Conditions: Well-differentiated Non-functional NET of Thoracic Origin Well-differentiated Non-functional NET of Gastrointestinal Origin Well-differentiated Non-functional NET of Pancreatic Origin Poorly-differentiated Gastroenteropancreatic Neuroendocrine Carcinoma
Keywords: Advanced or metastatic NET pNET GI NET thoracic NET GEP-NEC
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 116
Healthy volunteers: no

Brief summary:
This study aimed to investigate the efficacy and safety of PDR001 in patients with advanced or metastatic, well-differentiated, non-functional neuroendocrine tumors of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) that progressed on prior treatment.

Detailed description:
Two groups of adult patients with advanced (unresectable or metastatic) were included in this study:

* Well-differentiated (G1/2), non-functional, neuroendocrine tumor of GI, pancreatic or thoracic (lung/thymus) origin who have progressed on prior treatment
* Poorly-differentiated GEP-NEC who have progressed on or after one prior chemotherapy regimen.

The study was comprised of the following periods: screening, treatment, end of treatment (EOT), safety follow-up (30-Days, 60-Days, 90-Days, 120-Days, and 150-Days after the last dose of PDR001) and post-treatment efficacy follow-up. Subjects were treated with PDR001 as an infusion at a flat dose of 400 mg every 4 weeks (Q4W). Subjects were to continue study treatment beyond disease progression by RECIST 1.1 until disease progression as per irRECIST, as per BIRC, unacceptable toxicity, start of new antineoplastic therapy, withdrawal of consent, physician's decision, lost to follow-up, death, or study termination by the Sponsor.

Arms:
arm 1: Subjects with advanced or metastatic, well-differentiated, NET of pancreatic, GI, or thoracic origin or poorly-differentiated GEP-NEC, that have progressed on prior treatment were treated with 400mg PDR001 administered via intravenous infusion once every 4 weeks.

Interventions: intervention 1: PDR001
Intervention descriptions: intervention 1: PDR001 was administered at a dose of 400 mg via intravenous infusion once every 4 weeks (Q4W). PDR001 was administered on Day 1 of every cycle. Each cycle was 28 days.

Protocol document:
Prot_001.pdf: 
Clinical Development
PDR001 (Spartalizumab)
Oncology Clinical Protocol CPDR001E2201 / NCT02955069
An open label phase II study to evaluate the efficacy and 
safety of PDR001 in patients with advanced or metastatic, 
well-differentiated, non-functional neuroendocrine tumors 
of pancreatic, gastrointestinal (GI), or thoracic origin or 
poorly-differentiated gastroenteropancreatic 
neuroendocrine carcinoma (GEP-NEC), that have 
progressed on prior treatment
Authors
 
Document type
Amended Protocol Version
EUDRACT number
2016-002522-36
Version number
03 (Clean)
Development phase
II
Document status
Final
Release date
24-May-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 15-Jan-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................6
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Amendment 3 (24-May-2018)...........................................................................................12
Amendment 2 (12-Jan-2018).............................................................................................14
Amendment 1 (27-Apr-2017)............................................................................................16
Protocol summary:.............................................................................................................20
1
Background........................................................................................................................24
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............24
1.1.1
Current treatment options......................................................................25
1.2
Introduction to investigational treatment(s) and other study treatment(s).............28
1.2.1
Overview of PDR001............................................................................28
2
Rationale............................................................................................................................31
2.1
Study rationale and purpose...................................................................................31
2.2
Rationale for the study design ...............................................................................32
2.3
Rationale for dose and regimen selection..............................................................33
2.4
Rationale for choice of comparators drugs............................................................34
2.5
Risks and benefits..................................................................................................34
3
Objectives and endpoints...................................................................................................35
4
Study design ......................................................................................................................36
4.1
Description of study design ...................................................................................36
4.1.1
Study flow.............................................................................................37
4.2
Timing of interim analysis and design adaptations ...............................................39
4.3
Definition of end of study......................................................................................39
4.4
Early study termination..........................................................................................40
5
Population..........................................................................................................................40
5.1
Patient population..................................................................................................40
5.2
Inclusion criteria ....................................................................................................40
5.3
Exclusion criteria...................................................................................................42
6
Treatment...........................................................................................................................45
6.1
Study treatment......................................................................................................45
6.1.1
Dosing regimen.....................................................................................45
6.1.2
Ancillary treatments..............................................................................45


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6.1.3
Rescue medication ................................................................................46
6.1.4
Guidelines for continuation of treatment ..............................................46
6.1.5
Treatment duration................................................................................46
6.2
Dose escalation guidelines.....................................................................................48
6.3
Dose modifications................................................................................................48
6.3.1
Dose modification and dose interruption..............................................48
6.3.2
Dose adjustments for QTcF prolongation.............................................60
6.3.3
Follow-up for toxicities.........................................................................60
6.4
Concomitant medications ......................................................................................61
6.4.1
Permitted concomitant therapy .............................................................61
6.4.2
Permitted concomitant therapy requiring caution and/or action...........62
6.4.3
Prohibited concomitant therapy ............................................................62
6.4.4
Use of bisphosphonates (or other concomitant agents).........................63
6.5
Patient numbering, treatment assignment..............................................................63
6.5.1
Patient numbering .................................................................................63
6.5.2
Medication number assignment ............................................................63
6.5.3
Treatment blinding................................................................................63
6.6
Study drug preparation and dispensation...............................................................63
6.6.1
Study treatment packaging and labeling ...............................................64
6.6.2
Drug supply and storage........................................................................64
6.6.3
Study drug compliance and accountability ...........................................64
6.6.4
Disposal and destruction .......................................................................65
7
Visit schedule and assessments .........................................................................................65
7.1
Study flow and visit schedule................................................................................65
7.1.1
Molecular pre-screening........................................................................77
7.1.2
Screening...............................................................................................77
7.1.3
Run-in period ........................................................................................79
7.1.4
Treatment period...................................................................................79
7.1.5
Discontinuation of study treatment .......................................................79
7.1.6
Withdrawal of consent ..........................................................................80
7.1.7
Follow up for safety evaluations...........................................................81
7.1.8
Follow-up for efficacy evaluations .......................................................81
7.1.9
Survival follow-up ................................................................................81
7.1.10
Lost to follow-up...................................................................................81
7.2
Assessment types...................................................................................................82
7.2.1
Efficacy assessments.............................................................................82


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7.2.2
Baseline imaging assessments...............................................................83
7.2.3
Post-baseline imaging assessments.......................................................84
7.2.4
Timepoints at which progression is determined locally........................85
7.2.5
Timepoints without locally determined progression.............................86
7.2.6
Safety and tolerability assessments.......................................................86
7.2.7
Pharmacokinetics and immunogenicity (IG) assessment......................91
93
7.2.9
Resource utilization...............................................................................97
7.2.10
Patient reported outcomes.....................................................................97
8
Safety monitoring and reporting........................................................................................99
8.1
Adverse events.......................................................................................................99
8.1.1
Definitions and reporting ......................................................................99
8.1.2
Laboratory test abnormalities..............................................................100
8.1.3
Adverse events of special interest.......................................................101
8.2
Serious adverse events.........................................................................................101
8.2.1
Definitions...........................................................................................101
8.2.2
Reporting.............................................................................................102
8.3
Emergency unblinding of treatment assignment .................................................103
8.4
Pregnancies..........................................................................................................103
8.5
Warnings and precautions....................................................................................103
8.6
Data Monitoring Committee................................................................................103
8.7
Steering Committee .............................................................................................103
9
Data collection and management.....................................................................................104
9.1
Data confidentiality .............................................................................................104
9.2
Site monitoring ....................................................................................................104
9.3
Data collection.....................................................................................................105
9.4
Database management and quality control..........................................................105
10 Statistical methods and data analysis ..............................................................................106
10.1
Analysis sets ........................................................................................................106
10.1.1
Full Analysis Set .................................................................................106
10.1.2
Safety set .............................................................................................106
10.1.3
Per-Protocol set ...................................................................................106
10.1.4
Dose-determining analysis set.............................................................106
10.1.5
Pharmacokinetic analysis set...............................................................107
10.1.6
Other analysis sets...............................................................................107
10.2
Patient demographics/other baseline characteristics ...........................................107


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10.3
Treatments (study treatment, concomitant therapies, compliance) .....................107
10.4
Primary objective.................................................................................................107
10.4.1
Variable...............................................................................................108
10.4.2
Statistical hypothesis, model, and method of analysis........................108
10.4.3
Handling of missing values/censoring/discontinuations.....................109
10.4.4
Supportive and Sensitivity analyses....................................................109
10.5
Secondary objectives ...........................................................................................109
10.5.1
Key secondary objective(s).................................................................109
10.5.2
Other secondary efficacy objectives ...................................................110
10.5.3
Safety objectives .................................................................................111
10.5.4
Pharmacokinetics ................................................................................113
10.5.5
Immunogenicity ..................................................................................113
10.5.6
CgA and NSE......................................................................................113
10.5.7
Resource utilization.............................................................................114
10.5.8
Patient-reported outcomes...................................................................114
115
115
115
10.7
Interim analysis....................................................................................................116
10.8
Sample size calculation........................................................................................117
10.9
Power for analysis of key secondary variables....................................................118
11 Ethical considerations and administrative procedures ....................................................118
11.1
Regulatory and ethical compliance......................................................................118
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................118
11.3
Informed consent procedures...............................................................................119
11.4
Discontinuation of the study................................................................................119
11.5
Publication of study protocol and results.............................................................119
11.6
Study documentation, record keeping and retention of documents.....................120
11.7
Confidentiality of study documents and patient records .....................................121
11.8
Audits and inspections.........................................................................................121
11.9
Financial disclosures............................................................................................121
12 Protocol adherence ..........................................................................................................121
12.1
Amendments to the protocol................................................................................121
13 References (available upon request)................................................................................122
14 Appendix .........................................................................................................................126
14.1
Appendix 1: RECIST 1.1 Novartis guideline version 3.2 ...................................126


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14.2
Appendix 2: irRECIST ........................................................................................150
14.3
Appendix 3: Safety follow-up flowchart .............................................................157
List of tables
Table 1-1
Clinical Experience in NET – Literature review of clinical studies .....26
Table 3-1
Objectives and related endpoints ..........................................................35
Table 6-1
Dose and treatment schedule.................................................................45
Table 6-2
Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related 
diarrhea/colitis.......................................................................................50
Table 6-3
Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related liver 
laboratory alterations.............................................................................51
Table 6-4
Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related skin 
events.....................................................................................................52
Table 6-5
Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related 
nephritis.................................................................................................53
Table 6-6
Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related 
pneumonitis...........................................................................................53
Table 6-7
Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related 
encephalitis............................................................................................54
Table 6-8
Mandatory dose modification requirements and recommended 
clinical management guidelines for potential immune-related 
endocrine events....................................................................................55
Table 6-9
Mandatory dose modification requirements and recommended 
clinical management guidelines for infusion reaction events and 
cytokine release syndrome....................................................................56
Table 6-10
Mandatory dose modification requirements and recommended 
clinical management guidelines for “other” potential immune-
related AEs of special interest...............................................................57
Table 6-11
Mandatory dose modification requirements and recommended 
clinical management guidelines for hematologic adverse events 
suspected to study treatment .................................................................58
Table 6-12
Mandatory dose modification requirements and recommended 
clinical management guidelines for non-hematologic adverse 
events suspected related to study treatment ..........................................59


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Table 6-13
Supply and storage of study treatments ................................................64
Table 7-1
Visit evaluation schedule ......................................................................66
Table 7-2
Imaging Assessment Collection Plan....................................................83
Table 7-3
ECOG performance status scale............................................................87
Table 7-4
Central Clinical laboratory parameters collection plan.........................88
Table 7-5
Local Clinical laboratory parameters collection plan ...........................88
Table 7-6
Local ECG collection plan....................................................................91
Table 7-7
Pharmacokinetic and immunogenicity blood collection log.................92
94
Table 7-9
PRO questionnaires...............................................................................98
Table 10-1
Operating characteristics for the full population of well-
differentiated NET group ....................................................................117
Table 10-2
Probability of observing at least 3 responders in a cohort with more 
than 10% true response rate ................................................................117
Table 10-3
Operating characteristics for the poorly-differentiated GEP-NEC 
group ...................................................................................................118
Table 10-4
Posterior probability of a true ORR in the poorly-differentiated 
GEP-NEC group corresponding to at least moderate efficacy 
( >/=10% ORR)...................................................................................118
List of figures
Figure 4-1
Study design..........................................................................................37
Figure 4-2
Study flow.............................................................................................39


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List of abbreviations
ADA
Anti-drug Antibodies
AE
Adverse Event
AESI
Adverse events of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
BIRC
Blinded Independent Review Committee
BUN
Blood Urea Nitrogen
CgA
Chromogranin A
CMO&PS
Chief Medical Office and Patient Safety
CNS
Central nervous system
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CSR
Clinical study report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Trough plasma concentration
DCR
Disease Control Rate
DILI
Drug-induced liver injury
DLT
Dose Limiting Toxicity
DoR
Duration of Response
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status
EORTC
European Organisation for Research and Treatment of Cancer’s core quality of life 
questionnaire
EOT
End of Treatment
EQ-5D-5L
EuroQol 5 Dimension questionnaire
FAS
Full Analysis Set
FPFV
First patient first visit
GEP-NET
Gastroenteropancreatic NET
GEP-NEC
Gastroenteropancreatic neuroendocrine carcinoma
GGT
Gamma-glutamyl transpeptidase
GI
Gastrointestinal
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL
High Density Lipoprotein
HIV
Human Immunodeficiency Virus
HNSTD
Highest Non-Severely Toxic Dose
HRQoL
Health-related quality of life
IA
Interim Analysis
IASLC
International Association for the Study of Lung Cancer
i.v.
intravenous(ly)
IEC
Independent Ethics Committee
IG
Immunogenicity
IHC
Immunohistochemistry 
IFN-γ
interferon-gamma
IL-1
Interleukin-1


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IL-6
Interleukin-6
INR
International normalized ratio
irAE
Immune-related adverse events
irDoR
Immune-related Duration of Response
irORR
Immune-related Overall Response Rate
irPFS
Immune-related Progression Free Survival
IRB
Institutional Review Board
irRECIST
Immune-related RECIST
IRT
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System
LAR
Long-Acting Release
LDH
Lactate dehydrogenase
LLOQ
Lower limit of quantification
LPFT
Last patient first treatment
LPLV
Last patient last visit
mAb(s)
monoclonal Antibody(ies)
mo
Month/s
mOS
median overall survival
mPFS
median PFS
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NET
Neuroendocrine Tumor
NSE
Neuron Specific Enolase
ORR
Overall Response Rate
OS
Overall Survival
PD
Progressive disease
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression Free Survival
PK
Pharmacokinetics
PNET
Pancreatic NET
PPoS
predictive probability of success
PR
Partial response
PRO
Patient-reported outcomes
PRRT
Peptide Radionuclide Receptor Therapy
PT
Prothrombin time
QoL
Quality of Life
QTcF
Corrected QT interval based on Fridericia’s formula
RECIST
Response Evaluation Criteria In Solid Tumors
RFS
Relapse-Free-Survival
RP2D
Recommended phase two dose
R Value
ALT/ALP in x ULN
SAE
Serious Adverse Event
SAP
The Statistical Analysis Plan (SAP) is a regulatory document which provides evidence of 
preplanned analyses
SC
Steering Committee
SD
Stable Disease
SOP
Standard Operating Procedure
SSA
Somatostatin Analogs


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TBIL
Total bilirubin
TIL(s)
Tumor Infiltrating Lymphocyte(s)
TNF-α
Tumor necrosis factor alpha
Treg
regulatory T cells
TSH
Thyroid Stimulation Hormone
TTP
Time to progression
TTR
Time To Response
WOCBP
Women of childbearing potential


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study patient
Blinded Independent 
Review Committee
A third party review committee which provides an independent, unbiased and impartial 
assessment of disease response or progression for each patient enrolled in a clinical 
trial. The BIRC is blinded to all sites and subject identifying information as well as the 
results of the local assessment. Independent reviews of images and/or clinical data are 
performed independently of and separate from the reviews performed by investigators 
at clinical sites. Assessments from site investigators or other third party reviewers will 
not be provided to the image vendor since these evaluations may bias the image 
vendors’ reviewers’ assessments.
Cycles
Number and timing or recommended repetitions of therapy are usually expressed as 
number of days (e.g.: q28 days)
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
Medication number
A unique identifier on the label of each study treatment package which is linked to one 
of the treatment groups of a study
Other study 
treatment
Any drug administered to the patient as part of the required study procedures that was 
not included in the investigational treatment
Personal Data
Patient information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes patient identifier information, study 
information and biological samples.
Subject Number 
(Subject 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.
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
Stop study 
participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the patient 
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 
interruption 
Includes any delay or withholding of study treatment for any reason as well as an 
interruption during an infusion of study treatment for any reason
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any reason
Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints
Withdrawal of 
consent
Withdrawal of consent 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 
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Amendment 3 (24-May-2018)
Amendment rationale
Recruitment into Part 1 of the study completed on 20-Sep-2017 with 116 patients (of 
approximately 110 planned) enrolled. A planned interim analysis as well as an additional 
efficacy analysis (to inform decision to start part 2) were performed with data cut-off dates of 
29-Nov-2017 and 09-Feb-2018, respectively. The key efficacy and safety results of the two 
analyses are summarized in Section 1.2.1.2. No new safety signals were identified in the interim 
analysis. As of 15-May-2018, recruitment into Part 2 has not opened and no patients were
enrolled into Part 2. 
The major rationale for protocol amendment 3 is to remove the possibility to expand the study 
to Part 2 when at least 20% overall response rate (ORR) per RECIST 1.1 by central radiology 
review is observed in any of the cohorts of the well-differentiated NET group. While the results 
of the additional efficacy analysis (Section 1.2.1.2) demonstrated an ORR of 20% in the thoracic 
cohort of the well-differentiated NET group and met the criterion for starting Part 2, no 
overwhelming supportive evidence of strong efficacy was observed on other endpoints. 
Moreover, all other cohorts showed ORR below 10%. Based on this, there was a change in the 
clinical development strategy for PDR001, which will no longer be developed as a single agent 
immunotherapy in NET, and the study will not be expanded into Part 2. Importantly, this change 
is not due to safety concerns.   
Due to revoking Part 2, no further patient will be enrolled in the study and the primary analysis 
will provide results for all enrolled patients. Consequently, the following modifications will be 
implemented after the primary analysis cut-off date (10-Aug-2018):

Tumor response assessments will be performed according to local or institutional 
standards of care and when clinically indicated.

Removal of tumor response assessments by the Blinded Independent Review Committee
(BIRC); tumor response will be assessed locally.

Removal of post-treatment efficacy follow-up. There will be no change to the safety 
follow-up or survival follow-up.

Removal of the Patient Reported Outcomes (PRO) data collection.
Additional changes to the protocol include:

Following the release of Investigator Brochure Edition 7.1, changes to the Risks and 
Benefit section have been implemented and the contraception requirement for male
participants has been updated. Condom use for males receiving monoclonal antibodies is 
no longer required since monoclonal antibodies are not genotoxic due to their high 
molecular weight, and are not expected to interact with DNA. In addition, they have a low 
distribution to the semen, a relatively small volume of semen is delivered to the vagina, 
and there is very low absorption. Fetal harm from semen delivery is therefore biologically 
implausible. 

Withdrawal of consent language was updated to reflect the European Economic Area 
General Data Protection Regulation (GDPR) requirements.

Editorial changes and text corrections were made for clarification, where required.


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined font for insertions.
The following sections were changed:
Section 1.1.1: updated to reflect FDA approval of 177 Lu-Dotatate for treatment of somatostatin 
receptor positive for GEP-NETsSection 1.2.1.2: added study results of Interim Analysis
Sections 2.2: deleted Part 2 expansion
Section 3: deleted objectives for Part 2 expansion
Section 4.1: deleted Part 2 expansion and updated treatment duration for patients ongoing after 
primary analysis cutoff date
Figure 4-1: deleted Part 2 expansion
Section 4.1.1: updated section to reflect that post-treatment efficacy follow-up, ePRO collection 
and central radiology review will no longer be performed after primary analysis cutoff date
Sections 4.2 and 4.3: deleted Part 2 expansion
Section 5: deleted inclusion criterion 13 due to removal of Part 2 and exclusion criterion 25 as 
male contraception is no longer required
Sections 6.1, 6.1.1 and 6.6.2: deleted introduction of the PDR001 liquid formulation due to the 
removal of Part 2 (liquid formulation was supposed to be introduced in Part 2)
Section 6.1.5: updated treatment duration for patients ongoing after primary analysis cutoff date
Section 7: updated Visit Schedule and Assessment Table 7-1 with change in efficacy 
assessments frequency for ongoing patients and discontinuation of post treatment efficacy 
follow-up, central radiology review after primary analysis cutoff date and clarified that PK/IG 
samples will not be collected after primary analysis cutoff date unless if requested by the 
investigator . There are no change in assessment frequency prior to primary analysis cutoff date.
Section 7.1.5: updated treatment duration for patients ongoing after primary analysis cutoff date
Section 7.1.6: updated as per the European Economic Area General Data Protection Regulation 
(GDPR) requirements
Section 7.1.7: updated to confirm that there is no change in the safety evaluations after the 
primary analysis cutoff date
Section 7.1.8: updated section to reflect discontinuation of post treatment efficacy follow-up 
after primary analysis cutoff date
Section 7.2.1, 7.2.3, 7.2.4 and 7.2.5: updated sections to reflect change in efficacy assessments 
frequency for ongoing patients and discontinuation of post treatment efficacy follow-up, and 
central radiology review including expedited review after primary analysis cutoff date
Section 7.2.7: highlighted and clarification added that no additional PK and IG samples will be 
collected for the patients still ongoing on the study, unless requested by the Investigator, after 
primary analysis cutoff.


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Section 7.2.10: updated section to reflect discontinuation of ePRO collection after primary 
analysis cutoff date
Section 10: updated to remove the possiblity to expand the study to Part 2
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.
Summary of previous amendments
Amendment 2 (12-Jan-2018)
Amendment rationale 
The first patient signed the informed consent on 14 February 2017. As of 05 January 2018, 95
patients with well-differentiated non-functional NET and 21 patients with poorly differentiated 
GEP-NEC have been treated with at least one dose of PDR001. The enrollment in part 1 is 
completed and the study is currently ongoing. 
Amendment 2 includes the following modifications:

Inclusion of Part 2 (Expansion part) aiming to further characterize the efficacy and safety 
of PDR001 single agent in any of the well-differentiated NET cohorts if antitumor activity 
is observed in Part 1. Each of the well-differentiated cohorts (GI, thoracic, pancreatic) will 
enroll additional 60 patients if we observe at least 20% ORR per RECIST 1.1 and central 
radiology review in the corresponding cohort.

Possibility to implement the PDR001 liquid formulation for patients treated in Study Part 
2 (expansion part).Addition of an inclusion criterion regarding life expectancy of at least 3 
months for patients treated in Study Part 2. This would decrease the occurrence of deaths 
during the screening period and before the first tumor assessment scheduled 8 weeks after 
the first treatment dose. 
Rationale for possible expansion of Well-differentiated NET:
Well-differentiated, non-functional NETs of the thorax, gastrointestinal tract and pancreas are 
rare and heterogeneous, clinically important group of neosplasms with a different clinical 
management and available therapeutic options. The management of patients with metastatic 
NETs includes systemic and biological treatment strategies such as molecular targeted therapies 
with everolimus and sunitinib, PRRT and chemotherapy. PD-L1 expression emerged as a
potential prognostic factor for survival in NET; showing that patients with PD-L1 negative 
tumors experience a longer survival as compared to PD-L1 positive however limited data is 
available regarding the treatment effect of checkpoint inhibitors in NET (Kim 2016; Fan 2016; 


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Mehnert 2017). There are no available treatment options with proven efficacy post everolimus 
failure and a limited number of agents approved specifically in NET of GI and lung origins,
representing an unmet need. Considering the high level of heterogeneity between different NET 
origins, if an activity signal is observed in any of the 3 cohorts, an expansion in the sample size 
will be performed to better assess the efficacy of PDR001 in that specific NET subgroup.
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 1.1.1: updated treatment options with most updated data

Section 2.2: added part 2 (expansion) for well-differentiated cohort 

Section 3: added primary and key secondary objectives
for part 
2

Section 4.1: added definition of part 2 expansion

Figure 4-1: updated study design for part 2

Section 4.1.1: clarified 150-day safety follow-up schedule

Section 4.3: updated definition of end of study

Section 5.2: Added new Inclusion criterion 13 for patients enrolled in Part 2: life 
expectancy of at least 3 months

Section 6.1: added new formulation of study treatment (PDR001 100 mg / 4 mL 
concentrate for solution for infusion)

Section 7.1: added time window for EOT visit

Section 7.2.1: added information about cytology

Section 10: updated to reflect the possibility to expand and analyze well-differentiated 
NET cohorts 

Section 13: added new references

Other minor clarifications and editorial changes.
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 1 (27-Apr-2017) 
Amendment rationale 
The first patient signed the informed consent on February 14, 2017. As of 24-Apr-2017, 7
patients have been treated with at least one dose of PDR001.  
Amendment 1 includes the following modifications:

Adding a group of approximately 20 patients with advanced or metastatic, poorly-
differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC). This cohort 
is added because of the following reasons: 1) biological rationale supporting the potential 
efficacy of immunotherapy; 2) currently there is no approved treatment and no consensus 
on the standard of care upon progression on 1st line chemotherapy.   

Removing the possibility of stopping the study early for futility at the time of the protocol 
defined interim analysis. By the time of the planned interim analysis, enrollment is 
expected to be completed. A formal interim analysis of preliminary efficacy and safety 
data will be kept, but the study will not be stopped for efficacy reasons regardless of 
efficacy results and the study will continue until mature data for all patients become
available.

Modifying the inclusion criterion 4 and adding exclusion criterion 27. “No history of 
carcinoid syndrome” was removed from this inclusion criterion since this condition may
be present during the course of the disease but may have resolved with appropriate 
treatment and therefore not present at the time of enrollment. A period of 3 months 
without any evidence of carcinoid symptoms and somatostatin analogs treatment has been 
defined prior to study entry. 

Modifying the inclusion criterion 9. The tumor sample should be taken within 6 months 
but not more than 24 months (instead of 12 months) prior to start of study treatment. 
Extending the collection period from a maximum of 12 months to 24 months improves 
recruitment 
 
.

Adding exclusion criterion 26. Interstitial lung disease was observed in ongoing PDR001 
studies.

Removing the maximum treatment duration of 24 months. The limit on treatment duration 
is removed to provide the option of continuing study treatment for those patients who 
present clinical benefit and have not progressed during the first 24 months of treatment 
and still fulfils the criteria to continue study treatment.   

Extending the treatment window from +/- 4 days to +/- 7 days based on investigators’ 
feedback that more time is required between routine blood collection and start of study 
treatment.

Modifying the exclusion criteria 13 for QTcF from > 450 to > 480 msec on screening 
ECG or congenital long QT syndrome because monoclonal antibodies such as PDR001 
have low potential for QT prolongation.

Updating safety information according to release of Investigator Brochure edition 6

Clarifying the definition of on-treatment period for safety analysis to align reporting with 
data collection. Main safety analysis will be performed based on data collected up to 30 


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days after discontinuation of study treatment. Additional analyses will be performed to 
report data up to 150 days after discontinuation of PDR001. 

Other minor clarifications and editorial changes.
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.

Title: updated to include poorly-differentiated GEP-NEC patients

Section 1.1: added additional details of neuroendocrine tumor classification

Section 1.1.1: added treatment strategies for poorly-differentiated GEP-NEC

Section 1.2.1.2: deleted details of six safety notifications and replaced with an overview of 
new safety information from IB version 6

Section 2: added rationale for including poorly-differentiated GEP-NEC group

Section 3: modified objectives to include poorly-differentiated GEP-NEC group

Section 4: added poorly-differentiated GEP-NEC group to study design

Section 4.2: deleted futility interim analysis and replaced with interim analysis

Section 4.3: updated end of study definition

Section 4.4: updated early study termination language

Section 5.1: added poorly-differentiated GEP-NEC group to patient population

Section 5.2: modified criteria as below:

inclusion criterion 3: included poorly-differentiated GEP-NEC group

inclusion criterion 4: deleted “no history of carcinoid syndrome” and added time 
window for active symptoms

inclusion criterion 5: added prior treatment for poorly-differentiated GEP-NEC group

inclusion criterion 6: added radiological documentation for poorly-differentiated 
GEP-NEC group

inclusion criterion 9: extended time window for tumor sample collection from 1 year 
to 24 months and added specific criterion for poorly-differentiated GEP-NEC

Section 5.3: modified criteria as below:

exclusion criterion 1: updated to exclude well-differentiated, grade 3 neuroendocrine 
tumors; poorly differentiated neuroendocrine carcinoma of any origin (other than 
GEP-NEC); including NEC of unknown origin, adenocarcinoid, and goblet cell 
carcinoid. 

exclusion criteria 6 and 11: deleted these criteria

exclusion criterion 13: updated QTcF to > 480 msec

exclusion criterion 14: updated

exclusion criterion 26: added criterion to exclude patients with known history or 
current interstitial lung disease or non-infections pneumonitis

exclusion criterion 27: added criterion to exclude patients using somatostatin analogs 
or other medications to control active symptoms of carcinoid syndrome.


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
Note: the deletion of exclusion criteria 6 and 11 did not change the numbering of the 
existing exclusion criteria

Section 6.1.1: updated dosing window to +/- 7 days and pharmaceutical form

Sections 6.1.5 and 7.1.4: deleted maximum treatment duration of 24 months

Section 6.1.5.1: clarified absence of irPD criteria

Section 6.3.1.2: 

added other skin events in Table 6-4 and autoimmune diabetes in Table 6-8 with 
details regarding dose modification and clinical management guidelines

deleted example of non-corticosteroid immunosuppressive medication in Table 6-6 

Section 6.4.3: updated prohibited medication list 

Section 6.5.2: updated to include poorly-differentiated GEP-NEC group

Section 6.6: clarified post infusion monitoring

Section 7.1: changes are described below:

updated time windows for scans, ePRO and Day 1 of subsequent cycles

clarified suspected SAE collection up to end of survival follow-up in Table 7-1

added tumor characteristic collection as part of proliferative assessment in Table 7-1

Section 7.1.2: added poorly-differentiated GEP-NEC group and collection of necrosis 
from pathology report

Section 7.1.5: deleted end of treatment reason “completed”

Section 7.2.4: clarified expedited review requirements

Section 7.2.6.4: added ECOG performance status scale table

Section 7.2.6.5: added new section to include details of change in functional status of 
carcinoid syndrome

Section 7.2.6.6.4: added new section for coagulation

Section 7.2.6.6.7: added new section for CgA and NSE

Section 7.2.6.7.1: updated Table 7-6

Section 7.2.7: updated Table 7-7 (dose reference ID) and clarified collection timing for 
pre-dose sample and end of infusion sample collection

Section 7.2.8: updated Table 7-8: clarified tumor collection timepoints for well-
differentiated NET and GEP-NEC and added a new archival tumor sample collection 
(older than 24 months)

Sections 8.2.2 and 8.4: updated to reflect new name for Novartis safety group

Section 10: reflected changes to statistical considerations for including poorly-
differentiated GEP-NEC group and removal of the possibility for early stopping due to 
futility at the interim analysis

Section 13: added new references

Section 14: updated appendix 14.2 for consistency with Novartis guidelines


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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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Protocol summary: 
Title
An open label phase II study to evaluate the efficacy and safety of PDR001 in patients 
with advanced or metastatic, well-differentiated, non-functional neuroendocrine tumors 
of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-differentiated
gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) that have progressed 
on prior treatment
Brief title
Study of efficacy and safety of PDR001 in patients with advanced or metastatic, well-
differentiated, non-functional neuroendocrine tumors of pancreatic, gastrointestinal 
(GI), or thoracic origin, or poorly-differentiated GEP-NEC
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
● Although many advances with checkpoint inhibitors have been made in other tumor 
types, the data generated in NETs is limited with no clinical experience available to 
date. Recent correlative studies conducted in NETs have assessed the expression of 
PD-L1 and correlated tumor differentiation with poor clinical outcome. 
● Tumor-infiltrating lymphocytes (TILs) have been shown to predict survival in 
numerous malignancies. A robust T cell infiltration is associated with improved RFS 
following resection of intermediate-grade NETs, whereas the presence of a tumor 
environment rich in Tregs correlated with shorter OS after treatment. These findings 
suggest that the immune-modulation of the phenotype of T cells may play a role in 
clinical outcome.  
● Clinical data available from one patient with histologically confirmed metastatic 
atypical pulmonary carcinoid treated in the ongoing phase I study with PDR001 in solid 
advanced tumors [CPDR001X2101] showed an immune-related partial response with 
dramatic resolution of multiple liver and pleural metastases. Patient has been on 
therapy for nine months, and at the last tumor imaging assessment a sustained partial 
response according to RECIST 1.1 criteria was observed with sustained regression in 
all areas of tumor.
Primary Objective 
and Key 
Secondary 
Objective
Primary objective:
●To estimate the antitumor activity (assessed as ORR per RECIST 1.1) of PDR001 as 
a single agent in the well-differentiated NET and the poorly-differentiated GEP-NEC 
groups.
Key secondary objective:
● To estimate efficacy (DoR per RECIST 1.1) of PDR001 in the well-differentiated NET 
and poorly-differentiated GEP-NEC groups.   
Secondary 
Objectives
Other secondary 
● To assess the safety and tolerability of PDR001 in each group and in the overall 
study population.
● To evaluate in each group additional efficacy parameters per RECIST 1.1 and per 
Immune Response Criteria irRECIST as well as 1-year and 2-year OS rate
● To evaluate biochemical response to treatment (based on CgA and NSE) in each 
group
● To characterize the pharmacokinetics of PDR001 with 400 mg flat dose Q4W in 
each group
● To characterize patient’s health-related quality of life with PDR001 in each group
● To evaluate the prevalence and incidence of immunogenicity in each group
Study design
This is a phase II, single-arm, open-label, multi-center study.
Population
Patients with unresectable advanced or metastatic, well-differentiated, non-functional 
NETs of GI, pancreatic or thoracic origin, or poorly-differentiated GEP-NEC who have 
progressed on or after prior available treatments. 
● A total of approximately 90 patients will be enrolled in the well-differentiated group, 
with approximately 30 patients enrolled in each cohort based on tumor origin. 
Approximately 20 patients will be enrolled in the poorly-differentiated GEP-NEC group, 
for a total number of approximately 110 patients.


