed based on the PAS for PDR001 arm. Patient data may be 
removed on an individual basis. PK parameters will be calculated using noncompartmental 
methods and summarized as described in Table 2-8. The PK parameters considerd primary are 
AUCinf, AUCtau (AUC0-672h), AUClast, Cmax, and Tmax. Other PK parameters (CL, Vz, 
T1/2) are considered as secondary. All primary PK parameters will be summarized and all PK 
parameters will be listed.
The descriptive statistics of all pharmacokinetic parameters in the Table 2-8 for both Cycle 1 
and Cycle 3 will include arithmetic and geometric mean, median, SD, and CV, geometric CV, 
minimum and maximum.
Summary statistics will be presented for PDR001 serum concentrations at each scheduled time 
point. Descriptive graphical plots of individual serum concentration versus time profiles and 
mean concentration versus time profiles will be generated by cycle.
Table 2-8
PK parameters – descriptive statistics
Parameters
Descriptive statistics
AUCinf, AUCtau (AUC0-672h), 
AUClast, Cmax, Tmax, T1/2, Racc, 
CL, Vz, Clast, Tlast
Mean, standard deviation, CV% mean, geometric mean, 
CV% geometric mean, median, minimum and maximum
CV% = coefficient of variation (%) = sd/mean*100
CV% geometic mean = sqrt (exp (variance for log transformed data)-1)*100
2.9.1
Data handling principles
Zero concentrations will not be included in the geometric mean calculation. Since Tmax is
generally evaluated by a nonparametric method, median values and ranges will be given for this 
parameter.
Missing concentration values will be reported as is in data listings. Concentration values below 
Lower limit of quantitation will be handled as zero in summary statistics, and reported as is in 
data listings. Any missing pharmacokinetic parameter data will not be imputed.
2.9.2
Immunogenicity
The presence and/ titer of anti-PDR001 antibodies, at each scheduled time point, will be listed 
by patients. Overall immunogenicity may be summarized when sample size is sufficient.
2.9.2.1
Sample ADA Status
Each IG sample is assessed in a three tiered anti-drug anti-body (ADA) testing approach. All 
IG samples are analyzed in the initial screening assay (first tier). Samples testing negative in 
the screening assay are not subject to a confirmatory assay. Samples testing positive in the 
screening assay are then subjected to the confirmatory assay to demonstrate that ADA are 
specific for the therapeutic protein product (second tier). The titer of confirmatory positive 
samples will be subsequently determined in the titration assay (third tier). Samples identified as 


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positive in the confirmatory assay are considered ADA positive. Samples can test negative in 
either the screening or confirmatory assay but for analysis purposes they are not differentiated. 
The following properties of each sample will be provided in the source data: 
Result of assay according to pre-specified confirmatory cut point: ADA positive (yes) or 
ADA negative (no)
Titer (for positive samples): numerical representation of the magnitude of ADA response
Drug tolerance level: highest drug concentration that does not interfere in the ADA 
detection method
Fold titer change (i.e. x-fold): threshold for determining treatment boosted
Sample ADA status is determined based on the following definitions:
ADA-inconclusive sample: Sample where assay is ADA negative and PDR001 PK 
concentration at the time of IG sample collection is greater than or equal to the drug 
tolerance level or missing.  
Unevaluable sample: Sample where assay is not available.
Determinant sample: Sample that is neither ADA-inconclusive nor unevaluable.
The following definitions apply only to determinant samples:
ADA-negative sample: Determinant sample where assay is ADA negative and PDR001 
PK concentration at the time of IG sample collection is less than the drug tolerance level. 
ADA-positive sample: Determinant sample where assay is ADA positive.
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding determinant baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing:

treatment-induced ADA-positive sample: ADA-positive sample post-baseline with 
ADA-negative sample at baseline. 

treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with 
titer that is at least the fold titer change greater than the ADA-positive baseline titer.

treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with 
titer that is less than the fold titer change greater than the ADA-positive baseline titer.
NOTE: PK concentrations which are flagged for exclusion will still be used to determine ADA-
inconclusive and ADA-negative samples.
The following summaries of ADA sample status (n and %) will be provided using 
Immunogenicity prevalence set: 

ADA-positive samples (i.e. ADA prevalence), both overall and by time point (including 
baseline). For summaries by time point, the denominator is the number of subjects at 
that time point with a determinant sample.
Listings will be provided of sample ADA status (including titer for positive samples).


