Clinical trial NCT04390763
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: NIS793 spartalizumab gemcitabine nab-paclitaxel mPDAC TGFβ PD-1 Phase II
Sponsor: Novartis Pharmaceuticals
Start date: 2020-10-16; Completion date: 2024-05-02
Enrollment: 164 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this Phase II study is to assess the efficacy and safety of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel in previously untreated mPDAC.

Detailed description:
This is a randomized, parallel arms, open-label, multi-center, Phase II study to evaluate the efficacy and safety of NIS793 with and without spartalizumab in combination with gemcitabine/nab-paclitaxel in participants with first-line metastatic pancreatic ductal adenocarcinoma (mPDAC).

The study started with a Safety Run-in to assess the safety and tolerability of NIS793 in combination with spartalizumab and standard of care (SOC) gemcitabine/nab-paclitaxel. Doses defined for each study treatment, as part of this quadruplet were administered in the Randomized part in the quadruplet/triplet/doublet-based treatment arms.

The Randomized part opened after the Safety Run-in had completed. Participants were randomized in a 1:1:1 ratio to one of the three treatment arms:

* Arm 1: NIS793 with spartalizumab and gemcitabine/nab-paclitaxel
* Arm 2: NIS793 with gemcitabine/nab-paclitaxel
* Arm 3: gemcitabine/nab-paclitaxel

Arms: arm 1: Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel arm 2: Combination of NIS793 + spartalizumab + gemcitabine + nab-paclitaxel arm 3: Combination of NIS793 + gemcitabine + nab-paclitaxel arm 4: gemcitabine + nab-paclitaxel
Interventions: intervention 1: NIS793 intervention 2: Spartalizumab intervention 3: gemcitabine intervention 4: nab-paclitaxel
Intervention descriptions: intervention 1: anti-TGFb antibody. NIS793 2100 mg every 2 weeks by intravenous (i.v.) infusion. intervention 2: anti-PD-1 antibody. spartalizumab 400 mg every 4 weeks by i.v. infusion. intervention 3: SOC chemotherapy. Gemcitabine (1000 mg/m\^2 on Days 1, 8, and 15) i.v. given as per label. intervention 4: SOC chemotherapy. Nab-paclitaxel (125 mg/m\^2 on Days 1, 8, and 15) i.v. given as per label.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
NIS793 
Clinical Trial Protocol CNIS793B12201 / NCT04390763
A phase II, open label, randomized, parallel arm study of 
NIS793 (with and without spartalizumab) in combination 
with SOC chemotherapy gemcitabine/nab-paclitaxel, and 
gemcitabine/nab-paclitaxel alone in first-line metastatic 
pancreatic ductal adenocarcinoma (mPDAC) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2020-000349-14 
Version number: 
v04 (Clean) 
Clinical Trial Phase: 
II 
Release date: 
18-Apr-2022
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020 


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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 
Protocol summary .............................................................................................................. 14 
Amendment 04 (April 2022) ............................................................................................. 18 
Amendment 03 (April 2021) ............................................................................................. 20 
Amendment 02 (August 2020) .......................................................................................... 25 
Amendment 01 (July 2020) ............................................................................................... 26 
1 
Introduction ....................................................................................................................... 27 
1.1 
Background ............................................................................................................ 27 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment ................................................................................................ 27 
1.1.2 
Introduction to investigational treatments ............................................. 28 
1.2 
Purpose .................................................................................................................. 34 
2 
Objectives and endpoints ................................................................................................... 35 
2.1 
Primary estimands ................................................................................................. 36 
2.2 
Secondary estimands ............................................................................................. 37 
3 
Study design ...................................................................................................................... 39 
3.1 
Description of study design ................................................................................... 39 
4 
Rationale ............................................................................................................................ 41 
4.1 
Rationale for study design ..................................................................................... 41 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 42 
4.3 
Rationale for choice of combination and comparator drugs .................................. 43 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 43 
4.5 
Risks and benefits .................................................................................................. 43 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 44 
5 
Study Population ............................................................................................................... 44 
5.1 
Inclusion criteria .................................................................................................... 44 
5.2 
Exclusion criteria ................................................................................................... 45 
6 
Treatment ........................................................................................................................... 48 
6.1 
Study treatment ...................................................................................................... 48 
6.1.1 
Investigational and control drugs .......................................................... 48 
6.1.2 
Additional study treatments .................................................................. 50 
6.1.3 
Treatment arms...................................................................................... 50 


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6.1.4 
Treatment duration ................................................................................ 50 
6.2 
Other treatment(s) .................................................................................................. 51 
6.2.1 
Concomitant therapy ............................................................................. 52 
6.2.2 
Prohibited medication ........................................................................... 53 
6.3 
Participant numbering, treatment assignment, randomization .............................. 53 
6.3.1 
Participant numbering ........................................................................... 53 
6.3.2 
Treatment assignment, randomization .................................................. 54 
6.4 
Treatment blinding ................................................................................................ 54 
6.5 
Dose evaluation and dose modification ................................................................. 55 
6.5.1 
Dose evaluation guidelines ................................................................... 55 
6.5.2 
Guidelines for dose evaluation .............................................................. 56 
6.5.3 
Definitions of dose limiting toxicities (DLTs) ...................................... 56 
6.5.4 
Dose modifications ................................................................................ 58 
6.5.5 
Follow-up for toxicities ......................................................................... 66 
6.6 
Additional treatment guidance ............................................................................... 68 
6.6.1 
Treatment compliance ........................................................................... 68 
6.7 
Preparation and dispensation ................................................................................. 69 
6.7.1 
Handling of study treatment and additional treatment .......................... 69 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 69 
7 
Informed consent procedures ............................................................................................ 71 
8 
Visit schedule and assessments ......................................................................................... 72 
8.1 
Screening ............................................................................................................... 79 
8.1.1 
Information to be collected on screening failures ................................. 79 
8.2 
Participant demographics/other baseline characteristics ....................................... 80 
8.3 
Efficacy .................................................................................................................. 80 
8.3.1 
Tumor imaging ...................................................................................... 80 
8.3.2 
Appropriateness of efficacy assessments .............................................. 82 
8.4 
Safety ..................................................................................................................... 82 
8.4.1 
Physical examination ............................................................................ 82 
8.4.2 
Vital signs.............................................................................................. 83 
8.4.3 
Height and weight ................................................................................. 83 
8.4.4 
Performance status ................................................................................ 83 
8.4.5 
Laboratory evaluations .......................................................................... 83 
8.4.6 
Electrocardiogram (ECG) ..................................................................... 85 
8.4.7 
Pregnancy .............................................................................................. 86 
8.4.8 
Appropriateness of safety measurements .............................................. 86 


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8.5 
Additional assessments .......................................................................................... 86 
8.5.1 
Pharmacokinetics .................................................................................. 86 
8.5.2 
Biomarkers ............................................................................................ 90 
9 
Study discontinuation and completion .............................................................................. 93 
9.1 
Discontinuation and completion ............................................................................ 93 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 93 
9.1.2 
Withdrawal of informed consent/Opposition to use data//biological 
samples .................................................................................................. 95 
9.1.3 
Lost to follow-up ................................................................................... 95 
9.1.4 
Early study termination by the sponsor ................................................. 96 
9.2 
Study completion and post-study treatment .......................................................... 96 
9.2.1 
End of study .......................................................................................... 96 
9.2.2 
Post-treatment follow-up ....................................................................... 97 
9.2.3 
Safety follow-up .................................................................................... 97 
9.2.4 
Survival follow-up ................................................................................ 97 
10 Safety monitoring and reporting ........................................................................................ 98 
10.1 
Definition of adverse events and reporting requirements ...................................... 98 
10.1.1 
Adverse events ...................................................................................... 98 
10.1.2 
Serious adverse events ........................................................................ 100 
10.1.3 
SAE reporting...................................................................................... 101 
10.1.4 
Pregnancy reporting ............................................................................ 101 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 102 
10.2 
Additional Safety Monitoring .............................................................................. 103 
10.2.1 
Data Monitoring Committee ............................................................... 103 
11 Data Collection and Database management .................................................................... 103 
11.1 
Data collection ..................................................................................................... 103 
11.2 
Database management and quality control .......................................................... 103 
11.3 
Site monitoring .................................................................................................... 104 
12 Data analysis and statistical methods .............................................................................. 105 
12.1 
Analysis sets ........................................................................................................ 106 
12.1.1 
Full Analysis Set ................................................................................. 106 
12.1.2 
Safety Set ............................................................................................ 106 
12.1.3 
Dose-Determining Set ......................................................................... 106 
12.1.4 
Pharmacokinetic Analysis Set ............................................................. 107 
12.1.5 
Immunogenicity Analysis Set ............................................................. 107 
12.2 
Participant demographics and other baseline characteristics ............................... 107 




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151 
151 
154 
16.3 
Appendix 3: List of concomitant medications ..................................................... 155 
16.3.1 
Permitted medication to be used with caution .................................... 155 
16.4 
Appendix 4: Statistical considerations – Algorithmic based approach for 
Safety Run-in part ................................................................................................ 156 
16.5 
Appendix 5: Bayesian model set-up and prior specifications ............................. 157 
16.5.1 
Statistical model .................................................................................. 157 
16.5.2 
Prior specifications .............................................................................. 157 
List of tables 
Table 1-1 
Potential overlapping toxicities ............................................................. 33 
Table 2-1 
Objectives and related endpoints .......................................................... 35 
Table 4-1 
Rationale for study design ..................................................................... 41 
Table 6-1 
Investigational and control drug ............................................................ 49 
Table 6-2 
Starting dose and dose level-1 that may be evaluated during the 
first 28 days period of the Safety Run-in part ....................................... 55 
Table 6-3 
Criteria for defining dose-limiting toxicities applicable during the 
DLT period (cycle 1 = 28 days) of the Safety Run-in part ................... 57 
Table 6-4 
Dose reduction for nab-paclitaxel and gemcitabine applicable in 
the Safety Run-in part (after Cycle 1) and in the Randomized part 
(all Arms) .............................................................................................. 59 
Table 6-5 
Dose modifications of NIS793 and spartalizumab for adverse drug 
reactions suspected to be related to NIS793/spartalizumab. Safety 
Run-in part (after Cycle 1) and Randomized part ................................. 59 
Table 6-6 
Dose modifications of gemcitabine/nab-paclitaxel for 
hematological toxicities suspected to be related to 
gemcitabine/nab-paclitaxel. Safety Run-in part (after Cycle 1) and 
Randomized part (as per locally approved labels) ................................ 65 
Table 6-7 
Dose modifications of gemcitabine/nab-paclitaxel for non-
hematological toxicities suspected to be related to 
gemcitabine/nab-paclitaxel. Safety Run-in part (after the Cycle 1) 
and Randomized part (as per locally approved labels) ......................... 66 
Table 6-8 
Guidance to rule out possible alternative causes of observed LFT 
abnormalities ......................................................................................... 68 
Table 8-1 
Visit windows........................................................................................ 73 
Table 8-2 
Assessment schedule ............................................................................. 74 
Table 8-3 
Imaging assessment collection plan ...................................................... 80 
Table 8-4 
ECOG performance status ..................................................................... 83 


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Table 8-5 
Laboratory assessment .......................................................................... 84 
Table 8-6 
Pharmacokinetic blood collection log - NIS793 and spartalizumab 
in Safety Run-in part and Randomized Arms 1 & 2 ............................. 88 
Table 8-7 
Pharmacokinetic blood collection log - gemcitabine and nab-
paclitaxel in Safety Run-in part and Randomized part (all Arms) ........ 89 
Table 8-8 
Biomarker sample collection plan ......................................................... 91 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 102 
Table 12-1 
Non-compartmental pharmacokinetic parameters .............................. 116 
Table 12-2 
Operating characteristics for scenarios with 100 participants, 
60 events, and a 3-month delayed effect ............................................. 120 
Table 16-1 
Response criteria for target lesions ..................................................... 132 
Table 16-2 
Response criteria for non-target lesions .............................................. 134 
Table 16-3 
Overall lesion response at each assessment ........................................ 136 
Table 16-4 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 144 
Table 16-5 
Options for event dates used in PFS, TTP, duration of response ........ 145 
 
 153 
Table 16-7 
List of CYP substrates, inhibitors and inducers of CYP3A4, and 
inhibitors of CYP2C8 to be used with caution.................................... 155 
Table 16-8 
Dose evaluation scenarios (NIS793 with spartalizumab and 
gemcitabine/nab-paclitaxel) ................................................................ 156 
Table 16-9 
Probabilities to declare a success under various scenarios, 
assuming a 3-month delayed effect ..................................................... 161 
Table 16-10 
Operating characteristics for scenarios with 100 participants, 
60 events, and a 2-month delayed effect ............................................. 162 
Table 16-11 
Operating characteristics for scenarios with 100 participants, 
60 events, and no delayed effect ......................................................... 162 
List of figures 
Figure 3-1 
Study design .......................................................................................... 39 
Figure 3-2 
Study flow in Safety Run-in part .......................................................... 40 
Figure 3-3 
Study flow in Randomized part............................................................. 41 
Figure 6-1 
Study drug administration ..................................................................... 49 
Figure 16-1 
Prior distribution for Arm 3 PFS ......................................................... 158 
Figure 16-2 
Full prior distribution for Arms 1 and 2 PFS ...................................... 159 
 


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List of abbreviations 
ADA 
Antidrug Antibodies 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BLQ 
Below the Limit of Quantitation 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
C-FAS 
Complete Full Analysis Set 
CK 
Creatine Kinase 
Cmax 
Maximum observed drug concentration 
CNS 
Central Nervous System 
CRF 
Case Report/Record Form (paper or electronic) 
CR 
Complete Response 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DCR 
Disease Control Rate 
DDI 
Drug-Drug Interaction 
DDS 
Dose Determining Set 
DILI 
Drug-Induced Liver Injury 
dFdU 
2',2'-difluoro-deoxyuridine 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECLIA 
Enhanced Chemiluminescent Assay 
ECM 
Extra-cellular Matrix 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EoT 
End of Treatment 
ERCP 
Endoscopic Retrograde Cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GLDH 
Glutamate Dehydrogenase 


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GLP 
Good Laboratory Practice 
h 
Hour 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human immunodeficiency virus 
HR 
Hazard Ratio 
IA 
Interim Analysis 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
 
 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IP 
Intraperitoneal 
irAE 
Immune related Adverse Event 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KD 
Constant of Dissociation 
LC-MS/MS 
Liquid Chromatography-Mass Spectrometry 
LDH 
Lactate Dehydrogenase 
LFT 
Liver function test  
LLOQ 
Lower Limit Of Quantification 
MedDRA 
Medical dictionary for regulatory activities  
mg 
milligram(s) 
mL 
milliliter(s) 
mPDAC 
Metastatic Pancreatic Ductal Adenocarcinoma 
MSI 
Microsatellite Instability 
Nab 
Neutralizing antibody 
NOAEL 
No Observed Adverse Event Level 
NSCLC 
Non-Small Cell Lung Cancer 
NTproBNP 
N-terminal pro b-type natriuretic peptide 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PAS 
Pharmacokinetic Analysis Set 
 