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Key Inclusion 
criteria
● Pathologically confirmed, advanced (unresectable or metastatic):
● Well-differentiated (G1/2) based on local pathology report, non-functional 
neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) 
origin.
● Poorly-differentiated GEP-NEC based on local pathology report
● No active symptoms related to carcinoid syndrome during the last 3 months prior to 
start of study treatment.
● Patients must have received prior treatment for advanced disease:
● Well-differentiated NET group:
● Thoracic (lung and thymus origin) cohort: 
● Thymus origin: at least one prior systemic therapy according to 
investigator’s choice.
● Lung origin: at least one prior systemic therapy is required, which must 
include everolimus. 
● GI cohort: at least two prior systemic regimens, which must include 
everolimus. Prior systemic therapies may include: somatostatin analogs, 
PRRT, and/or chemotherapy.
● PNET cohort: at least two prior systemic regimens, which must include 
everolimus or sunitinib. Prior systemic therapies may include: somatostatin 
analogs, PRRT, and/or chemotherapy.
Note: For well-differentiated NET, prior treatment with interferon alpha is 
allowed provided that it is not the last treatment received prior to study entry 
● Poorly-differentiated GEP-NEC group: At least one prior chemotherapy 
regimen according to Investigator’s choice.
● Tumor biopsy material must be provided for all patients 
 
:
● Well-differentiated (G1/2) NET: Biopsy material must be provided following the 
diagnosis of metastatic disease. The tumor sample must be collected from a 
metastatic site not previously irradiated and should preferably be taken within 6 
months but not more than  24 months prior to start of study treatment. 
●Poorly-differentiated  GEP-NEC: Biopsy material must be collected from the 
primary tumor or from a metastatic site not previously irradiated, taken not more 
than 24 months prior to start of study treatment.
● Radiological documentation of disease progression:      
● Well-differentiated NET group: disease progression while on/or after the last 
treatment; progression must have been observed within 6 months prior to start of 
study treatment (i.e. maximum of 24 weeks from documentation of progression 
until study entry). Disease must show evidence of progression based on scans 
performed not more than 12 months apart.     
● Poorly-differentiated GEP-NEC group: disease progression while on/or after 
prior treatment
● At least one measurable lesion assessed by CT and/or MRI according to RECIST 
1.1. Note: Any lesions which have been subjected to percutaneous therapies or 
radiotherapy should not be considered measurable, unless the lesion has clearly 
progressed since the procedure.
Key Exclusion 
criteria
● Well-differentiated, grade 3 neuroendocrine tumors; poorly differentiated 
neuroendocrine carcinoma of any origin (other than GEP-NEC) including NEC of 
unknown origin, adenocarcinoid, and goblet cell carcinoid
● Pretreatment with interferon as last treatment prior to start of study treatment.
● Prior treatment for study indication with:
    ● Antibodies or immunotherapy within 6 weeks before the first dose of study 
treatment.
    ● PRRT administered within 6 months of the first dose.
    ● Systemic antineoplastic therapy (including cytotoxic chemotherapy, and toxin 
immune-conjugates) or any experimental therapy within 14 days or 5 half-lives, 
whichever is longer, before the first dose of study treatment. For cytotoxic agents that 


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have major delayed toxicities a washout period of more than 6 weeks is required 
(examples are nitrosoureas and mitomycin C).
    ● Tyrosine kinase inhibitors within 14 days or 5 half-lives, whichever is longer, 
before the first dose of study treatment.
    ● Prior PD-1- or PD-L1-directed therapy.
    ● Cryoablation, radiofrequency ablation, or trans-arterial embolization of   hepatic 
metastases within 2 months before the first dose of study treatment.
● History of severe hypersensitivity reactions to other monoclonal antibodies which in 
the opinion of the investigator may pose an increased risk of a serious infusion 
reaction.
● Known history or current interstitial lung disease or non-infections pneumonitis.
● Use of somatostatin analogs or any other medications administered to control active 
symptoms related to carcinoid syndrome during the last 3 months prior to start of study 
treatment.
Investigational 
and reference 
therapy
PDR001 (flat dose, 400mg, Q4w); Drug formulation (PDR001 100 mg powder for 
solution for infusion)
Efficacy 
assessments
Radiological tumor assessments performed (per RECIST 1.1 and irRECIST)
before the primary analysis cut-off date (10-Aug-2018):
● At screening
● Treatment Period: Every 8 weeks from Cycle 1 Day 1 for the first 13 cycles and 
every 12 weeks from Cycle 13 Day1 thereafter 
● EOT: If a scan was not conducted within 30 days prior to end of study treatment  
● Efficacy follow-up: Continue same schedule as during treatment period until blinded 
independent review committee (BIRC) confirmed irRECIST progression
Survival phone calls Q3 months after safety and efficacy follow up period.
Radiological tumor assessments performed after the primary analysis cut-off 
date (10-Aug-2018):
●Treatment Period: Assessments scheduled according to local or institutional 
standards of care, and when clinically indicated, until locally-determined disease 
progression (per RECIST 1.1 or irRECIST). All tumor response assessments will be 
performed by investigator locally and reported in the eCRF.
●EOT: no scan is needed to be perfomed at EOT 
Survival phone calls Q3 months after safety and efficacy (if applicable) follow up 
period(s).
Safety 
assessments
● Physical examination
● ECOG Performance status (PS)
● Weight and vital signs
● 12-lead ECGs
● Laboratory assessments, including hematology, chemistry, thyroid function, 
coagulation, hepatitis testing, urinalysis, and cytokine analysis
● Pregnancy testing for women of child-bearing potential
● Adverse events (AEs), the severity, the relationship to study treatment and the 
seriousness
There will be no changes in safety assessments after the primary analysis cut-
off date (10-Aug-2018).
Other 
assessments
Other assessments performed before the primary analysis cut-off date (10-Aug-
2018):
● Pharmacokinetics (Ctrough) and Immunogenicity (ADA)
 
● Patient reported outcomes assessment by the European Organization for Research 
and Treatment of Cancer quality of life (EORTC QLQ-C30) and EuroQoL (EQ-5D) 
questionnaire
 


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Data analysis
No formal hypothesis testing will be used for the primary analysis. The primary efficacy 
variable of the study is overall response rate (ORR), defined as the proportion of 
patients with best overall response (BOR) of complete response (CR) or partial 
response (PR), as per RECIST 1.1 and blinded independent central review. 
● Well-differentiated NET Group:
The response rate on all patients with 95% two-sided confidence interval (exact 
method) will be computed. In the absence of an established control treatment, ORR 
reported in the placebo arms of studies in NET can serve as a reference. A 3% ORR is 
therefore considered as a reasonable reference while an improvement up to 10% is 
considered as clinically meaningful in this patient population.
The study will be considered a success in this group if both of the following conditions 
are met:
a. a clinically relevant response rate of at least 10% is observed
b. 95% two-sided CI for ORR excludes the value 3%. 
● Poorly-differentiated GEP-NEC Group:
Estimates of the ORR along with 95% confidence intervals will be presented and the 
interval probabilities for the true ORR lying within the intervals stated below will be 
assessed:
0 - <3% unacceptable efficacy
3% - <10% limited efficacy
10% - <20% moderate efficacy
20% clinically relevant efficacy.
Key words
PDR001, immunotherapy, PNET, GI NET, thoracic NET, GEP-NEC


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Neuroendocrine tumors (NETs) are heterogeneous entities with a pathological interrelation 
originating from the diffuse neuroendocrine cell system. While NETs are not frequent, their 
prevalence has been increasing over the last 20 years (Yao 2008). Furthermore, their incidence 
has also increased, rising to 5 per 100,000 in recent years from 1 per 100,000 in the early 1970s 
(Dong 2012). However, it is not fully proven that this increase is a result of better recognition 
of these pathologic entities or rather a true increase of the incidence of the disease. NETs can 
be further sub classified according to their embryologic origin: hindgut (rectum and distal 
colon), midgut (proximal large bowel, ileum, appendix and jejunum) and foregut (stomach, 
duodenum, thymus and lung) (Dong 2012). The majority of NETs are located in the gastro-
intestinal (GI) tract (more than 60% of all NETs and they are also known as 
gastroenteropancreatic NETs [GEP-NETs]) or in the lungs (almost 30%). The most frequent 
sites of primary GEP-NET are the: small intestine (28%), appendix (20%), pancreas (16%), 
rectum (15%), colon (13%) and stomach (9%). Distant metastases at diagnosis are relatively 
rare for primary tumors of the appendix (3%), rectum (6%) and stomach (15%); whereas the 
metastases are more frequent for small intestine (45%), pancreas (42%) and colon (40%) 
(Frilling 2014).
Neuroendocrine tumors are classified into 3 broad histologic categories based on tumor 
differentiation: well-differentiated (G1); intermediate-grade (G2); and poorly-differentiated, 
high grade tumors (NCCN Guidelines V1.2017). Neuroendocrine carcinomas represent 
approximately only 15% of all NETs (Yao 2008). Tumor differentiation and tumor grade often 
correlate with mitotic count and Ki-67 proliferation index (Kloppel 2010; Rekhtman 2010). The 
gastroenteropancreatic (GEP) tract is the most common site of extrapulmonary NET accounting 
for 35% to 55% of all neuroendocrine tumors originating from the lung (Garcia Carbonero 
2016).
The classification of neuroendocrine tumors in functioning or non-functioning is based on the 
presence of symptoms that accompany these syndromes secondary to the secretion of hormones, 
neuropeptides, and/ or neurotransmitters (functioning tumors). Non-functioning tumors are 
considered to be neoplasms of neuroendocrine differentiation that are not associated with 
symptoms attributed to the hypersecretion of metabolically active substances. Presentation of 
non-functional tumors is either due to an incidental finding or a tumor mass effect (Gut 2015).
Well-differentiated NETs are characterized by an indolent course; however, curative surgery is 
often not possible because the majority of patients present with metastatic disease at the time 
of diagnosis, with regional or distant tumor spread seen in 50% of patients (Yao et al 2008).
Poorly-differentiated neuroendocrine carcinomas are characterized by a high proclivity to 
metastatic dissemination even in patients with localized tumors (Strosberg 2010). 
Approximately two thirds of patients present with advanced disease dominated by site-specific 
tumor-derived symptoms and a syndrome characteristic of advanced cancer (anorexia, weight 
loss and fatigue) (Strosberg 2010).


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1.1.1
Current treatment options
In patients with well-differentiated G1 or G2 inoperable NET, the treatment goal is to control 
secretory symptoms (if the tumor is functional), to control tumor growth, and to prolong 
survival. Biotherapy with somatostatin analogs (SSAs) remains the mainstay of symptomatic 
therapy as well as an active treatment to control disease burden in well differentiated NET of 
lung, GI or pancreatic origin (NCCN Guidelines v13 2015; Igarashi 2015; Noel-Savina 2013). 
Specifically with regards to gastrointestinal NET, different studies have assessed SSA treatment 
demonstrating superiority versus placebo: 

PROMID study included treatment-naive patients with metastatic midgut NET; results 
showed that octreotide LAR (long-acting release) increased time to tumor progression 
(TTP) when compared to placebo from 6 months to 14.3 months (p=0.000072) (Rinke 
2009). 

CLARINET study included patients with advanced, well or moderately differentiated, 
nonfunctioning, non-progressing GEP-NET; results showed that lanreotide treatment was 
associated with significantly prolonged median PFS (mPFS) when compared to placebo 
(not reached vs. 18.0 months, p<0.001) (Caplin 2014).
The phase III NETTER-1 study confirmed the efficacy of peptide radionuclide receptor therapy 
(PRRT) in patients with well-differentiated midgut NETs after failure of octreotide treatment. 
This study evaluated 177Lu-DOTATATE plus octreotide LAR vs. octreotide LAR. The mPFS 
was 8.4 months with octreotide LAR and the median PFS was not reached with 177Lu-
DOTATATE (HR = 0.21; P < .0001). The estimated rate of PFS at month 20 was 65.2% (95% 
CI, 50.0 to 76.8) in the 177Lu-DOTATATE group and 10.8% (95% CI, 3.5 to 23.0) in the 
control group. Tumor response rate was 3% and 18.8% with octreotide LAR and 177Lu-
DOTATATE,
respectively (Strosberg 2016,
Strosberg 2017). In Sep-2017, 177Lu-
DOTATATE received approval in the EU for the treatment of unresectable or metastatic, 
progressive, 
well 
differentiated 
(G1 
and 
G2), 
somatostatin 
receptor 
positive 
gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults. In Feb-2018 177Lu-
DOTATATE received FDA approval for the treatment of somatostatin receptor-positive GEP-
NETs, including foregut, midgut, and hindgut neuroendocrine tumors in adults.
Limited antineoplastic therapy options are currently available for patients with progressive 
metastatic NET of GI and lung origin:

RADIANT-2 study included patients with advanced functional NET and assessed 
everolimus-octreotide vs. placebo-octreotide. Results showed a mPFS of 16.4 months 
(95% CI 13.7–21.2) in the experimental arm vs. 11.3 (8.4–14.6) months in the placebo 
arm (HR 0.77, 95% CI 0.59–1·00; p=0.026) (Pavel 2011). 

Cytotoxic therapy appears to provide a modest benefit. Although different agents have 
been evaluated (including capecitabine, temozolamide, streptozocin, doxorubicin), 
response rates are generally low and no PFS benefit have been clearly demonstrated 
(NCCN guidelines 2015).  

RADIANT-4 study included patients with advanced, progressive non-functional NET of 
GI or lung origin. Everolimus demonstrated superiority over placebo in terms of PFS 
showing a 52% relative risk reduction of progression/death in favor of everolimus (HR: 
0.48; 95% CI: 0.35, 0.67) (p<0.001) (Yao 2016). Based on these results, submissions 


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worldwide have thus far led to marketing authorization of everolimus in progressive, 
nonfunctional NET of GI or lung origin in over 41 countries including the US, EU, 
Canada, and Japan.
The systemic treatment options for non-functional advanced pancreatic NET (PNET) include 
chemotherapy, somatostatin analogs and targeted agents such as everolimus and sunitinib. Both 
targeted agents, sunitinib and everolimus, are approved by health authorities worldwide for the 
treatment of advanced PNET based on the pivotal studies described below:

RADIANT-3 study included patients with advanced and progressive PNET and assessed 
everolimus vs. placebo (Yao 2011). The study results showed that mPFS was 11.0 months 
with everolimus as compared with 4.6 months with placebo (HR=0.35; P<0.001). Subset 
analyses of RADIANT-3 showed that the PFS effect of everolimus was independent of 
prior or concurrent SSA therapy or chemotherapy.

A randomized phase III study evaluated sunitinib in patients with progressive metastatic 
PNET. The study was stopped before the predefined analysis; the investigator-assessed 
mPFS for sunitinib arm was 11.4 months compared to 5.5 months in the placebo arm, 
resulting in a HR of 0.42 (p=0.0001) (Raymond 2011). 

Furthermore, cytotoxic therapy (including streptozocin, temozolamide, doxorubicin, 
dacarbazine) has been assessed in a number of regimens in PNET yielding response rates 
in the range of 8%-39% with limited long-term disease control. As of today, there is no 
panel consensus on which cytotoxic regimen is preferred (NCCN 2015). Streptozocin is 
the only FDA-approved agent among the cytotoxic agents for use in patients with 
advanced PNET.
Recently, the Keynote 028 study reported results of pre-treated patients with PD-L1-positive, 
advanced carcinoid (=25) or PNET (=16) treated with pembrolizumab as single agent. The 
study results showed an ORR of 12% and 6% in carcinoid group and PNET group, respectively 
(no Complete Response was observed). The majority of patients have stable disease as best 
overall response, in 60% and 88% in carcinoid group and PNET group, respectively. The 
duration of disease stabilization was above 6 months in 32% of patients with carcinoid tumors 
and 31% of patients with PNET. The mPFS in carcinoid group was 5.6 months (95% CI, 3.5 to 
10.7) and in PNET group was 4.5 months (95% CI, 3.6 to 8.3); the mOS observed in both 
cohorts was 21 months (Mehnert 2017).
Table 1-1 provides an overview of the clinical experience summarized in literature of various 
therapies in NET.
Table 1-1
Clinical Experience in NET – Literature review of clinical studies
Study
Treatment
Population
ORR
PFS/TTP
OS
Ph II PROMID 
study (n=90)
(Rinke 2009)
Octreotide 
LAR vs. 
Placebo (1:1)
G1/2 Midgut
No ORR
SD: 66.7%
mPFS:
LAR: 14.3 mo
Placebo: 6 mo
HR: 0.81 at 84 
mo
Ph III CLARINET 
study (n=204) 
(Caplin 2014)
Lanreotide vs. 
Placebo
Advanced, well-
mod. 
differentiated 
G1/2 NET (GI, 
pancreas, 
unknown origin) 
NR*
mPFS:
Lanreotide: not 
reached
Placebo:18 mo 
Cross-over 
(difficult 
assessment), 
not different 
between 
groups


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Study
Treatment
Population
ORR
PFS/TTP
OS
Ph III RADIANT-
2 study (n=429)
(Pavel 2011) 
Everolimus 
+Octreotide 
vs. 
Placebo-
Octreotide
Functional NET 
(GI, lung, 
pancreas). Low/ 
intermediate 
grade (24% 
functional)
Everolimus-
Octreotide: 
2.3%
Placebo-O: 
1.9%
mPFS: 
Everolimus-
Octreotide: 16.4 
mo
Placebo: 11.3 mo
NR
Ph III RADIANT-
4
Study (n=302) 
(Yao 2016)
Everolimus vs. 
Placebo
NET GI or lung 
origin G1/2 non-
functional
Everolimus: 
2%
Placebo: 1%
mPFS:
Everolimus: 11.0 
mo
Placebo: 3.9 mo
HR: 0.64;95% 
CI: 0.40, 1.05; 
p= 0.037
Ph II Carcinoids 
and pNET study  
(n=109)
(Kulke 2008)
Sunitinib
(2L, prior 
chemo 
allowed)
Carcinoid (n=41)
pNET (n=66)
Carcinoid: 
2.4%
pNET: 16.7%
mTTP**:
carcinoid:10.2 
mo
pNET: 7.7 mo
1-yr OS rate
Carcinoid: 
83.4%;
pNET:81.1%
Ph III pNET 
study
(n=171)
(Raymond 2011)
Sunitinib vs. 
Placebo (1:1)
G1/2 advanced 
pNET
Sunitinib: 
9.3%
Placebo: 0%
mPFS:
Sunitinib:11.4 mo
Placebo: 5.5 mo
HR: 0.42 
(p=0.001
HR: 0.41 
p=0.02
Ph III RADIANT-
3 pNET study 
(n=410)
(Yao 2011)
Everolimus vs. 
Placebo
(pretreated 
SSA, Chemo)
Advanced, low or 
intermediate 
grade
pNET
Everolimus: 
4.8%
Placebo 2.0%
mPFS:
Everolimus: 11 
mo
Placebo: 4.6 mo
NR
Phase III 
NETTER-1  
Midgut NET
(n= 299) 
(Strosberg 2016)
PRRT + OCT 
vs. OCT)
Advanced, well-
differentiated
Midgut
PRRT: 1.8%
OCT: 3%
mPFS: 
PRRT: Not 
reached
OCT: 8.4 mo 
HR: 0.209
NR
*NR = Not reported
** mTTP = median Time To Progression
The treatment strategies of poorly-differentiated neuroendocrine carcinoma are often 
extrapolated from the treatment paradigm of small cell lung cancer (SCLC) (Sorbye 2014). 
There are no prospective studies conducted in gastroenteropancreatic neuroendocrine 
carcinoma (GEP-NEC), most of the studies reported are retrospective with limited sample size. 
Based on its established role in SCLC, cisplatin and etoposide is the most widely used regimen 
in GEP-NET in the front line setting with response rates in the range of 42% to 67% and median 
survival of approximately 15 to 19 months (Moertel 1991; Mirty 1999). More recent data 
suggest that the clinical outcome in patients with GEP-NEC may be worse than previously 
reported. In a retrospective study, 252 patients with advanced GEP-NEC received 
cisplatin/etoposide or carboplatin/ etoposide (Sorbye 2013) reporting an ORR of 31%, median 
PFS of 4 months with a median survival of 11 months. No differences in outcome were observed 
when comparing cisplatin-based treatment versus carboplatin-based treatment. Upon 
progression on front line platinum based therapy, no standard therapy has been established for 
GEP-NEC. Retreatment with cisplatin is an option as well as different regimens are considered 
(including FOLFOX, XELOX, temozolamide plus capecitabine) as well as single agent therapy 
(including temozolamide, irinotecan, taxanes or amrubicin) (Garcia-Carbonero 2016). On small 
retrospective studies, the response rates ranges from 18% to 31%; with a median PFS of 
approximately 4 months and survival in the range of 6 to 9 months (Hadoux 2013; Hentic 2012; 
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1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of PDR001 
PDR001 is a high-affinity, ligand-blocking, humanized IgG4 antibody directed against 
Programmed Death-1 (PD-1) receptor that blocks the binding of PD-L1 and PD-L2. PD-1 is a 
critical immune-checkpoint receptor that is expressed on CD4 and CD8 T cells upon activation 
(Freeman 2008). Engagement of PD-1 by its ligands, PD-L1 and PD-L2, transduces a signal 
that inhibits T-cell proliferation, cytokine production, and cytolytic function (Riley 2009). 
Monoclonal antibody (mAb) inhibitors of immunological checkpoints, including PD-1 and PD-
L1, have demonstrated significant antitumor activity in patients with various solid tumors. For 
further details please refer to the latest PDR0001 [Investigator’s Brochure].
1.2.1.1
Non-clinical experience of PDR001
PDR001 binds specifically and with high affinity to human PD-1 and enhances interleukin-2 
production in ex-vivo lymphocyte stimulation assays. It does not cross react with rodent PD-1; 
therefore, toxicology studies were performed only in cynomolgus monkeys where there was 
acceptable cross reactivity with monkey PD-1. Repeat administration of PDR001 to monkeys 
was tolerated at all doses tested up to 100 mg/kg/week for 5 weeks in the GLP toxicology single-
agent study. No test article-related in-life, mortality, organ weight changes, or macroscopic 
findings were noted. There were no PDR001-related effects seen in any of the safety 
pharmacology endpoints assessed (cardiovascular, neurobehavioral, and respiratory). 
Macrophage infiltrates into the splenic white pulp were observed in animals given 100 
mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around the 
injection site blood vessel (saphenous vein) in a few animals given ≥25 mg/kg/week. These 
PDR001-related microscopic changes were fully reversible after an eight week recovery. 
Additionally, mostly low grade mononuclear infiltrates in the vascular and perivascular space 
in several tissues of main and recovery treated animals and in recovery controls were observed 
but with a slightly higher incidence in treated animals. No evidence of parenchymal damage 
was associated with the vascular/perivascular changes in any of the organs examined and the 
changes were not associated with any frank tissue injury. Dose-proportional exposure to 
PDR001 in each dose group was confirmed. Anti-drug antibodies (ADA) to PDR001 were 
observed in some PDR001 treated cynomolgus monkeys. A trend of reduced drug exposure was 
observed in these ADA-positive animals. Based on the toxicology studies with PDR001 as a 
single-agent, the Highest Non-Severely Toxic Dose (HNSTD) dose is 100 mg/kg. For further 
details, please refer to the latest PDR001 [Investigator’s Brochure].
1.2.1.2
Clinical experience of PDR001
At the time of the release of the protocol amendment 2; three studies assessing PDR001 single 
agent in patients with advanced solid tumors as well as other malignancies (including melanoma, 
non-small cell lung cancer, triple negative breast cancer and anaplastic thyroid cancer) have 
reported preliminary safety data included in the Investigator Brochure version 6.


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CPDR001X2101 Study:
A summary of preliminary clinical safety information reported from the first-in-human study is 
provided below (cut-off date 14-Nov-2016):
A total of 160 patients were exposed to PDR001 single-agent. In the phase I part of the study, 
58 patients had been treated at doses of 1 mg/kg Q2W (16 patients) for up to 78 weeks, 3 mg/kg 
Q2W (15 patients) for up to 60 weeks, 10 mg/kg Q2W (11 patients) for up to 34 weeks, 3 mg/kg 
Q4W (6 patients) for up to 33 weeks and 5 mg/kg Q4W (10 patients) for up to 57 weeks. In the 
phase II part of the study, 102 patients had been treated in five groups: NSCLC 400 mg Q4W 
(33 patients), NSCLC 300 mg Q3W (1 patient), melanoma 400 mg Q4W (24 patients), TNBC 
400 mg Q4W (40 patients) and anaplastic thyroid cancer 400 mg Q4W (4 patients). In the phase 
II part of the study, the median duration of exposure to study treatment was 8.0 weeks (range 
1.0 - 35.1). No Dose Limiting Toxicities (DLTs) were reported. One-hundred twenty seven 
patients (79.4 %) have permanently discontinued study treatment, 5 due to an AE, 97 due to 
progression of disease, 8 due to subject/guardian decision, 4 due to physician decision and 13 
due to death. None of the deaths were attributed to study treatment. 
Of the 160 patients treated, 79 (49.4 %) experienced AEs (all grades) suspected to be related to 
study treatment. Most frequent suspected AEs (≥ 5 % of patients) included fatigue (24 patients, 
15.0 %), nausea (14 patients, 8.8 %), pruritus (13 patients, 8.1 % ), diarrhea (12 patients, 7.5 %) 
and hypothyroidism (10 patients, 6.3 %). Of the 160 patients treated, 84 (52.5 %) experienced 
grades 3 or 4 AEs regardless of relationship to study drug. Of these grades 3/4 AEs, the 
following were suspected to be related to study treatment: two cases of vomiting and individual 
cases of increased ALT, increased AST, hypocalcemia, increased lipase, autoimmune hepatitis, 
autoimmune colitis, nausea, hyperglycemia, decreased lymphocyte count, and decreased weight. 
SAEs regardless of relationship to study drug, were reported in 61 (38.1 %) patients. Seven 
serious adverse events (SAEs) were observed in five patients were suspected to be related to 
study treatment per investigator’s assessment. 
CPDR001X1101 Study:
A summary of preliminary clinical safety information reported from this study conducted in 
Japanese patients with solid tumors is provided below (cut-off date 25-Nov-2016):
Eighteen patients had been enrolled and treated with PDR001 at doses of1 mg/kg Q2W (6 
patients) for up to 27 weeks, 3 mg/kg Q2W (6 patients) for up 28 weeks, and 10 mg/kg Q2W 
(6 patients) for up to 14 weeks. No DLTs were reported. Sixteen patients (88.9 %) have 
permanently discontinued study treatment, 2 patients (11.1 %) due to an AE, 6 patients (33.3 %) 
due to progression of disease, and 8 patients (44.4 %) due to physician or subject/guardian 
decision. AEs suspected to be related to study treatment: Of the 18 patients treated, 11 patients 
(61.1 %) experienced AEs (all grades) suspected to be related to study treatment. The most 
frequent suspected (≥ 10 % of patients) AEs included maculo-papular rash (4 patients, 22.2 %), 
ALP increased (2 patients, 11.1 %) and malaise (2 patients, 11.1 %). Of the 18 patients treated, 
nine patients (50.0 %) experienced grade 3 or grade 4 AEs regardless of relationship to study 
drug. Of note, one grade 3 ALT increased and one grade 3 creatine phosphokinase increased 
were suspected to be related to study treatment. SAEs, all grades, regardless of relationship to 
study drug, were reported in 7 (38.9 %) patients. Two SAEs (grade 2 myositis and grade 1 


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interstitial pneumonia) were suspected to be related to study treatment per investigator’s 
assessment.
CPDR001X2201 Study: 
A summary of preliminary clinical safety information reported from this study conducted in 
patients with nasopharyngeal carcinoma is provided below (cut-off date: 02-Dec-2016):
Thirty-two patients had been enrolled and treated with PDR001 at the dose of 400 mg Q4W for 
up to 23 weeks. Fourteen patients (43.8 %) have permanently discontinued study treatment, 11 
(34.4 %) due to progression of disease, 1 (3.1 %) due to physician decision, 1 (3.1 %) due to 
subject/guardian decision and 1 (3.1 %) due to death (caused by progressive disease). Eighteen 
(56.3 %) patients are still on treatment. Of the 32 patients treated, 16 (50%) experienced AEs 
(all grades) suspected to be related to study treatment. The most frequent suspected AEs 
included fatigue, pyrexia, rash and hyponatremia (each in 3 patients, 9.4%), pneumonia, 
asthenia, decreased appetite and malaise were observed in 2 patients (6.3%). Of the 32 patients, 
11 (34.4 %) experienced grade 3 or grade 4 AEs regardless of relationship to study drug. Grade 
3 or 4 AEs suspected to be related to PDR001 were observed in 5 (15.6 %) patients. These 
included 3 patients with hyponatremia (9.4 %), 2 patients with pneumonia (6.3 %) and 1 patient 
with decreased appetite (3.1 %). SAEs, all grades, regardless of relationship to study drug, were 
reported in 7 (21.9 %) patients treated with PDR001. Three patients experienced an SAE 
suspected to be related to study drug.
For additional details on the monotherapy studies above mentioned or on ongoing studies with 
PDR001 in combination with other agents, please refer to the PDR001 Investigator Brochure.
CPDR001E2201 Study: Results of the interim and additional efficacy analysis
Planned interim analysis was performed with a data cut-off of 29-Nov-2017 after approximately 
30 patients in the well-differentiated NET group had undergone the first 3 radiological 
assessments, had shown disease progression, or had discontinued efficacy follow-up for any 
other reason. The full analysis set included 95 patients in the well-differentiated NET group (30 
patients in the thoracic cohort, 33 patients in the pancreatic cohort and 32 patients in the GI 
cohort) and 21 patients in the poorly-differentiated GEP-NEC group. Median duration (range) 
of follow-up (from treatment to data cut-off date) was 5.3 months (3.7-8.5 months) and 3.6 
months (2.3-4.6 months) in the well-differentiated NET and poorly-differentiated GEP-NEC 
groups, respectively. With this limited follow up, the overall response rate (ORR) per RECIST 
1.1 based on central radiology review was 3.2% in the well-differentiated NET group (10.0 % 
in the thoracic cohort, 0% in the pancreatic cohort, and 0% in the GI cohort) and 0% in the 
poorly-differentiated GEP-NEC group.
Safety analysis excluded events occuring 30 days after study treatment discontinuation. The 
most common adverse events (AEs) (≥15% in all patients; all grades) reported at the time of 
the interim analysis were fatigue (34.7% in well-differentiated NET cohort and 14.3% in
poorly-differentiated GEP-NEC cohort), pyrexia (25.3% and 9.5%, respectively), diarrhea (20.0% 
and 14.3%, respectively), nausea (16.8% and 28.6%, respectively), abdominal pain (18.9% and 
9.5%, respectively), and constipation (16.8% and 14.3%, respectively). The most common 
grade 3/4 AEs (≥2 of patients in each group) in well-differentiated NET cohort were abdominal 
pain and anemia (each in 4 patients), hypertension (3 patients), and fatigue and dyspnoea (each


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in 2 patients). Abdominal pain, cough and back pain (each in 2 patients) were the most common 
grade 3/4 AEs in poorly-differentiated GEP-NEC cohort. No fatal SAEs were reported at the 
time of this analysis. 
An additional efficacy analysis was performed with a data cut-off of 09-Feb-2017. The ORR 
per RECIST 1.1 based on central radiology review, was 7.4% (7 patients with partial response 
[PR]) in the well-differentiated NET group and 4.8% (1 patient with PR) in the poorly-
differentiated GEP-NEC group. In the well-differentiated NET group, the ORR in 3 different 
cohorts were: 20.0% in the thoracic cohort (6 patients with PR of 30 evaluated; assessments of 
response duration was limited by the 2 deaths observed among 6 responders), 3.0% in the 
pancreatic cohort (1 patient with PR of 33 evaluated), and 0 in the GI cohort (of 32 evaluated; 
however, 1 unconfirmed PR was reported in the GI cohort at the time of the cut-off). 
The study is ongoing and further assessments for efficacy and safety continue. The primary 
analysis of the study will be performed 1 year after Last Patient First Treatment (LPFT) in the 
initially enrolled well-differentiated NET group.
2
Rationale
2.1
Study rationale and purpose
During tumorigenesis, cancer cells from a wide range of tumor types exploit immune 
checkpoint pathways, such as PD-1, 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 to improved cytolytic activity towards tumors. 
Additionally, PD-1 blockade is associated with a reduced numbers of regulatory T cells (Tregs) 
at the tumor site (Wang 2009, Mangsbo 2010).
Monoclonal antibody (mAb) inhibitors of immunological checkpoints, including anti-PD-1 and 
anti-PD-L1, have demonstrated significant antitumor activity in patients with various solid 
tumors. Two mAbs targeting PD-1, pembrolizumab and nivolumab, have demonstrated 
significant single agent activity in melanoma, non-small cell lung cancer, renal cancer, head 
neck cancer and Hodgkin's lymphoma among other solid tumors (Topalian 2012, Hamid 2013b, 
Topalian 2014, Seiwert 2014, Motzer 2015, Gillison 2016; Ansell 2015). 
Although many advances with checkpoint inhibitors have been made in other tumor types, the 
data generated in NETs is limited with no clinical experience available to date. Recent 
correlative studies conducted in NETs have assessed the expression of PD-L1 and correlated 
tumor differentiation with poor clinical outcome (Kim 2016; Cives 2016). 
Tumor-infiltrating lymphocytes (TILs) have been shown to predict survival in numerous 
malignancies. The importance of TILs in PNET and NET with liver metastases was assessed 
by immunohistochemistry (IHC) in a cohort of 126 patients who had undergone resection. 
Analysis of intermediate-grade NETs indicated that a dense T cell (CD3+) infiltrate was 
associated with a median relapse-free-survival (RFS) of 128 months compared with 61 months 
for those with low levels of intratumoral T cells infiltrate (P = 0.05, univariate analysis). 
Examination of liver metastasis revealed that a low level of infiltrating regulatory T cells (Treg, 
FoxP3+) was a predictor of prolonged survival (P < 0.01, univariate analysis). Therefore a 


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robust T cell infiltration is associated with improved RFS following resection of intermediate-
grade NETs, whereas the presence of a tumor environment rich in Tregs correlated with shorter 
OS after treatment (Katz 2010). These findings suggest that the immune-modulation of the 
phenotype of T cells may play a role in clinical outcome.  
PD-L1 and PD-1 expression was assessed by immunohistochemical analysis in tumor samples 
of 80 patients with lung NET showing a 59% and 51.3% expression rate, respectively (Fan 
2016). A similar analysis was conducted on 20 corresponding cancer-adjacent tissue specimens 
revealing an expression rate of 25% and 20% for PD-L1 and PD-1, respectively. PD-L1 
expression was significantly related to tumor stage and histological type (carcinoids, SCLC, 
LCNEC) (p=0.014). Survival analysis demonstrated a correlation with PD-L1 expression in 
tumor cells (8.9 months in PD-L1 Positive vs. 25.6 months in PD-L1 Negative); this correlation 
was also observed in tumor in TILs (8.9 months in PD-L1 Positive vs. 26.8 months in PD-L1 
Negative). This results suggest that PD-L1 expression can be useful prognostic marker for 
survival.
PD-L1 expression on tumor cells was analyzed by immunohistochemistry in 32 patients with 
GEP-NET showing a 22% expression rate in tumors (Kim 2016). PD-L1 expression was 
significantly associated with high-grade tumors (p=0.008). Moreover, the status of PD-L1 
expression could predict survival; the median overall survival (mOS) was 16.0 months in 
patients with PD-L1–positive tumors and 24.8 months in those with PD-L1 negative tumors
(p=0.037).
Clinical data available from one patient with histologically confirmed metastatic atypical 
pulmonary carcinoid treated in the ongoing PDR001 phase I study in solid advanced tumors 
[CPDR001X2101] showed an immune-related partial response with resolution of multiple liver 
and pleural metastases. The patient is a non-smoker, and tumor histology has been confirmed 
by central pathology as consistent with atypical carcinoid. Interestingly, tumor from this patient 
harbored 19 non-synonymous mutations only on the whole exome sequencing, suggesting that 
mutational burden in carcinoid tumors may not be the main driver of response to immune 
checkpoint inhibitors therapy. Patient has been on therapy for nine months, and at the last tumor 
imaging assessment a sustained partial response according to RECIST 1.1 criteria was observed 
with sustained regression in all areas of tumor (Naing 2016).
2.2
Rationale for the study design
A single arm study with a primary endpoint of overall response rate (ORR) with supportive key 
secondary endpoint of duration of response (DoR) is proposed to assess the safety and efficacy 
of PDR001 in two different groups of patients:

Patients with well-differentiated (G1 or G2) non-functional, unresectable advanced or 
metastatic NETs of GI, pancreatic or thoracic origin who have progressed on or after prior 
available treatments. 

Patients with advanced or metastatic poorly-differentiated GEP-NEC who have progressed 
on or after one prior chemotherapy regimen. 
A total of approximately 90 patients will be enrolled in the well-differentiated group, with 
approximately 30 patients enrolled in each cohort based on tumor origin. Approximately 20 
patients will be enrolled in the poorly-differentiated GEP-NEC group.


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For patients with well-differentiated non-functional NET who present with disease progression 
after treatment with prior therapy (SSAs, cytotoxic agents and/or targeted therapies depending 
on the anatomical tumor site), there are currently no approved therapies improving the clinical 
outcome (Section 1.1). For patients with poorly-differentiated GEP-NEC no treatments are 
currently approved and currently there is no consensus with regards to the standard of care upon 
progression on first line treatment which typically consists of chemotherapy.   
In the absence of an established treatment to be considered as control, and based on the fact that 
ORR endpoint is appropriate to detect early signs of efficacy in the absence of a control (see 
below), a single arm study design has been proposed. 
A single arm design with an endpoint of ORR with DoR as a key secondary endpoint has been 
utilized as a primary means of evaluation in disease settings where an appropriate comparator 
may not necessarily exist or where currently available therapy does not provide sufficient 
evidence of benefit. Specifically in patients with well-differentiated NET, a considerably long 
overall survival and heterogeneity of survival prognostic factors make a survival endpoint 
unsuitable for an early read-out of treatment efficacy for a novel agent (Yao 2008). The study 
design as proposed is expected to provide initial evidence of benefit by showing an 
improvement in ORR, supported by duration of response, which based on clinical experience 
with PD-1 inhibitors, should serve as an appropriate surrogate to predict clinical benefit. A 
uniformly low ORR has been reported in well-differentiated NET from all tumor origins in 
patients receiving placebo or best supportive care in randomized studies (ranging from 0% to 
2%), (Table 1-1). In patients with advanced and progressive NETs, where available treatments 
have failed, an improvement in terms of ORR would be a relevant indicator of treatment 
efficacy. 
With regards to poorly-differentiated GEP-NEC, there are limited published results, mostly 
from retrospective studies reporting on small series of patients with advanced /metastatic
disease. For this reason, the analysis of the data from this group of patients intends to explore 
the antitumor activity of PDR001 in this population with a high unmet medical need. 
2.3
Rationale for dose and regimen selection
In study [CPDR001X2101], PDR001 single-agent was administered as an intravenous infusion 
over 30 minutes at doses ranging from 1 to 10 mg/kg on an every 2 weeks (Q2W) schedule or 
at 3 and 5 mg/kg every 4 weeks (Q4W) schedules. Approximately dose-proportional increase 
in exposure (C1D1 AUC0-336) was observed with doses from 1 to 10 mg/kg and no DLTs were 
observed. Accumulation of approximately 2.1-3.4-fold was observed with Q2W dosing and 1.6-
2.2-fold with Q4W dosing. Population PK analysis indicated that the changes in exposure due 
to patient weight differences are minimal across the anticipated weight range of 30 to 150 kg 
for the patient population. Therefore, a flat dosing scheme was selected. Two recommended 
phase II dosing regimens have been established: 300 mg Q3W and 400 mg Q4W flat dosing 
schedules. A flat dose of 400 mg Q4W or 300 mg Q3W is expected to achieve a mean steady-
state Ctrough value higher than the ex vivo EC50 for antigen-stimulated IL-2 production, a 
translational biomarker for PD-1 blockade (Patnaik et al, 2015). Based on the safety profile 
observed in study [CPDR001X2101] (Section 1.2) and the expected Ctrough values, 400 mg 
Q4W is expected to be a safe and efficacious dose. 