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2.9.2.2
Subject ADA status
Any IG sample collected after 150 days of the last dose of PDR001 will not be used for 
summaries or derivations and will only be included in the listing.
Subject ADA status is defined as follows:

Treatment-induced ADA-positive subject: subject with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample. 

Treatment-boosted ADA-positive subject: subject with ADA-positive sample at 
baseline and at least one treatment-boosted ADA-positive sample.

Treatment-unaffected ADA-positive subject: subject with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-
unaffected ADA-positive sample. 

Treatment-reduced ADA-positive subject: subject with ADA-positive sample at 
baseline and at least one post baseline determinant sample, all of which are ADA-
negative samples. 

ADA-negative subject: subject with ADA-negative sample at baseline and at least one 
post baseline determinant sample, all of which are ADA-negative samples.  

Inconclusive subject: subject who does not qualify as treatment-induced ADA-positive, 
treatment-boosted
ADA-positive, treatment-unaffected ADA-positive, treatment-
reduced ADA-positive, or ADA-negative.  
The following summaries of ADA subject status (n and %) will be provided using 
Immunogenicity incidence set: 

Treatment-boosted ADA-positive subjects; denominator is the number of subjects with 
ADA-positive sample at baseline. 

Treatment-induced ADA-positive subjects; denominator is the number of subjects with 
ADA-negative sample at baseline. 

ADA-negative subjects: denominator is the number of subjects in Immunogenicity
incidence set.

ADA-positive subjects (i.e. ADA incidence): calculated as the number of treatment-
boosted ADA-positive and treatment-induced ADA-positive subjects; denominator is 
the number of subjects in Immunogenicity incidence set. 
Listings will be provided of subject ADA status.
2.10
Biomarkers
2.10.1
Introduction
As a project standard only biomarkers collected in the clinical database will be analyzed. 
 
 
 


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There may be circumstances when a decision is made to stop sample collection, or not perform 
or discontinue the analysis of blood / archival tumor samples / fresh tumor biopsies / fine needle 
aspirates due to either practical or strategic reasons (e.g. issues related to the quality and/or 
quantity of the samples or issues related to the assay). Under such circumstances, the number 
of samples may be inadequate to perform a rigorous data analysis and the available data will 
only be listed and potentially summarized.
2.10.2
Outline of the data analysis
Additional analyses that may be performed after the completion of the final (end-of-study) CSR 
will be documented in separate reports. These analyses may include but are not limited to the 
meta-analysis of data from this study combined with data from other studies or the analysis of 
biomarkers generated from samples collected during the study but analyzed after the database 
lock and completion of the CSR. The data analysis will be described in an addendum of the 
SAP or in a stand-alone analysis plan document, as appropriate.
2.10.3
Biomarker objectives
The biomarker objectives and corresponding endpoints are described in Table 1-1.
2.10.4
Biomarker analysis data
The Full Analysis Set will be used for all biomarker analysis. All statistical analyses of 
biomarker data will be performed on patients treated with PDR001 with biomarker data. Table 
2-9 listed the biomarker, collection time and purpose of analysis.
Table 2-9
Sample biomarker summary table
Biomarker
Timepoint
Sample
Purpose of analysis
Immune-related 
genes, including but 
not limited to PD-L1, 
CD8, LAG-3, and TIM-
3
Screening/Baseline
Newly obtained or 
archival tumor 
sample
Assess potential 
predictive markers of 
efficacy of PDR001
Immune-related 
genes, including but 
not limited to PD-L1, 
CD8, and TIM-3
Anytime between 
C3D1 and End of 
Treatment
Newly obtained 
tumor sample
Assess the 
pharmacodynamic 
effect of PDR001 in 
tumor sample
Cytokine analysis 
markers, including but 
not limited to IFN-γ, 
TNF-α, IL-6
C1D1 (pre-dose)
C1D8
C1D15 
C2D1 (pre-dose)
C2D8
C2D15 
End of Treatment
Blood sample for 
plasma cytokine 
analysis
Assess the 
pharmacodynamic 
effect of PDR001 in 
peripheral blood