 
PD 
Progressive Disease 
PD-1 
Programmed Death-1 
PDAC 
Pancreatic Ductal Adenocarcinoma 
PD-L1 
Programmed Death-Ligand 1 


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PFS 
Progression Free Survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
pM 
picomolar 
PR 
Partial Response 
PT 
Prothrombin Time 
QTcF 
QT interval corrected by Fridericia’s formula 
RAP 
The Report and Analysis Plan  
RD 
Recommended dose  
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardized MedDRA Query 
SOC 
Standard Of Care 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T1/2 
Terminal half-life 
TGFβ 
Transforming Growth Factor β 
TTP 
Time To Progression 
ULN 
Upper Limit of Normal 
vs 
versus 
WHO 
World Health Organization  
WoC 
Withdrawal of Consent 




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Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the 
informed consent. This number is the definitive, unique identifier for the 
participant and should be used to identify the participant throughout the 
study for all data collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-
up) which are described in the Protocol. Periods define the study 
phases and will be used in clinical trial database setup and eventually 
in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data 
includes participant identifier information, study information and 
biological samples. 
Premature participant 
withdrawal 
Point/time when the participant exits from the study prior to the 
planned completion of all study drug administration and/or 
assessments; at this time all study drug administration is discontinued 
and no further assessments are planned 
Randomization number 
A unique identifier assigned to each randomized participant 
Screen Failure 
A participant who did not meet one or more criteria that were required 
for participation in the study 
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a 
dataset, a spreadsheet or even hard-coded data, such as paper or 
eSource 
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 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant 
Study treatment 
Any drug or combination of drugs   or intervention administered to the 
study participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Study treatment 
discontinuation 
When the participant permanently stops taking any of the study drug(s) 
prior to the defined study treatment completion date (if any) for any 
reason; may or may not also be the point/time of study discontinuation  
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the 
combination, and may consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment 
to which comparison will be made. These might be individual 
interventions, combinations of interventions administered concurrently, 
e.g. as add-on to standard of care, or might consist of an overall 
regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of 
interest, which might or might not be the same as the study treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is 
required to address the clinical question. The specification of the 
variable might include whether the participant experiences an 
intercurrent event. 
Withdrawal of study 
consent (WoC) / 
Withdrawal of consent from the study occurs only when a participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 


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Opposition to use of data 
/biological samples 
to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries 
where collection and processing of personal data is justified by a 
different legal reason than consent. 
 


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Protocol summary 
Protocol number 
CNIS793B12201 
Full Title 
A phase II, open label, randomized, parallel arm study of NIS793 (with and 
without 
spartalizumab) 
in 
combination 
with 
SOC 
chemotherapy 
gemcitabine/nab-paclitaxel, and gemcitabine/nab-paclitaxel alone in first-line 
metastatic pancreatic ductal adenocarcinoma (mPDAC) 
Brief title 
Study of efficacy and safety of NIS793 (with and without spartalizumab) in combination 
with SOC chemotherapy in first-line metastatic pancreatic ductal adenocarcinoma 
(mPDAC) 
Sponsor and 
Clinical Phase 
Novartis, Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to evaluate the efficacy and safety of NIS793 with and without 
spartalizumab in combination with SOC chemotherapy gemcitabine/nab-paclitaxel in 
first-line metastatic pancreatic ductal adenocarcinoma. 
The blockade of TGFβ with and without PD-1 in combination with chemotherapy may 
reduce fibrosis in PDAC, while restoring chemo-sensitivity and T-cell cytotoxic activity 
ultimately improving clinical response rate and durability in first-line mPDAC. 
Primary 
Objective(s)  
Safety Run-in part: 
To assess the safety and tolerability of NIS793 with spartalizumab in combination with 
gemcitabine/nab-paclitaxel. 
Randomized part:  
To evaluate the Progression Free Survival (PFS) per Investigator assessment of NIS793 
with and without spartalizumab in combination with gemcitabine/nab-paclitaxel versus 
SOC chemotherapy gemcitabine/nab-paclitaxel. 
Secondary 
Objectives 
Randomized part: 
To evaluate the safety and tolerability of NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel 
To assess the preliminary anti-tumor activity of NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel 
To assess Overall Survival (OS) of NIS793 with and without spartalizumab in combination 
with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel 
To assess the CD8 and PD-L1 status of the participants at screening and on treatment 
versus gemcitabine/nab-paclitaxel 
To characterize the incidence of immunogenicity of NIS793 and spartalizumab in 
combination with gemcitabine/nab-paclitaxel 
To characterize the pharmacokinetics (PK) of NIS793, spartalizumab, gemcitabine/nab-
paclitaxel in combination treatment or alone (gemcitabine/nab-paclitaxel) 


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Study design 
This study consists of two parts: 
A Safety Run-in part of NIS793 with spartalizumab in combination with gemcitabine/nab-
paclitaxel 
A Randomized part parallel arms of NIS793 with and without spartalizumab in 
combination 
with 
gemcitabine/nab-paclitaxel 
versus 
gemcitabine/nab-paclitaxel. 
Participants will be randomized in a 1:1:1 ratio. 
The Randomized part will be initiated following review of Safety Run-in part data (clinical, 
PK, and laboratory data) in a safety review meeting.  
Study population 
The study will include adult participants with metastatic pancreatic ductal 
adenocarcinoma (mPDAC) who have not received any prior systemic anti-cancer 
treatment for metastatic disease.  
Key Inclusion 
criteria 
Participants with histologically or cytologically confirmed treatment naïve metastatic 
adenocarcinoma of the pancreas with measurable disease per RECIST 1.1. 
Participants must have a site of disease amenable to biopsy, be candidate for tumor 
biopsy, and must be willing to undergo a tumor biopsy at screening and during therapy 
on the study. 
ECOG performance status ≤ 1 
Key Exclusion 
criteria 
Previous radiotherapy, surgery (note: placement of biliary stent is allowed), 
chemotherapy or investigational therapy for the treatment of metastatic disease. 
Participants having received previous chemotherapy in the adjuvant setting 
Participants with MSI-H pancreatic adenocarcinoma 
Participants with a diagnosis of pancreatic neuroendocrine tumors (NETs), acinar, or islet 
cell tumors 
Participants amenable to potentially curative resection 
Presence of symptomatic CNS metastases or CNS metastases that require local CNS-
directed therapy 
History of severe hypersensitivity reactions to other monoclonal antibodies 
Malignant disease other than that being treated in the study 
Systemic chronic steroid therapy (>10mg/day prednisone or equivalent) or any 
immunosuppressive therapy 
Known history of testing positive for HIV infection 
Active HBV and HCV infection 
Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment 
Active, known or suspected autoimmune disease 
History of or current pneumonitis or interstitial lung disease 


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Study treatment 
Safety Run-in part: 
NIS793 i.v. 2100 mg (or 1400 mg in case dose level -1 is required) Q2W plus 
spartalizumab i.v. 400 mg Q4W plus nab-paclitaxel i.v. 125 mg/m2 plus gemcitabine i.v. 
1000 mg/m2 
Randomized part (participants will be treated at the dose confirmed to be safe after 
Safety Run-in part): 
Arm 1: NIS793 plus spartalizumab plus gemcitabine plus nab-paclitaxel 
Arm 2: NIS793 plus gemcitabine plus nab-paclitaxel 
Arm 3: gemcitabine plus nab-paclitaxel 
A cycle of treatment is defined as 28 days. 
Efficacy 
assessments 
Radiological tumor assessment by Investigator per RECIST 1.1 at screening, every 
8 weeks for first year, then every 12 weeks. 
Survival assessments every 12 weeks after safety and efficacy follow-up period 
Pharmacokinetic 
assessments  
Concentrations and derived PK parameters of NIS793, spartalizumab, gemcitabine and 
nab-paclitaxel 
Antidrug antibodies (ADA) prevalence at baseline and ADA incidence on treatment (anti-
NIS793 and anti-spartalizumab) 
Key safety 
assessments 
Physical examination 
ECOG performance status 
Vital signs 
Laboratory assessments 
ECGs 
Monthly pregnancy testing for women of childbearing potential 
Adverse events (AEs), severity, relationship to study treatment and seriousness 
Other 
assessments 
 
Data analysis 
Safety Run-in part 
The primary safety objective is to assess the safety and tolerability of NIS793 with 
spartalizumab and gemcitabine/nab-paclitaxel and to identify the dose to be tested in 
Randomized part.  
The dose to be tested in Randomized part will be primarily assessed based on the 
incidence of dose limiting toxicities (DLTs). Safety and tolerability will be additionally 
evaluated based on the incidence of (serious) adverse events, changes in laboratory 
values, vital signs, ECGS and dose interruptions, reductions, and dose intensity. 
The decision to proceed with the Randomized part will be taken based on safety observed 
during Safety Run-in part. 
Randomized part 
The primary efficacy estimand is to characterize the anti-tumor activity of NIS793 with 
and without spartalizumab in combination with gemcitabine/nab-paclitaxel. 
The primary analysis may be performed when both or either of the following criteria are 
met:  
Approximately 60 participants (who comply with the FAS criteria) have experienced a 
PFS event (documented progression as per RECIST 1.1 or death due to any cause) in 
the NIS793 with spartalizumab and gemcitabine/nab-paclitaxel (Arm 1) and 
gemcitabine/nab-paclitaxel (Arm 3) arms.  




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Amendment 04 (April 2022) 
Amendment rationale 
The main purpose of this amendment is to allow for potential interim analysis (IA) where 
statistical analyses by treatment arm can be conducted. While study is open label, by treatment 
arm analyses were not allowed in previous protocol version. The IA will be used to support 
future NIS793 development and will have no impact on the current study design and conduct.  
Further minor changes have been made to correct inconsistencies. 
Study update 
The CNIS793B12201 study started enrollment on 16-Oct-2020. As of 28-Mar-2022, 78 
participants have been treated in the study: 11 participants in the Safety Run-in part and 67 in 
the Randomized part. 
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. 
Glossary of terms: 
• Definition of Withdrawal of consent / Opposition to use of data /biological samples was 
updated in order to align with Section 9.1.2 Withdrawal of informed consent/Opposition 
to use data/biological samples. 
Section 4.4 Purpose and timing of interim analyses/design adaptations: 
• Addition of potential interim analysis in the Randomized part of the study.  
Section 5.2 Exclusion criteria: 
• Clarification that women are considered post-menopausal if they satisfy criteria at least 
six weeks prior to enrollment to the study.  
Section 6.4 Treatment blinding: 
• Addition of language that will allow statistical analysis by treatment arm in case of 
interim analysis. 
Section 6.7.1 Handling of the study treatment and additional treatment: 
• Wording was added to allow destruction of unused study treatment, drug labels and 
packaging at the site.  
Section 10.1.3 SAE reporting: 
• SAE reporting section was updated to clarify that initial and follow-up information 
about SAEs should be reported to Novartis immediately, without delay and under no 
circumstances later than 24h after obtaining knowledge of the event or follow-up 
information about the event.  
Section 12 Data analysis and statistical methods: 


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• Addition of possibility for a primary clinical study report, prior to the end of the study.  
• Adjustment of number of events for primary analysis from 60 to approximately 60 to 
provide more flexibility for timing of primary analysis.  
Section 12.7 Interim analyses: 
• Addition of potential interim analysis in the Randomized part of the study. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
 








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Table 8-7 Pharmacokinetic blood collection log – gemcitabine and nab-paclitaxel in Safety 
Run-in and Randomized part (all Arms): 
• Collection window of Cycle 4 Day 2 PK samples was prolonged from 2h to 4h, to allow 
more flexibility in sample collection. 
• Addition of DILI as a reason for collection of unscheduled PK sample.  
 
 
  
  
  
 
Section 9.1.2 Withdrawal of informed consent/Opposition to use data/biological samples 
• Withdrawal of informed consent was clarified to clearly differentiate withdrawal of 
informed consent and discontinuation from the study. 
Section 10.1.4 Pregnancy reporting: 
• Pregnancy outcomes will be collected for up to one year. 
Section 12 Data analysis and statistical methods: 
• Addition of secondary safety analysis and overall survival analysis as part of the primary 
analysis readout to better inform ongoing Phase III trial at the time of the primary 
analysis.   
 
 
Section 12.2 Participant demographics and other baseline characteristics: 
• Removal of duplication of language detailing categorical and continuous data 
presentation. 
Section 12.3 Treatments:  
• Redundant text was deleted. 
Section 12.5.1.1 Handling of intercurrent events of secondary estimands: 
• New section was added 
Section 12.5.1.2 Handling of missing values not related to intercurrent events: 
• New section was added  
Section 12.8 Sample size calculation: 
• Change in the accrual of participants in the Randomized part from 20 to 15 per month for 
the three arms, based on the accrual rate from the Safety Run-in part. 
Table 12-2 Operating characteristics for scenarios with 100 participants, 60 events, and a  
3-month delayed effect: 
• Addition of information regarding the underlying assumptions for the simulation of 
scenarios. 
• Correction of operating characteristics. 
Appendix 5 Bayesian model set-up and prior specifications: 
• Correction of Table 16-9 and addition of Table 16-10 and Table 16-11, accounting for 
additional scenarios as part of the sensitivity analysis. 