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2.4
Rationale for choice of comparators drugs 
Not applicable
2.5
Risks and benefits
PDR001 is a humanized IgG4 monoclonal antibody which belongs to a class of agents known 
as immune-checkpoint inhibitors specifically anti-PD-1/PD-L1. This class of compounds has 
demonstrated significant improvement in efficacy combined with a tolerable and manageable 
safety profile, thus supporting recent regulatory approvals in melanoma, non-small cell lung 
cancer, squamous cell carcinoma of the head and neck, bladder cancer, renal cancer and
Hodgkin’s lymphoma.
Immune-checkpoint inhibitors including anti-PD-1/PD-L1 may be associated with the 
occurrence of immune-mediated adverse events (irAE). In general, irAE can potentially involve 
every organ system but gastrointestinal (colitis), dermatologic, hepatic (hepatitis), pulmonary 
(pneumonitis), renal (nephritis) and endocrine toxicities (hypothyroidism, hyperthyroidism, 
diabetes, hypophysitis and hypopituitarism) are the most frequent and rarely CNS (encephalitis). 
These side effects are generally manageable but fatal events have been reported in some cases 
with checkpoint inhibitor compounds (Eggermont 2015; Larkin 2016; Hofmann 2016). 
Appropriate eligibility criteria as well as specific dose modification and stopping rules along 
with AE management guidelines (provided in Section 6.3.1), are included in this protocol. 
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced adverse events i.e., skin toxicity and diarrhea are 
provided in Section 6.3.1.2. The risks to patients in this trial may be minimized by compliance 
with the eligibility criteria and study procedures as well as, close clinical monitoring. There 
may be unforeseen risks with PDR001 which could be serious. Refer to preclinical toxicity and 
or clinical data found in the latest [Investigator’s Brochure].
For patients with unresectable locally advanced or metastatic non-functioning NETs 
progressing on or after currently available therapies, available treatment options are limited 
(Section 1.1). For this reason, PDR001 treatment may provide clinical benefit which will be 
measured as tumor shrinkage (ORR) and time-related parameters (including duration of 
response, PFS, and OS rates at 1 and 2 years). 
The efficacy endpoints will be assessed as per RECIST 1.1 (Appendix 1). Patients may continue 
treatment beyond disease progression by RECIST 1.1 and until disease progression by 
irRECIST if the criteria stipulated in Section 6.1.5.1 are met. This measure intends to minimize 
the risk of early treatment discontinuation for patients who are receiving immune- based 
treatment and experiencing clinical benefit and to allow enough time for the patient’s immune 
system to elicit an effective antitumor response, if it were to develop. 
Taking into consideration the safety profile observed so far, the unmet medical need in this 
population of patients with NET after treatment failure with available standard therapy and the 
measures implemented in the protocol to minimize the risks described above, the benefit-risk 
assessment is deemed acceptable to conduct this study in patients with NETs as part of the 
global clinical development of PDR001.


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3
Objectives and endpoints
Objectives and related endpoints are described in the table below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint(s)
Analysis
Primary
Refer to Section 10.4
To estimate the antitumor activity of 
PDR001 as a single agent in the well-
differentiated NET and poorly-
differentiated GEP-NEC groups.
ORR (confirmed PR and CR) according 
to blinded independent review committee 
(BIRC) radiological assessment by 
RECIST 1.1
Key secondary
Refer to Section 10.5.1
To estimate efficacy of PDR001 in the 
well-differentiated NET and poorly-
differentiated GEP-NEC groups
Duration of Response (DoR) by RECIST 
1.1 and as per BIRC
Other secondary
Refer to Section 10.5.2
To assess the safety and tolerability of 
PDR001 in each group and in the 
overall study population
Frequency and severity of adverse 
events
Other safety data as considered 
appropriate
Refer to Section 10.5.3
To evaluate additional efficacy 
parameters in the well-differentiated 
NET and poorly-differentiated GEP-
NEC groups
Disease Control Rate (DCR),
Time to Response (TTR),
PFS by RECIST 1.1 and as per BIRC
Immune Response Criteria by irRECIST 
and as per BIRC (irORR, irDoR, irTTR, 
irDCR, irPFS)
1-year and 2-year overall survival (OS) 
rate
Refer to Section 10.5.2
To evaluate biochemical response to 
treatment (based on CgA and NSE) in 
the well-differentiated NET and poorly-
differentiated GEP-NEC groups
Changes from baseline in CgA and NSE 
Refer to Section 10.5.6
To characterize the pharmacokinetics 
of PDR001 with 400 mg flat dose Q4W 
in the well-differentiated NET and 
poorly-differentiated GEP-NEC groups
PK parameters (e.g. Ctrough) 
Refer to Section 10.5.4
To characterize patient’s health-related 
quality of life with PDR001 in the well-
differentiated NET and poorly-
differentiated GEP-NEC groups
Global health status/QOL score of the 
EORTC QLQ-C30 and the index score of 
the EQ-5D-5L 
Refer to Section 10.5.8
To evaluate the prevalence and 
incidence of immunogenicity in the well-
differentiated NET and poorly-
differentiated GEP-NEC groups
Antidrug antibodies (ADA) prevalence at 
baseline and ADA incidence on-treatment
Refer to Section 10.5.5


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4
Study design
4.1
Description of study design
This is a phase II, single-arm, open-label, multi-center study in patients with

Well-differentiated, non-functional, grade 1 or 2, neuroendocrine tumors of pancreatic, GI 
or thoracic (including lung and thymus) origins and 

Poorly-differentiated GEP-NEC 
All patients must have progressed on or after the last treatment. (as described in Section 5.1).
A total of approximately 90 patients will be enrolled in the well-differentiated group, with 
approximately 30 patients enrolled in each cohort based on tumor origin. Approximately 20 
patients will be enrolled in the poorly-differentiated GEP-NEC group, for a total number of 
approximately 110 patients.
Treatment duration 
Patients will receive PDR001 at the dose of 400 mg Q4 weeks at flat dosing. Patients will 
continue to receive the assigned study treatment until disease progression by RECIST 1.1 or as 
per irRECIST (see below), unacceptable toxicity, start of a new anti-neoplastic therapy, 
withdrawal of consent, physician’s decision, lost to follow-up, death or the study is terminated 
by the sponsor.
Patients may continue study treatment beyond disease progression by RECIST 1.1 until disease 
progression as per irRECIST, as per BIRC (if criteria stipulated in Section 6.1.5.1 are fulfilled), 
unacceptable toxicity, start of new anti-neoplastic therapy, withdrawal of consent, physician’s 
decision, lost to follow-up, death, or the study is terminated by the sponsor. In case of 
continuation of study treatment beyond disease progression by RECIST 1.1, the patient will 
continue assessments as defined in Section 7. While the investigator is waiting for the results 
from the central imaging vendor confirming disease progression, the patient should continue on 
study treatment. However, during this time, the investigator should do whatever is medically 
necessary for his/her patient.


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After the primary analysis cut-off date (10-Aug-2018):

Response assessments by BIRC will no longer be performed.

Patients, who are on treatment but have not yet progressed per local tumor response 
assessment, will continue study treatment until documentation of disease progression by 
RECIST 1.1 as per local investigator assessment, unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, physician’s decision, subject/guardian decision, 
lost to follow-up, death or the study is terminated by the sponsor. These patients will be 
permitted to continue study treatment beyond initial PD as per RECIST 1.1 until 
confirmed irPD per local assessment (until 2 consecutive irPDs), as described in Section 
6.1.5.1.

Patients who are on treatment beyond disease progression per local tumor response 
assessment (tumor assessment performed before the primary analysis cut-off date (10-
Aug-2018)) are allowed to continue study treatment as long as the patient derives clinical 
benefit from the treatment according to investigator’s best clinical judgement (e.g. no 
deterioration of performance status, no rapid increase in tumor burden, no clinical 
situation requiring alternative treatment), or until unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, lost to follow-up, death, or the study is 
terminated by the sponsor.
Figure 4-1
Study design
4.1.1
Study flow
The study is comprised of the following periods:

Screening

Treatment


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
End of Treatment (EOT)

Safety follow-up: patients will be followed for safety at 30-Days, 60-Days, 90-Days, 120-
Days, and 150-Days after the last dose of PDR001 (Section 7.1.7)

Post-treatment efficacy follow-up: 

Before the primary analysis cut-off date (10-Aug-2018), patients who discontinue 
treatment for reasons other than irRECIST PD will have tumor assessments per Table 
7-1 until withdrawal of consent, death, lost to follow-up, or eventual irRECIST PD 
per BIRC even if new antineoplastic treatment (ANP) is started (Sections 7.1.8 and
Section 7.2.1)

After the primary analysis cut-off date (10-Aug-2018), post-treatment efficacy 
follow-up will be discontinued. Therefore, any patients, who are in post-treatment 
efficacy follow-up at the time of the primary analysis cut-off date, will enter the 
survival follow-up after completion of the safety follow-up. If clinically indicated, 
patients may continue to undergo tumor response assessments during the safety 
follow-up according to local or institutional standard of care; however these tumor 
response assessments will no longer be reported in the eCRF.

Survival follow-up: patients will be followed for survival every 3 months after the 
completion of safety or efficacy follow-up, whichever is last
For a diagram of the study flow, see Figure 4-2. Patients will undergo safety and efficacy 
assessments during screening, treatment, and follow-up as outlined in Table 7-1 visit evaluation 
schedule.
This study will use third-party vendors for central imaging, central laboratory, ePRO (e.g., 
electronic tablet devices to collect patient-reported outcomes (PRO) data), and eligibility 
checklist plus drug supply management via Interactive Response Technology (IRT). After the 
primary analysis cut-off date (10-Aug-2018) ePRO and central tumor response assessments will 
no longer be performed and/or collected. 


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Figure 4-2
Study flow
*After the the primary analysis cut-off date (10-Aug-2018), post-treatment efficacy follow-up will no 
longer be performed.
4.2
Timing of interim analysis and design adaptations
A planned interim analysis (IA) will be conducted after approximately 30 patients in the well-
differentiated NET group have undergone the first 3 radiological assessments (expected around 
week 24) or have shown disease progression or have discontinued efficacy follow-up for any 
other reason. All available efficacy and safety data from well-differentiated NET and poorly 
differentiated GEP-NEC groups up to the cut-off date will be used for the IA and reviewed by 
the Steering Committee (see Section 10.7 for more details). It is expected that at the time of the 
interim analysis all patients from the poorly-differentiated GEP-NEC group have undergone at 
least 2 radiological assessments. The study will not be stopped at the interim analysis for 
efficacy reasons regardless of results and will be continued until mature data from all patients
become available.
4.3
Definition of end of study
Cut-off date for the primary analysis will be 1 year after Last Patient First Treatment (LPFT) in 
the initially enrolled well-differentiated NET group. This analysis will include data from 
patients with well-differentiated NET and poorly-differentiated GEP-NEC groups who were 
enrolled in the study. It is expected that at the time of this analysis all patients from the original 
poorly-differentiated GEP-NEC group will have at least 11 months follow-up. This analysis
will be summarized in the clinical study report (CSR).
If the analysis results are not conclusive or do not meet the pre-specified study criteria (refer to
Section 10.4), the treatment continuation for patients who are benefitting from PDR001 


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treatment will be assessed on a case-by-case basis in consultation with the sponsor. Patients 
who discontinue study treatment will complete the safety follow-up period. 
The end of study is defined as the earliest occurrence of one of the following :

All patients have discontinued treatment and completed safety follow-up period.

If another clinical study becomes available that can continue to provide treatment with 
PDR001 in this patient population and all ongoing patients are eligible to be transferred to 
that clinical study (and do not meet any discontinuation criteria from study 
CPDR001E2201). 

At the end of the study, every effort will be made to continue provision of investigational 
treatment outside this study through an alternative setting to patients who in the opinion of 
the Investigator are still deriving clinical benefit.
4.4
Early study termination 
If the study is stopped for safety reasons, recruitment will be terminated, and the treatment 
continuation of patients who are deriving benefit from PDR001 treatment will be assessed on a 
case-by-case basis in consultation with the sponsor. 
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 and the same assessments should be performed 
as described in Section 7.1.6 for a discontinued or withdrawn 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 IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The study will include two groups of adult patients with advanced (unresectable or metastatic): 

Well-differentiated (G1/2), non-functional, neuroendocrine tumor of GI, pancreatic or 
thoracic (lung/thymus) origin who have progressed on prior treatment

Poorly-differentiated GEP-NEC who have progressed on or after one prior chemotherapy 
regimen. 
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 met.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures 
2. Adult males or females ≥ 18 years at screening.
3. Pathologically confirmed, advanced (unresectable or metastatic):


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
Well-differentiated (G1 /2) based on local pathology report, non-functional 
neuroendocrine tumor of GI, pancreatic or thoracic (including lung and thymus) 
origin.

Poorly-differentiated GEP-NEC based on local pathology report
4. No active symptoms related to carcinoid syndrome during the last 3 months prior to start 
of study treatment.
5. Patients must have received prior treatment for advanced disease:

Well-differentiated NET group:
a. Thoracic (lung and thymus origin) cohort: 

Thymus origin: at least one prior systemic therapy according to investigator’s 
choice 

Lung origin: at least one prior systemic therapy is required, which must include 
everolimus. 
b. GI cohort: at least two prior systemic regimens, which must include everolimus. Prior 
systemic therapies may include: somatostatin analogs, PRRT, and/or chemotherapy.
c. pNET cohort: at least two prior systemic regimens, which must include everolimus 
and/or sunitinib. Prior systemic therapies may include: somatostatin analogs, PRRT 
and/or chemotherapy.
Note: For well-differentiated NET, prior treatment with interferon alpha is allowed 
provided that it is not the last treatment received prior to study entry. 

Poorly-differentiated GEP-NEC group: at least one prior chemotherapy regimen
according to Investigator’s choice.
6. Radiological documentation of disease progression :

Well-differentiated NET group: Disease progression while on/or after the last 
treatment, and this progression must have been observed within 6 months prior to 
start of study treatment (i.e. maximum of 24 weeks from documentation of 
progression until study entry). Disease must show evidence of radiological disease 
progression based on scans performed not more than 12 months apart.

Poorly-differentiated GEP-NEC group: Disease progression while on or after prior 
treatment.
7. At least one measurable lesion assessed by CT and/or MRI according to RECIST 1.1. 
Note: Any lesions which have been subjected to percutaneous therapies or radiotherapy 
should not be considered measurable, unless the lesion has clearly progressed since the 
procedure.
8. Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-
2.
9. Tumor biopsy material must be provided for all patients 
 
:

Well-differentiated (G1/2) NET: Biopsy material must be provided following the 
diagnosis of metastatic disease. The tumor sample must be collected from a 
metastatic site not previously irradiated and should preferably be taken within 6 
months but not more than 24 months prior to start of study treatment.


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
Poorly-differentiated GEP-NEC: Biopsy material must be collected from the primary 
tumor or from a metastatic site not previously irradiated, taken not more than 24 
months prior to start of study treatment.
10. Women of childbearing potential must have had a negative serum pregnancy test within 
72 hours prior to the start of study treatment. Highly effective contraception must be used 
while on study.
11. Patient is deemed by the investigator to have the ability and means to be compliant with 
the protocol (treatment and follow-up).
12. Patient must meet the following laboratory values at the screening visit: 
Absolute Neutrophil Count ≥1.5 x 109/L
Platelets ≥75 x 109/L
Hemoglobin (Hgb) ≥9 g/dL 
Serum creatinine <1.5 mg/dL   
Total bilirubin ≤1.5 x ULN 
Aspartate transaminase (AST) ≤ 3.0 x ULN, except for patients with liver metastasis, 
if AST ≤5.0 x ULN 
Alanine transaminase (ALT) ≤ 3.0 x ULN, except for patients with liver metastasis, if 
ALT ≤5.0 x ULN 
5.3
Exclusion criteria
Patients eligible for inclusion in this study must not meet any of the following criteria:
1. Well-differentiated, grade 3 neuroendocrine tumors; poorly-differentiated neuroendocrine 
carcinoma of any origin (other than GEP-NEC); including NEC of unknown origin, 
adenocarcinoid, and goblet cell carcinoid.
2. Pretreatment with interferon as last treatment prior to start of study treatment
3. Prior treatment for study indication with:
a. Antibodies or immunotherapy within 6 weeks before the first dose of study treatment.
b. PRRT administered within 6 months of the first dose.
c. Systemic antineoplastic therapy (including cytotoxic chemotherapy, and toxin 
immune conjugates) or any experimental therapy within 14 days or 5 half-lives, 
whichever is longer, before the first dose of study treatment. For cytotoxic agents that 
have major delayed toxicities a washout period of more than 6 weeks is indicated 
(examples are nitrosoureas and mitomycin C).
d. Tyrosine kinase inhibitors within 14 days or 5 half-lives, whichever is longer, before 
the first dose of study treatment.
e. Prior PD-1- or PD-L1-directed therapy.
f.
Cryoablation, radiofrequency ablation, or trans-arterial embolization of hepatic 
metastases within 2 months before the first dose of study treatment.
4. Systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any 
immunosuppressive therapy 7 days prior to planned date for first dose of study treatment. 
Topical, inhaled, nasal and ophthalmic steroids are allowed.


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5. Any untreated central nervous system (CNS) lesion. However, patients are eligible if: a) 
all known CNS lesions have been treated with radiotherapy or surgery and b) patients
remained without evidence of CNS disease progression ≥ 4 weeks after treatment and c) 
patients must have discontinued corticosteroid therapy for ≥ 2 weeks.
7. 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 and any completely resected carcinoma in situ.
8. Major surgery, open biopsy, or significant traumatic injury within 2 weeks prior to start of 
study treatment. Note: Minor procedures and percutaneous biopsies or placement of 
vascular access device require 7 days wash-out period prior to start of study treatment
9. Anticipation of the need for major surgical procedure during the course of the study
10. Radiation therapy within 4 weeks prior to start of study treatment (palliative radiotherapy 
to bone lesions allowed within 2 weeks prior to study treatment start)
12. History of severe hypersensitivity reactions to other monoclonal antibodies which in the 
opinion of the investigator may pose an increased risk of a serious infusion reaction.
13. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following:
Clinically significant and/or uncontrolled heart disease such as congestive heart failure 
requiring treatment (New York Heart Association (NYHA) grade ≥ 2)

Uncontrolled hypertension with or without antihypertensive medication. Initiation or 
adjustment of antihypertensive medication is allowed prior to screening or clinically 
significant arrhythmia,

QTcF >480 ms on screening ECG or congenital long QT syndrome, acute myocardial 
infarction or unstable angina pectoris < 3 months prior to study entry.
14. Autoimmune disease that has required systemic treatment (i.e. disease modifying agents, 
steroids, or immunosuppressive drugs). Stable and adequate controlled endocrinopathies 
requiring replacement therapy (i.e. thyroid hormones, insulin, or physiologic 
corticosteroids) are not considered as systemic treatment and therefore are allowed. 
15. Active infection requiring systemic antibiotic therapy.
16. Known history of testing positive for Human Immunodeficiency Virus (HIV) infection.
17. Patients with active Hepatitis B infection (HBsAg positive) will be excluded.
Note: Patients with prior Hepatitis B (anti-HBc positive, HBsAg and HBV-DNA 
negative) infection are eligible.
18. Patients with positive test for hepatitis C ribonucleic acid (HCV RNA).
Note: Patients in whom HCV infection resolved spontaneously (positive HCV antibodies 
without detectable HCV-RNA) or those that achieved a sustained virological 
response after antiviral treatment and show absence of detectable HCV RNA ≥ 6 
months (with the use of IFN-free regimes) or ≥ 12 months (with the use of IFN-based 
regimes) after cessation of antiviral treatment are eligible.
19. 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.


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20. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment.
21. Presence of ≥ CTCAE grade 2 toxicity (except alopecia, peripheral neuropathy, and 
ototoxicity, which are exclusion criteria if ≥ CTCAE grade 3) due to prior cancer therapy.
22. Not able to understand and to comply with study instructions and requirements.
23. Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test within 
72 hours prior to initiating study treatment. Note: Low levels of hCG may also be 
considered a tumor marker, therefore if low hCG levels are detected, another blood sample 
at least 4 days later must be taken to assess the kinetics of the increase and transvaginal 
ultrasound must be performed to rule out pregnancy.
24. 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 stopping treatment with PDR001. Highly effective 
contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment
c. Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient
d. 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 
Note: 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 (i.e. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with
or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to 
enrollment. In the case of oophorectomy alone, a woman is considered not of child bearing 
potential only when her reproductive status has been confirmed by follow up hormone level 
assessment.
26. Known history or current interstitial lung disease or non-infections pneumonitis.
27. Use of somatostatin analogs or any other medications administered to control active 
symptoms related to carcinoid syndrome during the last 3 months prior to start of study 
treatment.


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6
Treatment
6.1
Study treatment
For this study, the investigational drug is PDR001. The study treatment is defined as PDR001. 
PDR001 is supplied as PDR001 100 mg powder for solution for infusion. PDR001 will be 
diluted in dextrose 5% in water (D5W). Due to incompatibility, 0.9% sodium chloride solution 
must not be used. PDR001 will be administered at a dose of 400 mg every 4 weeks given as a 
30 minute infusion. 
PDR001 infusion must take place in a facility with appropriate resuscitation equipment 
available at the bedside and a physician readily available during the period of drug 
administration.
All dosages prescribed and administered to patients and all dose interruptions and changes 
during the study must be recorded on the Dosage Administration Record (DAR) eCRF page.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and route of 
administration
Strength
Frequency and/or 
Regimen
Dose 
Administered
PDR001
Powder for solution for infusion in 
vial for i.v. infusion
4 x 100 mg vials
Every 4 weeks
400 mg
PDR001 will be administered via intravenous infusion over 30 minutes (up to 2 hours, if 
clinically indicated) once every 4 weeks (+/- 7 days window). PDR001 will be administered on 
Day 1 of every cycle. Each cycle is 28 days. The actual date of Cycle Day 1 will be used to 
project the dates of future cycles. The dose may be interrupted for up to 12 weeks. The safety 
assessments (as per Table 7-1 and Section 7.2.2) should be performed according to the actual 
day of infusion.
6.1.2
Ancillary treatments 
Patients should not receive pre-medication to prevent infusion reaction before the first infusion 
of PDR001 as a way to determine if pre-medication is necessary. If a patient experiences an 
infusion reaction, he/she may receive pre-medication prior to 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 
normal cardiopulmonary status. If a patient experiences a severe anaphylactic/anaphylactoid 
reaction, the infusion should be discontinued immediately. The patient may only resume study 
treatment 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 Section 6.3.1.2.


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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.
6.1.3
Rescue medication 
Not applicable
6.1.4
Guidelines for continuation of treatment 
Not applicable
6.1.5
Treatment duration
All patients will begin treatment on Cycle 1 Day 1. 
Prior to the primary analysis cut-off date (10-Aug-2018), patients will continue study treatment 
until disease progression per RECIST 1.1 or irRECIST (see below), as per BIRC, unacceptable 
toxicity, start of new anti-neoplastic therapy, withdrawal of consent, physician’s decision, 
subject/guardian decision, lost to follow-up, death or the study is terminated by the sponsor. 
While the investigator is waiting for the results from the central imaging vendor to confirm
disease progression, the patient should continue on study treatment. However, during this time, 
the investigator should do whatever is medically necessary for his/her patient.
After the primary analysis cut-off date (10-Aug-2018):

Response assessments by BIRC will no longer be performed.

Patients, who are on treatment but have not yet progressed per local tumor response 
assessment, will continue study treatment until documentation of disease progression by 
RECIST 1.1 as per local investigator assessment, unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, physician’s decision, subject/guardian decision, 
lost to follow-up, death or the study is terminated by the sponsor. These patients will be 
permitted to continue study treatment beyond initial PD as per RECIST 1.1 until 
confirmed irPD per local assessment (until 2 consecutive irPDs), as described in Section 
6.1.5.1.

Patients, who are on treatment beyond disease progression per local tumor response 
assessment (tumor assessment performed before the primary analysis cut-off date [10-
Aug-2018]), are allowed to continue study treatment as long as the patient derives clinical 
benefit from the treatment according to investigator’s best clinical judgement (e.g. no 
deterioration of performance status, no rapid increase in tumor burden, no clinical 
situation requiring alternative treatment), or until unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, lost to follow-up, death, or the study is 
terminated by the sponsor. 
6.1.5.1
Treatment beyond disease progression
Emerging clinical data indicate that patients may derive benefit from continuing study treatment 
despite initial evidence of disease progression (Section 2.5). 


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Prior to the primary analysis cut-off date (10-Aug-2018), patients treated with PDR001 will be 
permitted to continue study treatment beyond initial disease progression as per RECIST 1.1 
until disease progression per irRECIST, as per BIRC, unacceptable toxicity, start of new anti-
neoplastic therapy provided they meet all of the following criteria:

Absence of disease progression per irRECIST, as per BIRC, confirmed by 2 consecutive 
assessments

The continuation of treatment beyond progression will not delay an imminent intervention 
to prevent serious complications of disease progression

Patients exhibit adequate tolerance to study treatment

Patient performance status is stable 
Patients who meet the above criteria should continue study treatment beyond initial disease 
progression per RECIST 1.1 and continue all study procedures as outlined in Section 7. The 
reasons for the patient continuing treatment will be documented in the eCRF.  
In case of clinical deterioration or suspicion of disease progression, a follow-up imaging
assessment should be performed promptly rather than waiting for the next scheduled assessment. 
Treatment with PDR001 in patients who are no longer deriving clinical benefit or have disease 
progression as per irRECIST by BIRC confirmed by 2 consecutive assessments must be 
discontinued.
After the primary analysis cut-off date (10-Aug-2018):

Response assessments by BIRC will no longer be performed.

Patients, who are on treatment but have not yet progressed per local tumor response 
assessment, will continue study treatment until documentation of disease progression by 
RECIST 1.1 as per local investigator assessment, unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, physician’s decision, subject/guardian decision, 
lost to follow-up, death or the study is terminated by the sponsor. These patients will be 
permitted to continue study treatment beyond initial PD as per RECIST 1.1 until 
confirmed irPD per local assessment (until 2 consecutive irPDs) provided they meet all of 
the following criteria:

Absence of disease progression per irRECIST, confirmed by 2 consecutive 
assessments

The continuation of treatment beyond progression will not delay an imminent 
intervention to prevent serious complications of disease progression

Patients exhibit adequate tolerance to study treatment

Patient performance status is stable 

Patients who meet the above criteria should continue study treatment beyond initial 
disease progression per RECIST 1.1 and continue study procedures as outlined in 
Section 7. The reasons for the patient continuing treatment will be documented in the 
eCRF.

Patients, who are on treatment beyond disease progression per local tumor response 
assessment (tumor assessment performed before the primary analysis cut-off date (10-
Aug-2018)), are allowed to continue study treatment as long as the patient derives clinical 
benefit from the treatment according to investigator’s best clinical judgement (e.g. no 


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deterioration of performance status, no rapid increase in tumor burden, no clinical 
situation requiring alternative treatment), or until unacceptable toxicity, start of new anti-
neoplastic therapy, withdrawal of consent, lost to follow-up, death, or the study is 
terminated by the sponsor.
6.2
Dose escalation guidelines
Not applicable
6.3
Dose modifications
6.3.1
Dose modification and dose interruption
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions are 
mandated in order to allow patients to continue study treatment. Dose interruption for PDR001 
includes delaying or withholding treatment for any reason as well as interrupting treatment 
during an infusion.
The following sections address specific instructions for mandatory dose modifications and 
recommended management of adverse events considered suspected to be related to PDR001.
6.3.1.1
Dose modification and dose interruption for PDR001
General dose modification instructions:
No changes in the dose of PDR001 are allowed.  
AEs are to be graded according to NCI-CTCAE v4.03 (ctep.cancer.gov). All dose interruptions 
and the reasons for dose interruption must be documented in the eCRF.  
Treatment of patients with AEs suspected to be related to PDR001 including those of potential 
immune-mediated etiology (irAE) (see definition in Section 6.3.1.2.1) must be permanently 
discontinued if the following occurs within 12 weeks:

AEs do not recover to ≤ grade 1 or baseline 

The dose of steroids (for the management of irAEs) is > 10 mg/day prednisone or 
equivalent (or as indicated in the tables below)
The 12 weeks’ period starts from the time an irAE reaches a severity grade that requires 
PDR001 interruption.
6.3.1.2
Dose Modification requirements for potential immune- mediated 
adverse events 
6.3.1.2.1 Identification of and management requirements for AEs of potential 
immune-mediated etiology (irAE)
Adverse events of special interest (AESI) include AEs of a potential immune-mediated etiology 
(irAE) that are associated with PDR001 treatment. An irAE may be experienced by patients 
treated with PDR001 due to its mechanism of action; it is predicted based on the reported prior 
experience with other immunotherapies that have a similar mechanism of action. Investigators 


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must be vigilant and must carefully identify AEs that may be suggestive of potential irAEs as 
their appearance may be sub-clinical and early diagnosis is critical for its adequate management 
and resolution. 
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), lung 
(pneumonitis), kidneys (nephritis) and endocrine systems (a variety of endocrinopathies) and 
rarely CNS (encephalitis). Serological, immunological and histological assessments should be 
performed as deemed appropriate by the investigator, to verify the potential immune-related 
nature of the AE, and exclude a neoplastic, infectious or metabolic origin of the AE.
Severe grade or persistent lower grade irAEs typically require interrupting or permanently 
discontinuing treatment and administration of systemic steroids or other non-corticosteroid 
immunosuppressive medication when systemic steroids are not effective. Early recognition of 
irAEs and initiation of treatment are critical to reduce the risk of complications, since the 
majority of irAEs are reversible with the use of steroids and other immune suppressants. 
Patients should be instructed to return to the study site as soon as possible (instead of waiting 
for their next scheduled visit) if they experience symptoms consistent with an irAE. Patients 
who experience a new or worsening irAE should be contacted and/or evaluated by the study 
site more frequently. 
Based on literature from compounds with similar mechanism of action of PDR001, instructions 
have been developed regarding how to identify, assess severity and manage irAEs that may 
occur in patients receiving PDR001. The dose modification requirements and AE management 
guidelines for the potential irAEs are provided in the following tables: diarrhea/colitis (Table 
6-2), hepatitis (liver laboratory alterations) (Table 6-3), skin (rash) (Table 6-4), nephritis (Table 
6-5), pneumonitis (Table 6-6), encephalitis (Table 6-7), endocrinopathies (Table 6-8), PDR001-
infusion reaction & cytokine release syndrome (Table 6-9), and other potential immune-related 
AEs of special interest (Table 6-10). Any grade 4 irAE must result in permanent discontinuation 
of PDR001.  
Under the category of OTHERS (Table 6-11 and Table 6-12) are included several irAE of 
interest that must be managed specifically and for which not specific guidance are provided in 
the table below. OTHERS include (but is not restricted to) the following events: autoimmune 
neuropathy, demyelinating polyneuropathy, Guillain-Barre, myasthenia Gravis-like syndrome, 
non-infectious myocarditis, non-infectious pericarditis, pancreatitis and rapid onset of grade 3 
fatigue in the absence of disease progression.
Patients receiving PDR001 may experience irAEs other than those listed in this document;
therefore, all AEs of unknown etiology associated with drug exposure should be evaluated to 
determine if they are possibly immune-related. In cases where the specific irAEs are not listed 
in the tables below, the investigator should follow the dose modification requirements in 
Section 6.3.1.3 which details the measures to be taken for suspected (they could be potentially 
immune-related or non-immune-related) AEs. Investigators are encouraged to contact the 
sponsor as needed to discuss cases that warrant separate discussion outside of the scope of the 
current instructions. 


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The dosing modification requirements are mandatory; however, the AE management guidelines 
are recommendations and can be modified according to local practices. The management of 
irAEs may include initiation of antibiotics for prophylaxis against opportunistic infections.
Table 6-2
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related diarrhea/colitis
Diarrhea/Colitis (NCI-CTCAE v4.03)
Grade
Recommended Adverse Event management 
guidelines
Mandatory Dose 
Modification requirements
Grade 1 (< 4 bowel 
actions per day over 
baseline) mild
Grade 2 (4-6 bowel 
actions per day over 
baseline) and / or 
abdominal pain/ 
blood in stool.
● Diet
● Hydration
● Loperamide: initially 4 mg, followed by 2 mg every 
four hours or after every unformed stool; maximum 16 
mg/day. Continue until diarrhea free for 12 hours;
● Diarrhea > 24h: loperamide 2 mg every two hours; 
maximum 16 mg/day. Consider adding oral antibiotics.
● Diarrhea > 48hrs: loperamide 2 mg every two hours; 
maximum 16 mg/day. Consider other second-line 
therapies for diarrhea (e.g: (octreotide, oral 
diphenoxylate) and oral antibiotics
● If Grade 2 and no improvement in 5 days may require 
oral steroids
● If Grade 2 diarrhea persists >1 week consider GI 
consultation and endoscopy to evaluate for colitis.
● If Grade 2 persists for 5 days and worsening of 
symptoms or diffuse ulcerations and bleeding seen on 
endoscopy, commence steroids at a dose of 0.5-
1mg/kg per day of prednisolone (or IV equivalent) and 
continue until symptoms improve to Grade 1. If no 
improvement occurs, manage as per Grade 3. Steroids 
can be tapered as per Section 6.3.1.2.2.
● Sigmoidoscopy and biopsy can be considered and 
may assist in determining the duration of steroid taper 
based on the evidence of macroscopic and microscopic 
inflammation.
● Continue PDR001 
treatment
● If diarrhea is Grade 2, 
despite loperamide at 2 mg 
every two hours for > 48hrs:
● Interrupt PDR001 until 
diarrhea recovers to Grade 
≤1 and then restart PDR001 
treatment at the same dose 
and schedule.
Grade 3 Diarrhea: 
Increase of ≥7 
stools per day over 
baseline; 
incontinence; 
hospitalization 
indicated; limiting 
self-care ADL;
Grade 3 Colitis: 
Severe abdominal 
pain; change in 
bowel habits; 
medical intervention 
indicated; peritoneal 
signs
● Clinical evaluation and hospitalization mandatory; rule 
out bowel perforation and intravenous hydration.
● Consider consultation with gastroenterologist and 
confirmation biopsy with endoscopy.
● In addition to symptomatic treatment (diet, hydration, 
loperamide, antibiotics if indicated); initiate immediate 
treatment with intravenous steroids 
(methylprednisolone 125 mg) followed by high dose 
oral steroids (prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) is recommended. 
● When symptoms improve to ≤Grade 1, steroid taper 
should be done as per Section 6.3.1.2.2.
● Taper over 6 to 8 weeks in patients with diffuse and 
severe ulceration and/or bleeding.
● If no improvement in 2-3 days: consider initiating 
infliximab 5mg/kg and continue steroids. (Infliximab is 
contraindicated in patients with sepsis or a perforation). 
Upon symptomatic relief initiate a prolonged steroid 
taper over 45 to 60 days. 
● If symptoms worsen during steroid reduction, initiate a 
re-tapering of steroids starting at a higher dose of 80 or 
100 mg followed by a more prolonged taper and 
administer infliximab.
1st occurrence: 
● Interrupt PDR001 until 
diarrhea/colitis recovers to 
Grade ≤1 or baseline
● Once recovered restart 
PDR001 treatment at the 
same dose and schedule 
and after appropriate steroid 
tapering (if initiated).
● AE resolution to ≤ Grade 1 
or baseline must occur within 
a period of 12 weeks since a 
Grade 3 event has been 
identified, otherwise PDR001 
must be permanently 
discontinued
2nd occurrence:
Permanently discontinue 
PDR001


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Diarrhea/Colitis (NCI-CTCAE v4.03)
Grade
Recommended Adverse Event management 
guidelines
Mandatory Dose 
Modification requirements
● If symptoms persist despite the above treatment a 
surgical consult should be obtained.
Grade 4: Life-
threatening 
consequences; 
urgent intervention 
indicated
Same as Grade 3
Permanently discontinue 
PDR001 
Table 6-3
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related liver laboratory 
alterations
Abnormal liver function tests
Severity
Recommended Adverse Event management 
guidelines
Mandatory Dose 
Modification requirements
Grade 2: AST or ALT > 
3x ULN to ≤ 5.0x ULN 
and/or bilirubin > 1.5x 
ULN to ≤ 3x ULN (if 
patient meets criteria for 
Hy’s law, refer to Section 
6.3.3.1)
Monitor hepatic laboratory tests more frequently 
(every 2-3 days) until returned to baseline values
● Interrupt PDR001 
treatment until recovery to 
Grade ≤1 or baseline**
● Once recovered 
restart PDR001 treatment at 
the same dose and 
schedule
Grade 3 or 4: AST or 
ALT >5.0xULN and/or 
bilirubin > 3.0x ULN 
● Monitor hepatic laboratory tests more frequently 
(every 2-3 days) until returned to baseline values. 
● Consider appropriate consultation* with hepatologist 
and liver biopsy to establish etiology of hepatic injury, 
if necessary
● If after 2-3 days new liver assessment shows 
worsening of laboratory test consider to initiate 
treatment with steroids prednisolone 1-2 mg/kg/day or 
IV equivalents.
● Add prophylactic antibiotics for opportunistic 
infections
● When symptoms improve to Grade ≤1, a steroid 
taper with dexamethasone 4 mg every 4 hours or 
prednisone at 1 to 2 mg/kg should be started and 
continued over no less than 4 weeks.
● If serum transaminase levels do not decrease 48 
hours after initiation of systemic steroids, oral 
mycophenolate mofetil 500 mg every 12 hours may be 
given.
● Infliximab is not recommended due to its potential 
for hepatotoxicity
Permanently discontinue 
PDR001**
* Send viral serology looking for hepatitis A, B, C & CMV and rule out any potential cause of liver injury (i.e. 
alcohol, other medications, etc.)
**For patients with liver metastasis who begin treatment with grade 2 AST or ALT, if AST or ALT increase by 2 
times relative to baseline and last for at least 1 week then the patient should be discontinued
Note: For additional information on follow-up of potential drug induced liver injury cases, refer to Section 6.3.3.1.