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Biomarker
Timepoint
Sample
Purpose of analysis
2.10.5
Data analysis of biomarkers
Basic analysis and reporting are specified in Table 2-10.
Percent change is calculated as ((visit i - baseline)/baseline)*100.
Fold change is calculated as visit i /baseline.
Table 2-10
Reporting of analysis
Biomarker
Report
Immune-related genes, 
including PD-L1, CD8, LAG-
3 and TIM-3 from tumor 
sample
Listing of biomarkers, including demographic variables, 
collect time point, levels and clinical endpoints.
Summary table: levels at each time point (baseline and 
post-baseline) and change/percent change/fold change 
from baseline at each time point. Descriptive statistics 
include N, mean, standard deviation, % CV, median, 
minimum and maximum. For fold change, geometric mean 
and geometric % CV will also be included.
Summary tables: PFS will be summarized for subjects with
a. PD-L1 high (PD-L1 >= 50%)/mid (PD-L1 1% - 50%)/low 
(PD-L1 < 1%) expression at baseline and 
b. CD8 < 1% CD8 ≥ 1% expression at baseline using the 
Kaplan-Meier (KM) method. Median PFS, with 
corresponding 90 CI, and 25th and 75th percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 
1997) will be presented. KM estimates for PFS proportions 
at specific timepoints, along with 95% CI (Greenwood’s 
formula, Kalbfleisch and Prentice 2002) will also be 
provided.
Cytokine analysis markers, 
including but not limited to 
IFN-γ, TNF-α, IL-6 from 
blood sample
Summary table: levels at each time point (baseline and 
post-baseline) and change/percent change/fold change 
from baseline at each time point. Descriptive statistics 
include N, mean, standard deviation, % CV, median, 
minimum and maximum. For fold change, geometric mean 
and geometric % CV will also be included.
Listing of biomarkers, including demographic variables, 
collect time point, levels and clinical endpoints.
2.11
Patient reported outcomes
Not Applicable.


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2.13
Interim analyses
No formal interim analyses are planned.
3
Sample size calculation
Assuming a 2:1 randomization ratio of PDR001 vs. Comparator, 70 events (PD or death) are to 
be observed in the randomized Phase II to provide 85% power to detect a 0.55 hazard ratio in 
terms of PFS (corresponding to a median PFS of 10 months in PDR001 group and 5.5 months 
in the Comparator group), using a log-rank test at a 1-sided significance level of 0.1.
Considering a uniform recruitment time of about 14 months and a 15% drop out rate at 12 
months, approximately 114 patients need to be randomized in a 2:1 ratio to the two arms in 
order to observe 70 events after approximately 6 months follow up (approximately 20 months 
after FPFV):

76 patients to the PDR001 arm

38 patients to the control arm
EAST® trial design software v5.4 is used to compute the sample size.
4
Change to protocol specified analyses
4.1
Planned analyses due to COVID-19 
The COVID-19 pandemic had minimal impact on this study because at the start of the pandemic, 
the vast majority of subjects had discontinued the study treatment and completed the safety 
follow-up phase. COVID-19 specific protocol deviations will be listed.
5
Appendix
5.1
Baseline
For PDR001 and Chemotherapy arm:
For safety assessments/events, baseline is the last available and valid assessment performed or 
value measured within 28 days before the first administration of study treatment, unless 
otherwise stated under the related assessment section. For demographic data (including age, sex, 
race, ethnicity, height, baseline weight and ECOG performance status) baseline value outside 
the 28 days window may be reported as long as it is the last available and valid assessment 
performed or value measured before the first administration of study treatment . Baseline can 
be the day before first treatment administration or the same day as first treatment administration 
if a pre-dose assessment/value is available (e.g., ECG, PK samples, samples for biomarkers).