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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Amendment 02 (August 2020) 
Amendment rationale  
The purpose of this amendment is to address the following Health Authorities’ request: 
• To state that sexually active males have to use a condom while taking study treatment 
and for 180 days after stopping treatment. 
• To include instruction to follow contraception recommendations and other 
precautionary measures required by locally approved SmPC of gemcitabine and nab-
paclitaxel. 
Study update 
At the time of this amendment, this protocol is under review by Health Authorities of the 
participating countries and recruitment has not yet started. 
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 5.2 Exclusion criteria: 
• Change of the duration of contraception for sexually active males from 90 to 180 days 
after stopping study treatment.  
• Simplified language for the duration of contraception for women of childbearing 
potential on study treatment.  
• Added instruction to follow local prescribing information for SOC with regards to 
contraception and other precautionary measures. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 


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Amendment 01 (July 2020)  
Amendment rationale  
The purpose of this amendment is to address the following Health Authorities request: 
• To revise the protocol so that Grade 3 diarrhea lasting for > 72 hours is a DLT. 
Additional editorial changes have been made to clarify or correct the language in some 
sections.  
Study update 
At the time of this amendment this protocol is under review by Health Authorities of the 
participating countries and recruitment has not yet started. 
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 5.2 Exclusion criteria 
• Correction of a typo in renal exclusion criterion 4, from serum creatinine < ULN to 
serum creatinine > ULN.  
• Correction of a typo in hepatic exclusion criterion 4 to clarify Gilbert’s syndrome 
participants are not eligible for listed lab parameters.  
Section 6.5.3 Definitions of dose limiting toxicities (DLTs) 
• Table 6-3: Change of DLT definition for Grade 3 diarrhea from events 
lasting > 7 days to > 3 days. 
Section 8 Visit schedule and assessments 
• Update of Table 8-2 Assessment schedule to align ECG schedule with Section 8.4.6 
and collection of Concomitant medications until 30 days safety follow-up as per 
Section 9.2.3 
Section 8.5.1.1 Pharmacokinetic blood collection and handling 
• Update of footnote in Table 8-7 to correct C1D1 pre-dose gemcitabine PK sample 
should be collected prior to nab-paclitaxel dosing 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  


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1 
Introduction 
1.1 
Background 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
1.1.1.1 
Pancreatic ductal adenocarcinoma (PDAC) 
Pancreatic ductal adenocarcinoma (PDAC) represents a significant public health burden, being 
the fourth-leading cause of cancer-related death, with an estimated 45,750 deaths and 56,770 
new cases in 2019 in the US (American Cancer Society - Cancer facts & figures 2019). Despite 
progress in the management of PDAC, the overall 5-year survival rate for all stages combined 
is 
8%, 
decreasing 
to 
3% 
for 
patients 
presenting 
with 
advanced 
disease 
(American Cancer Society - Cancer facts & figures 2019). In the absence of improvements in 
early diagnosis and treatment, PDAC will likely become the second leading cause of death by 
2030 (Akerberg et al 2017). 
The development of effective chemotherapies in PDAC has been limited with only modest 
improvements in survival. Gemcitabine monotherapy was established as the standard of care 
(SOC) for first-line patients with advanced PDAC from 1997 to 2011 (Burris et al 1997). 
More recently, FOLFIRINOX, a combination of 5-fluorouracil, folinic acid, irinotecan plus 
oxaliplatin has demonstrated superiority to gemcitabine alone, with an overall survival (OS) of 
11.1 months vs 6.7 months (Lambert et al 2017, Conroy et al 2011). However, due to toxicity 
associated with this combination regimen, FOLFIRINOX is reserved for patients with good 
performance status. The combination of gemcitabine plus nab-paclitaxel in advanced PDAC 
was shown to improve OS in comparison to gemcitabine alone, with an OS of 8.3 months vs 
6.7 months, and a more favorable safety profile than FOLFIRINOX (Von Hoff et al 2013). 
Based on the above studies, FOLFIRINOX and gemcitabine plus nab-paclitaxel were approved 
as first-line treatment of advanced PDAC in 2011 and 2013, respectively. Despite these 
approved chemotherapies for the treatment of first-line PDAC, OS 5 year-rate remains below 
10%, thus highlighting the need for innovative therapeutic options. 
Checkpoint inhibitors have shown limited activity as monotherapy in PDAC with no objective 
response reported with BMS-936559, a PD-L1 antibody tested in advanced PDAC 
(Brahmer et al 2012) and disease control rate (DCR) of 6% with durvalumab monotherapy in a 
randomized phase 2 trial in second line metastatic PDAC (mPDAC) (O’Reilly et al 2019). 
Consistent with these results, the dMMR status that predicts response to PD-1/PD-L1 blockade 
in solid tumors has been reported to have a low incidence of 1.6% in PDAC (Le et al 2017). 
One of the reasons for the poor response to therapeutic treatment in PDAC has been attributed 
to the extensive stromal response in this indication. PDAC displays in fact the most prominent 
desmoplastic reaction of all epithelial tumors (Erkan et al 2012, Neesse et al 2011), 
characterized by an abundance of activated stroma and progressive accumulation of 
extracellular matrix proteins. While intra-tumoral fibrosis in PDAC is known to correlate with 
poor survival even after resection (Watanabe et al 2003, Erkan et al 2008), this dense tumor 
microenvironment also constitutes a mechanical obstacle to the penetration of therapies to the 
tumor parenchyma (Feig et al 2012). More recently, desmoplasia in PDAC has been also 


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associated with a state of immune exclusion, depicting the prevalent accumulation of tumor 
infiltrating immune cells within peritumoral regions and their paucity in the tumor core. 
Altogether, these attributes strongly contribute to the lack of efficacy of standard therapies, as 
well as immunotherapies in PDAC. New agents targeting the desmoplastic tumor 
microenvironment may therefore represent an opportunity to establish novel therapeutic 
paradigms in the treatment of PDAC. 
In this context, TGFβ-blockade offers the potential to address some of the aberrations of the 
PDAC microenvironment, due to of its pleiotropic effects on stroma. In particular, TGFβ plays 
a pivotal role in the activation of pancreatic stellate cells (PSC), the most abundant type of 
fibroblasts in the pancreas and the chief organizers of the desmoplastic reaction. PCSs are 
quiescent in normal tissues, but upon activation, they adopt a myofibroblast-contractile 
phenotype, secreting and remodeling the stiff extracellular matrix characteristic of the PDAC 
microenvironment (Apte et al 2004). As the expression of TGFβ increases throughout disease 
progression, so does the conversion of stellate cells into myofibroblasts, as well as the fibrotic 
response.  
Notably, studies have shown that TGFβ signaling components are often genetically silenced in 
the pancreatic cancer cells, disabling the tumor intrinsic suppressive activity of TGFβ and 
cooperating instead with other genetic alterations to promote tumor initiation and malignant 
progression (Jakowlew 2006, Neuzillet et al 2014). Loss of function or truncating mutations of 
TGFβRI, TGFβRII, Smad2, and Smad4 genes have all been reported in PDAC 
(Riggins et al 1997, Schutte et al 1996). Loss of 18q21 chromosome that harbors the Smad4 
gene, for example, is observed in 60% of pancreatic cancer (Hahn et al 1996a, Hahn et al 1996b) 
and has been suggested to promote KRAS-driven malignant transformation of pancreatic duct 
cells (Leung et al 2013). Smad4 inactivation also correlates with aggressive tumor cell behavior 
and is therefore associated with worse prognosis (Hahn et al 1996a, Blackford et al 2009). 
TGFβRII mutations are also common in PDAC, accounting for about 4-7% of pancreatic 
cancers (Lin and Feng 2005, Hansel et al 2003, Goggins et al 1998), while mutations in TGFβRI 
are found in 2% of them (Hansel et al 2003, Goggins et al 1998, Hahn et al 1996a, 
Achyut and Yang 2011). These molecular alterations likely represent a mechanism for 
pancreatic cancer cells to grow and spread in an overly high TGFβ microenvironment. 
1.1.2 
Introduction to investigational treatments 
1.1.2.1 
Overview of NIS793 
NIS793 is a recombinant human anti-TGFβ IgG2 mAb that belongs to the IgG2/λ isotype 
subclass and binds TGFβ1 and TGFβ2 with high affinity and, to a lesser extent, TGFβ3. 
1.1.2.1.1 Non-clinical experience with NIS793 
The extracellular domains of the three TGFβ isoforms are highly conserved across human, 
cynomolgus monkey and rodents. Human and cynomolgus monkey share a 100% sequence 
identity for all three isoforms of TGFβ. Rodent TGFβ differs from the human/monkey by one 
amino acid for TGFβ1 and TGFβ3 and by 3 amino acids for TGFβ2. This results in a greater 
than 97% sequence identity among species.  


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For the non-clinical toxicology of NIS793, refer to NIS793 Investigator’s Brochure. Briefly, 
before the first entry in humans, NIS793 was investigated in tissue cross-reactivity studies and 
in a 13-week rat toxicity study up to 10mg/kg/wk i.v. as well as in a 4-week cynomolgus 
monkey toxicity study up to 16mg/kg/wk i.v. both followed by 4-week recovery period. In the 
rat, minimal to mild non-adverse effects were observed in liver, kidney, bone, and eyelids, 
which could reflect inhibition of the tissue homeostatic effects of TGFβ with NIS793 (bone, 
eyelids). For the effects in liver and kidney, the relation to treatment and inhibition of TGFβ is 
not clear and could indicate incidental findings or an increase in normal rat specific background 
findings. In the monkey study, assessments of safety pharmacology endpoints were included. 
No adverse effects on cardiovascular, central nervous system or respiratory function were 
observed. Overall, no observed adverse event level (NOAEL) were set to 10mg/kg in the rat 
study and to 16mg/kg in the cynomolgus study. 
In a rat non-GLP pharmacology model of lung fibrosis, valvulopathy in the heart was found at 
NIS793 at 30mg/kg intraperitoneal, every second day (IP, Q2D) after 14 days. The exposure 
levels in these animals were in the clinically relevant range. In currently evaluated 8-week dose 
range finding and tolerability studies in rats and monkeys, adverse findings were observed in 
the kidney (tubulo-interstitial nephritis with tubular hypertrophy/hyperplasia) and the vascular 
system (vascular inflammation, vascular necrosis and endothelial cell hyperplasia) of 
cynomolgus monkeys at 65 mg/kg/wk i.v., and in the heart (cardiac valvulopathy) of rats at 30 
and 90 mg/kg/wk i.v.. Toxicokinetic and anti-drug antibody data are not yet available. Based 
on modeling and simulation projections of exposure in rats and monkeys, these findings likely 
occurred at exposure comparable to those achieved in participants in current oncology trials. 
Preclinical studies in tumor-bearing mice have shown that NIS793 was sufficient to impair 
myofibroblast differentiation in the tumor microenvironment, supporting the hypothesis that 
TGFβ-blockade could represent a valid approach to target intratumoral fibrosis development. 
The observed reduction in the numbers of myofibroblasts in mice treated with NIS793 was 
accompanied by an increase in the number of tumor-infiltrating T cells, as determined by FACS 
assessment of tumor disaggregates. NIS793 was also shown to significantly augment the overall 
response to PD1-blockade in mice, leading to greater tumor regression and extended survival 
as compared to aPD-1 alone. 
1.1.2.1.2 Clinical experience with NIS793 
NIS793 is currently evaluated as a single agent and in combination with spartalizumab in 
CNIS793X2101 first-in-human study. As of clinical data cut-off date, 03-Jun-2019, a total of 
43 participants have been treated with NIS793 (liquid or lyophilisate formulation) as a single 
agent 
(NIS793: 
0.3-1 
mg/kg 
Q3W) 
or 
in 
combination 
with 
spartalizumab 
(NIS793/spartalizumab: 0.3 mg/kg/100 mg Q3W and 0.3-30 mg/kg/300 mg Q3W). 
Four participants (9.3%) were ongoing. No participants experienced a dose limiting toxicity 
(DLT). Twenty nine participants discontinued study treatment (27 for progressive disease, one 
for adverse events (AEs) and one for death). 
After the clinical cut-off date, 11 additional participants were treated with NIS793 Q2W 
regimen (20 and 30 mg/kg) in combination with spartalizumab (400 mg Q4W) and none of 
them experienced a dose limiting toxicity (DLT). 


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Forty-two participants (97.7%) reported one or more AEs of any grade and 22 participants 
(51.2%) reported one or more AEs grade 3/4 (regardless of causality) during the course of the 
study until the clinical data cut-off date, 03-Jun-2019. The most frequently reported AEs 
regardless of causality, any grade were fatigue: (16 participants, 37.2%), nausea 
(14 participants, 32.6%), vomiting (13 participants, 30.2%), constipation (12 participants, 
27.9%), decreased appetite, anemia, dyspnoea, and pyrexia (each 10 participants, 23.3%). 
The most frequent grade 3/4 AEs regardless of causality were fatigue, anemia, and 
hypercalcemia (each three participants, 7.0%), and these were all grade 3. Grade 4 AEs reported 
were blood bilirubin increased, reduced general condition, and intracranial hemorrhage, which 
were all not suspected AEs. Twenty participants (46.5%) reported one or more AEs suspected 
to be study drug related during the course of the study until the cut-off date. The most frequently 
reported AEs considered suspected to be study treatment related were fatigue (six participants, 
14%), rash (four participants, 9.3%), hypothyroidism, nausea and pruritus (each three 
participants, 7.0%). Reported AEs were all of lower grade (≤grade 2) with the exception of one 
AE drug eruption and one AE decreased appetite, both of grade 3. Nineteen participants (44.2%) 
experienced at least one serious adverse event (SAE) regardless of causality. Two of these SAEs 
were reported as suspected to be related to study treatment (grade 2 and 3 drug eruption); both events 
were reported in one participant treated with NIS793 0.3mg/kg + spartalizumab 300 mg Q3W. 
As of clinical data cut-off date, the preliminary PK data of NIS793 have been characterized in 
the CNIS793X2101 study. Following administration of NIS793, dose-proportional increased 
exposure (i.e. Cycle 1 Cmax and AUClast) with moderate accumulation (~ 2.0-fold) between 
cycles 1 and 3 was observed.The recommended dose (RD) has been determined as NIS793 
30 mg/kg Q3W in combination with spartalizumab which is comparable to a flat dose of 
2100 mg (equivalent of 30 mg/kg when using body weight of 70 kg) NIS793 and 300 mg 
spartalizumab, Q3W in solid tumor participants. 
For more details, please refer to NIS793 Investigator’s Brochure. 
Based on the clinical experience with NIS793 from the ongoing first-in-human study 
CNIS793X2101 study, the safety profile of NIS793 is acceptable for continued clinical 
development. 
1.1.2.2 
Overview of spartalizumab 
1.1.2.2.1 Non-clinical experience with spartalizumab 
Spartalizumab binds specifically and with high affinity to human PD-1. In Biacore assays, the 
KD of spartalizumab on human PD-1 is 0.827 nM. The affinity of spartalizumab for 
cynomolgus PD-1 is 0.929 nM, nearly the same for human PD-1, as noted above. 
Spartalizumab has been evaluated in a 5-week GLP toxicology study in cynomolgus monkeys 
(once weekly i.v. dosing at 0, 6, 25 or 100 mg/kg for a total of five doses) with safety 
pharmacology endpoints. Additional control and high dose animals were maintained for an 
eight week recovery period. There were no test article-related effects on in-life parameters, 
mortality, organ weight changes, or macroscopic findings. Test article related histopathological 
findings comprised macrophage infiltrates in the spleen (100 mg/kg/week) and low grade 
mononuclear infiltrates in the vascular and perivascular space (≥ 6 mg/kg/week). In a 