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Table 6-4
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related skin events
Rash Events (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Grade 1: Rash covering 
< 10% Body Surface 
Area (BSA)
● Initiate prophylactic and symptomatic 
treatment measures.
● Consider use of topical corticosteroids 
or urea containing creams in combination 
with oral antipruritics or moderate 
strength topical steroid (hydrocortisone 
2.5% cream or fluticasone propionate 
0.5% cream)
● Reassess after 2 weeks.
Continue PDR001 treatment
Grade 2: 10-30% of BSA
● If tolerable, treat as per Grade 1; 
● If intolerable, initiate systemic steroids 
(e.g. oral prednisolone 0.5-1mg/kg daily) 
and consider dose interruption until 
tolerable or recovery to grade ≤1 or 
baseline; once recovered, resume 
PDR001 treatment at the same dose and 
schedule.
● If symptoms persist or recur consider 
skin biopsy.
Continue PDR001 treatment
AE resolution to ≤1 or baseline must 
occur within a period of 12 weeks since 
Grade 2 event has been identified, 
otherwise PDR001 must be 
permanently discontinued.
Grade 3: More than 30% 
of BSA
● Obtain a skin biopsy and dermatology 
consult. 
● Initiate systemic steroids with 1mg/kg 
of prednisolone or IV equivalent. 
1st occurrence: 
● Interrupt PDR001 until rash recovers 
to Grade ≤1 or baseline
● Once recovered restart PDR001 
treatment at the same dose and 
schedule  
AE resolution to ≤ Grade 1 or baseline 
must occur within a period of 12 weeks 
since intolerable Grade 3 event has 
been identified. Otherwise, PDR001 
must be permanently discontinued
2nd occurrence: 
Permanently discontinue PDR001
Grade 4: Life-threatening
Same as Grade 3 
Permanently discontinue PDR001
Other skin events 
Stevens-Johnson 
syndrome and toxic 
epidermal necrolysis
Institute supportive care as per 
institutional guidelines
Permanently discontinue PDR001


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Table 6-5
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related nephritis
Nephritis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Grade 1: 
Creatinine >ULN to 
≤1.5x ULN)
● Monitor creatinine weekly
● If creatinine return to baseline resume 
routine creatinine monitoring per protocol
● Promote hydration and cessation of 
nephrotoxic drugs
Continue PDR001 treatment
Grade 2: Creatinine >1.5 
to ≤3 x ULN
● Monitor creatinine every 2 to 3 days
● Initiate 0.5 to 1 mg/kg/day prednisone 
equivalents
● If worsening or no improvement: 1 to 2 
mg/kg/day prednisone equivalents 
● Consult with specialist and consider 
renal biopsy  
● Interrupt PDR001 until serum 
creatinine recovers to ≤ Grade 1 or 
baseline. 
● Once recovered restart PDR001 
treatment at the same dose and 
schedule 
AE resolution to ≤ Grade 1 must occur 
within a period of 12 weeks since 
Grade 2 event has been identified, 
otherwise PDR001 must be 
permanently discontinued.
Grade 3: Creatinine >3.0 
to <6 x ULN
● Monitor creatinine every 1 to 2 days
● Start 1 to 2 mg/kg/day prednisone 
equivalents 
● Consult with nephrologist 
1st occurrence: 
● Interrupt PDR001 until serum 
creatinine recovers to ≤Grade 1 or 
baseline. 
● Once recovered restart PDR001 
treatment at the same dose and 
schedule
AE resolution to ≤ Grade 1 or baseline 
must occur within a period of 12 weeks 
since the Grade 3 event has been 
identified, otherwise PDR001 must be 
permanently discontinued
2nd occurrence: 
Permanently discontinue PDR001.
Grade 4: Creatinine >6x 
ULN
● Monitor creatinine daily
● Initiate steroids with 1 to 2 mg/kg/day 
prednisone or equivalent
● Consult with nephrologist and consider 
renal biopsy
Permanently discontinue PDR001
Table 6-6
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related pneumonitis
Pneumonitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Grade 1: Radiographic 
changes only-
Asymptomatic
● CT scan (high-resolution with lung 
windows) recommended, with serial 
imaging to monitor for resolution or 
progression- re-image at least every 3 
weeks
● Monitor for symptoms every 2-3 days -
Clinical evaluation and laboratory work-
● Interrupt PDR001 until recovery to 
baseline.
● Once recovered, restart PDR001 
treatment at the same dose and 
schedule
If worsens, treat as Grade 2 or 3-4. 


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Pneumonitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
up for infection
● Monitoring of oxygenation via pulse 
oximetry recommended
● Consultation of pulmonologist 
recommended
AE resolution to ≤Grade 1 or baseline 
must occur within a period of 12 
weeks since Grade 1 event has been 
identified, otherwise PDR001 must be 
permanently discontinued
Grade 2: Symptomatic-
medical intervention 
indicated; limits 
instrumental ADLs
● CT scan (high-resolution with lung 
windows)
● Monitor symptoms daily, consider 
hospitalization
● Clinical evaluation and laboratory work 
up for infection
● Consult pulmonologist
● Pulmonary function tests - if normal at 
baseline, repeat every 8 weeks 
● Bronchoscopy with biopsy and/or BAL 
recommended
● Symptomatic therapy including 
corticosteroids if clinically indicated 
(systemic corticosteroids at a dose of 1 to 
2 mg/kg/day prednisone or equivalent as 
clinically indicated).
1st occurrence:
● Interrupt PDR001 until recovery to 
Grade ≤1 or baseline
● Once recovered restart PDR001 
treatment at the same dose and 
schedule
AE resolution to ≤ Grade 1 or baseline 
must occur within a period of 12 
weeks since Grade 2 event has been 
identified, otherwise PDR001 must be 
permanently discontinued.
If worsens treat as Grade 3 or 4
2nd occurrence:
Permanently discontinue PDR001 
treatment 
Grade 3: Severe 
symptoms; limits self-
care ADLs; oxygen 
indicated
Grade 4: Life-
threatening respiratory 
compromise
● CT scan (high-resolution with lung 
windows)
● Clinical evaluation and laboratory work-
up for infection
● Consult pulmonologist
● Pulmonary function tests-if < normal, 
repeat every 8 weeks until ≥ normal
● Bronchoscopy with biopsy and/or BAL 
if possible
● Treat with intravenous steroids 
(methylprednisolone 125 mg) as 
indicated. When symptoms improve to ≤ 
Grade 1, a high dose oral steroid 
(prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours).
● If IV steroids followed by high dose oral 
steroids does not reduce initial symptoms 
within 48 to 72 hours, consider non-
corticosteroid immunosuppressive 
medication.
Permanently discontinue PDR001
Table 6-7
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related encephalitis
Encephalitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Grade 1 (asymptomatic 
or mild symptoms)
Continue PDR001 treatment
Grade 2 
(New onset of moderate 
● Consider consulting neurology
● 0.5 to 1 mg/kg/day prednisone 
equivalents
1st occurrence: 
● Interrupt PDR001 until recovery to ≤ Grade 
1 or baseline. 


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Encephalitis (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
symptoms, limiting 
instrumental ADL)
● Once recovered restart PDR001 
treatment at the same dose and schedule. 
AE resolution to ≤ Grade 1 or baseline must 
occur within a period of 12 weeks since 
Grade 2 event has been identified, otherwise 
PDR001 must be permanently discontinued.
If worsens, treat as Grade 3-4
2nd occurrence: 
Permanently discontinue PDR001
Grade 3 or 4
(New onset of severe 
symptoms, limiting self-
care ADL, life-
threatening)
● Consider consulting neurology
● 1 to 2 mg/kg/day prednisone 
equivalents
Permanently discontinue PDR001
Table 6-8
Mandatory dose modification requirements and recommended clinical 
management guidelines for potential immune-related endocrine 
events
Endocrine events (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Asymptomatic, 
intervention not indicated 
(e.g. hyperthyroidism or 
hypothyroidism)
● If TSH <0.5x LLN, or TSH >2x ULN, or 
consistently out of range in 2 subsequent 
measurements, include free T4 at 
subsequent cycles as clinically indicated
● Consider endocrinologist consult
● If hypophysitis is considered, pituitary 
gland imaging should be considered (MRIs 
with gadolinium and selective cuts of the 
pituitary can show enlargement or 
heterogeneity and confirm the diagnosis)
● Repeat labs in 1 to 3 weeks/MRI in 1 
month if laboratory abnormalities persist 
but normal lab/pituitary scan
Continue PDR001 treatment
Symptomatic 
endocrinopathy (e.g., 
hypophysitis, adrenal 
insufficiency, 
hypothyroidism, 
hyperthyroidism)
● Consider Endocrinology consultation
● Rule out infection and sepsis with 
appropriate cultures and imaging
● Treat with an initial dose of 
methylprednisolone 1 to 2 mg/kg 
intravenously followed by oral prednisone 1 
to 2 mg/kg per day.
● Replacement of appropriate hormones 
may be required as the steroid dose is 
tapered
● Hypophysitis with clinically significant 
adrenal insufficiency and hypotension, 
dehydration, and electrolyte abnormalities 
(such as hyponatremia and hyperkalemia) 
constitutes adrenal crisis
● Consider hospitalization and intravenous 
methylprednisolone should be initiated.
1st occurrence: 
● Interrupt PDR001 until 
symptomatic recovery to mild (e.g. 
grade 1) or no symptoms
● Once recovered, restart 
PDR001 treatment at the same dose 
and schedule 
AE resolution to mild or no 
symptoms must occur within a 
period of 12 weeks since 
symptomatic endocrinopathy event 
has been identified, otherwise 
PDR001 must be permanently 
discontinued.


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Endocrine events (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
2nd occurrence:  
Permanently discontinue PDR001 
Autoimmune diabetes
(Grade 3 or symptomatic 
hyperglycemia)
Initiate anti-glycemic therapy (i.e. insulin) 
as medically indicated and monitor glucose 
levels regularly until metabolic control is 
achieved
Interrupt treatment until glucose 
returns to Grade 1 or baseline and 
then restart PDR001
Autoimmune diabetes
(Grade 4 hyperglycemia 
or life-threatening 
complications)
Same as Grade 3
Permanently discontinue PDR001
Table 6-9
Mandatory dose modification requirements and recommended clinical 
management guidelines for infusion reaction events and cytokine 
release syndrome 
Infusion reaction (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event management 
guidelines
Mandatory Dose
Modification requirements
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
Continue PRD001 treatment
Grade 2
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
● Stop Infusion
● Additional appropriate medical therapy may 
include but is not limited to:
● IV fluids
● Antihistamines
● NSAIDS
● Acetaminophen
● Narcotics
● Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator.
● If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate (e.g. 
from 100 mL/hr to 50 mL/hr). Otherwise dosing 
will be held until symptoms resolve and the 
patient should be re-premedicated for the next 
scheduled dose.
● Patient may be premedicated 1.5hr (± 30 
minutes) prior to infusion of PDR001 with:
● Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
● Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic).
1st occurrence:
Continue PRD001 treatment 
at the same dose and 
schedule with premedication
2nd occurrence: 
Despite premedication or 
prolongation of infusion, 
consider permanent 
discontinuation of PDR001.
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
● Stop Infusion
● Additional appropriate medical therapy may 
include but is not limited to:
● IV fluids
● Antihistamines
● NSAIDS
● Acetaminophen
● Narcotics
Permanently discontinue 
PDR001


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Infusion reaction (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event management 
guidelines
Mandatory Dose
Modification requirements
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
● Oxygen
● Pressors
● Corticosteroids
● Epinephrine
● Increase monitoring of vital signs as medically 
indicated until the patient is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated.
Table 6-10
Mandatory dose modification requirements and recommended clinical 
management guidelines for “other” potential immune-related AEs of 
special interest
Other- Autoimmune neuropathy, demyelinating polyneuropathy, Guillain Barre, Myasthenia Gravis- like 
syndrome, Non-infectious myocarditis, pericarditis, pancreatitis, and Grade 3 Fatigue with rapid onset in 
absence of disease progression 
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification 
requirements
Mild (Grade 1)
Provide symptomatic treatment
Continue PDR001 treatment
Moderate (Grade 2) or 
Grade 1 that does not 
improve with 
symptomatic treatment
● Provide symptomatic treatment
● Systemic corticosteroids may be 
indicated
● Consider biopsy for confirmation of 
diagnosis
● A specialist should be consulted
1st occurrence: 
● Interrupt PDR001 until recovery to ≤ 
Grade 1 or baseline. 
● Once recovered, may restart 
PDR001 treatment at the same dose and 
schedule
AE resolution to ≤ Grade 1 or baseline 
must occur within a period of 12 weeks 
since event has been identified, otherwise 
PDR001 must be permanently 
discontinued.
2nd occurrence: 
Permanently discontinue PDR001
Severe (Grade 3)
● All management for moderate irAEs 
and
● Initiate systemic corticosteroids 
(prednisone or equivalent) at a dose of 
1-2 mg/kg QD
1st occurrence: 
● Interrupt PDR001 until recovery to ≤ 
Grade 1 or baseline 
● May restart PDR001 treatment at the 
same dose and schedule
AE resolution to ≤ Grade 1 or baseline 
must occur within a maximum period of 12 
weeks since a Grade 3 event has been 
identified, otherwise PDR001 must be 
permanently discontinued.
2nd occurrence: 
Permanently discontinue PDR001
Grade 4
Refer to management of severe AEs
Permanently discontinue PDR001.


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6.3.1.2.2 Guidance for corticosteroids tapering for management of immune-related 
AEs
Reduce prednisone dose by 2.5- to 5.0-mg decrements every 3–7 days until physiologic dose (5 
to 7.5 mg of prednisone per day) is reached. Consider to complete tapering over a period of at 
least 4 weeks. Slower tapering of corticosteroids therapy may be recommended if the adverse 
event is not showing improvement. Once corticosteroid tapering is achieved at a level of 10 mg 
of prednisone/day (or equivalent), treatment with PDR001 can be restarted as indicated in the 
dose modification tables.
6.3.1.3
Dose modification requirements for adverse events suspected to be 
related to study treatment
The required dose modification and management of adverse events that are considered to be 
related to study medication and do not have specific management requirements noted elsewhere 
in the protocol are provided in Table 6-11 and Table 6-12. 
Table 6-11
Mandatory dose modification requirements and recommended clinical 
management guidelines for hematologic adverse events suspected to 
study treatment
Hematologic suspected AEs (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification requirements
Neutropenia
Grades 1, 2
NA
Continue PDR001 treatment
Grade 3, 4
Monitoring blood test more 
frequently (every 7 days for grade 
3, and 3-5 days for grade 4)
1st occurrence: 
● Interrupt PDR001 until toxicity recovers to Grade 
≤2 or baseline.
● Once recovered restart PDR001 treatment at 
the same dose and schedule
2nd occurrence: 
● Interrupt PDR001 until toxicity recovers to Grade 
≤2 or baseline
● Once recovered restart PDR001 treatment at 
the same dose and schedule
AE resolution to ≤ Grade 2 or baseline must occur 
within a maximum period of 12 weeks since Grade 
3 or 4 event has been identified, otherwise 
PDR001 must be permanently discontinued 
3rd occurrence: 
Permanently discontinue PDR001.  
Febrile Neutropenia
Apply Institutional guidelines
Follow- neutropenia Grade 4 requirements (above)
Thrombocytopenia (NCI-CTCAE v4.03)
Grade 1, 2, 3 
without clinical 
significant bleeding
Grade 3: monitoring blood test 
more frequently (every 7 days)
Continue PDR001 treatment


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Hematologic suspected AEs (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event 
management guidelines
Mandatory Dose Modification requirements
Grade 3 with clinical 
significant bleeding 
OR Grade 4
Grade 3: monitoring blood test 
more frequently (every 3-5 days)
1st occurrence:
● Interrupt PDR001 until toxicity resolves to Grade 
≤2 or baseline. 
● Once recovered restart PDR001 treatment at 
the same dose and schedule
2nd occurrence: 
● Interrupt PDR001 until toxicity resolves to Grade 
≤2 or baseline 
● Once recovered restart PDR001 treatment at 
the same dose and schedule
AE resolution to ≤ Grade 2 or baseline must occur 
within a maximum period of 12 weeks since Grade 
3 with clinically significant bleeding or Grade 4 
event has been identified, otherwise PDR001 must 
be permanently discontinued.  
3rd occurrence: 
Permanently discontinue PDR001.
Table 6-12
Mandatory dose modification requirements and recommended clinical 
management guidelines for non-hematologic adverse events 
suspected related to study treatment
Non-Hematologic suspected AEs (except Grade 2 alopecia, Grade 2 fatigue) (NCI-CTCAE v4.03)
Grade 
Recommended Adverse Event
management guidelines
Mandatory Dose Modification requirements
Grade 1-2 
tolerable
● Monitor closely
● Provide supportive care according 
to institutional standards
Continue PDR001 treatment at the same dose and 
schedule
Grade 2 
intolerable or
Grade 3
● Monitor closely
● Provide supportive care according 
to institutional standards
1st or 2nd occurrence:
● Interrupt PDR001 until toxicity recovers to Grade 
≤1 or baseline.
● Once recovered restart PDR001 treatment at 
the same dose and schedule
AE resolution to Grade ≤1 or baseline must occur 
within a maximum period of 12 weeks since 
intolerable Grade 2 or Grade 3 event has been 
identified, otherwise PDR001 must be permanently 
discontinued.  
3rd occurrence: 
Permanently discontinue PDR001
Grade 4
● Monitor closely
● Provide supportive care according 
to institutional standards
1st occurrence:
● Interrupt PDR001
● Consider permanently discontinuing 
PDR001. If benefit risk assessment support 
treatment continuation, restart PDR001 treatment 
at the same dose and schedule. 
2nd occurrence: 
Permanently discontinue PDR001


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6.3.2
Dose adjustments for QTcF prolongation
Not applicable
6.3.3
Follow-up for toxicities
Serologic, histologic (tumor sample) and immunological assessments should be performed as 
deemed appropriate by the Investigator to verify the immune-related nature of the AE and to 
exclude alternative explanations. Recommendations (Section 6.3) have been developed to assist 
investigators in assessing and managing the most frequently occurring irAEs.
Patients whose treatment is interrupted or permanently discontinued due to an irAE, 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 30 days, and 
subsequently at approximately 30-day intervals (or more frequently if required by institutional 
practices, or if clinically indicated), until resolution or stabilization of the event, whichever 
comes first. Appropriate clinical experts should be consulted as deemed necessary.
If an AE is suspected to be immune-related, the relevant immunological assessments (e.g. 
rheumatoid factor, anti-DNA Ab, etc.) should be performed. If cytokine release syndrome is 
suspected, the assessments outlined in Section 7.2.6.6.5 must be performed.
All patients must be followed-up for AEs and SAEs for 150 days following the last dose of 
PDR001. However, if the patient begins post-treatment antineoplastic medication during the 
period between the 30-Day safety follow-up and 150-Day safety follow-up, the collection of 
new SAEs and AEs unrelated to study medication will stop, and thereafter only suspected SAEs 
and suspected AEs will continue to be collected to Day 150. If SAEs suspected to be related to 
study medication occur beyond Day 150, information should also be collected. Section 6.3.3.1
outline the follow-up evaluations recommended for selected toxicities.
6.3.3.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.


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Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2 . A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.4
Concomitant medications 
6.4.1
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 except those 
prohibited in Section 6.4.3. The following list includes permitted concomitant therapies:

Medications to prevent or treat nausea or vomiting.

Anti-diarrheal medications (e.g., loperamide) for patients who develop diarrhea.

Pain medication to allow the patient to be as comfortable as possible.

Localized radiotherapy and treatment with bisphosphonates for pre-existing, painful 
bone/liver metastases is permitted. The radiotherapy must be listed on the CRF.

Immunosuppressive agents to treat suspected irAEs.

Nutritional support or appetite stimulants (e.g. megestrol).

Oxygen therapy and blood products or transfusions.

Limited-field palliative radiotherapy may be allowed as concomitant therapy. Such local 
therapies administered during the study treatment must be listed on the CRF.


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
Inactivated vaccines.

The patient must be told to notify the investigational site about any new medications 
he/she takes after the start of the study drug. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered during the study must be listed on the Concomitant 
Medications.
6.4.2
Permitted concomitant therapy requiring caution and/or action 
If a patient is using erythropoiesis stimulating agents (ESAs) prior to enrollment (at least 2 
weeks before start of study treatment), he/she may continue the treatment.
Anticoagulation and anti-aggregation agents are permitted if the patients are already at stable 
doses 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.
6.4.3
Prohibited concomitant therapy
During the course of the study, patients must not receive other additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate 
the immune responses. However, limited-field palliative radiotherapy may be allowed as 
concomitant therapy. Such local therapies administered during the study treatment must be 
entered into the CRF. Additionally, no other therapeutic monoclonal antibodies and no 
immunosuppressive medication may be administered while on this study unless given for the 
management of immune toxicity. 
The use of somatostatin analogs or any other medications administered to control active 
symptoms related to carcinoid syndrome is not permitted during the study unless there is a 
change to functional status (Section 6.4.4.1).
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of infusion reaction, irAEs, and for prophylaxis against imaging contrast dye 
allergy or 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 COPD requiring treatment for ≤3 weeks. If systemic corticosteroids are required for 
the control of infusion reactions or irAEs, it must be tapered and be at non-immunosuppressive 
doses (< 10 mg/day of prednisone or equivalent) before the next administration of study 
treatment. If the dose of prednisone or equivalent cannot be reduced to less than 10 mg/day 
before the administration of next dose of study treatment then PDR001 must be discontinued.
The use of live vaccines is not allowed through the whole duration of the study. Inactivated 
vaccines are allowed.
There are no prohibited therapies during the post-treatment follow-up period.


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6.4.4
Use of bisphosphonates (or other concomitant agents) 
Localized radiotherapy and treatment with bisphosphonates for pre-existing, painful bone/liver 
metastases is permitted. The radiotherapy must be listed on the concomitant Antineoplastic 
Therapy – Radiotherapy CRF.
6.4.4.1
Proposed language for other concomitant medications
The use of somatostatin analogs is permitted to control symptoms which are developed on study
in patients with neuroendocrine tumors changing to functional status.
6.5
Patient numbering, treatment assignment 
6.5.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the 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 Subject 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 Subject No. must 
not be reused for any other patient and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to start treatment for any reason, the reason 
will be entered into the Screening Disposition page.
IRT must be notified within 2 days that the patient was not treated as scheduled.
6.5.2
Medication number assignment 
All patients who fulfill all inclusion/exclusion criteria will be assigned to be treated with 
PDR001. No randomization will be performed in this study.
IRT will be used to assign a medication number for each PDR001 dose. The assignment of a 
patient to a particular cohort/group (pancreatic, GI, thoracic or GEP-NEC) will be coordinated 
and monitored by the sponsor.
6.5.3
Treatment blinding
Not applicable
6.6
Study drug preparation and dispensation
The dose administered to the patient and any study drug interruptions during the study must be 
recorded on the Dosage Administration Record CRF.
PDR001 will be provided as global clinical supply and will be packed and labeled under the 
responsibility of Novartis, Drug Supply Management.


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PDR001 will be administered intravenously as a 30 minute infusion (up to 2 hours, if clinically 
indicated). Clinical monitoring, during and post infusion, should be performed according to
local practice and institutional guidelines. Further instructions for the preparation and 
dispensation of PDR001 are described in the [Study Pharmacy Manual].
6.6.1
Study treatment packaging and labeling
Study treatment, PDR001, will be provided as global clinical open supply and will be packed 
and labeled under the responsibility of Novartis, Drug Supply Management. 
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength). 
Responsible site personnel will identify the study treatment package(s) to dispense by the 
medication number(s) assigned by IRT to the patient. Site personnel will add the patient number 
on the label. If the label has 2-parts (base plus tear-off label), immediately before dispensing 
the package to the patient, site personnel will detach the outer part of the label from the package 
and affix it to the patient’s source document.
6.6.2
Drug supply and storage
Study treatment must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [Investigator’s Brochure]. 
Table 6-13
Supply and storage of study treatments
Study treatments
Supply
Storage
PDR001
Centrally supplied by Novartis
Refer to study treatment label
6.6.3
Study drug compliance and accountability
6.6.3.1
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. Study drug interruptions of PDR001 must be specifically documented in the patient source 
documents and eCRF.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. 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.


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6.6.3.3
Handling of other study treatment
Not applicable.
6.6.4
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 lists all of the assessments and indicates with an “X”, when the visits are performed.
All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column).
Table 7-1 also lists all changes in assessments after cut-off date of primary analysis (10-Aug-
2018).
No paper CRF will be used as a source document. 
PRO data will be captured on an ePRO tablet and is considered the source document.
Allowed visit windows are specified as follows:
Visit name
Window 
Screening
A serum pregnancy test (local Lab)
-28 days
≤ 72 hours before first dose of study treatment
Enrollment and Cycle 1 Day 1
None (should occur on the same day)
Hematology, chemistry, coagulation, Chromogranin A (CgA), 
neuron specific enolase (NSE) and urinalysis for Cycle 1 
Day 1
≤ 4 days before first dose of study treatment
Day 1 of subsequent cycles
± 7 days
PK sampling
None (end-of-infusion samples should be 
collected within 30 min post infusion)
Scans
± 7 days (during treatment/follow-up)
PRO
± 7 days (during treatment/follow-up)
EOT
+ 7 days from the last PDR001 dose
30-Day safety follow-up visit
± 7 days
60-, 90-, 120-Day safety follow-up phone call/ visit
± 7 days
150-Day safety follow-up phone call or visit (visit for women 
of child-bearing potential (WOCBP) and phone call for all 
others) (Section 7.1.7)
± 14 days
Survival follow up
± 14 days
Every effort should be made to follow the schedule outlined in Table 7-1.


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Table 7-1
Visit evaluation schedule
Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
Obtain Informed 
Consent
D
11.3
X
Patient history
Demography
D
7.1.2.3
X
Inclusion/exclusion 
criteria
D
5
X
HIV history
S
5.3
X
Medical history
D
7.1.2.3
X
Diagnosis and extent of 
cancer
D
7.1.2.3
X
Proliferative activity 
assessment
D
7.1.2.
X
Presence of Necrosis
D
7.1.2.
X


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Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
Prior antineoplastic 
therapy
D
7.1.2.3
X
Prior/concomitant 
medications
D
7.1.2.3
X
From 30 days prior to starting study treatment until 150-Day safety follow-up or start of 
new antineoplastic medication, whichever is sooner.
If new antineoplastic medication is started then only medications relative to the 
suspected AEs/SAEs that are reported should be collected.
Prior/concomitant 
procedures and 
Significant Non-Drug 
Therapies
D
7.1.2.3
X
Continuous
Enrollment
Eligibility checklist 
(Contact IRT)
S
7.1.2.1
X
Drug Supply (Contact 
IRT)
S
6.5
X
X
X
X
Disposition 
Assessment (at the end 
of each study phase)
D
X
X
X
Physical examination
Physical examination
S
7.2.6.1
X
X
X
X
X


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Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
ECOG Performance 
status
D
7.2.6.4
X
X
X
X
X
Height 
D
7.2.6.3
X
Weight
D
7.2.6.3
X
X
X
X
X
Vital signs
D
7.2.6.2
X
X
X
X
X
Change in functional 
status of carcinoid 
syndrome
D
7.2.6.5
If applicable
Laboratory assessments
Hematology
D
7.2.6.6.1 
X
X
X
X
X
Chemistry
D
7.2.6.6.2 
X
X
X
X
X
Thyroid Panel- TSH
D
7.2.6.6.3 
X
X
X
X
Thyroid Panel- Free T3 
and Free T4
D
7.2.6.6.3 
X
Only if TSH is abnormal
Coagulation
D
7.2.6.6.4 
X
From Cycle 
1 Day 1, 
every 8 
weeks for 
If 
clinically 
indicated
If 
clinically 
indicated


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Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
the first 13 
cycles and 
every 12 
weeks 
thereafter
Urinalysis
(microscopic or 
macroscopic)
S
7.2.6.6 
X
X
X
X
X
Urine pregnancy test 
S
7.2.6.6.8 
X
X 
X 
X 
Serum pregnancy test
D
7.2.6.6.8 
X
X
X
X 
Hepatitis testing
D
7.2.6.6.6 
X
If clinically indicated, perform testing as needed
Cytokine for safety 
D
7.2.6.6.5 
X
Anytime when a suspected cytokine release syndrome occurs, immediately after the 
AE, and one week after occurrence of the AE
CgA and NSE levels
D
7.2.6.6.7 
X
X
X
X
Imaging 
Tumor evaluation per 
RECIST 1.1 and 
irRECIST
D
7.2.2
X
Before the primary analysis cut-off date (10-Aug-2018):
Treatment Period: Every 8 weeks counting from Cycle 1 Day 1 for the first 13 cycles and then 
every 12 weeks from Cycle 13 Day1 thereafter 
EOT: If a scan was not conducted within 30 days prior to end of study treatment  


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Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
Efficacy follow-up: Continue same schedule as during treatment period until BIRC confirmed 
irRECIST progression
After the primary analysis cut-off date (10-Aug-2018): 
Treatment Period: scheduled according to local or institutional standards of care and when 
clinically indicated, and continue until locally-determined disease progression (per RECIST 1.1 or 
irRECIST).
EOT: no scan needs to be perfomed at EOT 
Efficacy follow-up: Post-treatment efficacy follow-up will no longer be performed.
Chest, abdomen and 
pelvis CT or MRI (with 
iv contrast)
D
7.2.2
X
Before the primary analysis cut-off date (10-Aug-2018):
Treatment Period: Every 8 weeks counting from Cycle 1 Day 1 for the first 13 cycles and then 
every 12 weeks from Cycle 13 Day1 thereafter 
EOT: If a scan was not conducted within 30 days prior to end of study treatment  
Efficacy follow-up: Continue same schedule as during treatment period until BIRC confirmed 
irRECIST progression
After the primary analysis cut-off date (10-Aug-2018): 
Treatment Period: scheduled according to local or institutional standards of care and when 
clinically indicated, and continue until locally-determined disease progression (per RECIST 1.1 or 
irRECIST).
EOT: no scan needs to be perfomed at EOT
Efficacy follow-up: Post-treatment efficacy follow-up will no longer be performed.


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Protocol No. CPDR001E2201
Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
Brain CT or MRI
D
7.2.2
X
If positive at screening, follow same schedule as CT/MRI of chest, abdomen, and pelvis and if 
clinically indicated
Whole body bone scan
D
7.2.2
If clinically indicated
Localized bone CT, 
MRI or x-ray 
D
7.2.2
Only for lesions on whole body scan that are not visible on the chest, abdomen and pelvis scans. If lesions 
were documented at screening, follow same schedule as CT/MRI of chest, abdomen, and pelvis
12-lead ECG 
D
  
7.2.6.7.1 
X
From Cycle1 
Day1, every 
12 weeks 
X
If clinically indicated
Safety
Adverse events
D
8.1
● Suspected AEs up to 150-Day safety follow-up
● Non-suspected AEs up to 150-Day safety follow-up or start of new post treatment anti-neoplastic 
medication if administered during the period between the 30-Day safety follow-up and 150-Day 
safety follow-up, whichever is sooner
Serious Adverse 
Events
D
8.2
● Suspected SAEs up to 150-Day safety follow-up and beyond
● Non-suspected SAEs up to 150-Day safety follow-up or start of new post treatment anti-neoplastic 
medication if administered during the period between the 30-Day safety follow-up and 150-Day 
safety follow-up, whichever is sooner


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Protocol No. CPDR001E2201
Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months


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Protocol No. CPDR001E2201
Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
available 
visit)
Patient-reported Outcomes 
EORTC QLQ-C30
D
7.2.10
X
Before the primary analysis cut-off date (10-Aug-2018):
Treatment Period: Every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 
weeks from Cycle 13 Day1 thereafter
EOT: Collect at EOT Visit
30-day SafetyVisit: Collect at 30-Day Safety Follow-up Visit 
Efficacy follow-up: Continue same schedule as during treatment period until BIRC 
confirmed irRECIST progression


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Protocol No. CPDR001E2201
Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
After the primary analysis cut-off date (10-Aug-2018): 
ePROs collection will no longer be performed.
EQ-5D-5L 
D
7.2.10
X
Before the primary analysis cut-off date (10-Aug-2018):
Treatment Period: Every 8 weeks from Cycle 3 Day 1 for the first 13 cycles and every 12 
weeks from Cycle 13 Day1 thereafter
EOT: Collect at EOT Visit
30-day SafetyVisit: Collect at 30-Day Safety Follow-up Visit 
Efficacy follow-up: Continue same schedule as during treatment period until BIRC 
confirmed irRECIST progression
After the primary analysis cut-off date (10-Aug-2018): 
ePROs collection will no longer be performed
Study Drug Administration
Study Drug 
administration 
D
X
Verification for 
treatment beyond 
RECIST 1.1 
D
6.1.5.1
X


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Protocol No. CPDR001E2201
Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
progression (if 
necessary)
Blood sampling for PK
D
7.2.7 
Before the primary analysis cut-off date (10-Aug-2018):
Treatment period: 
At Day 1 of all cycles until Cycle 13 and Day 1 of every 6 cycles thereafter until Cycle 25
EOT
30-Day safety follow-up
150-Day safety follow-up for WOCBP
Unscheduled: 
At the time of PD based on RECIST 1.1 
At the time of PD based on irRECIST
After the primary analysis cut-off date (10-Aug-2018):
No additional PK samples will be collected for the patients still ongoing on the study, unless 
requested by the Investigator.
Immunogenicity (IG) 
sampling 
D
7.2.7 
Before the primary analysis cut-off date (10-Aug-2018):
Treatment period: 
At Day 1 of all cycles until Cycle 13 and Day 1 of every 6 cycles thereafter until Cycle 25
EOT
30-Day safety follow-up
150-Day safety follow-up for WOCBP
Unscheduled:


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Protocol No. CPDR001E2201
Day of cycle 
Category
Protocol Section
Screening 
period
Treatment period 
(cycle = 28 days)
Follow-up period
Screening
Cycle 1 Day 1
Subsequent cycles
Day 1
EoT
30-Day 
Safety 
follow-
up Visit
60-Day 
Safety 
follow-
up 
phone 
call
90-Day 
Safety
follow-
up 
phone 
call
120-
Day 
Safety
follow-
up 
phone 
call
150-Day 
safety follow-
up visit /
phone call
(visit for 
WOCBP and 
phone call 
for all others)
End of 
post 
treatm
ent 
follow-
up
Survival
F/U
(after 
safety 
and 
efficacy 
follow-
up)
-28 to -1
1
1
Every 3 
months
At the time of PD based on RECIST 1.1 
At the time of PD based on irRECIST
At the time of suspected irAEs
After the primary analysis cut-off date (10-Aug-2018):
No additional IG samples will be collected for the patients still ongoing on the study, unless 
requested by the Investigator.
Follow-up
Survival follow-up 
7.1.9
X
Antineoplastic 
therapies since 
discontinuation of study 
treatment 
D
7.1.9
X
X
X
X
X
X
X


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7.1.1
Molecular pre-screening
Not applicable.
7.1.2
Screening
Patients with non-functional, well-differentiated grade 1 or 2, progressing NETs of pancreatic, 
GI or thoracic (lung or thymic) origin or patients with poorly-differentiated GEP-NEC will be 
screened for eligibility during a maximum period of 28 days (Day -28 to Day -1) immediately 
prior to starting PDR001 on study Day 1. During this time, the inclusion and exclusion criteria 
will be assessed, and all screening assessments will be performed according to Table 7-1. Tumor 
tissue must be sent to a central laboratory within the screening timeframe as per eligibility 
criteria defined in Section 5.
The tumor pathology report must be verified by the study investigator to confirm histology and 
grade of neuroendocrine tumor (including mitotic count, Ki-67 index, and absence or presence 
of necrosis, as applicable). Data from previous tumor assessments (i.e. imaging scans) 
performed as part of the patient’s routine care (prior to enrolling in the trial) must be considered 
to fulfill eligibility criteria #6 (Section 5.2). Patient eligibility will be checked once all screening 
procedures are completed. Results of all screening evaluations must be reviewed by the 
investigator prior to enrollment into the study, in order, to assure that all inclusion and exclusion 
criteria have been satisfied. Only laboratory results from the central laboratory can be used to 
determine patient eligibility. 
An eligibility review and confirmation will be embedded in the IRT system. Please refer to and 
comply with detailed guidelines in the IRT manual. The IRT system will confirm the inclusion 
of eligible patients.
If a patient completed all screening evaluations and did not meet eligibility criteria, the patient 
is a screen failure. However, the investigator may choose to re-screen the patient. If the 
investigator chooses to re-screen the patient, the patient must sign a new ICF. All required 
screening evaluations must be performed again during re-screening; all re-screening evaluations 
must be performed within 28 days prior to the start of study treatment. Re-screening is allowed 
once per patient as long as the patient was not assigned a medication number for first dose by 
IRT. In this case the “Patient number” assigned to the patient initially will be used, and the 
patient will be identified by this number throughout his/her entire participation to the study. All 
re-screened evaluations must meet the eligibility criteria for the patient to receive treatment. If 
the patient completes all re-screening evaluations and still do not meet eligibility criteria, the 
patient is a screen failure.
For central laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted when initial results are out of the permitted range. In this case, 
the patient will not be required to sign another ICF, and the original patient ID number assigned 
by the investigator will be used. If the repeated laboratory result meets the criteria, that result 
may be used to determine eligibility. If the repeated laboratory result does not meet the criteria, 
the patient will be considered a screening failure.