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If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times.
If time is not recorded, a specific assessment performed the day of first dose administration will 
be considered as baseline if, according to protocol, it should be performed before the first dose.
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter.
For efficacy assessments/events, baseline is the last available and valid assessment performed 
or value measured within 28 days before the date of randomization. If pre-randomization 
assessment is not available, assessment within 7 days after randomization can also be 
considered as baseline assessment.
For crossover treatment group:
For safety and efficacy assessments/events: baseline is the last available and valid assessment 
performed before PDR001 dosing.
5.2
Handling of missing and partial dates
AE, Conmeds and safety assessment data imputation
Table 5-1
Imputation of start dates (AE, CM) 
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  


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Any AEs and CMs with partial/missing dates will be displayed as such in the data listings. Any 
AEs and CMs which are continuing as per data cut-off will be shown as ‘ongoing’ rather than 
the end date provided.  No imputation will be performed for AEs and CMs end dates.
Missing death date
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented:

If only day is missing, then impute max [(1 mmm-yyyy), min (last contact date + 1, cut-
off date)]. 

If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date +
1, cut-off date)].
Incomplete date of initial diagnosis of cancer, date of most recent recurrence 
and date of first recurrence/progression
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01-Jan.
Applying the cut-off to tumor assessment
For tumor related assessments, if an evaluation has some assessments done prior to cut-off date 
and others after the cut-off date, then the evaluation is considered post-cut-off date and will be 
excluded from analysis.
Prior anti-neoplastic therapy
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication start date will 
be used, except that ‘study treatment start date-1’ should be used other than ‘study treatment 
start date’ when applicable in the imputationEnd date: 
Imputed date = min (start date of study treatment-1, last day of the month), if day is missing;
Imputed date = min (start date of study treatment-1, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
For the patients who are randomized but never received study treatment, ‘randomization date’ 
should be used other than ‘start date of study treatment’ in the imputation.
New anti-neoplastic therapy
Start date:   

If Day is missing, then impute to the max (reference start date, first day of the month). 

Day and month are missing then impute to the max (reference start date, Jan 1).


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
If Year, Month and Day are missing then impute to reference start date

Reference start date will be last date of study drug + 1.  
End date: 
No imputation. 
5.3
Construction of waterfall graphs
Waterfall graphs will be used to depict anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of target lesions for each patient per 
RECIST 1.1 and total measured tumor burden (TMTB) per irRC (CPDR01X2201-Protocol-
Appendix 2). 
Note: Patients without any valid assessments to calculate a percentage change from baseline 
value will be excluded from the graphs. Assessments with an unknown overall response will be 
included as long as the sum of diameters of target lesions is correctly computed on the same 
lesions assessed at baseline.
Patients will be ordered in the graph from left (worst change) to right (best change).
1. Bars above the horizontal axis (0%) representing tumor growth,
2. Bars under the horizontal axis (0%) representing tumor shrinkage.
The total number of patients displayed in the graph (n) over the total number of patients in the 
FAS (N) will be shown. The best overall response (BOR) will be displayed above each of the 
displayed bars in the graph. Symbols will be used to differentiate groups of interest, i.e. study 
treatment group. A horizontal threshold line at -30% may be shown. A heatmap may be added 
in order to display per patient (matching with the bar on the waterfall plot) the information 
regarding biomarker status. Details will be provided in TFL shells.
6
References
Neuenschwander B, Capkun-Niggli G, Branson M, et al (2010) Summarizing historical 
information on controls in clinical trials. Clin Trials; 7:5-18.
Clopper CJ and Pearson ES (1934). The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika.; 26,(4):404-13.
Kaplan, EL and Meier, P (1958). Nonparametric estimation from incomplete observations. 
Journal of the American Statistical Association.;53:457-81.