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subsequent 14-week GLP toxicology study in cynomolgus monkeys, doses of 25 and 100 mg/kg 
(once weekly i.v. dosing for a total of 14 doses) were well tolerated. Microscopic findings 
included mononuclear cell infiltrates in several tissues. 
For further details, please refer to the Spartalizumab Investigator’s Brochure. 
1.1.2.2.2 Clinical experience with spartalizumab 
The first in human phase I/II study CPDR001X2101 is ongoing in participants with advanced 
malignancies and has completed enrollment. The dose escalation part of the study evaluated 
dose levels of 1, 3 and 10 mg/kg every two weeks (Q2W) and 3 and 5 mg/kg every 4 weeks 
(Q4W). No participant experienced a dose limiting toxicity (DLT). The pharmacokinetics (PK) 
analysis of the dose escalation data using a population approach and the expected wide 
therapeutic index of PD-1 inhibitors support the use of flat dosing for spartalizumab of 400 mg 
Q4W or 300 mg Q3W. The expected spartalizumab Ctrough concentrations using either dosing 
regimen exceed the EC50 for PD-1 blockade by approximately 75-fold in an ex vivo assay in 
peripheral blood mononuclear cells (PBMCs). Based on the available PK and safety data, the 
recommended phase 2 dose (RP2D) of spartalizumab has been declared as 400 mg i.v. Q4W or 
300 mg i.v. Q3W for combination treatment regimens for which this may be more convenient. 
Spartalizumab is currently being studied alone or in combination with other agents in ongoing 
phase I - III clinical trials. The toxicity profile appears to be similar to that of marketed inhibitors 
of PD-1 including the type, severity and frequency of occurrence of immune-mediated AEs. 
As observed with other PD-1 inhibitors, immune-mediated toxicities are reversible in many 
cases. In some cases, they may require treatment with corticosteroids. Certain toxicities are 
expected to be lifelong and may require replacement therapy with hormones, for example in the 
case of hypothyroidism. 
Overall, spartalizumab was well tolerated with a safety profile similar to those of other marketed 
anti-PD-1 antibodies. For further details, please refer to the Spartalizumab Investigator’s 
Brochure. 
1.1.2.3 
Overview of gemcitabine 
Gemcitabine is a pyrimidine analog which is metabolized to two active metabolites, 
gemcitabine diphosphate and gemcitabine triphosphate. The cytotoxic effects of gemcitabine 
are exerted through incorporation of gemcitabine triphosphate into DNA, resulting in inhibition 
of DNA synthesis and induction of apoptosis. Gemcitabine is cell-cycle phase specific (S and 
G1/S-phases) (Grindey et al 1990, Eli Lilly 1999). 
Gemcitabine is rapidly metabolized by cytidine deaminases in liver, kidney, blood and other 
tissue (Gilbert et al 2006). Drug elimination is mediated through renal excretion. Within one 
week of administration 92% to 98% of the dose was recovered, almost entirely in the urine 
(Eli Lilly 1999). 
The main toxicities of gemcitabine are elevated liver enzymes ((aspartate transaminase (AST) 
/aspartate aminotransaminase (ALT)) and alkaline phosphatase (ALP), nausea/vomiting, 
protein/hematuria, dyspnea, rash and myelosuppression (Moore et al 1992, Mertens et al 1993, 
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Gemcitabine is approved for use alone or with other drugs in pancreatic cancer, ovarian cancer, 
non-small cell lung cancer (NSCLC) and breast cancer (NCCN 2019, ESMO Guidelines 2015). 
Refer to local approved label for more details. 
1.1.2.4 
Overview of nab-paclitaxel 
Nab-paclitaxel is a microtubule inhibitor that promotes the assembly of microtubules from 
tubulin dimers and stabilizes microtubules by preventing depolymerisation. This stability results 
in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for 
vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or ‘bundles’ of 
microtubules throughout the cell cycle and multiple asters of microtubules during mitosis. 
The major route of elimination of nab-paclitaxel is hepatic and fecal (20% of the total dose 
administered). In vitro studies with human liver microsomes and tissue slices showed that 
paclitaxel in nab-paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8 
and 2 minor metabolites, 3’-p-hydroxypaclitaxel and 6α, 3’-p-didydroxypaclitaxel, by CYP3A4. The 
pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds 
that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. 
The main toxicities of nab-paclitaxel in combination with gemcitabine are fatigue, peripheral 
neuropathy, nausea/vomiting, alopecia, peripheral edema, diarrhea, pyrexia, appetite, rash, and 
dehydration (Von Hoff et al 2013).  
Nab-paclitaxel is approved for use alone or with other drugs in pancreatic cancer, NSCLC and 
breast cancer (NCCN 2019, ESMO Guidelines 2015). 
Refer to local approved label for more details. 
1.1.2.5 
Overview of the combination treatment 
1.1.2.5.1 Non-clinical experience with the combination treatment 
There is no non-clinical experience with NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel. 
1.1.2.5.2 Clinical experience with the combination treatment 
There is no clinical experience with NIS793 with and without spartalizumab in combination 
with gemcitabine/nab-paclitaxel. 
1.1.2.5.3 Potential for drug-drug interactions 
No specific drug–drug interactions studies were conducted for NIS793. NIS793 is a mAb, not 
metabolized by cytochrome P450 (CYP450) enzymes, or transported by P-glycoprotein (P-gp) 
or related ABC membrane transporters. In a cellular assay, TGFβ has been shown to alter the 
expression of certain CYP450 enzymes (Müller et al 2000). Changes in expression of CYP450 
enzymes with administration of NIS793 are unknown but considered unlikely. In addition, 
cytokines produced by activated lymphocytes may impact the levels of P-gp and the activity of 
CYP450 enzymes (Harvey and Morgan 2014, Dumais et al 2008, Renton 2005). The clinical 


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relevance of cytokines impacting levels of P-gp and CYP450 with administration of NIS793 is 
unknown but considered unlikely NIS793 Investigator’s brochure. 
Pharmacokinetic drug-drug interactions (DDIs) are not anticipated for spartalizumab because it 
is not expected to interact with drug metabolizing enzymes or transporters. To date, no 
dedicated DDI studies have been conducted with spartalizumab. Monoclonal antibodies such 
as spartalizumab are eliminated through protein catabolism, and not metabolized by CYP450 
enzymes or transported by P-gp or related ABC membrane transporters. The risk of DDI has 
been evaluated in multiple combination clinical studies with spartalizumab and appears to be 
very low PDR001 Investigator’s brochure; the experience with NIS793 to date appears to be 
similar NIS793 Investigator’s brochure. In summary, the potential for DDI between antibodies 
used in combination is considered highly unlikely. 
Paclitaxel is metabolized by CYP2C8 and CYP3A4. As per label, caution should be exercised 
when administering nab-paclitaxel concomitantly with medicines known to either inhibit or 
induce CYP2C8 or CYP3A4. 
Overall, the risk of DDIs between NIS793/spartalizumab and gemcitabine/nab-paclitaxel is 
anticipated to be low. Nevertheless, PK of gemcitabine/nab-paclitaxel in the presence and 
absence of NIS793 or spartalizumab will be characterized in this study to assess the DDIs. 
1.1.2.5.4 Expected overlapping toxicity 
Based on available preclinical and clinical safety data described in Section 1.1.2.1 and  
Section 1.1.2.2, the combination of NIS793 with and without spartalizumab in combination 
with gemcitabine/nab-paclitaxel may have associated toxicities that may overlap (Table 1-1). 
The AEs associated with NIS793 and spartalizumab are detailed in Section 6.5, in  
NIS793 Investigator’s brochure, PDR001 Investigator’s brochure, gemcitabine and nab-
paclitaxel local labels. 
All participants enrolled will be closely monitored for these potential overlapping toxicities as 
well as any unforeseen risk. 
Table 1-1 
Potential overlapping toxicities 
Drug 
Toxicities overlapping with NIS793/spartalizumab 
Gemcitabine/nab-
paclitaxel (see local 
drug label) 
Hematological toxicity (e.g. anemia, thrombocytopenia, leucopenia, 
neutropenia, febrile neutropenia) 
Pulmonary toxicity (e.g. pneumonitis) 
Gastrointestinal toxicity (e.g. nausea, vomiting, diarrhea, decreased 
appetite) 
Hepatic toxicity (e.g. increase in LFTs (Liver function tests)) 
Skin toxicity (e.g. maculopapular rash, rash, pruritus, Stevens-Johnson 
syndrome, toxic epidermal necrolysis) 
Constitutional (e.g. fatigue, asthenia, pyrexia) 
Hypersensitivity reaction/infusion reaction 
Embryo-fetal toxicity 


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1.2 
Purpose 
The prognosis of mPDAC remains extremely poor despite approved therapies with a median 
OS of 8.5 months and overall response rate of 23% with gemcitabine/nab-paclitaxel 
(Von Hoff et al 2013). Few effective treatment options exist, highlighting the significant unmet 
medical need in this disease. 
Pancreatic cancer is a highly desmoplastic tumor characterized by prominent deposition of 
collagen and extracellular matrix proteins such as hyaluronic acid, which altogether contribute 
to tissue structural rigidity and poor perfusion. These structural aberrations significantly reduce 
the penetration of macromolecules, hindering the tumor intake of therapeutics 
(Provenzano et al 2012). Activated stellate cells, the primary cell population responsible for the 
fibrotic response in PDAC, may further support the development of a chemoprotective 
microenvironment by directly scavenging drugs (Hessmann et al 2018), and through the 
secretion of factors that aid tumor cells escape the control of cytostatic and cytotoxic agents 
(Lotti et al 2013, Sun et al 2016, Nakasone et al 2012, Acharyya et al 2012, Hirata et al 2015). 
In addition to conferring physiological resistance to chemotherapeutic drugs the stromal 
elements of the tumor microenvironment possess great immunomodulatory potential 
(Turley et al 2015), and can therefore play a critical role in the poor response to 
immunotherapies reported in PDAC. T cells poorly migrate in areas of densely packed collagen, 
moving along the tumor stroma interface, they can also rarely penetrate tumor cell islets. 
Extra-cellular matrix (ECM) molecules (e.g. Hyaluronic acid, thrombospondin, and Tenascin 
C) directly promote T-cell dysfunction. Thus, PDAC presents as an immune excluded tumor 
associated with resistance to immune checkpoint inhibitors. 
High levels of TGFβ in the tumor microenvironment have been primarily linked to its 
tolerogenic potential in infiltrating immune cells. Moreover, TGFβ is also a key regulator of 
stromal cell activation and fibrosis in many pathological conditions (Pickup et al 2013). 
Recently, emerging data have identified TGFβ signaling in cancer-associated fibroblasts as well 
as a determinant of T-cell exclusion and poor response to immune checkpoints blockade 
(Mariathasan et al 2018, Tauriello et al 2018). 
The purpose of this Phase II study is to assess the efficacy and safety of NIS793 with and 
without 
spartalizumab 
in 
combination 
with 
gemcitabine/nab-paclitaxel 
versus 
gemcitabine/nab-paclitaxel in untreated mPDAC. The overarching hypothesis is that blockade 
of TGFβ in combination with SOC chemotherapy gemcitabine/nab-paclitaxel can reduce 
fibrosis in PDAC, restoring chemo-sensitivity and unleashing T-cell infiltration and activation. 
Whether anti-PD-1 can then restore immunological competency in mPDAC when combined 
with TGFβ inhibition will also be tested. Ultimately, these therapeutic combinations could 
improve the clinical response rate and durability in first-line mPDAC. 


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2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s)  
Safety Run-in part: 
• 
To assess the safety and tolerability of 
NIS793 + spartalizumab in combination with 
gemcitabine/nab-paclitaxel 
• 
Incidence of DLTs during the first 4 weeks of 
treatment 
• 
Safety: Incidence and severity of treatment 
emergent AEs and SAEs, changes between 
baseline and post-baseline laboratory 
parameters, vital signs, and ECG 
parameters 
• 
Tolerability: Dose interruptions, reductions 
and dose intensity 
Randomized part: 
• 
To evaluate the progression-free survival 
(PFS) of NIS793 with spartalizumab in 
combination with gemcitabine/nab-paclitaxel 
versus gemcitabine/nab-paclitaxel  
• 
To evaluate the PFS of NIS793 with 
gemcitabine/nab-paclitaxel versus 
gemcitabine/nab-paclitaxel 
 
• 
Progression-free survival based on 
Response Evaluation Criteria in Solid 
Tumors (RECIST1.1) as per local 
Investigator’s review 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
Randomized part 
 
• 
To evaluate the safety and tolerability of 
NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel 
versus gemcitabine/nab-paclitaxel 
• 
Incidence and severity of AEs and SAEs, 
including changes in laboratory values, vital 
signs and ECGs, dose interruptions, 
reductions, and dose intensity 
• 
To assess the preliminary anti-tumor activity 
of NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel 
versus gemcitabine/nab-paclitaxel 
• 
Overall response rate (ORR), Duration of 
response (DOR), Time to Progression (TTP) 
RECIST 1.1 as per local Investigator’s 
review 
• 
To assess Overall Survival (OS) of NIS793 
with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel 
versus gemcitabine/nab-paclitaxel 
• 
Overall Survival (OS) 
• 
To assess the CD8 and PD-L1 status of the 
participants at screening and on treatment 
versus gemcitabine/nab-paclitaxel 
• 
Change from baseline in CD8 and PD-
L1  IHC related markers 
• 
To characterize the incidence of 
immunogenicity of NIS793 and 
spartalizumab in combination with 
gemcitabine/nab-paclitaxel 
• 
Antidrug antibodies (ADA) prevalence at 
baseline and ADA incidence on-treatment 
(anti-NIS793 and anti-spartalizumab) 
• 
To characterize the pharmacokinetics (PK) 
of NIS793, spartalizumab, gemcitabine/nab-
paclitaxel in combination treatment or alone 
(gemcitabine/nab-paclitaxel) 
• 
Pharmacokinetic parameters (e.g. Ctrough, 
Cmax, AUClast) 
• 
PK concentration time profiles 


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2.1 
Primary estimands 
The primary clinical question of interest is: 
• What is the effect of NIS793 plus gemcitabine/nab-paclitaxel with and without 
spartalizumab relative to gemcitabine/nab-paclitaxel in prolonging time to death or 
radiological progression in first line mPDAC,  
- 
regardless of whether participants switched to a new anti-cancer therapy that is not part 
of their assigned treatment strategy or/and 
- 
regardless of whether participants discontinued treatment (due to COVID-19 or any 
reason not related to new anti-cancer therapy)?   
The justification for targeting these treatment effects is that we wish to estimate the relative 
effects of the treatment strategies in the presence of potentially a) a new anti-cancer therapy that 
is not a part of the assigned treatment strategy or/and b) a treatment discontinuation (due to 
COVID-19 or any reason not related to new anti-cancer therapy). 
The primary estimands are described by the following attributes: 
• Population: adult participants with mPDAC who have not received any systemic treatment 
for metastatic disease. Further details about the population are provided in Section 5. 
• Primary variable: Progression Free Survival (PFS), defined as time from randomization to 
first documented progression as per RECIST 1.1 or any-cause death. 
• Treatments of interest:  


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• Experimental treatments: NIS793 with spartalizumab and gemcitabine/nab-paclitaxel 
(Arm 1) and NIS793 with gemcitabine/nab-paclitaxel (Arm 2);  
• Standard of Care (SOC): gemcitabine/nab-paclitaxel (Arm 3).  
Further details about the investigational and control treatments are provided in Section 6. 
• Summary measure: PFS hazard ratio of: a) NIS793 with spartalizumab and 
gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel and b) NIS793 with 
gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel. 
Handling of intercurrent events: 
• New anti-cancer therapy initiated before observing PFS event will be handled using the 
treatment policy strategy, considering the new anti-cancer therapy as part of the treatment 
strategy. New anti-cancer therapy can refer to: 
1. The SOC administered in the trial. This case is applicable to participants of Arms 1 
and 2 switching to gemcitabine/nab-paclitaxel. 
2. Any anti-cancer therapy not administered in the trial, applicable to all three arms. 
• Treatment discontinuation related to COVID-19 will be handled using the treatment policy 
strategy, meaning that the participant will continue to be followed for progression per 
RECIST 1.1; 
• Treatment discontinuation for any reason not related to new anti-cancer therapy or to 
COVID-19 will be handled using the treatment policy strategy, meaning that the 
participant will continue to be followed for progression per RECIST 1.1. 
Refer to Section 12.4.2 for more details on primary estimands. 
2.2 
Secondary estimands 
The secondary clinical questions of interest are: 
• What is the preliminary anti-tumor activity of NIS793 plus gemcitabine/nab-paclitaxel with 
and without spartalizumab relative to gemcitabine/nab-paclitaxel in first line mPDAC,  
- 
regardless of whether participants switched to a new anti-cancer therapy that is not part 
of their assigned treatment strategy or/and 
- 
regardless of whether participants discontinued treatment (due to COVID-19 or any 
reason not related to new anti-cancer therapy)?  
• What is the overall survival (OS) of NIS793 plus gemcitabine/nab-paclitaxel with and 
without spartalizumab relative to gemcitabine/nab-paclitaxel in first line mPDAC,  
- 
regardless of whether participants switched to a new anti-cancer therapy that is not part 
of their assigned treatment strategy or/and 
- 
regardless of whether participants discontinued treatment (due to COVID-19 or any 
reason not related to new anti-cancer therapy)?  
The justification for targeting these treatment effects is that we wish to estimate the relative 
effects of the treatment strategies in the presence of potentially a) a new anti-cancer therapy that 
is not a part of the assigned treatment strategy or/and b) a treatment discontinuation (due to 
COVID-19 or any reason not related to new anti-cancer therapy). 