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Once the number of patients screened and enrolled is likely to ensure target enrollment in a 
cohort or the study, the sponsor will close the cohort or the study to further screening. In this 
situation, patients who screen failed will not be permitted to be re-screened.
7.1.2.1
Eligibility screening 
Once a patient is registered in the IRT for screening, patient eligibility will be checked after all 
screening procedures are completed. The eligibility checklist is embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
A patient who signed an Informed Consent Form but did not start treatment for any reason will 
be considered a screen failure. 
The data from a screen failure patient will be entered on the Screening Phase Disposition Page.
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 screen failures patients, unless the patient experienced a Serious Adverse Event during the 
Screening Phase (see Section 8 for SAE reporting details).
7.1.2.3
Patient demographics and other baseline characteristics
Data will be collected on patient characteristics including:

Demographic information (age, sex, race, height and weight),  

Other background or relevant medical history, including HIV history, cancer, disease 
baseline characteristics (diagnosis, history, and extent of cancer, prior anticancer therapies 
including surgery and local therapies such as radiotherapy), and 

Any other assessments that are done for the purpose of determining eligibility for 
inclusion in the study (i.e., ECOG Performance Status, complete physical examination, 
vital signs, hematology, blood chemistries including coagulation studies and urinalysis, 
pregnancy test only required for women of child-bearing potential, tumor imaging 
assessments, ECG, etc.).
All medications and significant non-drug therapies taken within 30 days prior to start of study 
treatment must be recorded on the Concomitant medication eCRF page and updated on a 
continual basis if there are any new changes to the medications.
Tumor imaging assessments will be performed for screening purposes and for determination of
patient eligibility. Results of scans (as described in Table 7-2) performed within 28 days prior 
to start of study treatment will also be used as baseline values, except for whole body bone 
scans (if applicable, for suspected or known bone metastases), which can be performed within 
6 weeks of start of study treatment. Chest, abdomen, and pelvis CT or MRI scans and brain CT 
or MRI scan are required to be performed at screening. See Section 7.2.1 Efficacy assessments 
for more details.
To determine eligibility, measurable and non-measurable lesions must be assessed. Target 
lesions must be identified prior to start of treatment. For definition of measurable and target 
lesions, please refer to Appendix 1.


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7.1.3
Run-in period 
Not applicable
7.1.4
Treatment period
Patients will start PDR001 intravenous infusion at a flat dose of 400 mg every 4 weeks on Cycle 
1 Day 1 and continue dosing until any of the criteria for study treatment discontinuation is met 
(Section 4.1). Patients will visit the site on Day 1 of each cycle (1 cycle = 28 days) or more 
frequently, if medically indicated. For details on study procedures during treatment, please see 
Table 7-1 Visit evaluation schedule.  
7.1.5
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 understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits, 
or become lost to follow-up for any other reason.
The investigator may discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being.
Patients may stop study treatment for any of the following reasons:

Adverse event(s) 

Progressive Disease

Protocol Deviation

Technical problems

Physician decision

Subject/guardian decision
Patients must stop study treatment for any of the following reasons:

Death

Pregnancy 

Study terminated by sponsor

Lost to follow-up
Patients who discontinue study treatment should not be considered withdrawn from the study. 
They should undergo an end of treatment visit and then enter the safety, efficacy, and survival 
follow-up periods. If they fail to return for these assessments for unknown reasons, every effort 
(e.g. telephone, email, and letter) should be made to contact them as specified in Section 7.1.10.
Prior to and after the primary analysis cut-off date (10-Aug-2018), in some circumstances 
patients may be allowed to continue to receive study treatment beyond disease progression as 
per RECIST 1.1 criteria (Section 6.1.5.1). These patients will continue assessments as outlined 
in Section 7, and will complete the EOT visit only after permanent discontinuation of study 
treatment.


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Patients who discontinue treatment prior to the primary analysis cut-off date (10-Aug-2018) for 
reasons other than irRECIST PD will have tumor assessments per Table 7-1 until withdrawal 
of consent, death, lost to follow-up or eventual irRECIST PD per BIRC even if new post 
treatment ANP is started.
After the primary analysis cut-off date (10-Aug-2018),  post-treatment efficacy follow-up will
be discontinued. Therefore, for patients who discontinue study treatment for any reasons after
the primary analysis cut-off date, post treatment efficacy follow-up will not be performed and 
these patients will enter the safety follow-up. If clinically indicated, patients may continue to 
undergo tumor response assessments during the safety follow-up according to local or 
institutional standard of care; however these tumor response assessments will no longer be 
reported in the eCRF.
The investigator must also contact the IRT to register the patient’s discontinuation from study
treatment.
7.1.5.1
Replacement policy
Not applicable
7.1.6
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 
anymore, and does not allow any further collection of personal data.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for this patient’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the 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.


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7.1.7
Follow up for safety evaluations
All patients must be followed for safety 150 days after the last dose of PDR001 (Appendix 3).
After the 30-Day on-site safety follow-up visit, patients will be followed (via telephone call or 
on-site visit if patient happens to be visiting the site) at 60, 90, 120 and 150 days after the last 
dose of PDR001. However, women of childbearing potential must return to the site for the 150-
Day safety follow-up visit, in order, to have a serum pregnancy test; for 60, 90, 120 days safety 
follow-up, women of childbearing potential will perform a urine pregnancy test at home.
All safety assessments should be completed as per Table 7-1. However, if the patient begins 
post treatment antineoplastic medication during the period between the 30-Day and 150-Day 
safety follow-up, the collection of new SAEs and AEs unrelated to study medication will stop,
and thereafter only suspected AEs and suspected SAEs will continue to be collected up to 150-
Day safety follow-up. Suspected SAEs will continue to be collected beyond the 150-Day safety
follow-up. Data collected should be added to the appropriate eCRF pages. 
There are no changes in safety evaluations after the primary analysis cut-off date. 
7.1.8
Follow-up for efficacy evaluations
Patients who discontinue treatment for reasons other than irRECIST PD will have tumor 
assessments per Table 7-1 until withdrawal of consent, death, lost to follow-up or eventual 
irRECIST PD per BIRC even if new post treatment ANP is started.
After the primary analysis cut-off date (10-Aug-2018),  post-treatment efficacy follow-up will 
be discontinued.  Therefore, for patients who discontinue study treatment for any reasons after 
the primary analysis cut-off date, post treatment efficacy follow-up will not be performed and 
these patients will enter the safety follow-up.  If clinically indicated, patients may continue to 
undergo tumor response assessments during the safety follow-up according to local or 
institutional standard of care; however, these tumor response assessments will no longer be 
reported in the eCRF.
7.1.9
Survival follow-up
Patients will enter the survival follow-up period once they complete the safety follow-up period 
or efficacy follow-up, whichever is last. Patients will then be contacted by telephone every 12 
weeks to follow-up on their survival status. Any new antineoplastic medications that have been 
started since the last contact date will also be collected during these phone calls.
7.1.10
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" (three 
documented attempts) by contacting the patient, family or family physician as agreed in the 
informed consent and by documenting in the source documents steps taken to contact the patient, 
e.g. dates of telephone calls, registered letters, etc. A patient should not be considered lost to 
follow-up until due diligence has been completed. Patients lost to follow up should be recorded 
as such on the appropriate Disposition CRF.


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7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.2 (Appendix 1) based on RECIST 1.1 (Eisenhauer et al 2009) and irRECIST 
(Appendix 2). The imaging assessment collection plan is presented in Table 7-2. Details of the 
central review process will be described in the independent review charter.
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. The results of the central evaluations 
will be used for primary analysis purposes. The local investigator’s assessment will be used for 
treatment decision making as described in Section 7.2.4.
Information regarding prior interventions (e.g., radiotherapy), pre-existing radiographic 
findings that mimic metastatic disease at baseline/screening and prior interventions should be 
transmitted to the imaging CRO via the Baseline Clinical Form along with the screening images 
for review by the independent radiologist. Sites must ensure the data entered on the form is 
consistent with the data entered in the clinical database.
Information regarding cytology results should be transmitted to the imaging CRO via the 
Cytology Form for all visits, when applicable, for review by the independent radiologist. Sites 
must ensure the data entered on the form is consistent with the data entered in the clinical 
database.
After primary analysis cut-off date (10-Aug-2018), medical imaging data and information 
regarding cytology results will no longer be collected and transmitted to the imaging Contract 
Research Organization (CRO) for central tumor response evaluation. Tumor response will be 
assessed locally by investigator, according to RECIST 1.1 (Appendix 1) and irRECIST 
(Appendix 2).


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Table 7-2
Imaging Assessment Collection Plan
Procedure
Screening
(Day -28 to Day -1)
During Treatment/Follow-up
(+/- 7 day window)
Chest, abdomen 
and pelvis CT or 
MRI (with 
contrast 
enhancement) 
Mandated
Before the primary analysis cut-off date (10-Aug-2018):
Treatment Period:
Every 8 weeks counting from Cycle 1 Day 1 for the first 13 
cycles and then every 12 weeks from Cycle 13 Day1 thereafter 
EOT: If a scan was not conducted within 30 days prior to end 
of study treatment.  
Efficacy follow-up: Continue same schedule as during 
treatment period until BIRC confirmed irRECIST progression
After the primary analysis cut-off date (10-Aug-2018):
Treatment Period: scheduled according to local or institutional 
standards of care and when clinically indicated, and continue 
until locally-determined disease progression (per RECIST 1.1 
or irRECIST)
EOT: No scan is needed at EOT visit.  
Efficacy follow-up: Post-treatment efficacy follow-up will no 
longer be performed.
Brain CT or MRI
Mandated
If lesions were documented at baseline, follow same schedule 
as CT/MRI of chest, abdomen, and pelvis
Whole body 
bone scan
If clinically indicated
If clinically indicated
Localized bone 
CT, MRI or X-
ray
For any lesions identified 
on the “clinically 
indicated” baseline whole 
body bone scan that are 
not visible on the chest, 
abdomen and pelvis CT 
or MRI
If lesions were documented at baseline, follow same schedule 
as CT/MRI of chest, abdomen, and pelvis
7.2.2
Baseline imaging assessments
Imaging assessments will be performed at screening 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 baseline images for this study. Any imaging assessments obtained after start 
of study treatment cannot be considered baseline images. 
The following assessments are required at screening:

Computed Tomography (CT) with IV contrast or Magnetic Resonance Imaging (MRI) of 
Chest, abdomen and pelvis 

The preferred radiologic technique is CT with intravenous (IV) contrast. If a patient is 
known to have a contraindication to CT contrast or develops a contraindication during 
the trial, a non-contrast CT of the chest (MRI is not recommended due to respiratory 
artifacts) plus a contrast-enhanced MRI (if possible) of the abdomen and pelvis 
should be performed

Brain CT with IV contrast or MRI scan


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
If brain lesions are documented at baseline, scans need to be continued following the 
same schedule as CT/MRI of chest, abdomen and pelvis. The same methodology as 
used at screening should be used. Contrast enhanced brain MRI is preferred.  
However, if MRI contrast is contraindicated, then MRI without contrast or CT 
with/without contrast is acceptable.

A whole body bone scan according to institutional guidelines [e.g. Tc-99 bone scan, whole 
body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-PET) or 
sodium fluoride positron emission tomography (NaF PET)], if clinically indicated.

Whole body bone scans is not required for any timepoint, unless clinically indicated. 
It will not be the routinely used tumor imaging to monitor the response to the therapy.  

If skeletal lesions are documented on the whole body bone scan at baseline, localized bone 
CT, MRI or x-ray will be performed to follow up these lesions with the same schedule 
used for the tumor assessment by CT/MRI as described in Table 7-2. 

CT or MRI of other metastatic sites not captured by any of the above listed images (e.g., 
neck), if clinically indicated.

If additional sites of disease are documented at screening, scans need to be continued 
following the same schedule as CT/MRI of chest, abdomen and pelvis. The same 
methodology as at screening should be used.

Chest x-rays and ultrasound must not be used to measure tumor lesions.
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.
7.2.3
Post-baseline imaging assessments
Imaging assessments as described in Table 7-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing (see 
Table 7-1). 
Prior to the primary analysis cut-off date (10-Aug-2018), imaging assessments for response 
evaluation will be performed every 8 weeks (+/- 7 days) until Cycle 13, and every 12 weeks 
(+/- 7 days) thereafter until disease progression per RECIST 1.1 or irRECIST per BIRC, death, 
lost to follow-up or withdrawal of consent. Imaging assessments should be scheduled using the 
date of first dose (Cycle 1 Day 1) as the reference date (not the date of the previous tumor 
assessment), and should be respected regardless of whether treatment with study treatment is 
temporarily withheld or unscheduled assessments performed. 
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 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 


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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 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
1.1 (Appendix 1) or per irRECIST (Appendix 2).
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging CRO for quality control and central review. 
After the primary analysis cut-off date (10-Aug-2018):

For patients on study treatment, imaging assessments will be scheduled according to local 
or institutional standard of care, as clinically indicated, and will continue until study 
treatment discontinuation.

Imaging data will no longer be centrally collected and transmitted to the imaging CRO.
Tumor response will be assessed locally according to RECIST 1.1 (Appendix 1) and 
irRECIST (Appendix 2).

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 planned
imaging assessment.
7.2.4
Timepoints at which progression is determined locally
All patients who have disease progression per RECIST 1.1 or disease progression per irRECIST 
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. For expedited requests, the scans will undergo 
expedited central review (within 5 business days from the time of image receipt at the imaging 
CRO and once all applicable queries are resolved) and the results of the central review will be 
communicated to the site. While the investigator is waiting for the results from the central 
imaging CRO confirming disease progression, the patient should continue on study treatment. 
However, during this time, the investigator should do whatever is medically necessary for 
his/her patient.
If the central review determines disease progression as per RECIST 1.1 (and the patient does 
not meet the criteria in Section 6.1.5.1) or disease progression per irRECIST, then the patient 
will discontinue study treatment and subsequent tumor assessments are only required if the 
patient has not met the criteria for disease progression per irRECIST as per the central imaging 
vendor. 
If the central review does not determine disease progression as per RECIST 1.1 or irRECIST, 
or the central reviewer determines disease progression as per RECIST 1.1, but the patient meets 


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the criteria in Section 6.1.5.1 to continue treatment, the patient should continue receiving the 
study treatment unless there is a medical need (i.e., rapid progression or clinical deterioration) 
for an immediate change in therapy. After the central reviewer determines disease progression 
per RECIST 1.1, an expedited review will be required only in case of disease progression 
determined locally per irRECIST at following assessments.
Patients will continue to have imaging performed as per protocol (Table 7-1) until the central 
review determines disease progression per irRECIST.
The imaging vendor will ensure that the central reviewers involved are blinded to the expedited 
status of the reading.
In summary, for expedited timepoints (assessed as PD by RECIST 1.1 or irRECIST by local):
Rapid image transmission to the central imaging CRO may be accomplished by uploading all 
digital images acquired by the Investigator in a secured website, while preserving the blinded 
status of the images.

If central radiology determines PD as per RECIST 1.1, or PD per irRECIST , the study 
site will be informed. This patient should then discontinue study drug unless the criteria 
are met to continue study treatment beyond disease progression per RECIST 1.1 as 
described in Section 6.1.5.1. An expedited review at future assessments will only be 
required if PD per irRECIST is determined by the local investigator.

If central radiology does not conclude PD as per RECIST 1.1 or PD as per irRECIST, the 
study site will be informed. As long as it is clinically acceptable, every effort should be 
made to continue the patient on study drug until PD as per irRECIST is determined by 
central review or for at least one subsequent radiological timepoint.
After the primary analysis cut-off date (10-Aug-2018):

Imaging data will no longer be centrally collected and transmitted to the imaging CRO. 
Patients who have disease progression per RECIST 1.1 or irRECIST as determined locally
do not require an expedited central review.

Tumor response will be assessed locally (i.e. by investigator) according to  RECIST 1.1 
(Appendix 1) and irRECIST (Appendix 2).
7.2.5
Timepoints without locally determined progression
All imaging timepoints without locally determined progression per RECIST 1.1 or PD as per 
irRECIST will be read on an ongoing, non-expedited basis as detailed in the imaging manual 
to be provided by the designated imaging CRO and independent review charter. Results of these 
readings will not be communicated to the sites.
After the primary analysis cut-off date (10-Aug-2018), imaging data will no longer be centrally 
collected and transmitted to the imaging CRO. 
7.2.6
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, weight, ECOG 
performance status, laboratory evaluations (including chemistry, hematology, hepatitis, 
coagulation, pregnancy, cytokines analysis), safety imaging (CT or MRI), and ECG as well as 


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collecting of the adverse events as well as collecting of the adverse events at every visit as 
indicated in Table 7-1. For details on AE collection and reporting, refer to Section 8.
7.2.6.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF. 
7.2.6.2
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature. 
7.2.6.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1.
7.2.6.4
Performance status
ECOG Performance status scale will be used as described in the Table 7-1 and Table 7-3.
Table 7-3
ECOG performance status scale
Score
Performance 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 housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
7.2.6.5
Change in functional status of carcinoid syndrome
If a patient with non-functional tumor develops symptoms related to carcinoid syndrome (e.g. 
flushing, diarrhea) the change to “functional status” and the use of concomitant medications to
control symptoms should be documented in the appropriate eCRF pages.


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7.2.6.6
Laboratory evaluations
Table 7-4
Central Clinical laboratory parameters collection plan 
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other) 
Chemistry
Albumin, Alkaline phosphatase, ALT , AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect 
Bilirubin, Total Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting) 
Coagulation
Screening: Prothrombin time (PT), International normalized ratio (INR]), Activated 
partial thromboplastin time (APTT)
At all subsequent visits indicated in Table 7-1: APTT
Thyroid
At screening: TSH (Thyroid Stimulation Hormone), Free T3 and Free T4
At the subsequent visits as indicated in Table 7-1: TSH only.
If TSH is abnormal, central lab will test Free T3 and Free T4
Hepatitis markers
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR 
Cytokines
IFN-γ, IL-6, IL-1,TNF-α
Neuron specific 
enolase (NSE) level
NSE
Chromogranin A 
(CGA) level
CGA
Table 7-5
Local Clinical laboratory parameters collection plan
Test Category
Test Name
Urinalysis
Local Laboratory: Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, 
Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
If dipstick is abnormal then perform local laboratory Microscopic Panel (Red Blood 
Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Pregnancy Test
A serum pregnancy test must be performed at screening (at the local laboratory) within 
≤ 72 hours before first dose of study treatment, at EOT, at 30-Day and 150-Day (for 
WOCBP) safety follow-up visits.
A local laboratory urine pregnancy test must be performed at day 1 of every cycle 
beginning with Cycle 2, and at home every 30-Day after 30-Day safety follow-up visit 
until 120-Day follow-up.
All laboratory parameters assessed for safety purposes will be evaluated centrally except for 
urinalysis and urine/serum pregnancy tests that will be performed locally (Table 7-4 and Table 
7-5). Samples for these parameters will be collected prior to the infusion of PDR001.
Local laboratory assessments may be performed if medically indicated or when the treating 
physician cannot wait for central laboratory results for decision making. In this particular 
situation, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis. 
The results of the local laboratory will be recorded in the eCRF if the following criteria are met:

A treatment decision was made based on the local results, or

There are no concomitant central results available
However, only laboratory results from the central laboratory can be used to determine patient 
eligibility.


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Details on the collections, shipment of samples and reporting of results by the central laboratory 
are provided to investigators in the [Laboratory Manual].
7.2.6.6.1 Hematology
Hematology tests are to be performed at each scheduled visit as indicated in Table 7-1 and Table 
7-4. Lab assessment done ≤ 4 days before first dose of study treatment are permitted to be used 
as Cycle 1 Day 1 labs and do not need to be repeated. Hematocrit, Hemoglobin, Platelets, Red 
blood cells, White blood cells, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils, Bands, Other) will be measured.
7.2.6.6.2 Clinical chemistry
The clinical chemistry panel will be performed as per the assessment schedule in Table 7-1 and 
Table 7-4. Lab assessment done ≤ 4 days before first dose of study treatment are permitted to 
be used as Cycle 1 Day 1 labs and do not need to be repeated. Blood urea, creatinine, total 
bilirubin, AST, ALT, alkaline phosphatase, sodium, potassium, calcium, phosphorous, albumin, 
and uric acid Albumin, Alkaline phosphatase, ALT , AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, Chloride, 
Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting) will be measured.
7.2.6.6.3 Thyroid function
Thyroid function will be performed at:

Screening: TSH, Free T3, Free T4

Day 1of subsequent cycles, EoT, 30-Day safety follow-up: TSH

If TSH is abnormal, central lab will test Free T3 and Free T4.
7.2.6.6.4 Coagulation
Coagulation test will be performed as described in Table 7-1 and Table 7-4:

At screening: Prothrombin time (PT), International normalized ratio (INR]), Activated 
partial thromboplastin time (APTT) 

At all subsequent visits: APTT
7.2.6.6.5 Cytokine analysis
Samples for the cytokine panel outlined in Table 7-4 will be collected at the following time 
points: 

Screening

On an ad-hoc basis in case a patient has an adverse event suspected to be a cytokine 
release syndrome (Table 7-1). In such case, this assessment should be performed at the 
following time points: 

within 5 hours (or as soon as possible) after the occurrence of the adverse event, 

one week after the occurrence of the adverse event. 


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Samples for cytokine panel at screening will be stored below -70°C.
7.2.6.6.6 Hepatitis marker
Hepatitis panels will be performed as per Table 7-4.
HBV-DNA serology (including HBV-DNA, HBsAg, HBsAb, HBcAb) and HCV RNA-PCR 
test will be performed at screening within 28 days prior to start of study treatment and as 
clinically indicated (hepatitis markers should be evaluated for precautionary safety monitoring 
of viral re-activation while on study treatment). 
During the screening period, patients must be screened for HBV and HCV (current or past 
history of infection). Careful medical history must be taken for all patients to look for risk 
factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, 
blood transfusions, etc.), and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light colored stools, right upper quadrant pain). 
Hepatitis B: 
At screening, all patients will be tested for: 

HBV-DNA level 

Hepatitis B surface antigen (HBsAg) 

Hepatitis B core antibody (HBcAb) 

Hepatitis B surface antibody (HBsAb) 
Hepatitis C: 
At screening, all patients will be tested for quantitative HCV RNA-PCR. 
After start of the study treatment and until 150-Day safety follow-up, testing for HBV and HCV 
should be performed if clinically indicated (for example: rule out viral causality in case of DILI).
7.2.6.6.7 CgA and NSE
The tumor markers, CgA and NSE, will be collected as described in Table 7-1.
7.2.6.6.8 Pregnancy and assessments of fertility
Serum and Urine pregnancy test will be performed as outlined in Table 7-5.
Women of child-bearing potential will have serum pregnancy tests within 72 hours prior to the 
first dose of study treatment. Monthly urine pregnancy tests will then be required to be 
performed on day 1 of every cycle beginning with Cycle 2, followed by serum pregnancy test 
at the End of Treatment visit, 30-Day and 150-Day Safety follow-up visit. During the follow-
up period after the 30-Day Safety Follow-up visit through the 120-Day follow-up telephone 
call, women of child-bearing potential will perform at-home urine pregnancy testing every 30 
days using kits provided. Women of child bearing potential must return to the site for the final 
pregnancy test (150-Day safety follow-up visit). For all pregnancy tests performed at home, the 
site personnel will follow-up with the patient via telephone call to collect the date and the test 
results and document the information in the patient’s source documents. For the 30-Day and 


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150-Day safety follow-up visits, the results of the serum pregnancy test must be also 
documented in the patient’s source documents and will be reported on the CRF.  
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study (on-treatment or during follow-up) should they have a positive pregnancy test.
7.2.6.7
Cardiac assessments 
7.2.6.7.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as per Table 7-6.
Table 7-6
Local ECG collection plan 
Cycle/weeks
Day
Time
ECG Type
Screening
Anytime
Anytime
12 Lead
Every 12 weeks starting from Cycle1 Day1, 
1
Pre-dose
12 Lead
EOT
1
Anytime
12 Lead
Unscheduled ECG, if clinically indicated
Anytime
12 Lead
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History CRF page. Clinically significant findings must be discussed 
with Novartis prior to enrolling the patient in the study. New or worsened clinically significant 
findings occurring after informed consent must be recorded on the Adverse Events CRF page.
7.2.7
Pharmacokinetics and immunogenicity (IG) assessment
The exact date and clock times of drug administration PK and IG blood draw will be recorded 
on the appropriate eCRF.
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein opposite to the arm used for infusion. 
A total of 5 mL of blood will be collected for PDR001 PK and IG analysis in serum (2 mL for 
PDR001 PK and 3 mL for IG).
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 (Table 7-7). After clotting, the resulting serum will 
be separated in aliquots and will be stored frozen until analysis. 
Refer to the [Laboratory Manual] for detailed instructions for the collection, handling, and 
shipment of PK and IG samples.
If patients experience a SAE or an AE leading to the discontinuation of the study treatment, an 
unscheduled PK blood sample should be obtained as close as possible to the event occurrence. 
If patients experience suspected immunologically related AE such as infusion-related reaction, 
hypersensitivity, cytokine release syndrome and anaphylaxis, an unscheduled IG blood sample 
should be obtained as close as possible to the event occurrence. The date and time of the last 
dose and the time of PK blood draw should be recorded.


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After the primary analysis cut-off date (10-Aug-2018), no additional PK and IG samples 
will be collected for the patients still ongoing on the study, unless requested by the 
Investigator.
Table 7-7
Pharmacokinetic and immunogenicity blood collection log 
Cycle
Day
Scheduled 
timepoint (hours)
Dose 
reference ID
PK Sample 
number
IG Sample 
number
1
1
Predose/0hrsa
1
101
201
1
1
End-of-Infusionb
1
102
2
1
Predose/0hrs
2
103
202
3
1
Predose/0hrs
3
104
203
3
1
End-of-Infusionb
3
105
4
1
Predose/0hrs
4
106
204
5
1
Predose/0hrs
5
107
205
6
1
Predose/0hrs
6
108
206
7
1
Predose/0hrs
7
109
207
8
1
Predose/0hrs
8
110
208
9
1
Predose/0hrs
9
111
209
10
1
Predose/0hrs
10
112
210
11
1
Predose/0hrs
11
113
211
12
1
Predose/0hrs
12
114
212
13
1
Predose/0hrs
13
115
213
19
1
Predose/0hrs
14
116
214
25c
1
Predose/0hrs
15
117
215
EoT
N/A
Anytime
N/A
118
216
30-Day Safety F/U visit
N/A
Anytime
N/A
119
217
150-Day Safety F/U visit (for 
women of childbearing 
potential)
N/A
Anytime
N/A
120
218
●Unscheduledd
●Unscheduled at the time of 
PD based on RECIST 1.1e
●Unscheduled at the time of 
PD based on irRECIST e
●Unscheduled at the time of 
suspected irAE (only IG 
sample)
N/A
Anytime
N/A
1001+
2001+
aAll predose samples must be collected immediately prior to starting the infusion (day of infusion)
bEnd-of-infusion samples should be collected within 30 minutes post-infusion.
cPK and immunogenicity samples will not be collected after cycle 25 even if the patient continues treatment beyond cycle 
25.
dUnscheduled PK and immunogenicity samples may be collected at any time if clinically indicated or at the Investigator’s 
discretion and must be sequentially numbered as 1001, 1002, 1003, etc. for PK samples, and 2001, 2002, 2003, etc. for 
immunogenicity samples.
eAn unscheduled PK sample and an unscheduled immunogenicity sample should be collected upon confirmed disease 
progression based on RECIST 1.1 and irRECIST.
Immunogenicity samples are collected together with PK samples. After the primary CSR data cut-off date no additional 
PK and IG samples will be collected for the patients still ongoing on the study, unless requested by the 


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Cycle
Day
Scheduled 
timepoint (hours)
Dose 
reference ID
PK Sample 
number
IG Sample 
number
Investigator.
Blood samples are collected from the arm opposite from infusion site.
7.2.7.1
Analytical method
Bioanalysis for pharmacokinetic and IG assessment will employ the validated assays:

The assay to quantify PDR001 will be a validated LCMS. The details of the assay will be 
documented in the [Bioanalytical Report].

The assay to quantify and assess the IG will be a validated three-tier ELISA assays 
(screening, confirmatory and titer assays). The details of the assay will be documented in 
the [Bioanalytical Report]. 


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7.2.9
Resource utilization
Not applicable
7.2.10
Patient reported outcomes
The European Organisation for Research and Treatment of Cancer’s core quality of life 
questionnaire (EORTC-QLQ-C30, version 3.0) and the EuroQoL 5-level instrument (EQ-5D-
5L, tablet version) will be used to evaluate patient-reported outcome measures of health-related 
quality-of-life, functioning, disease symptoms, treatment-related side effects, and global health 
status. The EORTC QLQ-C30 and EQ-5D-5L are recognized reliable and valid measures 
(Aaronson 1993, Rabin 2001) frequently used in clinical trials of patients with advanced or 
metastatic cancer. 
All patient-reported outcome (PRO) measures (e.g, EORTC QLQ-C30, EQ-5D-5L) will be 
administered before any study drug administrations at the visits indicated in Table 7-1 and Table 
7-9. Collections of PRO measures have a ±7 day window unless otherwise indicated.
All PRO data will be collected using an electronic tablet device and should be administered in 
the patient’s local language at the beginning of the study visit prior to any interaction with the 
study investigator including any tests, treatments or receipt of results from any tests to avoid 
biasing the patient’s perspective. Patients should be given sufficient space and time to complete 
all study questionnaires and all administered questionnaires should be reviewed for 
completeness. If missing responses are noted, patients should be encouraged to complete any 
missing responses. Attempts should be made to collect responses to all questionnaires for all 
patients, including data from the efficacy follow-up however, if patients refuse to complete 
questionnaires, this should be documented in study source records. Patient’s refusal to complete 
study questionnaires are not protocol deviations.
Completed questionnaires, including both responses to the questions and any unsolicited 
comments provided by the patient, must be reviewed and assessed by the investigator before 


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the clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records.
If an AE or SAE is confirmed then the physician should record the event as instructed in Section 
8 of this protocol. Investigators should not encourage the patients to change responses reported 
in questionnaires.
After the primary analysis cut-off date (10-Aug-2018), patient-reported outcome 
questionnaires (EORTC QLQ-C30, EQ-5D-5L) will no longer be collected.
Table 7-9
PRO questionnaires
Patient Questionnaires
Study Period
Visit
Time point
EORTC QLQ-C30
and
EQ-5D-5L
Screening
Day -28 to Day -1
Prior to any 
clinical 
assessments, 
drug dosing 
or diagnostic 
testing
Treatment*
Every 8 weeks from Cycle 3 Day 1 for the first 13 
cycles and every 12 weeks from Cycle 13 Day1 
thereafter
End of treatment*
EOT visit
Safety Follow-up*
30-Day Safety Follow-up visit
Efficacy follow-up* Continue same schedule as during treatment period 
until BIRC confirmed irRECIST progression
*After the primary analysis cut-off date (10-Aug-2018), patient-reported outcome questionnaires (EORTC QLQ-
C30, EQ-5D-5L) will no longer be collected.
7.2.10.1 EORTC QLQ-C30 
The EORTC QLQ-C30 contains 30 items and is composed of both multi-item scales and single-
item measures. These include five functional scales (physical, role, emotional, cognitive and 
social functioning), three symptom scales (fatigue, nausea/vomiting, and pain), six single items 
(dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global 
health status/QoL scale (Aaronson et al 1993). 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. Thus a high score for a functional scale represents a high / 
healthy level of functioning; a high score for the global health status / QoL represents a high 
QoL, but a high score for a symptom scale / item represents a high level of symptomatology / 
problems. All scoring will follow the scoring procedures defined by the EORTC Scoring 
Manual (Fayers et al 2001).
7.2.10.2 EQ-5D-5L 
The EQ-5D-5L (tablet version) is a standardized measure of health utility that provides a single 
index value for one’s health status. The EQ-5D-5L is frequently used for economic evaluations 
of health care and has been shown to be a valid and reliable instrument (The EuroQol Group 
1990, Rabin 2001). The EQ-5D-5L contains one item for each of five dimensions of HRQOL 
(i.e., mobility, self-care, usual activities, pain or discomfort, and anxiety or depression). 
Response options for each item vary from having no problems (e.g., “…no problems walking 
about”), moderate problems (e.g., “…some problems walking about”), or extreme problems 
(e.g., “…unable to walk about”). Patient responses to the five dimensions of HRQOL reflect a 
specific health state that corresponds to a population preference weight for that state on a 
continuous scale of 0 (death) to 1 (perfect health). A visual analog scale (ranging from 0 to 100) 


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is also included to capture patient’s rating of their overall health status. Higher scores of the 
EQ-5D-5L represent better health states. All scoring and handling of data will follow the User’s 
Guide defined by the EuroQoL Group (van Reenen and Janssen 2015).
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.
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 CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least: 

150 days following the last dose of PDR001 OR

Until the start of a new post treatment antineoplastic medication if administered during the 
period between the 30-Day safety follow up and 150-Day safety follow-up. If a patient 
starts a post treatment antineoplastic therapy after the 30-Day safety follow-up, then only 
adverse events suspected to be related to study treatment should be collected out to 150 
days after discontinuation of PDR001. 
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 and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
Grade 1 to 5 will be used to characterize the severity of the Adverse Event.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
through a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(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 (patient) 


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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 1-5)
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
4. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
5. 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 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), 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.
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 CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.


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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.
8.1.3
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. The following AESIs are discussed in detail in the latest [Investigator Brochure]:

Endocrinopathies (Hypothyroidism, hyperthyroidism, diabetes, hypophysitis and 
hypopituitarism)

Pneumonitis

Diarrhea/colitis

Hepatitis

Nephritis

Encephalitis

Skin/rash
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 
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
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent must be reported to Novartis within 24 hours of learning 
of its occurrence and until:

Suspected SAEs up to 150-Day safety follow-up and beyond

Non-suspected SAEs up to 150-Day safety follow-up or start of new post treatment anti-
neoplastic medication if administered during the period between the 30-Day safety follow-
up and 150-Day safety follow-up, whichever is sooner (see Appendix 3)
If a patient starts a post treatment antineoplastic therapy after the 30-Day safety follow-up, then 
only SAEs suspected to be related to study treatment should be collected out to 150 days after 
discontinuation of PDR001. SAEs suspected to be related to PDR001 will continue to be 
collected beyond the 150-Day safety follow-up visit.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the reporting period described above should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.  
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 


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the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring 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.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study 
treatment 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.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
Not applicable
8.7
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the 
trial.
The SC will ensure management of the study according to the protocol through recommending 
and approving modifications as circumstances require. The SC will review protocol 
amendments as appropriate. The SC will also develop recommendations for publications of 
study results including authorship rules. The details of the role of the Steering Committee will 
be defined in a Steering Committee charter.


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9
Data collection and management
9.1
Data confidentiality
Information about study patient 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 subject to revoke their authorization for use of their PHI.
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs and allow modification or verification of the entered 
data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
 PK sampling, Laboratory samples for hematology, 
chemistry, coagulation (analyzed by central laboratory), Imaging, patient questionnaires
(ePRO), will be collected at investigator sites.
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. The site staff designated by the investigator will enter the information required by the 
protocol onto the eCRFs as well as onto the designated CRO’s requisition form. One copy of 
the requisition form will be forwarded to the central lab along with the corresponding samples 
with required information (including study number, subject ID) and one copy will be retain by 
the site.
Patient questionnaires data will be entered into an electronic PRO by the patient. The system 
will be supplied by a vendor(s), who will also manage the database. The database will be sent 
electronically to Novartis personnel 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.


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10
Statistical methods and data analysis
Cut-off date for the primary safety and efficacy analysis will be 1 year after Last Patient First 
Treatment (LPFT) in the initially enrolled well-differentiated NET group. This analysis will 
include data from patients with well-differentiated NET and poorly-differentiated GEP-NEC 
groups. It is expected that at the time of this analysis all patients from the original poorly-
differentiated GEP-NEC group will have at least 11 months follow-up. This analysis will be 
summarized in a CSR.
The additional data for any patients continuing to be followed up past this time, as allowed by 
the protocol, will be further summarized in a final study report after all patients discontinued 
treatment and completed the safety follow-up. 
All analyses will be performed separately for the two groups of well-differentiated NET and 
poorly-differentiated GEP-NEC unless otherwise specified. Patients will be analyzed according 
to the group they were assigned at baseline. 
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. 
Except if otherwise specified, categorical data will be presented as contingency tables 
(frequencies and percentages). For continuous data summary statistics of 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 will not be included in 
analyses, but will be reported in the clinical study report (CSR) as separate listings.
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 
and who received one dose of any study treatment (i.e. at least one dose of PDR001 (including 
incomplete infusion)).  
10.1.2
Safety set
The Safety Set is defined in the same way as the FAS and includes all patients who received at 
least one dose of study treatment (i.e. at least one dose of the PDR001 (including incomplete 
infusion)). 
10.1.3
Per-Protocol set
Not applicable.
10.1.4
Dose-determining analysis set
Not applicable. 


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10.1.5
Pharmacokinetic analysis set
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one evaluable 
PDR001 PK concentration. For a concentration to be evaluable, patients are required to:

receive one of the planned treatments of PDR001 prior to sampling

for pre-dose samples, have the sample collected before the next dose administration

for end-of-infusion samples, have the sample collected within 2 hours post end of infusion
10.1.6
Other analysis sets 
Not applicable.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and
summarized descriptively for all patients for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical at baseline will be summarized by system organ 
class and preferred term for all patients.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in weeks to PDR001 as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics using the Safety set. 
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized for all patients and all dosing data will be 
listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for all patients. 
10.4
Primary objective
The primary objective is to estimate the antitumor activity of PDR001 as a single agent in well-
differentiated NET and poorly-differentiated GEP-NEC groups.


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10.4.1
Variable
The primary efficacy variable of the study is overall response rate (ORR), defined as the 
proportion of patients with best overall response (BOR) of complete response (CR) or partial 
response (PR), as per blinded independent review committee. ORR will be evaluated according 
to RECIST 1.1 (see Appendix 1 for details).
ORR will be calculated within each group based on the FAS and according to the ITT principle. 
10.4.2
Statistical hypothesis, model, and method of analysis
No formal hypothesis testing will be conducted. The objective of the study is to demonstrate 
the antitumor activity of PDR001 as measured by ORR.
The response rate within each group on the FAS population with 95% two-sided confidence 
interval (exact method) will be computed. 
Group 1: Well-differentiated NET 
The results in this group will be considered a success if both of the following conditions are 
met:
1. a clinically relevant response rate of at least 10% is observed
2. 95% two-sided CI for ORR excludes the value 3%. 
With 90 treated patients enrolled, the success corresponds to at least 9 responders observed (i.e. 
a response rate of 10% with [4.7; 18.1] 95% CI).
In the absence of historical comparator in this setting, response rates reported in placebo arms 
of previous randomized phase III studies in earlier lines of treatment can be considered as a 
valid historical reference for ORR in well-differentiated NET (Table 1-1). A 95% two-sided CI 
excluding the value 3% will ensure that the clinically relevant observed response rate is 
significantly higher than expected placebo response rate.
Group 2: Poorly-differentiated GEP-NEC
This group will enroll approximately 20 patients. Estimates of the ORR along with 95% two-
sided CI will be presented. Additionally, the interval probabilities for the true ORR lying within 
the intervals stated below will be computed.

0 - <3%    
unacceptable efficacy

3% - <10%    
limited efficacy

10% - <20%  
moderate efficacy

20%  
clinically relevant efficacy
For this analysis a prior distribution for the parameter of interest, ORR, must be specified. For 
the current study, the prior clinical assumption for PDR001 in the selected patient population is 
used in order to derive a minimally informative unimodal Beta prior distribution that reflects 
the level of uncertainty around ORR before starting the current trial (Neuenschwander et al 
2008). The prior mean ORR is set to be equal to 15% and the parameters of the minimally 
informative Beta prior distribution of ORR have been set up as follows:

a/(a+b) = 0.15


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
a = 0.176

b = 1.0
At the primary analysis, this prior distribution will be updated with observed ORR data and 
probabilities that the true ORR lies within the above intervals will be reported.
10.4.3
Handling of missing values/censoring/discontinuations
For the computation of ORR, all confirmed responses (CR or PR) reported up to the analysis 
cut-off will be included. Patients with no valid radiological assessment or unconfirmed 
responses will be considered as non-responders. In particular, patients with CR or PR at the last 
radiological assessment prior to cut-off and no response at the previous assessment are by 
definition unconfirmed and will be considered as non-responders for the primary analysis.
10.4.4
Supportive and Sensitivity analyses
A sensitivity analysis considering patients with unconfirmed PR or CR (i.e. with PR or CR at 
the last assessment prior to the cutoff and ongoing in efficacy follow-up) as responders may be 
performed.
Primary and sensitivity analyses will be repeated using overall response based on local review.
10.5
Secondary objectives
The key secondary objective in this study is to estimate efficacy of PDR001 in each group using
the duration of response per RECIST 1.1 and based on tumor response data per BIRC. 
Furthermore, tumor related endpoints such as disease control rate (DCR), time to response (TTR) 
and PFS will be evaluated based on RECIST 1.1 and irRECIST. Additional secondary endpoints 
include overall survival rate at 1 and 2 years, HRQoL, CgA and NSE, PK and safety.
Antitumor activity (assessed by ORR and DoR per RECIST 1.1 and BIRC) in each of the three 
well-differentiated NET cohorts (pancreatic, GI, thoracic) will also be evaluated as secondary 
endpoint. If heterogeneity in ORR is observed among the three cohorts, a probabilistic 
evaluation, using simulations or any other appropriate method, will be conducted in order to 
assess observed difference. Details will be provided in the statistical analysis plan (SAP).
10.5.1
Key secondary objective(s)
Duration of Response (DoR)
Duration of response (DOR) only applies to patients whose best overall response is complete 
response (CR) or partial response (PR) based on tumor response data per blinded independent 
central review. DOR will be evaluated according to RECIST 1.1 (see Appendix 1 for details).
The start date is the date of first documented response of CR or PR (i.e., the start date of 
response, not the date when response was confirmed), and the end date is defined as the date of 
the first documented progression or death due to underlying cancer. Patients continuing without 
progression or death due to underlying cancer will be censored at the date of their last adequate 
tumor assessment. DOR based on RECIST 1.1 will be listed and summarized for all patients in 
the FAS with confirmed BOR of CR or PR. 


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10.5.2
Other secondary efficacy objectives
All secondary efficacy endpoints according to RECIST 1.1 or irRECIST will be based on tumor 
assessments as per BIRC. The local radiology assessments will be used as supportive analysis.
10.5.2.1 Efficacy endpoints according to RECIST 1.1
Disease control rate (DCR) 
DCR is defined as the proportion of patients with best overall response of CR, PR or SD 
according to RECIST 1.1 criteria and as per central review (see Appendix 1 for details). 
DCR will be calculated based on the FAS. DCR and its 95% confidence interval will be 
presented for all patients. 
Time to response (TTR)
Time to response (TTR) is defined as the time from the date of start of treatment to the first 
documented response of either complete response (CR) or partial response (PR), which must 
be subsequently confirmed (although date of initial response is used, not date of confirmation). 
TTR will be evaluated according to RECIST 1.1 (see Appendix 1 for details). 
All patients in the FAS will be included in TTR calculations. Patients without a confirmed CR 
or PR will be censored at the study-maximum follow-up time (i.e., Last Patient Last Visit 
(LPLV)-First Patient First Visit (FPFV)) for patients with a PFS event (i.e., disease progression 
or death due to any cause), or at the date of the last adequate tumor assessment for patients 
without a PFS event. TTR will be listed and summarized for all patients. The distribution of 
time to response will be estimated using the Kaplan-Meier method only if a sufficient number 
of responses is observed. 
Progression-free survival (PFS)
PFS is defined as the time from the date of first dose to the date of the first documented 
radiological progression or death due to any cause. PFS will be assessed via central review 
according to RECIST 1.1 (see Appendix 1 for further details). PFS will be censored if no PFS 
event is observed before the analysis cut-off date. The censoring date will be the date of the last 
adequate tumor assessment prior to cut-off.
PFS based on RECIST 1.1 will be analyzed in the FAS population. The PFS distribution will 
be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for all patients. 
10.5.2.2 Efficacy endpoints according to irRECIST 
The definitions of the endpoints based on irRECIST are similar to those based on RECIST 1.1 
and are provided in the Appendix 2. The following endpoints will be analyzed in the same way 
as described above for the endpoints based on RECIST:

irORR

irDoR

irTTR


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
irDCR

irPFS.  
10.5.2.3 Overall survival rate at 1 year and 2 years
OS is defined as the time from date of start of treatment to date of death due to any cause. If a 
patient is not known to have died, then OS will be censored at the latest date the patient was 
known to be alive (on or before the cut-off date). The OS distribution will be estimated using 
the Kaplan-Meier method, and the Kaplan-Meier curves. 
Survival estimates at 1 year and at 2 years will be computed with 95% confidence interval.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented 
separately for the well-differentiated NET and the poorly-differentiated GEP-NEC groups. In 
addition, pooled safety analyses based on all patients will be produced.
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 PDR001 
3. Post-treatment period: starting at day 31 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. Additional summaries will be displayed 
to report deaths, all AEs, AEs related to study treatment, all SAEs and SAEs related to study 
treatment collected up to 150 days after last administration of PDR001.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI)
during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those starting during the post-treatment period will be flagged.
Project-specific AESIs should be defined in the case retrieval strategy (CRS) with regular 
updates whenever necessary, see also Section 8.1.3.


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10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be applicable.
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following listings/summaries will be generated separately for hematology, and 
biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE v4.03,

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the statistical analysis plan (SAP).
10.5.3.4 Other safety data
ECG

12-lead ECGs including PR, QRS, QT, QTcF intervals and heart rate (HR) will be 
obtained for each patient during the study. ECG data will be read and interpreted locally. 

Categorical Analysis of QT/QTc interval data based on the number of patients meeting or
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. In addition, a listing of these patients will be produced. 
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.


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10.5.3.5 Supportive analyses for secondary objectives
Efficacy analyses as per local review
The analyses based on the efficacy endpoints according to RECIST 1.1 and irRECIST 
(described in Section 10.5.2.1 and Section 10.5.2.2) will be repeated using local radiology 
review.
10.5.3.6 Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions. Reasons for dose interruptions and dose reductions will be 
listed and summarized (see Section 10.3).
10.5.4
Pharmacokinetics
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV%, SD, median, 
geometric mean, geometric CV%, minimum and maximum) for PDR001 concentrations will 
be presented at each scheduled timepoint. For PDR001, pre-dose concentrations collected 
before dose administration on Day 1 of Cycle 2+ are Ctrough.
All concentration data for PDR001 will be displayed graphically.
10.5.4.1 Data handling principles
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. 
Below the limit of quantitation (BLQ) values will be set to zero by the Bioanalyst, and will be 
displayed in the listings as zero and flagged. BLQ values will be treated as missing for the 
calculation of the geometric means and geometric CV%. 
10.5.4.2 Population pharmacokinetic analysis
If data permit, a mixed-effects model may be applied to the serum PDR001 concentration-time 
data to generate post hoc estimates of pharmacokinetic parameters using NONMEM to 
characterize PDR001 exposure. If there are sufficient data for analysis, the details of the 
population pharmacokinetic analyses will be provided in a separate reporting and analysis plan, 
and the results may be reported in a separate population pharmacokinetic report. Data from this 
and other studies may be pooled for analysis.
10.5.5
Immunogenicity
Immunogenicity will be characterized descriptively by tabulating anti-drug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment.
10.5.6
CgA and NSE
The biochemical response will be assessed using the change from baseline for CgA and NSE 
levels. 


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Change from baseline in CgA and NSE will be summarized using descriptive statistics for all 
patients. CgA and NSE values might be analyzed on the logarithmic scale if their observed 
distribution is found be right skewed.
 
 
10.5.6.1 Data handling principles
The lower limit of quantification (LLOQ) values for CgA and NSE will be specified by the 
laboratory running the assay.
Measures below the LLOQ will be handled as follows:

If the proportion of measures below LLOQ is below 15%, all values specified as below 
LLOQ will be imputed by half of the LLOQ and the standard set of summary statistics 
will be used.

If the proportion of measures below LLOQ is above 15%, but below 50%, an alternative 
choice of summary statistics requiring no imputation such as percentiles may be used.

Otherwise the data will be missing

When both baseline and post baseline values are below LLOQ, change from baseline will 
not be imputed and reported as missing.
Values below LLOQ will be shown as such in listings. All available data points obtained at 
scheduled and unscheduled visits will be considered for the analysis. 
10.5.7
Resource utilization 
Not applicable
10.5.8
Patient-reported outcomes 
The EORTC QLQ-C30 questionnaire and the EQ-5D-5L will be used to collect patient’s QoL 
data. The global health status/QoL scale score of the QLQ-C30 and the health status index score 
of the EQ-5D-5L are identified as the primary patient-reported outcome variables of interest.
Physical functioning, emotional functioning and social functioning scale scores of the QLQ-
C30, and overall health status of the EQ-5D-5L are identified as secondary patient-reported 
QoL variables of interest. 
Scoring of PRO data and methods for handling of missing items or missing assessments will be 
handled according to the scoring manual and user guide for each respective patient 
questionnaire (Fayers 2001; van Reenen and Janssen 2015). No imputation procedures will be 
applied for missing items or missing assessments. Five health states from the EQ-5D-5L will 
be converted to index values during the data analysis stage and will be further defined in the 
analysis plan. In addition, the visual analog scale (ranging from 0 to 100) from the EQ-5D-5L 
will be evaluated for patient’s rating of their overall health status.
The number of patients completing each questionnaire and the number of missing or incomplete 
assessments will be summarized for each scheduled assessment time points.
The FAS will be used for analyzing PRO data. No formal statistical tests will be performed. For 
the main analysis, patients with baseline and at least one non-missing post-baseline assessment


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will be included. All available data until the end of treatment will be used in the repeated 
measures models for longitudinal data to assess the treatment effect over time. 
A time-to-event approach may be considered as the secondary analysis, in which patients with 
no events will be censored at the latest available non-missing timepoint until end of treatment. 
Details will be specified in the SAP.
Descriptive statistics will be used to summarize the PRO scores and change from baseline in 
scales of the EORTC QLQ-C30 and health states, overall health status, and index values of the 
EQ-5D-5L at each scheduled assessment time point.


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10.7
Interim analysis
An interim analysis for preliminary assessment of PDR001 in this patient population will be 
conducted once at least 30 patients from the well-differentiated NET group have 3 radiological 
assessments (week 24) or have discontinued study for any other reason. All available efficacy 
and safety data from the well-differentiated NET and poorly-differentiated GEP-NEC groups 
up to the cut-off date will be used for IA and reviewed by the Steering Committee. It is expected 
that at the time of the interim analysis all patients from the poorly-differentiated GEP-NEC 
group have at least undergone 2 radiological assessments. The study will not be stopped at the 
interim analysis for efficacy reasons regardless of efficacy results and will continue until mature 
data for all patients become available. If the study is stopped for safety reasons, the treatment 
continuation of patients who are deriving benefit from PDR001 treatment will be assessed on a 
case-by-case basis in consultation with the sponsor.


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10.8
Sample size calculation
Group 1: Well-differentiated NET
In the absence of an established control treatment, ORR reported in the placebo arms of studies 
reported in Table 1-1 can serve as a reference in the well-differentiated NET group. A 3% ORR 
is therefore considered as a reasonable reference while an improvement up to 10% is considered 
as clinically meaningful in this patient population.
Total sample size of 90 patients was chosen such that with an observed 10% response rate, the 
corresponding 95% CI excludes the value 3%.
Approximately thirty patients will be recruited in each cohort NET cohort: pancreatic, GI and 
thoracic. 
Operating characteristics in the well-differentiated NET group are given in Table 10-1. A 
sample size of 90 patients ensures a 90% probability of success if the true ORR is 15%.
Table 10-1
Operating characteristics for the full population of well-differentiated 
NET group
True response rate 
Probability of observing 10% or more responders at the end of the study
10%
0.55
11%
0.67
12%
0.77
13%
0.84
14%
0.90
15%
0.94
In addition, Table 10-2 shows the probability of observing at least 3 responders in a cohort with 
30 patients under the assumption of true response rate of 10-20% in this cohort.
Table 10-2
Probability of observing at least 3 responders in a cohort with more 
than 10% true response rate
True response rate in a 
cohort
Probability of observing 3 or more responders in a cohort with 30 patients 
at the end of the study
10%
0.59
12%
0.72
14%
0.81
16%
0.88
18%
0.93
20%
0.96
Group 2: Poorly-differentiated GEP-NEC
Approximately 20 patients will be enrolled in the poorly-differentiated GEP-NEC group. The 
operating characteristics are shown in Table 10-3 and Table 10-4. With the planned sample size 
the probability to observe at least moderate efficacy (10% ORR) is more than 80% if the true 
ORR is 15%. Posterior probability of a true ORR of at least moderate efficacy was computed
for different scenarios assuming a minimally informative prior with Beta distribution and the 


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following parameters: a=0.176, b=1. Posterior probability of a true ORR to be 10% ORR is 
more than 70% if 3 responders are observed in 20 patients.
Table 10-3
Operating characteristics for the poorly-differentiated GEP-NEC group
True response rate 
Probability of observing 2 or more 
responders (10% ORR) in 20 patients 
Probability of observing 3 or more 
responders (15% ORR) in 20 
patients 
10%
0.61
0.32
12%
0.71
0.44
15%
0.82
0.60
18%
0.90
0.73
20%
0.93
0.79
Table 10-4
Posterior probability of a true ORR in the poorly-differentiated GEP-
NEC group corresponding to at least moderate efficacy ( >/=10% ORR) 
Number of observed responders in 20 patients
Posterior probability for a true ORR 10% 
1
15.8%
2
44.0%
3
71.4%
4
88.6%
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.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
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). 
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 


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present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports 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 the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) 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 CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless sponsor provides written 


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permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent 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
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14
Appendix
14.1
Appendix 1: RECIST 1.1 Novartis guideline version 3.2 
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 2 and the definition of best response in 
Section 3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions and 
rules for determination of best response. Section 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 4 of this 
guideline describes data handling and programming rules. This section is to be referred to in 
the SAP (Statistical Analysis Plan) to provide further details needed for programming.
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.
2.1
Definitions
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 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.


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
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.

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.
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 
3.2.8.
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 


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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.

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 major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. 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 new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned.

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.

Physical exams: Evaluation of lesions by physical examination is accepted when 
lesions are superficial, with at least 10mm size, and can be assessed using calipers. 

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by 
the protocol. 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 


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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 biopsies 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.

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.
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 CRF 
(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 2.1.1.

Nodal target: See Section 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.


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
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.
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 2-1) and non-target lesions (Table 2-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 2-3) as well as the presence or absence of new lesions.
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.
2.4.1.1
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.
2.4.1.2
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.


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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.
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.
2.4.2 Determination of target lesion response
Table 2-1
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.
In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on target 
lesion response and methodology change in Section 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 
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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 2-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 


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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 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 


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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. 

A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria.
2.4.3 Determination of non-target lesion response
Table 2-2
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 baseline2.
1.
The assignment of PD solely based on change in non-target lesions in light of target lesion response of CR, 
PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central reviewer 
does prevail..
2.
It is recommended that the investigator and/or central reviewer should use expert judgment to assign a Non-
UNK response wherever possible (see notes section for more details)
Notes on non-target lesion response

The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned.

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 there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK).

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 


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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 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.
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 CRF page.

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 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 2.2.
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 2-3.


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Table 2-3
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 2.4.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
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.
3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 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.
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.


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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).

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)
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment.
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 


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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/central blinded review/calculated (investigator)/calculated (central) 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.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth. 
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization.
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.


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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).
3.2
Time to event variables
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.
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint. 
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.
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.
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 
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3.2.4 PFS2
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”.
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol.
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments.
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen.
3.2.5 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.
3.2.6 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).


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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.
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.
3.2.7 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 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 


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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.
3.2.8 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.
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations.
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 3.2.8).


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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.
3.2.9 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.
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 non-
measurable disease is derived slightly differently according to Table 3-1.
Table 3-1
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 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.


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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.
3.2.10 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.
Based on definitions outlined in Section 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 3-2
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) Ignore clinical progression and follow 
situations above 
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
As per above 
situations
Progressed
F
New anticancer therapy given
(1) Ignore the new anticancer therapy and follow  
situations above (ITT approach) 
(2) Date of last adequate assessment prior to 
new anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) Date of secondary anti-cancer therapy
As per above 
situations
Censored
Censored
Event


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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in the 
protocol or RAP
Outcome
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 3.2.7.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 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.
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) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy.
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan. 
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 


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palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis.
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy.
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 3-2 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.
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).
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).
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.


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The end of treatment visit and its associated assessments should occur within 7 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

Technical problems

Subject/guardian decision

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
Death is a reason which “must” lead to discontinuation of patient from trial. 
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

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor
4.4
Medical validation of programmed overall lesion response
In order to be as objective as possible the RECIST programmed calculated response assessment 
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). This contrasts with the slightly 


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more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) 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.
4.5
Programming rules
The following should be used for programming of efficacy results:
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.
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 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.


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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.
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)’.
4.5.5 Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
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 (optional, see Table 3-2)

Death due 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 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:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“sponsor 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-


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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.


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14.2
Appendix 2: irRECIST
1
Introduction
Immune-related response criteria have been developed to better assess the patterns of response 
and progression with cancer immunotherapies (Wolchok et al. 2009, Nishino et al. 2013, 2014). 
This document outlines the working definitions and rules for immune-related response criteria 
based on RECIST 1.1 (irRECIST).
For definition of measurable and non-measurable lesions, methods of tumor measurement, 
baseline documentation of target and non-target lesions, eligibility based on measurable disease, 
follow-up evaluation of lesions, etc., refer to RECIST 1.1 (Appendix 1).
2
Baseline assessment of tumor burden
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. All other lesions present at baseline 
will be considered as non-target lesions. Together these present the baseline tumor burden.
The Total Measurable Tumor Burden (TMTB) at baseline is defined as the sum of diameters 
(SOD) of all target lesions.
3
Post-baseline assessment of tumor burden
Target, non-target and new lesions (measurable and non-measurable) will be evaluated at each 
post-baseline assessment. Target and non-target lesions identified at baseline will continue to 
be followed as target and non-target lesions, respectively. New measurable  lesions will be 
included in the TMTB which is defined as the SOD of target lesions and the new measurable 
lesions for post-baseline assessments. The nadir TMTB at a given time point ‘n’ is defined as 
the smallest TMTB observed for a given patient up to, but excluding that time point (i.e. from 
baseline to timepoint ‘n-1’).
A new measurable lesion is a newly observed lesion that was not present at baseline tumor 
assessment and is measurable as per RECIST 1.1. Overall a maximum of five new measurable 
lesions (nodal or non-nodal) can be included in the TMTB with a maximum of two new 
measurable lesions per organ. If there are more than 5 new measurable lesions in total, or more 
than 2 in the same organ at a post-baseline tumor evaluation, then the largest and most 
reproducible new measurable lesions should be included in TMTB. Note that two new 
measurable lesions per organ can be included in the TMTB irrespective of whether baseline 
target lesions were already identified in that organ or not. All other new lesions will be included 
in the overall tumor burden assessment as new non-measurable lesions.
A new measurable lesion included in the TMTB must always be included in TMTB for all 
subsequent tumor assessments. A new non-measurable lesion will always be followed as a non-
measurable lesion at subsequent tumor assessments even if it becomes measurable.
The overall tumor burden (OTB) includes the TMTB, non-target lesions and new non-
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4
Overall response assessment
An overall response assessment should occur at each post-baseline assessment, and will take 
into account the evaluation of the TMTB together with the status of non-target lesions and new 
non-measurable lesions.
Baseline non-target lesions
The response of non-target lesions primarily contributes to the overall response assessment of 
complete response (irCR), with persisting non-target lesions preventing irCR. Only a clear and 
unequivocal worsening of non-target lesions alone (i.e. worsening of the tumor burden which 
is substantial enough leading to discontinuation or change of therapy), would be indicative of 
irPD.
New lesions
A new lesion does not automatically indicate progressive disease. 
New measurable lesions are added to the SOD to obtain the TMTB as described in Section 
14.2.3 at each post-baseline tumor evaluation. All new lesions not selected as new measurable 
lesions for obtaining TMTB are considered as new non-measurable lesions and are followed 
qualitatively. Only an unequivocal progression of new non-measurable lesions (i.e. worsening 
of the overall tumor burden which is substantial enough leading to discontinuation or change of 
therapy) would be indicative of irPD. Persisting new non-measurable lesions prevent irCR.
Note: The designation of overall irPD solely on the basis of change in non-target disease or new 
non-measurable lesions in the face of no progression based on TMTB is expected to be 
uncommon.
4.1
Definition of response categories
The response categories at each post-baseline assessment are defined as follows:

Immune related Complete Response (irCR): Complete disappearance of all measurable 
and non-measurable lesions. In addition, any pathological lymph nodes must have a 
reduction in short axis to < 10 mm. 

TMTB may be greater than zero at the time of CR, if nodal lesions are included in 
TMTB. 

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 
determine the irCR.

Immune related Partial Response (irPR): At least 30% decrease in the TMTB compared 
to baseline and not qualifying for irPD or irCR 

Immune related Progressive Disease (irPD): At least a 20% increase in the TMTB 
compared to nadir. In addition to the relative increase of 20%, TMTB must also demonstrate 
an absolute increase of at least 5 mm. An unequivocal progression of existing non-target or 
new non-measurable lesions may also lead to irPD. 


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
Immune related Stable Disease (irSD): Neither a sufficient shrinkage to qualify for irPR 
or irCR, nor an increase in lesions, or a clear and unequivocal progression of existing non-
target or new non-measurable lesions that would qualify for irPD. 

Unknown for irRECIST (irUNK): Progression has not been documented and one or 
more target lesions or new measurable lesions observed at earlier assessment have not been 
assessed, or have been assessed using a significantly different method (i.e. prevents 
reasonable comparison to the prior assessments) than baseline (target lesions) or assessment 
of first occurrence (new measurable lesions). Note that if non-target or new non-measurable 
lesions have not been assessed at any given post-baseline time-point, then this will not lead 
to overall response irUNK. If the evaluation of any non-target lesion or new non-measurable 
lesion is not done, and all target lesions and other non-target lesions disappeared, irCR 
cannot be determined and overall response must be “irPR”.
Table 4-1
Overall response at each post-baseline assessment
Target and new measurable 
lesions based on (TMTB), * (%)
Non-target lesions and New non-
measurable lesions
Overall lesion response
- 100 [a], [b]
Absent
irCR 
- 100 [a], [b]
Stable/not evaluated
irPR 
≤-30 [b] 
Absent/Stable/not evaluated
irPR 
>-30 [b] and< +20 [c]
Absent/Stable/not evaluated
irSD
≥+20 [c]
Any
irPD 
Any
Unequivocal progression [e]
irPD 
[a] TMTB may be greater than zero at the time of irCR, if nodal lesions are included in TMTB
[b] Compared to baseline
[c] Compared to nadir 
[d] If worsening of non-target or new non-measurable lesions is substantial enough leading to discontinuation or 
change of treatment.  
4.1.1 Notes on lesion response
Reappearance of lesions
If the lesion reappears 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 the previous disappearance of the lesion is 
confirmed, then the investigator/radiologist has to decide between the following possibilities:

The lesion is a new lesion, in which case the overall tumor assessment should consider 
this appropriately either as a new measurable or new non-measurable lesion.

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 CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in the Table above. This applies to 
patients who have not achieved target response of irCR. For patients who have achieved 
irCR, please refer to below.
Progressive disease after complete response 


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Similar to RECIST 1.1, following a confirmed irCR, an irPD can subsequently only be assigned 
if any one of below is observed:

Either a non-nodal target or new-measurable lesion that disappeared earlier reappears at 
the same anatomical location. 

Any single nodal lesion gets >10mm in diameter and there is at least 20% increase in sum 
of the diameters of all nodal target and nodal new-measurable lesions relative to nadir 
with at least 5 mm increase in the absolute sum of the diameters.

Unequivocal progression based on non-target and new non-measurable lesions. 
Missing measurements
In cases where measurements are missing for one or more target or new-measurable lesions it 
is sometimes still possible to assign irPD 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 an irPD should be assigned. However, in other cases where an irPD 
cannot definitely be attributed, the target lesion response would be irUNK.
Nodal lesions

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.

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 nodal lesions less than 10 mm are considered normal, an irCR for target lesion 
response based on TMTB should be assigned when all nodal target and new-measurable 
lesions shrink to less than 10 mm and all non-nodal target lesions have disappeared.
Splitting and coalescence of lesions

Lesions split: In some circumstances, disease that is measurable as a target or new-
measurable lesion at baseline and appears to be one mass can split to become two or more 
smaller sub-lesions at subsequent assessments. 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 based on TMTB. The individual split lesions will not be considered 
as new lesions.

Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at earlier assessment(s) 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 


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a size of “0”mm should be entered for the remaining lesion numbers which have 
coalesced.
4.2
Confirmation of response or progression
Confirmation of irCR and irPR is required by a repeat assessment at least 4 weeks after the 
initial assessment. 
Confirmation of irPD is highly recommended particularly for difficult cases (i.e. mixed 
response, early appearance of new lesions/increase in measurable tumor burden in patients with 
stable or improving general status/clinical condition) or suspected pseudo-progression/tumor 
flare provided there is no rapid clinical deterioration. The irPD is confirmed if in a repeat tumor 
assessment at least 4 weeks later meets again the irPD criteria as defined in Section 4.1.
No confirmation is required for irSD.
4.3
Determination of Best overall response
For best overall response (BOR), in general all the details as specified in the RECIST 1.1 
appendix Section 14.1.3.1 will apply unless stated otherwise below or in the study protocol.
The best overall response for each patient is determined from the sequence of overall responses 
according to the following rules:

irCR = at least two determinations of irCR at least 4 weeks apart before confirmed 
progression. Note that there should not be any tumor assessment with an overall response 
of irPD in between 

irPR = at least two determinations of irPR or better at least 4 weeks apart before 
confirmed progression (and not qualifying for irCR). Note that there should not be any 
tumor assessment with an overall response of irPD in between 

irSD = at least one irSD assessment (or better) > 6 weeks after randomization/start of 
treatment and before confirmed progression (and not qualifying for irCR or irPR). 

irPD = confirmed immune related progression or immune related progression with no 
further adequate tumor assessments £ 12 weeks after randomization/ start of treatment (and 
not qualifying for irCR, irPR or irSD) 

irUNK = all other cases (i.e. not qualifying for confirmed irCR or irPR and without irSD 
after more than 6 weeks or early progression within the first 12 weeks) 

If the next tumor assessment is inadequate with an overall response of irUNK then the next 
adequate tumor assessment will be considered for confirmation. E.g. an irCR followed by 
irUNK followed by irPR will be a confirmed irPR.
Similar to RECIST 1.1 overall lesion response of irCR or irPR, after their confirmation, will 
remain the same or improve until confirmed irPD.
5
Only non-measurable disease at baseline
For patients with only non-measurable disease at baseline, unequivocal progression of non-
target lesions (i.e. worsening of the overall tumor burden which is substantial enough leading 
to discontinuation or change of therapy) will constitute an irPD. In addition, the appearance of 
new lesions (measurable or non-measurable) consistent with unequivocal progression taking 


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into account the overall disease burden will constitute an irPD. The absence of all non-target 
lesions and no new lesions will qualify for irCR. Otherwise the overall response will be 
considered as irNon-CR/Non-PD (irNCRNPD) similar to RECIST 1.1. The same rules for 
confirmation of irPD and irCR apply as specified above in Section 4.3. If any baseline non-
target lesion or a new lesions observed at an earlier post-baseline evaluation was not/could not 
be assessed at a later post-baseline tumor evaluation then the overall response will be irUNK.  
No confirmation is required for irNCRNPD. For the BOR the same definition as in Section 
14.2.4.3 applies for irCR, irPD and irUNK. For BOR of irNCRNPD the definition for irSD will 
be used. 
6
Definition of endpoints
Immune related overall response rate (irORR) is the proportion of patients with a best 
overall response of irCR or irPR. This is also referred to as ‘Objective response rate’ in some 
protocols or publications.
Immune related disease control rate (irDCR) is the proportion of patients with a best overall 
response of irCR or irPR or irSD. Patients with BOR of irNCRNPD will also be included in 
DCR if patients with non-measurable disease at baseline are in analysis set.  
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Immune related early progression rate (irEPR) is the proportion of patients with immune 
related progressive disease (irPD) within 12 weeks of the start of treatment.
6.1
Time to event endpoints
6.1.1 Progression-free survival
Immune related progression-free survival
(irPFS)
is the time from date of 
randomization/start of treatment to the date of event defined as the first documented assessment 
of irPD that was then confirmed or death due to any cause. Unconfirmed irPD without further 
adequate tumor assessments will be considered as a confirmed irPD. If a patient has not had an 
event, progression-free survival is censored at the date of last adequate tumor assessment. An 
adequate tumor assessment is a tumor assessment with overall response other than irUNK. Refer 
to RECIST 1.1 appendix for additional details on censoring rules. 
6.1.2 Time to progression
Immune related time to progression (irTTP) is the time from date of randomization/start of 
treatment to the date of event defined as the first documented assessment of irPD that was then 
confirmed or death due to underlying cancer. Unconfirmed irPD without further adequate tumor 
assessments will be considered as a confirmed irPD. If a patient has not had an event, time to 
progression is censored at the date of last adequate tumor assessment. An adequate tumor 
assessment is defined as a tumor assessment with overall response other than irUNK. Refer to 
RECIST 1.1 appendix for additional details on censoring rules.


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6.1.3 Time to treatment failure
Immune related time to treatment failure (irTTF)
is the time from date of 
randomization/start of treatment to the earliest of date of progression (confirmed irPD), date of 
death due to any cause, or date of discontinuation due to reasons other than ‘Protocol deviation’ 
or ‘Technical problems’. Unconfirmed irPD without further adequate tumor assessments will 
be considered as a confirmed irPD. The time to treatment failure for patients who did not 
experience treatment failure will be censored at last adequate tumor assessment. An adequate 
tumor assessment is defined as a tumor assessment with overall response other than irUNK.
6.1.4 Time to response
Immune related time to overall response (irCR or irPR) (irTTR) is the time between date 
of randomization/start of treatment until first documented response (confirmed irCR or irPR). 
Time to overall response will be censored for patients without confirmed irCR or irPR as 
described in RECIST 1.1 appendix.
6.1.5 Duration of response 
Immune related duration of overall response (irCR or irPR) (irDOR): For patients with a 
confirmed irCR or irPR the start date is the date of first documented confirmed response and 
the end date and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders are observed.
Immune related duration of overall complete response (irCR): For patients with a 
confirmed irCR the start date is the date of first documented confirmed irCR and the end date 
and censoring is defined the same as that for time to progression.
Immune related duration of stable disease (irCR/irPR/irSD): For patients with BOR of irCR 
(confirmed) or irPR (confirmed) or irSD the start and end date as well as censoring is defined 
the same as that for time to progression.
6.1.6 Definition of start and end dates for time to event variables
For the definition related to time to event variables refer to RECIST 1.1 Appendix 1 Section 
4.5.1.