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The secondary estimands are described by the following attributes: 
1. Population: adult participants with mPDAC who have not received any systemic treatment 
for metastatic disease. Further details about the population are provided in Section 5. 
2. Primary variables:  
• Best overall response (BOR) defined as the best response recorded from the start of 
the treatment until disease progression; 
• Duration of response (DOR) defined as the time from CR or PR to first documented 
progression as per RECIST 1.1 or any-cause death; 
• Time-to progression (TTP) defined as the time from randomization to first 
documented progression as per RECIST 1.1 or death due to underlying cancer; 
• OS defined as the time from randomization to death due to any cause. 
3. Treatments of interest:  
• Experimental treatments: NIS793 with spartalizumab and gemcitabine/nab-paclitaxel 
(Arm 1) and NIS793 with gemcitabine/nab-paclitaxel (Arm 2); 
• SOC: gemcitabine/nab-paclitaxel (Arm 3). 
Further details about the investigational and control treatments are provided in Section 6. 
4. Summary measures:   
• Overall response rate in a) NIS793 with spartalizumab and gemcitabine/nab-
paclitaxel b) NIS793 with gemcitabine/nab-paclitaxel and c) gemcitabine/nab-
paclitaxel; 
• DOR, TTP, and OS hazard ratio of: a) NIS793 with spartalizumab and 
gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel and b) NIS793 with 
gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel. 
Handling of intercurrent events: 
• New anti-cancer therapy initiated before observing the event of interest (related to anti-
tumor activity and OS) will be handled using the treatment policy strategy, considering the 
new anti-cancer therapy as part of the initially assigned treatment strategy.  
New anti-cancer therapy can refer to: 
1. The SOC administered in the trial. This case is applicable to participants of Arms 1 
and 2 switching to gemcitabine/nab-paclitaxel; 
2. Any anti-cancer therapy not administered in the trial, applicable to all three arms. 
• Treatment discontinuation related to COVID-19 will be handled using the treatment policy 
strategy, meaning that the participant will continue to be followed for the event of interest 
(related to anti-tumor activity and OS); 
• Treatment discontinuation for any reason not related to new anti-cancer therapy or to 
COVID-19 will be handled using the treatment policy strategy, meaning that the participant 
will continue to be followed for the event of interest (related to anti-tumor activity and OS). 


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Refer to Section 12.5.1 for more details on secondary estimands. 
3 
Study design 
3.1 
Description of study design 
This is a randomized, parallel arms, open-label, multi-center, Phase II study to evaluate the 
efficacy and safety of NIS793 with and without spartalizumab in combination with 
gemcitabine/nab-paclitaxel in participants with first-line mPDAC. 
The study is expected to enroll at least 156 participants. An overview of the study design is 
depicted in Figure 3-1. 
Figure 3-1 
Study design 
 
 
Safety Run-in part 
The study will start with a Safety Run-in part to assess the safety and tolerability of NIS793 
in combination with spartalizumab and SOC gemcitabine/nab-paclitaxel. Doses defined for 
each study treatment, as part of this quadruplet will be administered in the Randomized part 
in the quadruplet/triplet/doublet-based treatment arms (refer to Figure 3-1). At least six 
participants will be enrolled in the Safety Run-in part. 
NIS793 will be administered at a flat dose of 2100 mg every 2 weeks, spartalizumab at a flat 
dose of 400 mg every 4 weeks. Gemcitabine (1000 mg/m² on days 1, 8 and 15) and 
nab-paclitaxel (125 mg/m² on days 1, 8 and 15) will be given as per label.  


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A safety review meeting, as described in the Section 6.5.2.1, will take place when six enrolled 
participants have completed 4 weeks treatment, or discontinued earlier due to DLT. The dose 
decision will be guided by an algorithm specified in Section 6.5.2. If decision to modify the 
dosing regimen is made at this time, an additional safety review of the new dosing regimen will 
take place after six additional participants have been enrolled and completed 4 weeks treatment 
or have discontinued earlier due to DLT.  
Refer to Figure 3-2 for an overview of the Safety Run-in part study flow. 
Figure 3-2 
Study flow in Safety Run-in part 
 
EOT: end of treatment; FU: follow-up 
Randomized part 
After the Safety Run-in part has been completed, the randomization part will open and 
approximately 150 participants will be randomized in a 1:1:1 ratio to one of the three treatment 
arms:  
• Arm 1: NIS793 with spartalizumab and gemcitabine/nab-paclitaxel 
• Arm 2: NIS793 with gemcitabine/nab-paclitaxel 
• Arm 3: gemcitabine/nab-paclitaxel 
Participants in any randomized arm will be treated according to each study treatment 
dose,including gemcitabine/nab-paclitaxel (dose label), declared to be safe in the Safety Run-in 
part.  


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Refer to Figure 3-3 for an overview of the study flow in Randomized part. 
Figure 3-3 
Study flow in Randomized part 
 
R: randomization; EOT: end of treatment; FU: follow-up 
4 
Rationale 
4.1 
Rationale for study design 
The design of this Phase II, parallel arms, open label study was chosen to characterize the 
clinical activity, safety and tolerability of NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel in participants with previously untreated 
mPDAC. 
Table 4-1 
Rationale for study design 
Study Design Aspect 
Rationale 
Participant population 
The study will enroll previously untreated metastatic PDAC 
Two-part study 
The Safety Run-in part to assess the safety and tolerability of the 
combination NIS793 with spartalizumab and gemcitabine/nab-
paclitaxel will precede the Randomized part that will assess the 
efficacy of the different combinations (refer to Figure 3-1) 
Randomization (1:1:1 ratio) 
Randomization will ensure reduction of treatment assignment bias. 
Participants will be randomized at 1:1:1 ratio 
Comparator treatment 
Worldwide study conducted  with gemcitabine/nab-paclitaxel, which is 
approved chemotherapy in the first-line treatment of mPDAC 


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4.2 
Rationale for dose/regimen and duration of treatment 
In this study, the selection of the dose and regimen is based on the currently available preclinical 
and clinical safety, efficacy and PK, information from the first-in-human clinical trial 
CNIS793X2101 and labels for approved chemotherapy gemcitabine/nab-paclitaxel. 
In CNIS793X2101 study, the NIS793 plus spartalizumab recommended dose (RD) has been 
determined as 2100 mg (equivalent of 30 mg/kg when using body weight of 70 kg) 
Q3W/300 mg Q3W in solid tumor participants. 
In this study, Q2W regimen for NIS793 and Q4W regimen for spartalizumab i.v. are chosen to 
coordinate with the administration cycle of the chemotherapy (gemcitabine and nab-paclitaxel). 
NIS793 at 2100 mg Q2W plus spartalizumab at 400 mg Q4W will be evaluated. NIS793 was 
well tolerated in CNIS793X2101 study across all tested doses (0.3 to 30 mg/kg) and dosing 
regimens (Q2W and Q3W), with no significant safety signal detected during DLT period. 
Although there was no clear pattern between systemic exposure of NIS793 and/or dose and 
clinical efficacy, accumulation of total TGFβ-1 levels under treatment (Q3W or Q2W regimens) 
with NIS793 at the dose of 30 mg/kg Q2W supports sustained target engagement in systemic 
circulation over the dosing period. In addition, in vitro data (projected steady state trough level 
after 2100 mg NIS793 Q2W above IC90 concentration, RD-2019-00226), preclinical data 
(projected steady state trough level after 2100 mg NIS793 Q2W above concentration from 
preclinical efficacy study associated with high risk (~23%) of relapse to NIS793, 
RD-2019-00227; RD-2019-00228) generated for NIS793 and published data from M7824, 
another anti-TGFβ molecule (projected steady state trough level after 2100 mg NIS793 Q2W 
similar to that observed for M7824 (Strauss et al 2018)) further support CNIS793X2101-based 
assessment of RD. Overall, as no safety issues have been reported in participants who received 
NIS793 at 30 mg/kg Q2W, a flat dose of 2100 mg Q2W was selected to maximize the chances 
of seeing efficacy in PDAC, a highly desmoplastic tumor resistant to chemotherapy and immune 
checkpoint inhibitors, where other ECM-targeted agents have previously failed. 
Population PK analysis on the concentration data from the dose escalation phase of the study 
CNIS793X2101 was used to describe the PK characteristics of NIS793 including the impact of 
weight as a covariate on clearance and volume of distribution. The analysis suggested that the 
pharmacokinetics of NIS793 can be well described using a two compartment model with first 
order elimination from the central compartment. This is consistent with the observation that 
NIS793 PK appears dose proportional and time-independent based on the non-compartmental 
analyses. Although body weight (BW) is a covariate on clearance in the population PK model 
with the estimated exponent of 0.55 (CV%=40%) from the power model, the predicted exposure 
and trough (mean values and variability) concentration at steady state between weight-based 
and fixed dosing regimens were comparable across different BW categories. This analysis 
supports the use of fixed or flat dosing on a mg basis irrespective of participant body weight, as 
weight-based dosing does not decrease inter-individual variability. 
The proposed starting dose and regimen for NIS793/spartalizumab will be the recommended 
dose of 2100 mg Q2W/400 mg Q4W, as outlined above.  


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Overall, the risk of DDI between NIS793 or spartalizumab and gemcitabine or nab-paclitaxel 
is anticipated to be low. Nevertheless, PK of any study treatment will be characterized in this 
study to assess the DDI, if any, between NIS793 or spartalizumab and gemcitabine or nab-
paclitaxel. 
The dose of 400 mg Q4W spartalizumab (RD from first in human spartalizumab study) will be 
used in combination with NIS793. 
Approved doses for gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) will be 
administered on days 1, 8, and 15 of each 4 week-cycle (Refer to locally approved labels). 
For treatment duration, refer to Section 6.1.4. 
4.3 
Rationale for choice of combination and comparator drugs 
This Phase II study aims at exploring whether the reduction of intratumoral fibrosis through 
TGFβ inhibition in a highly desmoplastic, immune-excluded tumor such as mPDAC can relieve 
resistance to chemotherapy and immunotherapy.  
To this end, NIS793 will be combined with gemcitabine plus nab-paclitaxel, an approved 
chemotherapy regimen for the treatment of first-line mPDAC. This particular chemotherapy 
was chosen as a comparator treatment based on its tolerability profile and its common use in 
this setting. The dose and the dose regimen to be used are in accordance with each product 
labeling. 
To test whether anti-PD-1 can further improve the benefits of TGFβ inhibition and restore anti-
tumor immune responses, spartalizumab will be also tested in combination with NIS793 and 
gemcitabine/nab-paclitaxel. 
4.4 
Purpose and timing of interim analyses/design adaptations 
Safety Run-in part 
Refer to Section 12.7 for details on the Safety Run-in interim analysis (IA) for Randomized 
part dose decision. 
Randomized part 
IA of efficacy data of the Randomized part may be conducted to support decision making 
related to Sponsor’s clinical development of NIS793. Additional supportive analyses of 
available clinical data may be considered if appropriate. The IA of the Randomized part data is 
not planned to support formal design adaptations in the current Phase II study. 
4.5 
Risks and benefits 
Participants enrolled in this study are patients with previously untreated mPDAC for which 
treatment, even in the first-line setting, is associated with an extremely poor prognosis 
(Conroy et al 2011, Von Hoff et al 2013, Moore et al 2007). Preclinical studies supported 
TGFβ-blockade as a valid approach to target intratumoral fibrosis development. In addition 
based on the preliminary tolerability, target engagement, and response rates observed in the 
ongoing NIS793 FIH study, combinations of NIS793 with and without spartalizumab, and 
gemcitabine/nab-paclitaxel are thought to outweigh the risk in participants with first-line 


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mPDAC being evaluated in this study. This randomized study testing novel combinations of 
NIS793 with and without spartalizumab, in combination with SOC chemotherapy 
gemcitabine/nab-paclitaxel, offers the opportunity for those participants to be treated with a 
novel investigative therapy, however with no guarantee of improved benefit over SOC. 
Appropriate eligibility criteria, specific dose modification, and stopping rules, are included in 
this protocol. Recommended guidelines for prophylactic or supportive management of expected 
toxicities, including study-drug induced AEs, are provided in Section 6.2. 
The risk to participants in this study may be minimized by compliance with the eligibility 
criteria and study procedures, as well as close clinical monitoring. In addition, a Data 
Monitoring Committee (DMC) will review available data at defined intervals to guarantee 
participants’ safety. As with any clinical study, there may be unforeseen risks with any of the 
combinations studied that could be serious. Based on currently available data, potential 
overlapping toxicities between NIS793 and gemcitabine/nab-paclitaxel and between NIS793 
with spartalizumab and gemcitabine/nab-paclitaxel are expected and are described in 
Section 1.1.2.5.4. For further detail, refer to the latest NIS793 Investigator’s brochure and 
PDR001 Investigator’s brochure and gemcitabine and nab-paclitaxel labels. 
Women of childbearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the participant will 
not reliably comply, they must not be entered or continue in the study. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public Health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Study Population 
The study will include adult participants with metastatic pancreatic ductal adenocarcinoma who 
have not received any prior systemic anti-cancer treatment for metastatic disease. 
The Investigator or designee must ensure that only participants who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male or female ≥ 18 years of age at the time of informed consent.  
For Japan only: written consent is necessary both from the participant and his/her legal 
representative if he/she is under the age of 20 years. 