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Amended Protocol Version 03 (Clean)
Protocol No. CPDR001E2201
14.3
Appendix 3: Safety follow-up flowchart

SAP_000.pdf: 
Clinical Development 
PDR001 (Spartalizumab) 
Oncology Clinical Protocol CPDR001E2201 / NCT02955069
An open label phase II study to evaluate the efficacy and 
safety of PDR001 in patients with advanced or metastatic, 
well-differentiated, non-functional neuroendocrine tumors 
of pancreatic, gastrointestinal (GI), or thoracic origin or 
poorly-differentiated gastroenteropancreatic 
neuroendocrine carcinoma (GEP-NEC), that have 
progressed on prior treatment 
Statistical Analysis Plan (SAP) 
Author: 
 
Document type: 
SAP Documentation 
Document status: 
Final Amendment 1 
Release date: 
18-Sep-2018
Number of pages: 
53 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
06-
Feb-
2017 
Prior 
to 
DB 
lock 
Creation of 
final version 
N/A - First version 
NA 
12-
Jan-
2018 
Prior 
to 
DB 
lock 
Creation of 
Amendment 
1 
Modifications required due to protocol 
amendment and changes in study design 
and population with addition of patients with 
poorly-differentiated GEP-NEC 
 
 
Further details on Immunogenicity analyses 
added 
Various sections 
impacted due to 
protocol 
amendment 
 
 
Section 2.10.1 
18-
Sep-
2018 
Prior 
to 
DB 
lock 
Creation of 
Amendment 
2 
Modifications required to protocol 
amendment 
Various sections 
impacted due to 
protocol 
amendment 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 7 
2 
Statistical methods ............................................................................................................... 8 
2.1 
Data analysis general information ........................................................................... 8 
2.1.1 
General definitions .................................................................................. 9 
2.2 
Analysis sets .......................................................................................................... 12 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 14 
2.3.1 
Patient disposition ................................................................................. 15 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 17 
2.5 
Analysis of the primary objective .......................................................................... 19 
2.5.1 
Primary endpoint ................................................................................... 19 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.5.4 
Supportive analyses ............................................................................... 21 
2.6 
Analysis of the key secondary objective ............................................................... 23 
2.6.1 
Key secondary endpoint ........................................................................ 23 
2.6.2 
Statistical hypothesis, model, and method of analysis .......................... 23 
2.6.3 
Handling of missing values/censoring/discontinuations ....................... 23 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 23 
2.7.1 
Secondary endpoints ............................................................................. 24 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 25 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 27 
2.8 
Safety analyses ....................................................................................................... 28 
2.8.1 
Adverse events (AEs) ............................................................................ 28 
2.8.2 
Deaths .................................................................................................... 30 
2.8.3 
Laboratory data ..................................................................................... 30 
2.8.4 
Other safety data ................................................................................... 31 
2.9 
Pharmacokinetic endpoints .................................................................................... 32 


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2.10 
PD and PK/PD analyses......................................................................................... 33 
2.10.1 
Immunogenicity .................................................................................... 33 
 
 34 
2.11 
Patient-reported outcomes ..................................................................................... 34 
2.12 
CgA and NSE ........................................................................................................ 35 
 
 36 
 
 36 
 
 36 
 
 37 
 
 37 
 
 37 
 
 37 
2.14 
Interim analysis ...................................................................................................... 38 
3 
Sample size calculation ..................................................................................................... 38 
4 
Change to protocol specified analyses .............................................................................. 40 
5 
No probabilistic evaluation of heterogeneity between three cohorts in the well-
differentiated NET group will be performed. No other changes to the protocol 
specified analyses are included in this analysis plan. Appendix ....................................... 40 
5.1 
Imputation rules ..................................................................................................... 40 
5.1.1 
Study drug ............................................................................................. 40 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 41 
5.2 
AEs coding/grading ............................................................................................... 42 
5.3 
Laboratory parameters derivations ........................................................................ 42 
5.4 
Statistical models ................................................................................................... 51 
5.4.1 
Primary analysis .................................................................................... 51 
5.4.2 
Key secondary analysis ......................................................................... 51 
5.5 
Rule of derivation for immune related criteria ...................................................... 51 
6 
Reference ........................................................................................................................... 53 


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List of abbreviations 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
bid 
bis in diem/twice a day 
BIRC 
Blinded Independent Review Committee 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee  
FAS 
Full Analysis Set 
eCRF 
Electronic Case Report Form 
IVR 
Interactive Voice Response 
IWR 
Interactive Web Response 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report 
(CSR) of study CPDR001E2201, a single arm phase II, open-label study of PDR001 for the 
treatment of patients with advanced or metastatic well-differentiated, non-functional 
neuroendocrine tumors of pancreatic, gastrointestinal (GI), or thoracic origin or poorly-
differentiated gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC), that have 
progressed on prior treatment. 
The content of this SAP is based on protocol CPDR001E2201, version 03. The primary 
rationale for protocol amendment 3 is to remove the possibility to expand the study to Part 2 
when at least 20% overall response rate (ORR) per RECIST 1.1 by central radiology review is 
observed in any of the cohorts of the well-differentiated NET group. Based on the results of the 
interim analysis (IA), there was a change in the clinical development strategy for PDR001, 
which will no longer be developed as a single agent immunotherapy in NET, and the study will 
not be expanded into Part 2.  
All decisions regarding final analysis, as defined in the SAP document, have been made prior 
to database lock of the study data. 
1.1 
Study design 
 
This is a single arm  Phase II , open-label, multi-center study  evaluating  safety and efficacy 
of PDR001 in patients with advanced or metastatic well-differentiated, non-functional 
neuroendocrine tumors of pancreatic, GI, or thoracic origin or poorly-differentiated 
gastroenteropancreatic neuroendocrine carcinoma, that have progressed on prior treatment.  
   
The study will enroll approximately 90 patients in the well-differentiated NET group 
(approximately 30 patients in each of the three cohorts of pancreatic, GI, and thoracic origins) 
and approximately 20 patients in the GEP-NEC group for a total of approximately 110 
patients.  
 
Overall response rate (ORR) in well-differentiated NET and poorly-differentiated GEP-NEC 
groups, as assessed by Blinded Indepdent Review Committee (BIRC) review of tumor response 
and using RECIST 1.1 criteria, is the primary endpoint in this study. Duration of response  (DoR) 
is the key secondary endpoint. 
 
One interim analysis is planned after at least 30 patients in the well-differentiated NET group 
have undergone the first 3 radiological assessments (expected around week 24) or have shown 
disease progression or have discontinued efficacy follow-up for any other reason. All available 
efficacy and safety data from well-differentiated NET and poorly differentiated GEP-NEC 
groups up to the cut-off date will be used for the IA  
 
Cut-off date for the primary analysis will be 1 year after Last Patient First Treatment (LPFT) in 
the initially enrolled well-differentiated NET group. 


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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 
Primary 
 
To estimate the antitumor activity of 
PDR001 as a single agent in in the well-
differentiated NET and poorly-
differentiated GEP-NEC groups 
ORR (confirmed PR and CR) according to 
blinded independent review committee 
(BIRC) radiological assessment by 
RECIST 1.1 
Key secondary 
 
To estimate efficacy of PDR001 in the 
well-differentiated NET and poorly-
differentiated GEP-NEC groups   
Duration of Response (DoR) by RECIST 
1.1 and as per BIRC 
Other secondary 
 
To assess the safety and tolerability of 
PDR001 in each group and in the overall 
study population 
Frequency and severity of adverse events 
Other safety data as considered 
appropriate 
To evaluate additional efficacy parameters 
in the well-differentiated NET and poorly-
differentiated GEP-NEC groups 
Disease Control Rate (DCR), 
Time to Response (TTR), 
PFS by RECIST 1.1 and as per BIRC 
Immune Response Criteria by irRECIST 
and as per BIRC (irORR, irDoR, irTTR, 
irDCR, irPFS) 
1-year and 2-year overall survival (OS) 
rate 
 
 
To evaluate biochemical response to 
treatment (based on CgA and NSE) in the 
well-differentiated NET and poorly-
differentiated GEP-NEC groups 
Changes from baseline in CgA and NSE 
To characterize the pharmacokinetics of 
PDR001 with 400 mg flat dose Q4W in the 
well-differentiated NET and poorly-
differentiated GEP-NEC groups 
PK parameters (e.g. Ctrough)  
To characterize patient’s health-related 
quality of life with PDR001 in the well-
differentiated NET and poorly-
differentiated GEP-NEC groups  
Global health status/QOL score of the 
EORTC QLQ-C30 and the index score of 
the EQ-5D-5L 
To evaluate the prevalence and incidence 
of immunogenicity in the well-differentiated 
NET and poorly-differentiated GEP-NEC 
groups 
Antidrug antibodies (ADA) prevalence at 
baseline and ADA incidence on-treatment 
 
 


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2 
Statistical methods 
2.1 
Data analysis general information 
The interim and final analyses will be performed by Novartis. SAS version 9.4 or later software 
will be used to perform all data analyses and to generate tables, figures and listings. 
There are 1 interim and a primary analysis planned for the primary efficacy endpoint.  
The analysis cut-off date for the interim analysis will be established after 30 enrolled patients 
have completed 3 radiological assessments (approximately after 24 weeks of treatment) or  have 
shown disease progression or have discontinued efficacy follow-up for any other reason. The 
analysis cut-off date for the primary analysis of study data will be 1 year after LPFT in the 
initially enrolled well-differentiated NET group. The primary analysis data will be summarized 
in the clinical study report (CSR). 
For each of the analyses, all statistical analyses will be performed using all data collected in the 
database up to the data cutoff date. All data with an assessment date or event start date (e.g. 
vital sign assessment date or start date of an adverse event) prior to or on the cut-off date will 
be included in the analysis. Any data collected beyond the cut-off date will not be included in 
the analysis and will not be used for any derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ongoing. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 


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and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings. 
All analyses will be performed separately for the two groups of well-differentiated NET and 
poorly-differentiated GEP-NEC unless otherwise specified.  
 
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at  centers, no center effect 
will be assessed.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency 
tables; a missing category will be included as applicable. Percentages will be calculated using 
the number of patients in the relevant population or subgroup as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum). 
2.1.1 
General definitions  
Investigational drug and study treatment 
In this single-arm study evaluating efficacy and safety of spartalizumab (PDR001) as 
monotherapy, investigational drug or investigational treatment, will refer to the PDR001.  
The term investigational treatment may also be referred to as study treatment which is used 
throughout this document. 
Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) (e)CRF. The date of first administration of study drug will also be referred as 
start of investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as the last date when a nonzero 
dose of investigational drug is administered and recorded on DAR eCRF. The date of last 
administration of investigational drug will also be referred as end of investigational drug. 
Date of first administration of study treatment  
The date of first administration of study treatment is the same as the date of first administration 
of investigational drug or control drug.  
Date of last administration of study treatment  
The date of last administration of study treatment is the same as the date of last administration 
of investigational drug or control drug. 


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Study day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
 The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date; 
 The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date. 
 
The reference date for all assessments (safety, efficacy, PK, PRO, etc) is the start of study 
treatment.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is  reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment.  
If patients have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods  
For adverse event reporting 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 
administration of study treatment 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date) 
3. post-treatment period: starting at day 31 after last administration of study treatment. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).   


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Additional summaries will be displayed to report deaths, all AEs, AEs related to study treatment, 
all SAEs and SAEs related to study treatment collected up to 150 days after last administration 
of PDR001.  
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged. 
Last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following: 
 
Table 2-1 
Last contact date data sources  
Source data 
Conditions 
Last contact date/last date patient was known to 
be alive from Survival Follow-up page  
 
- Patient status is reported to be alive, lost to 
follow-up or unknown. 
Start/End dates from further antineoplastic 
therapy 
Non-missing medication/procedure term. 
Start/End* dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page 
 
No condition. 
Tumor (RECIST/irRECIST) assessment date 
 
Evaluation is marked as ‘done’. 
Verification for treatment beyond RECIST 1.1 PD 
At least one non-missing parameter value 
Laboratory/PK collection dates 
 
Sample collection marked as ‘done’.  
Vital signs date 
 
At least one non-missing parameter value 
Performance Status date 
 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date . The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring is coming from ‘Survival information’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival. 


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2.2 
Analysis sets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received one dose of any study treatment (i.e. at least one dose of PDR001 (including 
incomplete infusion)).   
Patients will be analyzed according to the treatment they have been assigned to. 
Safety 
The Safety Set is defined in the same way as the FAS and includes all patients who received at 
least one dose of study treatment (i.e. at least one dose of the PDR001 (including incomplete 
infusion).  
Pharmacokinetic analysis set (PAS) 
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one evaluable 
PDR001 PK concentration. For a concentration to be evaluable, patients are required to: 
 receive one of the planned treatments of PDR001 prior to sampling 
 for pre-dose samples, have the sample collected before the next dose administration 
 for end-of-infusion samples, have the sample collected within 2 hours post end of infusion 
Immunogenicity (IG) analysis sets  
The Immunogenicity prevalence set includes all subjects in the Full 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 2.9.1.1 for the definition of determinant.  
Patient Classification:  
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-3.  
Table 2-2 
Subject classification based on protocol deviations and non-PD 
criteria 
Analysis set 
Protocol deviations leading 
to exclusion 
Non protocol deviation 
leading to exclusion 
FAS  
No written inform consent 
No dose of study medication 
Safety set 
No written inform consent 
No dose of study medication  
PK Analysis Set 
No written inform consent 
No evaluable concentration 
Immunogenicity prevalence set 
No written inform consent 
No determinant baseline or 
post-baseline IG samlpe 


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Immunogenicity incidence set 
No written inform consent 
No determinant baseline and 
post-baseline IG sample 
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.   
 
 
 
2.2.1 
Subgroup of interest 
Subgroup analyses will be only performed in well-differentiated NET group. 
Efficacy 
The overall response rate will be summarized by the following subgroups to examine the 
homogeneity of treatment effect provided that the study meets the pre-specified criteria for 
primary efficacy based on the FAS:  
 Cohort  
 Sex  
 Race  
 PD-L1 expression with analyses for the following thresholds: 
 <1% vs ≥ 1% 
 <5% vs ≥ 5% 
 <10% vs ≥ 10% 
 <50% vs ≥ 50%   
 Age category (< 65 years, ≥65 years) 
 Tumor grade   
 ECOG PS  
 Occurrence of at least one immune-related AE (yes, no) 
 
Summary tables will only be produced if sufficient number of patients is present in each 
subgroup. Only the point estimate of the overall response rate and 95%-confidence intervals 
will be provided (see Sections 2.5 for further analysis details). The objective of the efficacy 
subgroup analysis is to demonstrate homogeneity of treatment effect in the above subgroups.  


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Safety 
Safety subgroup analyses will use the same method as for the analysis in the overall analysis 
set. Key safety analyses (deaths, SAEs, AESIs, AEs leading to discontinuations) will be 
repeated on safety set in the following subgroups: 
 Cohort 
 Age group (< 65 years, ≥ 65 years) 
 Sex 
 Race  
 Ethnicity  
 
The objective for carrying out these subgroup analyses is to identify potential safety issues 
that may be limited to a subgroup of patients, or safety issues that are more commonly 
observed in a subgroup of patients.  
Summary tables will only be produced if sufficient number of patients is present in each 
subgroup. Some grouping of classes will be considered for race and ethnicity. 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified.  
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. sex, age groups: <65 and ≥ 65 years, race, ethnicity, ECOG performance 
status, PD-L1 status) will be summarized by frequency counts and percentages; the number and 
percentage of patients with missing data will be provided. Continuous data (e.g. age, weight, 
height, body surface area, body mass index) will be summarized by descriptive statistics (N, 
mean, median, standard deviation, minimum and maximum).  
BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight at Baseline.  
Diagnosis and extent of cancer  
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer, details of tumor histology/cytology, 
histological grade, stage at initial diagnosis, time since initial diagnosis, time from initial 
diagnosis to first recurrence/progression (in months), time since most recent relapse/progression 
to start of study treatment (in months), stage at time of study entry, presence/absence of target 
and non-target lesions, number and type of metastatic sites involved.  
Note: Presence/absence of target and non-target lesions will be based on the data collected on 
RECIST target/non-target lesion assessment eCRF pages. Metastatic sites will be based on 
diagnosis page. 


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Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF will be summarized and listed. The summaries will be presented by primary 
system organ class (SOC) and preferred term (PT). Medical history and current medical 
conditions will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. The MedDRA version used for reporting will be specified in the CSR and as a 
footnote in the applicable tables/listings. 
Other 
All data collected at baseline, including child bearing potential 
 
 will be listed. 
2.3.1 
Patient disposition 
Enrollment by country and center will be summarized for all screened patients. The number 
(%) of treated patients included in the FAS will be presented. The number (%) of screened and 
not-treated patients and the reasons for screening failure will also be displayed. The number (%) 
of patients in the FAS who are still on treatment, who discontinued the study phases and the 
reason for discontinuation will be presented. 
The following summaries will be provided (with % based on the total number of FAS patients): 
 Number (%) of patients who are still on-treatment (based on the ‘End of Treatment 
Phase’ page not completed);  
 Number (%) of patients who discontinued the study treatment phase (based on the 
‘End of Treatment Phase’ page)  
 Primary reason for study treatment phase discontinuation (based on the ‘End of 
Treatment Phase’ page) 
 Number (%) of patients who have entered the post-treatment follow-up (based on 
the ‘End of Treatment Phase’ page); 
 Number (%) of patients who have discontinued from the post-treatment follow-up 
(based on the ‘End of Post-treatment follow-up page’); 
 Reasons for discontinuation from the post-treatment follow-up (based on ‘End of 
Post-treatment follow-up page’); 
 Number (%) of patients who have entered the survival follow-up (based on the 
‘End of Treatment Phase’ or ‘End of Post-treatment follow-up’ page). 
Protocol deviations 
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study specification document) for all patients. All 
protocol deviations will be listed. 
Analysis sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized. 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized for PDR001. Duration of exposure will be categorized into time 
intervals; frequency counts and percentages will be presented for the number(%) of subjects in 
each interval. The number (%) of subjects who have dose reductions or interruptions, and the 
reasons, will be summarized.  
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
The safety set will be used for all summaries and listings of study treatment.  
Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to PDR001: 
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1.  
The last date of exposure to study treatment is the planned end date of the last cycle in which 
the last non-zero dose of PDR001 was last administered (i.e last date of administration + 27 
day)). If the patient died or was lost to follow-up before the derived last date, the last date of 
exposure is the date of death or the date of last contact, respectively. If the derived last date of 
exposure goes beyond the data cutoff date, it should be truncated to the date of data cutoff. 
Summary of duration of exposure of PDR001 will include categorical summaries based on 28 
days interval and using descriptive statistics (mean, standard deviation etc). 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for PDR001.  
The planned cumulative dose for PDR001 refers to the total planned dose as per the protocol 
up to the last date of the administration.  
The actual cumulative dose  refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.  
The actual cumulative dose will be defined based on the days when the subject is assumed to 
have taken a non-zerodose during dosing periods.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  


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DI (mg / week) = Actual Cumulative dose (mg / week)  / Duration of exposure to study treatment 
(mg / week). 
For patients who did not take any drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (mg / week)  = Planned Cumulative dose (mg / week)  / Duration of exposure (mg / week). 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg / week)   / PDI (mg / week).   
Dose reductions, interruptions or permanent discontinuations 
The number of subjects who have dose reductions, permanent discontinuations, administration 
stopped/paused during the infusion or interruptions, and the reasons, will be summarized.  
‘Dose interrupted’, “Was drug administration stopped or paused“ and ‘Dose permanently 
discontinued’ fields from the Dosage Administration CRF pages (DAR) will be used to 
determine the dose reductions, dose interruptions, administration stopped/paused and 
permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’, ‘Reason for administration 
stopped or paused’ and ‘Reason for permanent discontinuation’ will be used to summarize the 
reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive dose administrations with different reasons will be 
counted as separate interruptions. However, if the reason is the same in this mentioned multiple 
entries on consecutive dose administrations, then it will be counted as one interruption.  
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level, where the regimen schedule is modified (less frequent administration of drug 
compared to previous regimen) or where the actual dose administered/total daily dose is lower 
than the calculated dose amount based on the prescribed dose. Therefore any dose change to 
correct a dosing error will not be considered a dose reduction.  Only dose change is collected 
in the CRF, number of reductions will be derived programmatically  based on the change and 
the  direction of the change. 
Treatment beyond RECIST1.1 progression 
The number of patients who continue treatment beyond RECIST1.1 progression according to 
BIRC assessment will be summarized. It includes all patients who received at least one dose of 
PDR001 (including incomplete infusion) after BIRC RECIST1.1 progression.  
2.4.2 
Prior, concomitant and post therapies 
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized for all 


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patients. Prior anti-neoplastic medications will be summarized by therapy type (e.g. 
chemotherapy, hormonal therapy, immune-oncology therapy etc.), setting (e.g. adjuvant, 
metastatic, etc.) and also by lowest ATC class and preferred term. Summaries will include total 
number of regimens, best response and time from last treatment to progression for the last 
therapy. The medication therapy type of any combination therapy will be classified based on 
the following order: immune-oncology therapy, chemotherapy, biologic therapy (other than 
immune-oncologic therapy), targeted therapy, hormonal therapy. For example, a combination 
therapy of chemotherapy and hormonal therapy will be classified as ‘chemotherapy’. For 
radiotherapy, time since last radiotherapy, locations and setting of last therapy will be 
summarized. For prior surgery, time since last surgery, procedure and residual disease of last 
therapy will be summarized.  
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery.  
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and WHO-DD 
version will be included in the footnote in the tables/listings.  
The above analyses will be performed using the FAS. 
Post treatment anti-cancer therapy 
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class and preferred term, by means of frequency counts and percentages using FAS. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and preferred term 
using frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. Concomitant medications with 
immunosuppressive intent will be summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Concomitant medications with immunosuppressive intent 
will be summarized by lowest ATC class and preferred term using frequency counts and 
percentages. These summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment. 


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Additional summaries will be provided to report medications starting between 31 days after last 
dose of study PDR001 and 150 days after last dose of PDR001.  
The safety set will be used for all concomitant medication tables. 
Duration of exposure to concomitant medication with immunosuppressive intent (days) = (last 
date of exposure to concomitant medication with immunosuppressive intent) – (date of first 
administration of concomitant medication with immunosuppressive intent) + 1 
Duration of exposure to concomitant medication with immunosuppressive intent will be 
summarized if relevant. In addition, the duration of exposure for the subset of subjects who 
experienced events of interest (i.e. AESIs, patients treated with concomitant medication with 
immunosuppressive intent) may be summarized. Descriptive statistics such as median, min, 
max will be presented. 
Time to initiation of concomitant medication with immunosuppressive intent is the time from 
start of treatment with PDR001 to first administration of concomitant medication with 
immunosuppressive intent. Patients who did not receive concomitant medication with 
immunosuppressive intent will be censored .The censoring date will be the earliest of the 
following dates:  
 death date, 
 new anticancer antineoplastic therapy start date,  
 end date of on-treatment period,   
 data cut-off date, 
 withdrawal of informed consent date. 
Time to initiation of concomitant medication with immunosuppressive intent will be 
summarized if relevant. Kaplan-Meier curves will be displayed as well as median and 95% 
confidence intervals for each treatment arm. In addition, time to occurrence for the subset of 
subjects who experienced events of interest (i.e. AESIs, patients treated with concomitant 
medication with immunosuppressive intent) may be summarized. Descripive statistics such as 
median, min, max will be presented. 
2.5 
Analysis of the primary objective 
The primary objective is to estimate the antitumor activity of PDR001 as a single agent in well-
differentiated NET and poorly-differentiated GEP-NEC groups. 
2.5.1 
Primary endpoint 
ORR is defined as the proportion of patients with best overall response (BOR) of complete 
response (CR) or partial response (PR) according to RECIST 1.1 (see Appendix 1 of the study 
protocol).  ORR will be calculated within each group based on the FAS using BIRC review of 
tumor assessment data. Patients with only non-measurable disease at baseline will be part of the 
analysis and will be included in the numerator only if a complete response was observed. Tumor 
assessments performed before the start of any further antineoplastic therapy (i.e. any additional 
secondary antineoplastic therapy or surgery) will be considered in the assessment of BOR. 
Limited-field palliative radiotherapy administered as concomitant therapy per protocol will not 


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be considered as new antineoplastic therapy. Localized radiotherapy and treatment with 
bisphosphonates for pre-existing, painful bone/liver metastases is permitted. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary efficacy analysis will be performed on the FAS. ORR will be summarized using 
descriptive statistics (N,%) along with 2-sided exact 95% confidence interval (CI) [Clopper and 
Pearson 1934]. 
Group 1: Well-differentiated NET 
In the absence of historical comparator in this setting, response rates reported in placebo arms 
of previous randomized phase III studies in earlier lines of treatment can be considered as a 
valid historical reference for ORR (see Table 1-1 in the protocol). Based on it, the response rate 
for placebo is expected to be ca. 3% and it is desired to ensure that the observed response rate 
for PDR001 is significantly higher than expected placebo response rate. Furthermore, a 
response rate of 10% is considered clinically meaningful among patients with advanced NET 
of GI, pancreatic or thoracic origin. 
Therefore, the results in this group will be considered a success if both of the following 
conditions are met: 
1. a clinically relevant response rate of at least 10% is observed 
2. the two-sided exact 95% CI excludes the value 3%.  
With 90 patients in the FAS, these criteria correspond correspond to at least 9 responders 
observed (i.e. a response rate of 10% with 95% CI: [4.7; 18.1]). 
Group 2: Poorly-differentiated GEP-NEC group  
This group will enroll approximately 20 patients. Estimates of the ORR along with 95% two-
sided CI will be presented. Additionally, the interval probabilities for the true ORR lying within 
the intervals stated below will be computed. 
 0 - <3%      
unacceptable efficacy 
 3% - <10%     
limited efficacy  
 10% - <20%   
moderate efficacy 
 20%   
 
clinically relevant efficacy     
 
For this analysis a prior distribution for the parameter of interest, ORR, must be specified. For 
the current study, the prior clinical assumption for PDR001 in the selected patient population is 
used in order to derive a minimally informative unimodal Beta prior distribution that reflects 
the level of uncertainty around ORR before starting the current trial (Neuenschwander et al 
2008). The prior mean ORR is set to be equal to 15% and the parameters of the minimally 
informative Beta prior distribution of ORR have been set up as follows: 
 a/(a+b) = 0.15 
 a = 0.176 


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 b = 1.0 
At the primary analysis, this prior distribution will be updated with observed ORR data and 
probabilities that the true ORR lies within the above intervals will be reported. 
2.5.3 
Handling of missing values/censoring/discontinuations 
For the computation of ORR, all confirmed responses (CR or PR) reported up to the analysis 
cut-off will be included. Patients with no valid radiological assessment or unconfirmed 
responses will be considered as non-responders. In particular, patients with CR or PR at the last 
radiological assessment prior to cut-off and no response at the previous assessment are by 
definition unconfirmed and will be considered as non-responders for the primary analysis. 
Patients with unknown or missing best overall response (BOR) will be counted as non-
responders. If there is no baseline tumor assessment, all post-baseline overall lesion responses 
are expected to be ‘Unknown’. If no valid post-baseline tumor assessments are available, the 
best overall response must be “Unknown” unless progression is reported. For the computation 
of ORR, these patients will be included in the FAS and will be counted as ‘non-responders’. 
2.5.4 
Supportive analyses 
A sensitivity analysis considering patients with unconfirmed PR or CR (i.e. with PR or CR at 
the last assessment prior to the cutoff and ongoing in efficacy follow-up) as responders may be 
performed if large delayed treatment effect is observed.  
The analysis of ORR will be repeated based on local review. 
 
Concordance analysis of BOR  
An assessment of the concordance between BIRC assessment and local assessment of the Best 
Overall Response for each subject will be provided. The calculation will be based on the percent 
agreement (the proportion of response outcomes that agree or match across both Independent 
Reviewer and Investigator Assessments):  
 Percent Agreement = (Number of matched responders + Number of matched non-responders) 
/ total number of subjects assessed. 
Subgroup analyses for the primary endpoint  
If both criteria for the primary efficacy analysis are met, the primary endpoint of ORR  will be 
summarized for the subgroups specified in Section 2.2.1 based on the primary analysis source 
(i.e. BIRC) and the same conventions as for the primary analysis.  
For each of the subgroups, the following analyses will be performed: 
 Proportion of patients with objective response 
 two-sided exact 95% CI 
Efficacy analyses in subgroups will be purely exploratory and are intended to explore the 
consistency of treatment effect.  


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Reasons for “Unknown” BOR 
Patients with ‘unknown’ BOR will be summarized by reason for having unknown status. The 
following reasons will be used: 
 No valid post-baseline assessment 
 All post-baseline assessments have overall lesion response UNK 
 New anti-neoplastic therapy started before first post-baseline assessment 
 SD or non-CR/non-PD too early   
 PD too late  
Note 1: A SD or Non-CR/Non-PD is considered as “SD too early”’ if the SD or Non-CR/Non-
PD is documented within first 6 weeks after treatment start date.  
Note 2: A PD is considered as “PD too late” if the first documentation of PD is recorded more 
than 12 weeks after treatment start date with no qualifying CR, PR or SD or Non-CR/Non-PD 
in between.   
Note 3: Special (and rare) cases where BOR is “unknown” due to both too early SD and too 
late PD will be classified as “SD too early”. 
Waterfall plot to depict anti-tumor activity 
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of all target lesions for each patient. 
Only patients with measurable disease at baseline will be included in the waterfall graphs.  
Special consideration is needed for assessments where the target lesion response is CR, PR or 
SD, but the appearance of a new lesion or a worsening of non-target lesions results in an overall 
lesion response of PD. As a conservative approach, such assessments will not be considered  
for  display as  bars  in  the  graph,  since  the  percentage  change  in  the  sum  of diameters of 
target lesions reflects the non-PD target lesion response, but the overall lesion response is PD. 
A patient with only such assessments will be represented by a special symbol (e.g. 
) in the 
waterfall graph. Assessments with “unknown” target lesion response and assessments with 
unknown overall response will be excluded from the waterfall plots. Patients without any valid 
assessments will be completely excluded from the graphs. 
The total number of patients displayed in the graph will be shown and this number will be used 
as the denominator for calculating the percentages of patients with tumor shrinkage and tumor 
growth. Footnote will explain the reason for excluding some patients (due to absence of any 
valid assessment). 
All possible assessment scenarios are described in Table 2-4. 
Table 2-3 
Inclusion/exclusion of assessments used in waterfall graph 
Criteria for inclusion/exclusion 
Possible sources of 
contradictions 
case 
Target response 
Overall lesion 
response 
Include 
in waterfall? 
Non-target 
response 
New lesion? 


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1 
CR/PR/SD 
PD 
Yes but as ‘ only 
PD 
any 
2 
CR/PR/SD 
PD 
Yes but as ‘ only 
any 
Yes 
3 
UNK 
UNK or PD 
No 
any 
any 
4 
CR/PR/SD 
UNK 
No 
UNK 
No 
5 
CR/PR/SD 
CR/PR/SD 
Yes as a bar 
SD/IR 
No 
6 
PD 
PD 
Yes as a bar 
any 
any 
 
Percentage change from baseline in the sum of diameters of all target lesions over the time will 
be displayed for individual patients. 
2.6 
Analysis of the key secondary objective 
The key secondary objective in this study is to estimate efficacy of PDR001 using the duration 
of response per RECIST 1.1 and based on tumor response data per BIRC. 
2.6.1 
Key secondary endpoint 
Duration of response (DOR) only applies to patients whose best overall response is complete 
response (CR) or partial response (PR) according to RECIST 1.1 based on BIRC review of 
tumor assessment data. The start date is the date of first documented response of CR or PR (i.e., 
the start date of response, not the date when response was confirmed), and the end date is 
defined as the date of the first documented progression or death due to underlying cancer.  
2.6.2 
Statistical hypothesis, model, and method of analysis 
DOR will be listed and summarized for all patients in the FAS with confirmed BOR of CR or 
PR. The duration of response will be presented graphically along with the duration of on-study 
follow-up and information about responses. The distribution of duration of response will be 
estimated using the Kaplan-Meier method and the median duration of response will be 
presented along with 95% confidence interval only if a sufficient number of responses is 
observed. A responders-only analysis will also be performed in this case. 
2.6.3 
Handling of missing values/censoring/discontinuations 
For DOR analysis patients continuing without progression or death due to underlying cancer 
will be censored at the date of their last adequate tumor assessment using the censoring rule 
described for PFS analysis.  
2.7 
Analysis of secondary efficacy objective(s) 
All secondary efficacy endpoints according to RECIST 1.1 or irRECIST will be based on tumor 
assessments as per BIRC. The local radiology assessments will be used as supportive analysis.  
Antitumor activity (assessed by ORR and DoR per RECIST 1.1 and BIRC) in each of the three 
well-differentiated NET cohorts (pancreatic, GI, thoracic) will also be evaluated as secondary 
endpoint.  
 


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2.7.1 
Secondary endpoints 
Disease control rate (DCR)  
DCR is defined as the proportion of patients with best overall response of CR, PR or SD 
according to RECIST 1.1 criteria and as per central review. DCR will be calculated using FAS 
and based on the BIRC tumor assessments.  
Time to response 
Time to response (CR or PR) is the time from date of treatment start to first documented 
response of CR or PR (which must be confirmed subsequently) using BIRC review of tumor 
assessment data and according to RECIST 1.1. All patients in the FAS will be included in the 
time to response calculation. Patients who did not achieve a confirmed PR or CR will be 
censored at: 
 the maximum follow-up time (i.e. FPFV -  LPLV used for the analysis) for patients who 
had a PFS event (i.e. either progressed or died due to any cause); 
 the last adequate tumor assessment date for all other patients. 
Progression-free survival (PFS) 
PFS is defined as the time from the date of first dose to the date of the first documented 
radiological progression or death due to any cause. PFS will be assessed via central review 
according to RECIST 1.1. PFS will be censored if no PFS event is observed before the analysis 
cut-off date.  
If a patient has not progressed or died  at the analysis cut-off date, PFS will be censored at the 
date of the last adequate tumor evaluation date before the cut-off date. PFS events documented 
after the initiation of new anti-neoplastic therapy (i.e. RECIST 1.1. documented disease 
progression or death) will be considered provided tumor assessments continue after initiation 
of new cancer therapy.  Discontinuation due to disease progression (collected on the ‘End of 
treatment’ and ‘End of post treatment follow up’ disposition pages) without supporting 
objective evidence satisfying progression criteria per RECIST 1.1 will not be considered disease 
progression for PFS derivation.  
Efficacy endpoints according to irRECIST  
Immune related overall response rate (irORR) is the proportion of patients with a best 
overall response of irCR or irPR based on BIRC review of tumor assessment data. 
The best immune related overall response for each patient is determined from the sequence of 
immune related overall responses according to rules described in the irRECIST appendix of the 
protocol.  
Immune related duration of overall response (irDOR):  For patients with a confirmed irCR 
or irPR based on BIRC review of tumor assessment data. The start date is the date of first 
documented confirmed response and the end date and censoring is defined the same as that for 
time to progression. 


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Date of confirmed response is derived as followed: Response (irPR or irCR) should be 
confirmed by a second assessment no less than 4 weeks after the first assessment showing 
response. Date of response is then the date of the first of these two assessments. For 
confirmation of irCR the two assessments must be consecutive (intervening assessments of 
irUNK are permissable). For confirmation of irPR the two assessments do not need to be 
consecutive, but must not be separated by a pseudo-progression event. 
Immune related time to overall response (irTTR) is the time between date of start of 
treatment until first documented response (confirmed irCR or irPR). 
Immune related disease control rate (irDCR) is the proportion of patients with a best overall 
response of irCR or irPR or irSD. Patients with BOR of irNCRNPD will also be included in 
DCR if patients with non-measurable disease at baseline are in analysis set. 
Immune related progression-free survival (irPFS) is the time from date of start of treatment 
to the date of event defined as the first documented assessment of irPD that was then confirmed 
or death due to any cause. Unconfirmed irPD without further adequate tumor assessments will 
be considered as a confirmed irPD. If a patient has not had an event, progression-free survival 
is censored at the date of last adequate tumor assessment. An adequate tumor assessment is a 
tumor assessment with overall response other than irUNK.  
Immune related confirmed irPD is derived as described in section 5.5. 
Overall survival rate at 1 year and 2 years 
OS is defined as the time from date of start of treatment to date of death due to any cause. If a 
patient is not known to have died, then OS will be censored at the latest date the patient was 
known to be alive (on or before the cut-off date).  
2.7.2 
Statistical hypothesis, model, and method of analysis 
Disease control rate 
DCR will be calculated based on the FAS. DCR and its 95% confidence interval will be 
presented.  
Time to response 
TTR will be listed and summarized for all patients. The distribution of time to response will be 
estimated using the Kaplan-Meier method only if a sufficient number of responses is observed.  
Progression-free survival (PFS) 
PFS based on RECIST 1.1 will be analyzed in the FAS population. The PFS distribution will 
be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for all patients.  
Number of patients with a PFS event and number of patients censored for the PFS analysis will 
be summarized. In addition, a summary of reasons for PFS censoring will be provided based on 
the following reasons: 
1: Ongoing without event 


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2: Lost to follow-up 
3: Withdrew consent 
4: Adequate assessment no longer available 
5: Event after >=2 missing tumor assessments  
The PFS censoring reasons are defined in the following way.  
If the time interval between the last adequate tumor assessment (TA) date and the earliest of the 
following dates is smaller or equal to interval of 2 missing TAs: 
1. Analysis cut-off date,  
2. Date of consent withdrawal, 
3. Visit date of study treatment discontinuation or end of post-treatment follow-up 
discontinuation due to lost to follow-up. 
Then the PFS censoring reason will be: 
1. ‘Ongoing’,  
2. ‘Withdrew consent’,  
3. ‘Lost to follow-up’,   
If the time interval is larger than the interval of 2 missing TAs with no event observed. then the 
PFS censoring reason will always default to ‘Adequate assessment no longer available’. If the 
time interval between the last adequate TA date and the PFS event date is larger than the interval 
of 2 missing TA then the patient will be censored and the censoring reason will be 'Event 
documented after two or more missing tumor assessments'. Further details on the definition of 
last adequate assessment and two missing TAs are provided in Section 2.7.3. 
Efficacy endpoints according to irRECIST  
The following irRECIST endpoints will be analyzed in a similar way to the corresponding 
RECIST endpoints: 
 irORR 
 irDoR 
 irTTR 
 irDCR 
 irPFS.   
Overall Survival 
The survival distribution of OS distribution will be estimated using the Kaplan-Meier method 
and Kaplan-Meier curves.  
Survival estimates at 1 year and at 2 years will be computed with 95% confidence interval 
[Brookmeyer and Crowley 1982].  


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2.7.3 
Handling of missing values/censoring/discontinuations 
If a patient is not known to have died at the time of analysis cut-off, then OS will be censored 
at the date of last known date patient was alive, i.e., last contact date. 
The date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of CR, PR or SD  or non-CR/non-PD before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment will be used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) then the 
start date of treatment will be used. 
In particular, PFS will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event; the event occurred after two or more missing tumor assessments. The 
term “missing adequate tumor assessment” is defined as a tumor assessment not performed or 
tumor assessment with overall lesion response of “UNK”. The rule to determine number of 
missing TAs is based on the time interval between the date of last adequate tumor assessment 
and the date of an event. If the interval is greater than  twice the protocol-specified interval 
between the TAs and 2 times the protocol-allowed time window around assessments, then the 
number of missing assessments will be 2 or more. 
As per protocol, tumor assessments are expected to be performed every 8 weeks for the first 12 
months and every 12 weeks thereafter. 
Therefore: 
 if the last adequate tumor assessment is performed before end of week 36 (i.e. from study 
day 1 to study day 36*7=252) then the interval of 2 missing tumor asssessments is given as 
2*8+2=18 weeks (126 days); 
 if the last adequate tumor assessment is performed from end of week 36 up to end of week 
44 (i.e. from study day 253 to study day 44*7=308) then the interval of 2 missing tumor 
asssessments is given as 8+12+2=22 weeks (154 days); 
 otherwise, when the last adequate tumor assessment is performed after end of week 44 (i.e. 
from study day 44*7+1=309 onward), then the interval of 2 missing tumor asssessments is 
given as 2*12+2=26 weeks (182 days). 
These summaries on censoring reasons will be produced for PFS by investigator  and BIRC.  
Refer to Table 2-5 for censoring and event date options and outcomes for PFS. 
Table 2-4 
Outcome and event/censor date for PFS analysis 
Situation 
Date 
Outcome 
No baseline assessment 
Date of start of treatment 
Censored 
Progression or death at or 
before next scheduled 
Assessment 
Date of progression (or 
death) 
Progressed 
 
Progression or death after 
exactly one missing assessment 
Date of progression (or 
death) 
Progressed 
 


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Situation 
Date 
Outcome 
Progression or death after two or 
more missing assessments 
Date of last adequate 
assessment prior to 
missed assessment  
Censored 
 
No progression (or death) 
Date of last adequate 
assessment  
Censored 
 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim 
Date of last adequate 
assessment  
  
 
Censored 
 
New anticancer therapy given 
prior to protocol defined 
progression  
Ignore the new 
anticancer therapy and 
follow situations above  
As per above situations 
Death before first PD 
assessment 
Date of death 
Progressed 
  
2.8 
Safety analyses 
All safety analyses will be based on the safety set. All listings and tables will be presented 
separately for the well-differentiated NET and the poorly-differentiated GEP-NEC groups. In 
addition, pooled safety analyses based on all patients will be produced. 
2.8.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring during on treatment period. Additional summaries 
will be displayed to report all AEs, AEs related to study treatment, all SAEs and SAEs related 
to study treatment collected up to 150 days after last administration of PDR001. 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 with start date outside of on-
treatment period 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 investigational arm. 
The following adverse event summaries will be produced using the safety set; overview of 
adverse events and deaths, AEs by SOC and PT, summarized by relationship, seriousness, 
leading to treatment discontinuation, leading to dose interruption/adjustment, requiring 
additional therapy, requiring immunosuppressive medication and leading to fatal outcome. In 


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addition, a summary of serious adverse events with number of occurrences will be produced 
(an occurrence is defined as >1 day between start and prior end date of record of same preferred 
term).  
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 5% 
and on on-treatment serious adverse events and SAE suspected to be related to study treatment 
will be provided by system organ class and preferred term on the safety set population. 
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 SOC and PT. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Data analysis of AESIs 
An adverse event of special interest (AESI) 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 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 patients with at least one event of the AESI 
occurring during on treatment period will be summarized. 
Summaries of these AESIs will be provided (specifying grade, SAE, relationship, leading to 
treatment discontinuation, leading to dose adjustment/interruption, hospitalization, death, 
requiring immunosuppressive medication etc.). Additional summaries will be provided to report 
all AESIs, AESIs related to study treatment, all serious AESIs and serious AESIs related to 
study treatment collected during the on-treatment period and up to 150 days after last 
administratio n of PDR001. 
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.  


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2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths will be produced by system organ class and 
preferred term. Additional summary will be displayed to report all deaths up to 150 days after 
last administration of PDR001. 
All deaths  will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects.  
2.8.3 
Laboratory data 
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
then 150 days after the last study treatment administration date (see Section 2.1.1). 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment): 
 Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline. 
 Shift tables using CTC grades to compare baseline to the worst on-treatment  value  
 For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment  value. 
 Trends of lab parameter values over time (baseline and selected on-treatment timepoints) 
should be displayed via boxplots  based on time windows  and corresponding tables 
displaying the statistics used for the box plots by the selected time points.  
 
The following listing will be produced for the laboratory data: 
 Listing of all CTC grade 3 or 4 laboratory toxicities 
Liver function parameters  
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per Novartis 
Liver Toxicity guidelines will be summarized: 
The following summaries will be produced: 
 ALT or AST > 3xULN  
 ALT or AST > 5xULN 
 ALT or AST > 8xULN 
 ALT or AST > 10xULN 
 ALT or AST > 20xULN 
 TBL > 2xULN 
 TBL > 3xULN 


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 ALT or AST > 3xULN & TBL > 2xULN 
 ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN   
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Data handling 
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses. 
Data analysis 
12-lead ECGs including PR, QRS, QT, QTcF and RR intervals will be obtained central/local 
for each subject during the study. ECG data will be read and interpreted locally.  
The number and percentage of subjects with notable ECG values will be presented.  
 QT, QTcF 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤  60ms 
- 
Increase from Baseline of > 60 ms 
 HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
 PR 
- 
Increase from baseline >25% and  to a value > 200 ms 
- 
New value of > 200 ms 
 QRS 
- 
Increase from baseline >25% and  to a value > 120 ms 
- 
New values of QRS > 120 ms 
2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg) 
Data handling 
Vital signs collected on treatment will be summarized.  


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Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-6  
below. 
Table 2-5 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body 
temperature 
>= 39.1  
- 
 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented.          
2.9 
Pharmacokinetic endpoints   
PK Concentrations 
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV% mean, SD, 
median, geometric mean, CV% geo-mean, minimum and maximum) for PDR001 
concentrations will be presented at each scheduled time point for the Pharmacokinetic analysis 
set. For PDR001, pre-dose concentrations collected before dose administration on Day 1 of 
Cycle 2+ are Ctrough. 
 
All individual PDR001 concentration data will be listed for the Safety set. 
Handling of PK data below LLOQ or missing 
All concentration values below the lower limit of quantitation (LLOQ) (i.e. <0.25 ng/mL) are 
set to zero by the Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ 
values will be treated as zero in any calculations of summary statistics, and treated as missing 
for the calculation of the geometric means and their CV%.  
Missing values for any PK data will not be imputed and will be treated as missing. 


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2.10 
PD and PK/PD analyses 
2.10.1 
Immunogenicity 
2.10.1.1 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 
positive in the confirmatory assay are considered ADA positive and are further characterized in 
the neutralization assay to indicate the presence of neutralizing antibodies (NAb). 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 the ADA 
response 
 Presence of Nab (for positive samples, if NAb assay results are available): yes or no 
 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: 
o 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.  
o ADA-positive sample: Determinant sample where assay is ADA positive. 
o ADA-positive NAb sample: Determinant sample where assay is ADA positive 
and presence of NAb = yes. 
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: 


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o treatment-induced ADA-positive sample: ADA-positive sample post-baseline 
with ADA-negative sample at baseline.  
o 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. 
o 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) and ADA-positive NAb samples, 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). 
 
2.11 
Patient-reported outcomes 
The EORTC QLQ-C30 questionnaire and the EQ-5D-5L will be used to collect patient’s QoL 
data. The FAS will be used for analyzing PRO data. The global health status/QoL scale score 
of the QLQ-C30 and the health status index score of the EQ-5D-5L are identified as the primary 
patient-reported outcome variables of interest. Physical functioning, emotional functioning and 
social functioning scale scores of the QLQ-C30, and overall health status of the EQ-5D-5L are 
identified as secondary patient-reported QoL variables of interest.  


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High scores in the EORTC QLQ-C30 correspond to a higher response level. Thus a high score 
for a functional scale represents a high / healthy level of functioning; a high score for the global 
health status / QoL represents a high QoL, but a high score for a symptom scale / item represents 
a high level of symptomatology / problems.  Higher scores in the EQ-5D-5L correspond to 
better health states or overall health status. 
Established estimates for the minimal important differences (MID) for each measure will be 
used to interpret change from baseline scores. For the EORTC QLQ-C30 a change of 10 will 
be defined as the MID [Osoba 1998]. For the EQ-5D-5L, a change in the index score of 0.08 
and a changes in the VAS of 7 will be defined as the MID [Pickard 2007]. 
EORTC QLQ-C30 subscale scores will be calculated by first obtaining the raw scores through 
adding up the item responses on the questions which make up each domain and then applying 
the linear transformation to the raw scores in accordance with the respective scoring manual 
provided by the developer (Fayers 2001). No imputation procedures will be applied for missing 
items or missing assessments. 
For EQ-5D-5L health states will be converted to index value, during data analysis stage, based 
on the EQ-5D crosswalk value set for the UK using the time trade-off method (van Hout 2015). 
If any one of the five items is missing, the index value will be set to missing.  In addition, the 
visual analog scale (ranging from 0 to 100) from the EQ-5D-5L will be evaluated for patient’s 
rating of their overall health status. 
The PRO instruments are planned to be administered during screening and every 8 weeks after 
first day of treatment during the first 12 months, and every 12 weeks thereafter until the end of 
treatment. PRO assessments will continue to be collected during the efficacy follow-up after 
the end of treatment.  
The baseline is defined as the last PRO assessment on or before the first day of treatment.  
Descriptive statistics will be used to summarize the PRO scores and change from baseline for 
scales of the EORTC QLQ-C30 and health states, overall health status, and index values of the 
EQ-5D-5L at each scheduled assessment time point by cohort. Data obtained after the end of 
treatment will be summarized separately. Additionally, analysis by responder/non-responder 
may be performed if sufficient number of responders is observed.  
2.12 
CgA and NSE 
The biochemical response will be assessed using the change from baseline for CgA and NSE 
levels.  
Change from baseline in CgA and NSE will be summarized using descriptive statistics for all 
patients. CgA and NSE values might be analyzed on the logarithmic scale if their observed 
distribution is found be right skewed.  
Data handling principles 
The lower limit of quantification (LLOQ) values for CgA and NSE will be specified by the 
laboratory running the assay. 
Measures below the LLOQ will be handled as follows: 


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 If the proportion of measures below LLOQ is below 15%, all values specified as below 
LLOQ will be imputed by half of the LLOQ and the standard set of summary statistics will 
be used. 
 If the proportion of measures below LLOQ is above 15%, but below 50%, an alternative 
choice of summary statistics requiring no imputation such as percentiles may be used. 
 Otherwise the data will be missing 
 When both baseline and post baseline values are below LLOQ, change from baseline will 
not be imputed and reported as missing. 
All available data points obtained at scheduled and unscheduled visits will be considered for 
the analysis.  


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2.14 
Interim analysis 
An interim analysis for preliminary assessment of PDR001 in this patient population will be 
conducted once at least 30 patients from the well-differentiated NET group have 3 radiological 
assessments (week 24) or have discontinued study for any other reason. All available efficacy 
and safety data from the well-differentiated NET and poorly-differentiated GEP-NEC groups 
up to the cut-off date will be used for IA. The study will not be stopped at the interim analysis 
for efficacy reasons regardless of efficacy results and will continue until mature data for all 
patients become available. 
 
3 
Sample size calculation 
Group 1: Well-differentiated NET 
In the absence of an established control treatment, ORR reported in the placebo arms of studies 
reported in Table 1-1 of the protocol can serve as a reference. A 3% ORR is therefore considered 
as a reasonable reference while an improvement up to 10% is considered as clinically 
meaningful in this patient population. 
Total sample size of 90 patients was chosen such that with an observed 10% response rate, the 
corresponding 95% CI excludes the value 3%. 
Approximately thirty patients will be recruited in each cohort NET cohort: pancreatic, GI and 
thoracic.  
Operating characteristics in the well-differentiated NET group are given in Table 3-1. A sample 
size of 90 patients ensures an 90% probability of success if the true ORR is 15%. 
Table 3-1 
Operating characteristics for the full population 
True response rate  
Probability of observing 10% or more responders at the end of the study* 
10% 
0.55 
11% 
0.67 
12% 
0.77 
13% 
0.84 
14% 
0.90 


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15% 
0.94 
In addition, Table 3-2 shows the probability of observing at least 3 responders in a cohort with 
30 patients under the assumption of true response rate of 10-20% in this cohort. 
Table 3-2 
Probability of observing at least 3 responders in a cohort with more 
than 10% true response rate 
True response rate in a 
cohort 
Probability of observing 3 or more responders in a cohort with 30 patients 
end of the study* 
10% 
0.59 
12% 
0.72 
14% 
0.81 
16% 
0.88 
18% 
0.93 
20% 
0.96 
Group 2: Poorly-differentiated GEP-NEC 
Approximately 20 patients will be enrolled in the poorly-differentiated GEP-NEC group. The 
operating characteristics are shown in Table 3-3 and Table 3-4. With the planned sample size 
the probability to observe at least moderate efficacy (10% ORR) is more than 80% if the true 
ORR is 15%. Posterior probability of a true ORR of at least moderate efficacy was computed 
for different scenarios assuming a minimally informative prior with Beta distribution and the 
following parameters: a=0.176, b=1. Posterior probability of a true ORR to be 10% ORR is 
more than 70% if 3 responders are observed in 20 patients. 
Table 3-3 
Operating characteristics for the poorly-differentiated GEP-NEC group 
True response 
rate  
Probability of observing 2 or more 
responders (10% ORR) in 20 patients  
Probability of observing 3 or more 
responders (15% ORR) in 20 
patients  
10% 
0.61 
0.32 
12% 
0.71 
0.44 
15% 
0.82 
0.60 
18% 
0.90 
0.73 
20% 
0.93 
0.79 
Table 3-4 
Posterior probability of a true ORR in the poorly-differentiated GEP-
NEC group corresponding to at least moderate efficacy (≥10% ORR) 
Number of observed 
responders in 20 
patients 
Posterior probability for 
a true ORR 10%  
1 
15.8% 
2 
44.0% 
3 
71.4% 
4  
88.6% 
 


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4 
Change to protocol specified analyses 
5 
No probabilistic evaluation of heterogeneity between three 
cohorts in the well-differentiated NET group will be 
performed. No other changes to the protocol specified 
analyses are included in this analysis plan. Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:  
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available:  
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.   
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:  
            Use EOT date 
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date:  
            Use last day of the Month (mm) 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:  
Use the treatment start date 
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed. 


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5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
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   
Table 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last treatment date plus 150 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
day, month 
 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
day 
 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided.  


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5.1.2.1 
Other imputations 
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence  
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan.  
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment 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 the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number.  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. 
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. 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).  
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 4.03 at the time of analysis will be used. For laboratory 


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tests where grades are not defined by CTCAE v4.03, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC.  
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) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, 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 will be assigned as described above for grading 
 


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Table 5-3 
CTC grades for laboratory values in Novartis Oncology (based on CTCAE v4.03 – June 2010)      
                                                                                                                                  CTC Grades(1) 
Lab 
test 
(toxicity) 
SI 
unit 
Lab 
test 
(NCDS
)  
Normal 
ranges 
(Merck 
manual, July 2015) and 
conversion factors 
0 
1 
2 
3 
4 
 
Hematology 
 
 
 
 
 
WBC ↓ 
109/L 
WBC 
3.9 – 10.7 x 109/L 
 
LLN 
< LLN - 3.0 x 
109 /L 
< 3.0 – 2.0 x 
109 /L 
< 2.0 – 1.0 x 
109 /L 
< 1.0 x 
109 /L 
WBC 
(2)  
(Leukocytosis) 
109/L 
WBC 
 
 
- 
- 
> 100 x 109 /L 
- 
Hemoglobin 
(2)  
(Anemia)  
g/L 
HGB 
120 - 160 g/L or 7.4 - 9.9 
mmol/L 
(F)  
140 - 170 g/L or 8.7 – 10.6 
mmol/L (M) 
 
LLN 
< LLN - 100 g/L 
< LLN - 6.2 
mmol/L 
< 100 - 80 g/L 
< 6.2 - 4.9 
mmol/L 
< 
80 
g/L 
< 4.9 mmol/L 
- 
Hemoglobin ↑ 
g/L 
HGB 
(16.113 x mmol/L = g/L) 
 
Increase >0-20 
g/L above ULN 
Increase >20-
40 g/L above 
ULN 
Increase >40 
g/L 
above 
ULN 
- 
Platelets ↓ 
109/L 
PLAT 
150 - 350 x 109/L 
 
LLN 
< LLN - 75.0 x 
109/L 
< 75.0 - 50.0 x 
109 L 
< 50.0 - 25.0 x 
109/L 
< 25.0 x 
109 /L 
Neutrophils (3)↓ 
109/L 
NEUT 
 
2x1
09 /L 
< 2.0 - 1.5 x 109 
/L 
< 1.5 - 1.0 x 109 
/L 
< 1.0 - 0.5 x 
109 /L 
< 0.5 x 
109 /L 


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Lymphocytes 
(3)↓ 
109/L 
LYM 
  
1.5
x109 
/L 
< 1.5 - 0.8 x 109 
/L 
< 0.8 - 0.5 x 109 
/L 
< 0.5 - 0.2 x 
109 /L 
< 0.2 x 
109 /L 
Lymphocytes ↑ 
109/L 
LYM 
 
 
- 
> 4 - 20 x 109 /L > 20 x 109 /L 
- 
Biochemistry 
 
 
 
 
 
AST ↑ 
U/L 
AST 
0 - 35 U/L or  0 – 0.58 ukat/L  
(60 x ukat/L = U/L) 
  
ULN 
> ULN – 3.0 x 
ULN 
> 3.0 - 5.0 x 
ULN 
> 5.0 - 20.0 x 
ULN 
> 20.0 x 
ULN 
ALT ↑ 
U/L 
ALT 
0 - 35 U/L or  0 – 0.58 ukat/L 
(60 x ukat/L = U/L) 
  
ULN 
> ULN – 3.0 x 
ULN 
> 3.0 - 5.0 x 
ULN 
> 5.0 - 20.0 x 
ULN 
> 20.0 x 
ULN 
Total bilirubin ↑ 
umol/
L 
BILI 
5.1 – 20.5 umol/L or 0.3 – 
1.2 
mg/dL  
(17.1 x mg/dL = umol/L)  
  
ULN 
> ULN - 1.5 x 
ULN 
> 1.5 - 3.0 x 
ULN 
> 3.0 - 10.0 x 
ULN 
> 10.0 x 
ULN 
Alk. 
Phosphatase ↑ 
U/L 
ALP 
36 - 92 U/L or  0.5 - 1.5 
ukat/L    
(60 x ukat/L = U/L) 
  
ULN 
> ULN - 2.5 x 
ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 20.0 x 
ULN 
> 20.0 x 
ULN 
Creatinine (4)↑ 
umol/
L 
CREA
T 
61.9 - 115 umol/L or 0.7 – 
1.3 
mg/dL  
(88.4 x mg/dL = umol/L) 
  
ULN 
> ULN - 1.5 x 
ULN  
> 1.5 - 3.0 x 
ULN 
> 3.0 - 6.0 x 
ULN 
> 6.0 x 
ULN 
Creatinine 
kinase (4)↑ 
U/L 
CK 
30 - 170 U/L or 0.5 – 2.83 
ukat/L 
(60 x ukat/L = U/L) 
  
ULN 
> ULN - 2.5 x 
ULN 
> 2.5 - 5.0 x 
ULN 
> 5.0 - 10.0 x 
ULN 
> 10.0 x 
ULN 
Albumin 
(2)  
(Hypoalbumine
mia)  
g/L 
ALB 
35 - 55 g/L or 3.5 to 5.5 g/dL 
  
  
LLN 
< LLN - 30 g/L 
 < 30 - 20 g/L 
< 20 g/L 
- 


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Total 
Cholesterol ↑ 
mmol/
L 
CHOL 
3.88 – 5.15 mmol/L or 150 - 
199 
mg/dL  
(38.67 x mg/dL = mmol/L) 
  
ULN 
> ULN - 7.75 
mmol/L 
> ULN - 300 
mg/dL 
> 7.75 -10.34 
mmol/L 
> 300 – 400 
mg/dL 
>10.34-12.92 
mmol/L 
> 400 – 500 
mg/dL 
>12.92 
mmol/L 
> 
500 
mg/dL 
Lipase ↑ 
U/L 
LIPAS
E 
<95 U/L or <1.58 ukat/L  
(60 x ukat/L = U/L) 
  
ULN 
 > ULN - 1.5 x 
ULN 
> 1.5 - 2.0 x 
ULN 
> 2.0 - 5.0 x 
ULN 
> 5.0 x 
ULN 
Amylase ↑  
U/L 
AMYL
ASE 
0 - 130 U/L or 0 – 2.17 
ukat/L 
(60 x ukat/L = U/L) 
  
ULN 
 > ULN - 1.5 x 
ULN 
> 1.5 - 2.0 x 
ULN 
> 2.0 - 5.0 x 
ULN 
> 5.0 x 
ULN 
Uric 
acid 
(2)  
(Hyperuricemia) 
umol/
L 
URAT
E 
150 - 470 umol/L or 2.5 – 8 
mg/dL  
(59.48 x mg/dL = umol/L) 
  
ULN 
> ULN – 10 
mg/dL  
> ULN – 595 
umol/L 
- 
- 
> 
10 
mg/dL 
> 
595 
umol/L 
ULN = Upper Limit of Normal range; LLN = Lower Limit of Normal range   
 
                                                                                                                                  CTC Grades(1) 
Lab 
test 
(toxicity) 
SI 
unit 
Lab 
test 
(NCDS
) 
Normal 
ranges 
(Merck 
manual, July 2015) and 
conversion factors 
0 
1 
2 
3 
4 
 
Phosphorus(2)    
(Hypophosphate
mia) 
mmol/
L 
PHOS 
0.97 – 1.45 mmol/L or 3.0 - 
4.5 
mg/dL 
(0.32 x mg/dL = mmol/L) 
  
LLN 
< LLN - 2.5 
mg/dL 
< LLN - 0.8 
mmol/L 
< 2.5 - 2.0 
mg/dL 
< 0.8 - 0.6 
mmol/L 
 < 2.0 - 1.0 
mg/dL 
 < 0.6 - 0.3 
mmol/L 
< 
1.0 
mg/dL 
< 
0.3 
mmol/L 


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Calcium 
(corrected) 
(2) 
(Hypercalcemia) 
mmol/
L 
CACA
LC 
2.2 - 2.6 mmol/L or 9 - 10.5 
mg/dL  
(0.2495 x mg/dL = mmol/L) 
 
ULN 
> ULN - 11.5 
mg/dL 
> ULN - 2.9 
mmol/L 
> 11.5  - 12.5 
mg/dL 
> 2.9 - 3.1 
mmol/L 
> 12.5 - 13.5 
mg/dL 
> 3.1 - 3.4 
mmol/L 
> 
13.5 
mg/dL 
> 
3.4 
mmol/L 
Calcium 
(corrected) 
(2) 
(Hypocalcemia) 
mmol/
L 
CACA
LC 
 
 
LLN 
< LLN - 8.0 
mg/dL 
< LLN - 2.0 
mmol/L 
< 8.0 - 7.0 
mg/dL 
< 2.0 - 1.75 
mmol/L 
< 7.0 - 6.0 
mg/dL 
< 1.75 - 1.5 
mmol/L 
< 
6.0 
mg/dL 
< 
1.5 
mmol/L 
Magnesium 
(2) 
(Hypermagnese
mia) 
mmol/
L 
MG 
0.62 – 0.99 mmol/L or 1.5 – 
2.4 
mg/dL  
(0.4114 x mg/dL = mmol/L) 
 
ULN 
> ULN - 3.0 
mg/dL 
> ULN - 1.23 
mmol/L 
- 
> 3.0 – 8.0 
mg/dL 
> 1.23 – 3.3 
mmol/L 
> 
8.0 
mg/dL 
> 
3.3 
mmol/L 
Magnesium 
(2) 
(Hypomagnese
mia) 
mmol/
L 
MG 
 
 
LLN 
< LLN - 1.2 
mg/dL 
< LLN - 0.5 
mmol/L 
< 1.2 - 0.9 
mg/dL 
< 0.5 - 0.4 
mmol/L 
< 0.9 - 0.7 
mg/dL 
< 0.4 - 0.3 
mmol/L 
< 
0.7 
mg/dL 
< 
0.3 
mmol/L 
Glucose 
(non-
fasting) 
(2) 
(Hyperglycemia
) 
mmol/
L 
GLUC
SN 
<7.8 
mmol/L 
or 
<140 
mg/dL  
(0.05551 x mg/dL = mmol/L) 
 
ULN 
- 
> ULN - 250 
mg/dL 
> ULN - 13.9 
mmol/L 
> 250 - 500 
mg/dL 
> 13.9 - 27.8 
mmol/L 
> 
500 
mg/dL 
> 
27.8 
mmol/L 
Glucose 
(fasting) 
(2) 
(Hyperglycemia
) 
mmol/
L 
GLUC
SF 
3.9 – 5.8 mmol/L or 70 - 105 
mg/dL  
(0.05551 x mg/dL = mmol/L) 
 
ULN 
> ULN - 160 
mg/dL 
> ULN - 8.9 
mmol/L 
> 160 - 250 
mg/dL 
> 8.9 - 13.9 
mmol/L 
> 250 - 500 
mg/dL 
> 13.9 - 27.8 
mmol/L 
> 
500 
mg/dL 
> 
27.8 
mmol/L 


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Glucose 
(2) 
(Hypoglycemia) 
mmol/
L 
GLUC
SN/GL
UCSF 
 
 
LLN 
< LLN - 55 
mg/dL 
< LLN - 3.0 
mmol/L 
< 
55 
- 
40 
mg/dL 
< 3.0 - 2.2 
mmol/L 
< 40 - 30 
mg/dL 
< 2.2 - 1.7 
mmol/L 
< 
30 
mg/dL 
< 
1.7 
mmol/L 
Potassium 
(2) 
(Hyperkalemia) 
mmol/
L 
K 
3.5 
- 
5.0 
mmol/L 
(0.2558 x mg/dL = mEq/L = 
mmol/L) 
 
ULN 
> ULN - 5.5 
mmol/L 
> 5.5 - 6.0 
mmol/L 
> 6.0 - 7.0 
mmol/L 
> 
7.0 
mmol/L 
Potassium 
(2) 
(Hypokalemia) 
mmol/
L 
K 
 
 
 
LLN 
< LLN - 3.0 
mmol/L 
- 
< 3.0 - 2.5 
mmol/L 
< 
2.5 
mmol/L 
Sodium 
(2) 
(Hypernatremia) 
mmol/
L 
SODIU
M 
136 
- 
145 
mmol/L 
(0.435 x mg/dL = mEq/L = 
mmol/L) 
 
ULN 
> ULN - 150 
mmol/L 
> 150 - 155 
mmol/L 
> 155 - 160 
mmol/L 
> 
160 
mmol/L 
Sodium 
(2) 
(Hyponatremia) 
mmol/
L 
SODIU
M 
 
 
 
LLN 
< LLN - 130 
mmol/L 
- 
< 130 - 120 
mmol/L 
< 
120 
mmol/L 
Triglyceride (2) ↑ 
 
mmol/
L 
TRIG 
< 2.82 mmol/L or < 250 
mg/dL  
(0.01129  x mg/dL = umol/L) 
< 
150  
< 
1.71  
 150 - 300 
mg/dL 
 1.71 – 3.42 
mmol/L 
> 300 - 500 
mg/dL 
> 3.42 – 5.7 
mmol/L 
> 500 - 1000 
mg/dL 
> 5.7 – 11.4 
mmol/L 
> 1000 
mg/dL 
> 
11.4 
mmol/L 
Coagulation 
 
 
 
 
 
INR (2)↑ 
1 
INR 
0.8 – 1.2  
  
ULN 
> ULN - 1.5 x 
ULN  
> 1.5 - 2.5 x 
ULN 
> 2.5 x ULN 
- 
Activated partial 
thromboplastin 
time(2)↑ 
sec 
APTT 
25 - 35 sec 
  
ULN 
> ULN - 1.5 x 
ULN  
> 1.5 - 2.5 x 
ULN 
 
> 2.5 x ULN 
  
-  


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Fibrinogen (4)↓ 
g/L 
FIBRI
NO 
1.5 – 3.5 g/L or 150 – 350 
mg/dL   
(0.01 x mg/dL = g/L) 
  
LLN 
< LLN - 0.75 x 
LLN  
< 0.75 - 0.5 x 
LLN  
< 0.5 - 0.25 x 
LLN  
< 0.25 x 
LLN  
 
ULN = Upper Limit of Normal range; LLN = Lower Limit of Normal range   
(1) =  LAB CTC grades 1, 2, 3, 4 overrule the study specific (central or local) normal range criteria, e.g. if ULN of Sodium is 151 
mmol/L and the value is 151 mmol/L, CTC grade 2 is assigned although the value is  ULN. 
(2) =  Life-threatening consequences and/or hospitalization are not considered for determination of LAB CTC grades 3 and 4. 
Concomitant usage of anticoagulation therapy (for INR and Fibrinogen) is not considered either.  
(3) =  Values and LNRs for blood differentials can be given as %, absolute values should then be calculated using WBC. Generally,  1.5 
x 109 /L (lymphocytes) and  2 x 109 /L (neutrophils) are considered as LAB CTC grade 0 
(4) =  For Creatinine and Fibrinogen, the comparison with baseline is not considered for derivation of LAB CTC grades  
LAB - CTC grades in Novartis Oncology (26Oct15) 


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5.4 
Statistical models 
5.4.1 
Primary analysis 
Analysis of binary data 
No formal hypothesis testing will be performed. Responses will be summarized in terms of 
percentage rates with 95% CIs. An exact binomial confidence interval (implemented using SAS 
procedure FREQ with EXACT statement for one-way tables) will be calculated [Clopper and 
Pearson 1934].  
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – 0.05)) two-sided Pearson-Clopper CI.  
5.4.2 
Key secondary analysis 
Analysis of time to events data 
 
Kaplan-Meier estimates 
An estimate of the survival function will be constructed using Kaplan-Meier (product-limit) 
method as implemented in PROC LIFETEST with METHOD=KM option. The PROC 
LIFETEST statement will use the option CONFTYPE=LOGLOG. 
Kaplan-Meier estimates of the survival function with 95% confidence intervals at specific 
time points will be summarized. The standard error of the Kaplan-Meier estimate will be 
calculated using Greenwood’s formula [Collett 1994]. 
 
Treatment of ties 
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties.  
5.5 
Rule of derivation for immune related criteria  
 
Immune related confirmed irPD is derived as followed: 
Confirmed progression 1 (type 1, cPD1) is declared if a patient has 2 consecutive tumor 
assessments at least 4 weeks (28 days) apart both showing disease progression. Assessments 
with an irUNK response or irPD assessments < 28 days after initial irPD, are discarded. 
The first irPD is flagged as cPD1 while all subsequent irPDs are flagged as xPD1. 
Sequence of assessments 
Instructions 


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1    irPD 
2    irUNK 
3    irPD (Assessment 1 + 30 days) 
 Assessment 3 is ≥28 days after Assessment 1  
 Assessment 3 represents confirmation of irPD at 
assessment 1 
 Assessment 1 irPD is flagged cPD1 
 Assessment 3 irPD is flagged xPD1 
1    irSD 
2    irPD 
3    irPD (Assessment 2 + 20 days)  
4    irPD (Assessment 2 + 30 days) 
 Assessment 3 is < 28 days after Assessment 2 
 Assessment 4 is ≥ 28 days after Assessment 2  
 Assessment 4 represents confirmation of irPD at 
assessment 2 
 Assessment 2 irPD is flagged cPD1 
 Assessment 3 and 4 irPDs are flagged xPD1 
The date of progression is the date of the assessment flagged as cPD1. 
 
Confirmed progression 2 (type 2, cPD2) is declared if a patient discontinues treatment 
following a single irPD with no subsequent assessments. Assessments with an irUNK response 
or irPD assessments < 4 weeks (28 days) after initial irPD, are discarded. Discontinuation of 
treatment is obtained from EOT case report form. 
The assessment is flagged as cPD2 and subsequent irPDs (<28 days after first PD) are flagged 
as xPD2.  
The table below shows two hypothetical data scenarios and programming instructions. 
 
Sequence of assessments 
Instructions 
1    irSD 
2    irPD 
-     EOT 
 Patient withdraws after initial progression (Assessment 
2) without confirmation 
 Assessment 2 irPD is flagged as cPD2 
1    irPD 
2    irPD (Assessment 1  + 20 
days) 
-     EOT  
 Assessment 2 irPD is <28 days after Assessment 1, so 
does not represent confirmation 
 However, patient has completed treatment  
 Assessment 1 irPD is flagged cPD2 
 Assessment 2 irPD is flagged xPD2 
The date of progression is the date of the assessment flagged as cPD2. 
Unconfirmed progression. Patients with a single irPD, and no assessment of irSD or better 
(assessment with an irUNK response or irPD assessments < 4 weeks after initial irPD, are 
discarded) continuing  treatment at the time of the analysis will be considered as unconfirmed 
(uPD). 
 


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6 
Reference 
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41. 
Clopper CJ, Pearson ES (1934). The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika; 26, 404-413.  
CHMP (2013). Guideline on adjustment for baseline covariates - Draft. European Medicines 
Evaluation Agency, April 2013.  
Osoba D et al (1998) Interpreting the significance of changes in health-related quality-of-life 
scores. J Clin Oncol;16:139-144 
AS Pickard, MP Neary, D Cella (2007) : Estimation of minimally important differences in EQ-
5D utility and VAS scores in cancer. Health Qual Life Outcomes 5: 70  
van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-5L to 
EQ-5D-3L value sets. Value in Health  2012 Jul-Aug;15(5):708-15."