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3. Participants with histologically or cytologically confirmed treatment-naïve metastatic 
adenocarcinoma of the pancreas with measurable disease as per RECIST 1.1. 
4. Participants must have a site of disease amenable to biopsy, and be candidate for tumor 
biopsy according to the treating institution’s guidelines. Participants must be willing to 
undergo a tumor biopsy at screening and during therapy on the study. In the event a new 
biopsy cannot be safely performed at study entry, an archival sample (collected <6 months 
prior) may be substituted following documented discussion with Novartis. 
5. ECOG performance status ≤ 1. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this 
study. 
1. Previous radiotherapy, surgery (with exception of placement of biliary stent, which is 
allowed), chemotherapy or any other investigational therapy for the treatment of metastatic 
pancreatic cancer. Participants having received previous chemotherapy in the adjuvant 
setting. 
2. Participants amenable to potentially curative resection. 
3. Participants with a diagnosis of pancreatic neuroendocrine tumors (NETs), acinar, or islet 
cell tumors. 
4. Having out of range laboratory values defined as: 
Hematological: 
• Absolute neutrophil count (ANC) < 1.5 G/L 
• Platelet count < 100 G/L 
• Hemoglobin < 9 g/dL 
Coagulation: 
• PT/INR and PTT > 1.5 x ULN. Participants requiring therapeutic anticoagulants are 
eligible if coagulation parameters are within therapeutic range. 
Renal: 
• Serum creatinine > ULN or creatinine clearance (calculated using the 4-variable 
Modification of Diet in Renal Disease (MDRD) formula [eGFR in mL/min per 1.73 m2 
= 175 x SerumCr-1.154 x age-0.203 x 1.212 (if participant is black) x 0.742 (if female], 
or measured) < 60 mL/min. 


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Hepatic: 
• Total bilirubin > 1.5 x ULN (any elevated bilirubin should be asymptomatic at 
enrollment) except for participants with Gilbert’s syndrome who are not eligible if total 
bilirubin > 3 x ULN or direct bilirubin > 1.5 x ULN. 
• Albumin < 2.5 g/dL. 
• Aspartate transaminase (AST) > 3 x ULN, or AST > 5 x ULN for participants with 
metastatic disease in the liver. 
• Alanine transaminase (ALT) > 3 x ULN, or ALT > 5 x ULN for participants with 
metastatic disease in the liver. 
For participants with elevated ALT or AST at baseline, the values must be stable for 2 weeks 
and with no evidence of biliary obstruction by imaging. 
5. Participants with MSI-H pancreatic adenocarcinoma. 
6. Presence of symptomatic CNS metastases, or CNS metastases that require local 
CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of 
corticosteroids 2 weeks prior to study entry. Participants with treated symptomatic brain 
metastases should be neurologically stable (for 4 weeks post-treatment and prior to study 
entry) and at a dose of ≤ 10 mg per day prednisone or equivalent for at least 2 weeks before 
administration of any study treatment. 
7. History of severe hypersensitivity reactions to any ingredient of study drug(s) and other 
mAbs and/or their excipients. 
8. The participant exhibits any of the events outlined in the contra-indications or special 
warnings and precautions sections of gemcitabine and nab-paclitaxel as per locally 
approved labels. 
9. 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 (NYHA Grade ≥ 2), or clinically significant arrhythmia (including 
uncontrolled atrial flutter/fibrillation) 
• Acute myocardial infarction, unstable angina pectoris, coronary stenting, or bypass 
surgery < 6 months prior to study entry 
• Left ventricular ejection fraction < 50% 
• Elevated cardiac enzymes (troponin I) elevation > 2 x ULN 
• Cardiac valvulopathy ≥ Grade 2 
• Uncontrolled hypertension defined by a systolic blood pressure ≥ 160 mg and/or 
diastolic blood pressure ≥ 100 mg Hg 
• Medical history or current diagnosis of myocarditis 
10. Known history of testing positive HIV infection. 
11. Active HBV or HCV infection. Participants whose disease is controlled under antiviral 
therapy should not be excluded. 
12. Malignant disease, other than that being treated in this study, except for malignancies treated 
curatively and that have not recurred in the past 2 years prior to study treatment; completely 


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resected basal cell and squamous cell skin cancers, and any completely resected carcinoma 
in situ are not excluded. 
13. Active, known or suspected autoimmune disease. Participants with vitiligo, type I diabetes, 
residual hypothyroidism only requiring hormone replacement, psoriasis not requiring 
systemic treatment or conditions not expected to recur may be considered. 
14. History of or current interstitial lung disease or pneumonitis grade ≥ 2. 
15. Major surgery, open biopsy, or significant traumatic injury ≤ 4 weeks prior to start of study 
treatment.  
16. Systemic chronic steroid therapy (>10mg/day prednisone or equivalent) or any other 
immunosuppressive therapy within 7 days of the first dose of study treatment. Topical, 
inhaled, nasal and ophthalmic steroids are allowed. 
17. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment. 
18. Use of hematopoietic growth factors or transfusion support ≤ 2 weeks prior to start of study 
treatment. If growth factors were initiated more than 2 weeks prior to the first dose of study 
treatment and the participant is on a stable dose, they can be maintained. 
19. Any medical condition that would, in the Investigator’s judgment, prevent the participant’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results. 
20. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human Chorionic 
Gonadotropin (hCG) laboratory test. 
21. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 180 days after stopping medication. Highly effective 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant 
• Use of oral (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy (failure 
rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months, or as per locally approved label, before taking study treatment. 
Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 180 days after stopping study treatment. A condom is required for all sexually 


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active male participants to prevent them from fathering a child and to prevent delivery of study 
treatment via seminal fluid to their partner. In addition, male participants must not donate sperm 
for the time period specified above. Sexually active male participants and their partners who 
are women of childbearing potential should follow the contraception recommendations and any 
other precautionary measures as required by the local prescribing information for the anti-
cancer SOC.  
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the informed consent form (ICF). 
Women are considered post-menopausal and not of childbearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age- 
appropriate [generally age from 40 to 59 years], history of vasomotor symptoms [e.g. hot flush]) 
in the absence of other medical justification or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to 
enrollment to study. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment is she considered to be 
not of childbearing potential. 
22. Participant has conditions that are considered to have a high risk of clinically significant 
gastrointestinal tract bleeding or any other condition associated with or history of significant 
bleeding. 
6 
Treatment 
6.1 
Study treatment 
For this study, the investigational drugs are NIS793, an anti-TGFβ human monoclonal antibody, 
and spartalizumab, an anti-PD-1 receptor recombinant humanized monoclonal antibody. The 
study treatment is NIS793 with and without spartalizumab plus SOC treatment of gemcitabine 
plus nab-paclitaxel. 
6.1.1 
Investigational and control drugs 
The treatment period begins on Cycle 1 Day 1. The duration of each treatment cycle is 28 days. 
Refer to Figure 6-1 for sequence of drug dispensing and to Section 6.7.2 for drug prescribing 
and administration information.  
During the first cycle, participants should be closely observed and vital signs should be 
monitored more frequently if clinically indicated, during and for at least 2 hours after the 
infusions of NIS793 with and without spartalizumab. The same may be applied for the 
subsequent cycles of NIS793 with and without spartalizumab infusions if medical indicated. 
All dosages prescribed and administered to participants and all dose interruptions and changes 
during the study must be recorded on the study treatment eCRF (electronic Case Report/Record 
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Randomized Arm 3 
 
Arrows indicate the sequence of administration of study drugs. 
6.1.2 
Additional study treatments  
Not applicable.  
6.1.3 
Treatment arms 
Safety Run-in part 
All participants in the  Safety Run-in part will be enrolled in a unique treatment arm of NIS793 
with spartalizumab in combination with gemcitabine/nab-paclitaxel. 
Randomized part 
Participants will be randomized to one of the following three treatment arms in a “1:1:1” ratio 
• Arm 1: NIS793 + spartalizumab + gemcitabine + nab-paclitaxel 
• Arm 2: NIS793 + gemcitabine + nab-paclitaxel 
• Arm 3: gemcitabine + nab-paclitaxel 
6.1.4 
Treatment duration 
Participants will be treated until they experience unacceptable toxicity, disease progression per 
RECIST 1.1 as determined by Investigator (for exception please refer to Section 6.1.4.1), and/or 
treatment is discontinued at the discretion of the Investigator or the participant, or withdrawal 
of consent. 
If study treatment (any drug) is interrupted or delayed for > 12 weeks due to toxicity that is 
suspected to be related to treatment, study treatment will be permanently discontinued. 
For participants who still derive clinical benefit, continuation of study treatment may be 
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6.2.1 
Concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care 
(such as anti-emetics, anti-diarrheal) and safety of the participant are allowed. 
The participant must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment.  
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact the Novartis medical monitor before 
first study treatment dosing or allowing a new medication to be started. If the participant is 
already enrolled and is being treated with a prohibited medication, contact Novartis to determine 
if the participant should continue participation in the study. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
• Therapeutic treatment with hematopoietic colony-stimulating growth factors (G-CSF or 
GM-CSF) and erythroid stimulating agents may only be initiated after the Safety Run-
in. If a participant is using an erythroid stimulating agent prior to enrollment (at least 
2 weeks before start of study treatment), they may continue at the same dose. 
• Anticoagulation therapy is permitted if the participants are already at stable doses 
for >2 weeks (with the exception of  low molecular weight heparin) at time of first dose and 
adequate laboratory tests are performed  as clinically indicated per Investigator’s discretion 
and according to local practices. Participants who develop a new requirement for 
anticoagulant therapy during the conduct of the study may remain on study after 
documented discussion with the Novartis medical monitor. However, ongoing anticoagulant 
therapy should be temporarily discontinued to allow tumor sampling according to the 
institutional guidelines.  
• Anti-hypertensives are allowed as concomitant medications. However, because transient 
hypotension has been reported during infusions, consideration should be given to 
withholding anti-hypertensive medications for 12 hours prior to infusion with study 
treatment. 
• Participants with disease metastatic to bone may receive bone-stabilizing agents such as 
bisphosphonates or monoclonal antibodies intended for this purpose. 
• Caution should be exercised when administering nab-paclitaxel concomitantly with 
medicines known to inhibit or induce either CYP2C8 or CYP3A4 (refer to 
Appendix 3). 


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6.2.2 
Prohibited medication 
• During the course of the study, participants must not receive other additional 
investigational drugs, devices, chemotherapy, or any other therapies that may be active 
against cancer or that are intended to modulate an immune response.  
• However, limited-field palliative radiotherapy to non-target lesion(s) may be allowed as 
concomitant therapy after documented discussion with Novartis. Such local therapies 
administered during the study treatment must be listed on the eCRF. Study treatment must 
be interrupted during radiotherapy. 
• The use of systemic steroid therapy (at doses greater than 10 mg/day prednisone or 
equivalent) and other immunosuppressive drugs is not allowed, with the exception of: 
- 
Prophylactic use for participants with imaging contrast dye allergy. 
- 
Replacement-dose steroids (defined as 10 mg/day (or lower dose) of prednisone or 
equivalent dose of corticosteroids) in the setting of adrenal insufficiency.  
- 
Transient exacerbations of chronic inflammatory conditions such as COPD. 
Steroids must be reduced to 10 mg/day (or lower dose) of prednisone or equivalent dose 
of corticosteroids prior to the next treatment with NIS793 with and without 
spartalizumab. 
- 
Short 
course 
of 
systemic 
steroid 
therapy 
for 
early 
side 
effect 
of 
gemcitabine/nab-paclitaxel (e.g flu like syndrome) may be acceptable after documented 
discussion with Novartis.  
• The treatment of study treatment-related infusion reactions or study treatment-
related irAEs. Steroids must be reduced to ≤10 mg/day (or lower dose) of prednisone or 
equivalent dose of corticosteroids prior to the next study treatment administration.  
• Topical, inhaled, nasal and ophthalmic steroids are allowed.  
• The use of live vaccines is not allowed through the whole duration of the study. 
Inactivated vaccines are allowed. 
6.3 
Participant numbering, treatment assignment, randomization  
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is re-screened. The Participant No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the informed consent form, the participant is assigned 
to the next sequential Participant No. available. 
A new ICF will need to be signed if the Investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No. 


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6.3.2 
Treatment assignment, randomization 
All participants entering the screening phase will be registered in the Interactive Response 
Technology (IRT) system. The Investigator or his/her delegate will then contact the IRT once 
all the inclusion/exclusion criteria have been assessed to confirm whether the participants will 
start study treatment or not. 
In the Safety Run-in part, no randomization will be performed. All eligible participants will 
be assigned to treatment of NIS793 with spartalizumab and gemcitabine/nab-paclitaxel.  
In the Randomized part, all eligible participants will be randomized via IRT in a 1:1:1 ratio to 
one of the following treatment arms: 
• Arm 1: NIS793 plus spartalizumab plus gemcitabine/nab-paclitaxel 
• Arm 2: NIS793 plus gemcitabine/nab-paclitaxel 
• Arm 3: gemcitabine/nab-paclitaxel 
The IRT will assign a randomization number to the participant, which will be used to link the 
participant to a treatment arm and will specify a unique medication number for the first package 
of study treatment to be dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A participant randomization list will be produced by the IRT 
provider using a validated system that automates the random assignment of participant numbers 
to randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers. A separate medication list will be 
produced under the responsibility of Novartis Global Clinical Supply (GCS) using a validated 
system that automates the random assignment of medication numbers to packs containing the 
study treatment. 
The randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office. 
6.4 
Treatment blinding  
Treatment will be open to participants, Investigator staff, persons performing the assessments, 
and Novartis. In order to minimize the potential impact of the treatment knowledge, until the 
IA (Section 4.4) or the primary analysis is conducted, whichever occurs first, no aggregated 
statistical analyses (efficacy or safety across the study) shall be performed by treatment (other 
than analyses as specified in the study protocol). 




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6.5.2 
Guidelines for dose evaluation 
For the purpose of dose evaluation, at least six participants will be treated in Safety Run-in 
part. 
To be evaluable, participants must complete 4 weeks of treatment with the minimum safety 
evaluation and drug exposure or have a DLT within these 4 weeks of treatment for Randomized 
part dose regimen decision. Refer to Section 12.1.3 for more detail. 
Novartis clinical team and Investigators will assess clinical, PK and laboratory data of all 
participants having received any treatment in the study before the safety review meeting to 
decide on the NIS793 with and without spartalizumab in combination with 
gemcitabine/nab-paclitaxel dose regimen to be tested in Randomized part.  
Dose confirmation of NIS793 2100 mg Q2W with spartalizumab 400 Q4W in combination with 
gemcitabine/nab-paclitaxel will occur if the following conditions are met in the Safety Run-in 
part: 
• Six evaluable participants treated at this dose and regimen. 
• No more than one DLT has been observed out of six evaluable participants. 
• It is the dose recommended for participants after review of all clinical data by Novartis and 
Investigators in a safety review meeting. 
If one of the conditions specified above is not satisfied, dose confirmation cannot be declared 
and a second cohort may be treated at NIS793 1400 mg Q2W with spartalizumab 400 Q4W in 
combination with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. The same criteria 
are applied for this new dose and regimen. If dose confirmation cannot be declared on this lower 
dose, the Randomized part cannot start and the study will end. 
6.5.2.1 
Implementation of dose decision 
To implement the dose decision, the available toxicity information as defined in Section 6.5.2 
will be evaluated by the Investigators and Novartis study personnel (including the study 
physician and statistician) during a dose decision meeting by teleconference. Randomized part 
may not start until the Investigators receive written confirmation from Novartis indicating 
which dose regimen will be used.  
6.5.3 
Definitions of dose limiting toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an AE or abnormal laboratory value where the 
relationship to study treatment cannot be ruled out and is not clearly related solely to disease, 
disease progression, inter-current illness, or concomitant medications, occurs within the first 
28 days of treatment with NIS793 with spartalizumab in combination with gemcitabine/nab-
paclitaxel and meets any of the criteria included in Table 6-3. The National Cancer Institute 
Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for 
all grading. For the purpose of decision on dose to be tested in Randomized part, DLTs will 
be considered. 
The Investigator must notify the sponsor immediately of any unexpected CTCAE grade ≥ 3 
AEs or laboratory abnormalities.  








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Worst toxicity CTCAEa grade 
Recommended Dose Modification 
Ocular (uveitis, eye pain, blurred vision) 
Grade 1 
Continue study treatment without dose modification. 
Ophthalmology consultation. 
Grade 2 
Hold NIS793 and spartalizumab. 
Urgent ophthalmology consultation. 
Upon resolution to ≤ Grade 1 may consider resuming study treatment 
without dose reduction after discussion with the Novartis Medical 
Monitor and in consultation with ophthalmology. 
Grade 3 or Grade 4 
Discontinue study treatment. 
Urgent ophthalmology consultation. 
Pulmonary (pneumonitis) 
Grade 1 
Consider study treatment hold. 
Manage per institutional practice. 
Consider resuming study treatment upon radiographic evidence of 
improvement. 
Grade 2 
Hold study treatment. 
Pulmonary and infection workup. 
Upon resolution to ≤ Grade 1, may resume study treatment without 
dose modification. 
Grade 3 or Grade 4 
Discontinue study treatment. 
Cardiovascular 
ECG QTc-Interval prolonged; hypertension 
Grade 3 
Hold study treatment.  
Upon resolution to Grade ≤ 1 or baseline (hypertension, QTc) or 
< 30 msec difference from baseline (QTc) within ≤ 7 days, may 
resume study treatment without dose modification after discussion 
with the Novartis Medical Monitor. Baseline ECG refers to the ECG(s) 
collected at screening. 
Grade 4 
Discontinue study treatment. 
Other cardiovascular disorders 
Grade 2 (except myocarditis) 
Hold study treatment. 
Upon resolution to Grade ≤ 1 or baseline, may resume study 
treatment without dose modification after discussion with the Novartis 
Medical Monitor. 
Grade 2 myocarditis, or  
Grade ≥ 3 other cardiac disorders 
related to study treatment 
Discontinue study treatment. 
Cardiac valvulopathy 
Grade 2 
Hold study treatment.  
Repeat echocardiogram and assess cardiac function. Once resolved 
to Grade ≤ 1 or baseline, consider re-administration of treatment, if 
benefit outweighs the potential risk. 
Grade 3 
Discontinue study treatment. 
Gastrointestinal 
Diarrhea/colitis* 
Grade 1 
May continue study treatment without dose modification.  Manage per 
institutional standard guidelines which should include anti-diarrheal 
treatment, consideration of corticosteroid therapy, and hydration. 


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Worst toxicity CTCAEa grade 
Recommended Dose Modification 
Grade 2 
Hold study treatment. 
GI consultation. 
Upon resolution to ≤ Grade 1 and tapering of steroid requirement to 
≤ 10 mg prednisone per day, resume study treatment without dose 
modification after discussion with the Novartis Medical Monitor. 
Grade 3 
Hold study treatment. 
GI consultation. 
Upon resolution to ≤ Grade 1 and tapering of steroid requirement to 
≤ 10 mg prednisone per day, consider resuming study treatment after 
discussion with the Novartis Medical Monitor. 
Grade 4 
Discontinue study treatment. 
Isolated AST and/or ALT elevation 
Grade 2 AST and/or ALT 
Hold study treatment. 
Manage per institutional practice. 
Upon resolution to ≤ Grade 1 or baseline, consider resuming study 
treatment without dose modification. 
Grade 2 transaminitis with 
bilirubin >1.5 x ULN (unless Gilbert’s 
syndrome) 
Discontinue study treatment. 
Grade 3 AST and/or ALT 
Hold study treatment. 
Manage per institutional practices. 
Upon resolution to ≤ Grade 1 or baseline within 72 hours, consider 
resuming study treatment without dose modification after discussion 
with the Novartis Medical Monitor.  
If resolved in <=14 days, resume treatment without dose modification.  
If resolved in >14 days, consider dose modification of NIS793 with 
administration Q4W instead of Q2W, without any spartalizumab dose 
modification. 
Otherwise, discontinue study treatment. 
Grade 4 AST and/or ALT 
Discontinue study treatment. 
Concomitant elevation of AST and/or ALT and total bilirubin 
With normal AST/ALT and bilirubin at baseline: 
Grade 2 ALT and/or AST elevation 
( >3.0 x ULN) with bilirubin > 2.0 x 
ULN (unless Gilbert's syndrome) 
Hold study treatment. Assess if case is drug induced liver injury 
(DILI).  
• 
If no DILI confirmed, treat the identified cause according to 
institutional guidelines. Repeat LFTs within 48-72 hours, 
then monitor weekly, until enzyme levels resolve to 
≤ Grade 1 or baseline. After recovery, re-administration of 
study treatment could be considered only if Investigator 
assesses benefit to outweigh the risk. Any decision 
regarding re-administration of study drugs and dose regimen 
(NIS793 only) should be discussed with the Novartis Medical 
Monitor. 
• 
If DILI confirmed, discontinue study treatment. For additional 
information on follow-up of potential DILI cases, refer to 
Section 6.5.5.1. 
With abnormal ALT/AST at baseline: 
 


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ALT or AST >3.0 x baseline OR ALT 
or AST >8.0 x ULN [whichever is 
lower] combined with total 
bilirubin >2.0 x baseline AND >2.0 x 
ULN 
Same as above. 
Isolated total bilirubin elevation**/*** 
Grade 2 
Hold study treatment.  
Upon resolution to ≤ Grade 1, may continue study treatment without 
dose modification. 
Grade 3 
Hold study treatment. 
Upon resolution to ≤ Grade 1, may consider resuming study treatment 
after discussion with the Novartis Medical Monitor.   
Grade 4 
See footnote**/***.  Otherwise, discontinue study treatment. 
Asymptomatic amylase and/or lipase elevation**** 
Grade 3, not associated with 
symptoms or clinical manifestations of 
pancreatitis**** 
Continue study treatment.  
If levels do not resolve to ≤ Grade 2 within ≤ 14 days after the initial 
report, hold study treatment. 
Upon resolution to ≤ Grade 2, may resume study treatment without 
dose modification, after discussion with the Novartis Medical Monitor. 
Pancreatitis 
Grade 2/radiologic evidence 
Hold study treatment. 
Manage per institutional practice. 
Upon resolution to ≤ Grade 1, may resume study treatment without 
dose modification, if no clinical evidence of pancreatitis and after 
discussion with the Novartis Medical Monitor. 
Grade 3 or Grade 4 
Discontinue study treatment. 
Renal 
Serum creatinine 
Grade 2 
Hold study treatment. 
Manage per institutional practice. 
Upon resolution to ≤ Grade 1, may resume study treatment without 
dose modification after discussion with the Novartis Medical Monitor. 
Grade 3 or Grade 4 
Discontinue study treatment. 
Musculoskeletal 
Grade 2 or Grade 3 
Hold study treatment. 
Consider resuming study treatment without dose modification upon 
resolution to ≤ Grade 1 with appropriate management. 
Grade 4 
Discontinue study treatment. 
In some cases, resuming study treatment may be considered after 
discussion with the Novartis Medical Monitor and consultation with a 
rheumatologist. 
Endocrine 
Hypothyroidism or hyperthyroidism 
Grade 2 
May continue study treatment without dose modification. 
Management according to institutional practice. 
Grade 3 
Hold study treatment.  
Upon resolution to Grade ≤ 1 with appropriate management, may 
resume study treatment without dose modification. 


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Worst toxicity CTCAEa grade 
Recommended Dose Modification 
Grade 4 
May resume therapy following resolution or control with physiologic 
hormone replacement. 
Other endocrine disorders 
Grade 2 and Grade 3 
Hold study treatment.  
Upon resolution to Grade ≤ 1 with appropriate management, may 
resume study treatment without dose modification. 
Grade 4 
Hold study treatment. 
Grade 4 treatment-related endocrinopathies, such as  
adrenal insufficiency, adrenocorticotropic hormone  
(ACTH) deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone 
replacement (corticosteroids, thyroid hormones) or glucose-controlling 
agents, respectively, may not require discontinuation after discussion 
with and approval from the Novartis Medical Monitor. 
Neurology 
Grade 1 
Consider study treatment hold, particularly for clinical  
suspicion of Guillain-Barre syndrome, encephalitis, aseptic meningitis, 
transverse myelitis, or peripheral neuropathy. 
Grade 2 
Hold study treatment.   
In some cases, resuming study treatment may be  
considered after discussion with the Novartis Medical  
Monitor. 
Grade 3 or Grade 4 
Discontinue study treatment. 
Dermatology (rash) 
Grade 1 
Continue study treatment without dose modification. Topical steroids, 
antihistamines, topical emollients 
Grade 2 
Consider holding study treatment. 
Topical or oral steroids, antihistamines. 
If study treatment is held and resolution to ≤ Grade 1, resume study 
treatment without dose modification. 
Grade 3 or Grade 4 
Hold study treatment. 
Manage per institutional practice. 
After resolution to ≤ Grade 1, consider resuming study treatment after 
discussion with the Novartis Medical Monitor. 
Bullous dermatitis 
Hold study treatment. 
Grade 1-2 bullous dermatitis: discussion with the Novartis Medical 
Monitor is required before considering resuming study treatment.   
Grade 3 bullous dermatitis: consider resuming therapy after expert 
consultation and documented discussion with the Novartis medical 
monitor. 
Grade 4 bullous dermatitis: discontinue study treatment 
Stevens-Johnson syndrome (SJS), or 
Lyell syndrome/toxic epidermal 
necrolysis (TEN) 
Permanently discontinue study treatment 


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Worst toxicity CTCAEa grade 
Recommended Dose Modification 
Hematology 
Neutropenia  
Grade 3 or Grade 4 
Hold study treatment.  
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume 
study treatment without dose modification, after discussion with the 
Novartis Medical Monitor. 
Febrile neutropenia 
Grade 3 or Grade 4 
Hold study treatment. 
Upon resolution of fever and improvement of neutropenia to 
≤ Grade 2 or baseline, resume study treatment without dose 
modification, after discussion with the Novartis Medical Monitor. 
Thrombocytopenia 
Grade 3 
Hold study treatment. 
Upon resolution to ≤ Grade 2 or baseline, resume study treatment 
without dose modification. 
 
For Grade 3 associated with major bleeding, discontinue study 
treatment. 
Grade 4 
Discontinue study treatment. 
Anemia 
Grade 3 or Grade 4 
Hold study treatment.  
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume 
study treatment without dose modification. 
Lymphopenia 
Any grade 
Treatment-related lymphopenia does not require study treatment hold 
or discontinuation. 
Other laboratory adverse events, not specified elsewhere in table and not included in the 
consensus guidelines 
Grade 3 or Grade 4 
Hold study treatment.  
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification. 
Isolated Grade 4 electrolyte abnormalities not associated with clinical 
sequelae and corrected after appropriate management within 
72 hours of their onset do not require discontinuation. 
In the case of Grade 4 electrolyte imbalances associated with clinical 
sequelae, or not resolved to ≤ Grade 1 within 72 hours despite 
appropriate management, discontinue study treatment. 


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Worst toxicity CTCAEa grade 
Recommended Dose Modification 
Other non-laboratory adverse events, not specified elsewhere in table and not included in 
the consensus guidelines 
Grade 2 
Consider study treatment hold, at Investigator discretion. 
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification. 
Grade 3 
Hold study treatment. 
Upon resolution to ≤ Grade 1, resuming study treatment must be 
discussed with the Novartis Medical Monitor. 
Grade 4 
Discontinue study treatment. 
All dose modifications should be based on the worst preceding toxicity. 
a Common Toxicity Criteria for Adverse Events (CTCAE v5) 
*Note: anti-diarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea. 
**Note: If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and 
hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood 
smear and haptoglobin determination), then delay study treatment until resolved ≤ Grade 1, and resume study 
treatment at the discretion of the Investigator.  
***Note: an isolated bilirubin elevation is not typical for DILI. Bilirubin can be elevated either as part of a “Hy’s 
law” constellation with a preceding elevation of ALT/AST, or as part of a cholestatic reaction with simultaneous 
elevation of other cholestatic parameters (ALP, GGT). Isolated bilirubin can be seen in conjunction with drugs 
that inhibit bilirubin conjugation or excretion, but both scenarios do not typically represent liver injury. 
Alternative causes of bilirubin elevation should therefore, be ruled out before basing dose modification 
decisions on bilirubin values alone. 
****Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within one week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase.  
Table 6-6 
Dose modifications of gemcitabine/nab-paclitaxel for hematological 
toxicities suspected to be related to gemcitabine/nab-paclitaxel. 
Safety Run-in part (after Cycle 1) and Randomized part (as per locally 
approved labels) 
 


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• At Day 1, gemcitabine/nab-paclitaxel should not be administered if ANC is < 1.5 G/L OR 
platelets are <100 G/L. 
Table 6-7 
Dose modifications of gemcitabine/nab-paclitaxel for non-
hematological toxicities suspected to be related to gemcitabine/nab-
paclitaxel. Safety Run-in part (after the Cycle 1) and Randomized part 
(as per locally approved labels) 
Worst toxicity CTCAE Grade 
Recommended dose modification 
Pneumonitis 
Grade≥ 2  
• 
Discontinue gemcitabine and nab-paclitaxel promptly. 
• 
Treatment with steroids should be initiated as per local 
guidelines. 
Nervous system 
Peripheral neuropathy 
Grade 3 or Grade 4 
• 
Withhold nab-paclitaxel until improvement to ≤ Grade1. 
• 
Resume nab-paclitaxel to next lower dose level. 
• 
Dose of gemcitabine remains unchanged. 
Cutaneous toxicity  
Grade 2 or Grade 3 
• 
Reduce gemcitabine and nab-paclitaxel to next lower 
dose level. 
• 
Discontinue study treatment and discontinue 
participant from the study if toxicity persists. 
Gastrointestinal toxicity 
Mucositis or diarrhea 
Grade 3 or Grade 4 
• 
Withhold gemcitabine and nab-paclitaxel until improves 
to ≤ Grade 1. 
• 
Resume doses at next lower dose level. 
6.5.5 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for four weeks, and 
subsequently at approximately four weeks intervals, until resolution or stabilization of the 
event, whichever comes first. All participants must be followed for AEs and SAEs after 
discontinuation of study treatments. 
The emergence of Immune-Related AE (irAE) may be anticipated based on the mechanism of 
action of immunomodulatory therapies. 
An irAE is any clinically significant AE affecting any organ that is associated with study drug 
exposure, is consistent with an immune-mediated mechanism, and where alternative 
explanations have been investigated and ruled out or are considered to be unlikely. 
Serologic, histologic (tumor sample) and immunological assessments should be performed as 
deemed appropriate by the Investigator or specialist consultant to verify the immune-related 
nature of the AE. An empiric trial of corticosteroids may also contribute to understanding the 
etiology of a potential irAE.  
Consensus management algorithms for irAEs have been developed and are available to assist 
Investigators in assessing and managing irAEs (refer to Section 6.5.4).  
All participants must be followed-up for irAEs, AEs and SAEs as per Section 9.2.3. 


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6.5.5.1 
Follow-up on potential drug-induced liver injury (DILI) cases 
Transaminase increase combined with total bilirubin increase may be indicative of potentially 
severe DILI. These events should be considered as clinically important and assessed 
appropriately to establish the diagnosis. The required clinical information, as detailed below, 
should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• 
For participants with normal ALT and AST and total bilirubin value at baseline: AST 
or ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• 
For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT >3.0 x baseline] OR [ALT or AST > 8.0 x ULN], whichever occurs first, combined with 
[total bilirubin > 2.0 x baseline AND > 2.0 x ULN] 
Other possible causes of abnormal liver tests should be considered and their role clarified before 
DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT 
(gamma-glutamyl transferase), GLDH (glutamate dehydrogenase), prothrombin time 
(PT)/INR, alkaline phosphatase, albumin, and creatine kinase. If available, testing of GLDH is 
additionally recommended. 
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using CT, 
MRI, or duplex sonography. 
Perform 
relevant 
examinations 
(Ultrasound 
or 
MRI, 
Endoscopic 
retrograde 
cholangiopancreatography (ERCP)) as appropriate, to rule out an extrahepatic cause of 
cholestasis. Cholestasis (is defined as an ALP elevation > 2.0 x ULN with R value < 2 in 
participants without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
participants with bone metastasis). 
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. In clinical 
situations where it is suspected that ALP elevations are from an extrahepatic source, the GGT 
can be used if available. GGT may be less specific than ALP as a marker of cholestatic injury, 
since GGT can also be elevated by enzyme induction or by ethanol consumption. It is more 
sensitive than ALP for detecting bile duct injury. 
Table 6-8 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities. 


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Table 6-8 
Guidance to rule out possible alternative causes of observed LFT 
abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
• IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, 
HBV DNA; anti-HCV, HCV RNA, IgM & IgG anti-
HEV, HEV RNA 
CMV, HSV, EBV infection 
• IgM & IgG anti-CMV, IgM & IgG anti-HSV; 
IgM & IgG anti-EBV 
Autoimmune hepatitis 
• Antinuclear Antibodies (ANA) & Anti-Smooth 
Muscle Antibody (ASMA) titers, total IgM, IgG, 
IgE, IgA 
Alcoholic hepatitis 
• Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• Medical history: acute or chronic congestive 
heart failure, hypotension, hypoxia, hepatic 
venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
• Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
• Caeruloplasmin 
Hemochromatosis 
• Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes / glycogenic hepatitis). 
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant,” and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential treatment-induced liver injury.” All events should be followed up with the outcome 
clearly documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
NIS793, spartalizumab, gemcitabine and nab-paclitaxel will be administered at the 
investigational site following the schedule in Table 8-2. The date and time of all study treatment 
administrations during the study and any deviations from the protocol treatment schedule will 
be captured by the Investigator staff or delegates in the source document at each administration 
visit. All study treatments infused and returned must be recorded in the Drug Accountability 
Log. 


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6.7 
Preparation and dispensation 
Each study site will be supplied with NIS793 and spartalizumab in packaging as described under 
investigational and control drugs section (Section 6.1.1).  
For NIS793 and spartalizumab preparation prior to administration, please refer to 
NIS793B12201 Pharmacy Manual. A unique medication number is printed on the study 
medication label. Investigator staff will identify the study medication kits to dispense to the 
participant by contacting IRT and obtaining the medication number(s).  
For gemcitabine and nab-paclitaxel preparation and administration, please refer to locally 
approved labels.  
Study treatment, gemcitabine and nab-paclitaxel, will be sourced as local commercial supply 
(in the locally approved formulation and packaging configuration) and labeled in the country 
when possible. 
6.7.1 
Handling of study treatment and additional treatment 
Study treatment must be received by a designated person 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, all study treatment must be stored according to the 
instructions specified on the labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The Investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.  
At the conclusion of the study, and as appropriate during the course of the study, the Investigator 
will return all 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. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. 
6.7.2 
Instruction for prescribing and taking study treatment 
The dose and treatment schedule of each study treatment used in this study is described in 
Section 3.1. 
All kits of study treatment assigned by the IRT and locally supplied commercial drugs will be 
recorded in the IRT system. 




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Participants should be closely observed for potential infusion-related reactions including rigors, 
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever, and vital signs 
monitored more frequently if clinically indicated, during and for at least 2 hours of the first 
cycle of spartalizumab infusion. The same may apply for the subsequent spartalizumab 
infusions if medically indicated. Participants should be further provided instructions to notify 
study personnel if symptoms of infusion reaction occur after any spartalizumab infusion. 
Further instructions for the preparation and dispensation of spartalizumab are described in the 
study pharmacy manual. 
6.7.2.3 
Gemcitabine and nab-paclitaxel 
For instructions on preparation and dispensing of gemcitabine and nab-paclitaxel, refer to 
product labeling and the local guidance. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participants's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to Investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
Investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the NIS793 Investigator's Brochure, the PDR001 Investigator’s Brochure, and 
gemcitabine and nab-paclitaxel locally approved labels. This information will be included in 
the participant informed consent and should be discussed with the participant during the study 
as needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
Investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent during the study due to limits that prevent an on-site visit, 
Investigator may conduct the informed consent discussion remotely (e.g. telephone, 
videoconference) if allowable by a local Heath Authority. 


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Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
The following informed consents are included in this study: 
• Main study consent, which also included:  
• A subsection that requires a separate signature for the ‘Optional Consent for Additional 
Research’ to allow future research on data/samples collected during this study 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-2) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-2) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue the 
study for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, all dispensed study 
treatments should be reconciled, and the AE and concomitant medications recorded on the CRF. 
Assessments which are indicated to be performed at Screening and on C1D1, only need to be 
repeated at C1D1 if the Screening assessment was more than 3 days earlier. 
Laboratory and radiological assessments performed as part of standard of care prior to signing 
informed consent can be used if performed within the screening time window.  
During the course of the study visits, test procedures should occur on schedule whenever 
possible as per allowable visit windows specified in Table 8-1. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls and virtual contacts (e.g. tele consult) can replace on-site study visits, 
for the duration of the disruption until it is safe for the participant to visit the site again. 


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Table 8-1 
Visit windows 
Visit name 
Window 
Screening 
• 
Radiological evaluation 
• 
Pregnancy 
Day -21 to Day -1 
Day -28 to Day -1 
Within 3 days prior first dose of study treatment 
Cycle 1 Day 1 
Within 7 days after drug assignment (Safety 
Run-in part) or randomization (Randomized 
Part) in IRT  
Day 1 of subsequent cycles 
+ 3 days 
PK/IG
sampling 
Refer to Table 8-6 and refer to Table 8-7 
Tumor assessments 
± 7 days 
End of Treatment (EoT) 
Within 14 days of last dose of study treatment 
OR 
Within 14 days of the decision of discontinuation 
of study treatment 
Safety follow-up assessments 
± 7 days 


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Table 8-2 
Assessment schedule 
Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Screening 
C1 
C2 
C3 and subsequent 
cycles 
EOT 
Safety 1 
 
Disease 
progression 
Survival  
Day of cycle 
-21 to -1 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
 
30 
days 
90 
days  
150 
days  
 
 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical 
history/current medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent of 
cancer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking and alcohol 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MSI status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Germline mutations panel 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications and non-drug 
procedures 
Continuous 
 
 
Concomitant antineoplastic 
radiotherapy 
 
Continuous 
 
 
 
 
 
Physical Exam 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
S 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Screening 
C1 
C2 
C3 and subsequent 
cycles 
EOT 
Safety 1 
 
Disease 
progression 
Survival  
Day of cycle 
-21 to -1 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
 
30 
days 
90 
days  
150 
days  
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Performance status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Chemistry (full) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Chemistry (alleviated) 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
Urinalysis 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
CA 19-9 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
Troponin I and NTproBNP 
X 
 
 
 
 
 
 
C3D1, 
and D1 
of every 
third 
cycle, or 
as 
clinically 
indicated 
 
 
X 
 
 
 
 
 
Thyroid function (for 
Safety Run-in part and 
Randomized Arms 1 & 2) 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
HBV, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
S 
S 
 
 
S 
 
 
S 
 
 
S 
S (done monthly) 
 
 


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Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Screening 
C1 
C2 
C3 and subsequent 
cycles 
EOT 
Safety 1 
 
Disease 
progression 
Survival  
Day of cycle 
-21 to -1 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
 
30 
days 
90 
days  
150 
days  
 
 
Tumor evaluation as per 
RECIST 1.1 
 
 
X 
During treatment: starting on Cycle 3 Day 1, every 8 weeks until 
week 52, and then every 12 weeks until progression of disease as 
per RECIST 1.1, death, lost to follow-up or withdrawal of consent. 
X3 
 
 
 
X4 
 
ECG 
X 
As clinically indicated, as outlined in Section 8.4.6 
 
 
 
 
 
Cardiac imaging 
(echocardiogram or 
CT/MRI) 
X 
As clinically indicated or if cardiac enzyme increase ≥ 2x ULN (if normal at 
screening), or ≥ 2x baseline (if baseline value was elevated). 
 
 
 
 
 
Adverse Events 
Continuous 
 
Newly obtained tumor 
sample  
X2  
 
 
 
 
 
 
X5 (anytime 
between C3D2 
and C3D4) 
 
X6(optional) 
 
 
 
 
 
PK Sampling 
 
X (as per schedule outlined in Section 8.5.1.1) 
 
 
 
 
 
IG sampling 
 
X (as per schedule outlined in Section 8.5.1.1) 
 
 
 
 
 


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Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Screening 
C1 
C2 
C3 and subsequent 
cycles 
EOT 
Safety 1 
 
Disease 
progression 
Survival  
Day of cycle 
-21 to -1 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
 
30 
days 
90 
days  
150 
days  
 
 
NIS793 administration 
(Safety Run-in part, and 
Randomized Arms 1 & 2) 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
 
 
 
Spartalizumab 
administration (Safety 
Run-in part and 
Randomized Arm 1) 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
Gemcitabine & nab-
paclitaxel administration 
(Safety Run-in part, and 
all Randomized Arms) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
IRT 
Registration/Randomization 
X 
X (study treatment dispensing) 
 
X 
 
 
 
 
 


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Period 
Screening 
Treatment 
Follow-up 
 
Visit Name 
Screening 
C1 
C2 
C3 and subsequent 
cycles 
EOT 
Safety 1 
 
Disease 
progression 
Survival  
Day of cycle 
-21 to -1 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
 
30 
days 
90 
days  
150 
days  
 
 
Antineoplastic therapies 
since discontinuation 
 
 
 
X 
X 
X 
X 
 
Survival contact 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Disposition 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
1. Safety follow-up at: 30 days for all participants and 90 days for participants treated with NIS793 (Safety Run-in part and Randomized Arms 1 and 2) and 150 days for participants 
treated with spartalizumab (Safety Run-in part and Randomized Arm 1). 
2. At screening, archival tumor sample < 6 months is acceptable. 
3. If a scan was not conducted within 30 days prior to end of study treatment. 
4. Every 8 weeks until week 52 from first dose, then every 12 weeks until progression of disease. 
5. For participants discontinued between C2D15 and C3D1, biopsy should be collected at EoT visit. 
6. For Safety Run-in part and Randomized Arms 1 and 2: Newly obtained tumor biopsy is optional for participants who clinically benefited from the study treatment.  
X = assessment to be recorded in the clinical database or received electronically from a vendor 
S = assessment to be recorded in the source documentation only


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8.1 
Screening 
Screening 
The study IRB/IEC approved informed consent form must be signed and dated before any 
screening procedures are performed, except for laboratory and radiological evaluations, which 
were performed as part of the participant’s clinical standard of care within the acceptable 
screening window. 
Participants will be evaluated against study inclusion and exclusion criteria and safety 
assessments (refer to Table 8-2). Screening assessments must be repeated if performed outside 
of the specified screening window (Table 8-1). Participants must meet all inclusion and none 
of the exclusion criteria at screening in order to be eligible for the study. 
Laboratory test result(s) or symptoms that do not satisfy the eligibility criteria may be repeated 
or treated during the screening visit window. In the event that the repeated laboratory test(s) 
cannot be performed within 21 days, from the original screening visit, or do not meet the 
eligibility criteria, or other eligibility criteria have changed and are not met anymore, the 
participant is considered a screening failure. 
Re-screening of a participant who has failed screening may be allowed. In such cases, a new 
ICF must be signed; new participant ID will be assigned. All required screening assessments 
must be repeated if they do not meet the allowed time window for screening when the 
participant is re-screened for participation in the study. An individual participant can only be 
re-screened once for the study. 
8.1.1 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization in Randomized part, or prior to start treatment in Safety Run-in part will 
be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate Case Report Form. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a serious AE during the screening phase (see Section 10.1.3 for SAE 
reporting details). If the participant fails to be randomized, the Interactive Response Technology 
(IRT) must be notified within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g. participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form. 




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Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Localized bone CT, MRI or x-
ray 
For any lesions identified on the 
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 
CT or MRI of other metastatic 
sites (e.g., neck) 
If clinically indicated 
If lesions were documented at 
baseline, follow same schedule as 
CT/MRI of chest, abdomen, and 
pelvis 
8.3.1.1 
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 participant 
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 the 
first dose of treatment cannot be considered baseline images.  
If a participant is known to have a contraindication to CT i.v. contrast media or develops a 
contraindication during the trial, a non-contrast CT of the chest (MRI is not recommended due 
to respiratory artifacts, however if CT is not feasible per local regulations, MRI can be 
performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and pelvis should 
be performed. 
If brain metastases are suspected at baseline, brain MRI or CT should be completed. 
Contrast enhanced brain MRI is preferred, however, if MRI contrast is contraindicated, then 
MRI without contrast or CT with/without contrast is acceptable. 
If clinically indicated, a whole body bone scan should be performed per institutional standard 
of care (e.g., Tc-99 bone scan, whole body bone MRI, Fluorodeoxyglucose positron emission 
tomography (FDG-PET) or sodium fluoride (NaF) PET). Localized CT, MRI or X-rays should 
be acquired for all skeletal lesions identified on the screening whole body bone scan, which are 
not visible on the chest, abdomen and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate should be 
performed. 
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
8.3.1.2 
Post-baseline imaging assessments 
Imaging assessments as described in Table 8-3 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing 
(see Table 8-2). Imaging assessments for response evaluation will be performed every 8 weeks 
(+/- 7 days) during the first year, and every 12 weeks (+/- 7 days) thereafter until disease 
progression, death, lost to follow-up or withdrawal of consent.  
Imaging assessments should be scheduled using the Cycle 1 Day 1 date 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. 


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Additional imaging assessments may be performed at any time during the study at the 
Investigator’s discretion to support the efficacy evaluations for a participant, 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 
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) 
 
8.3.2 
Appropriateness of efficacy assessments 
The efficacy assessments selected are standard for this indication/participant population. 
Additional information can be found in Appendix 1 and Appendix 2 (RECIST 1.1 
). 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to Section 10.1. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur for safety monitoring and discussion of the participant´s 
health status until it is safe for the participant to visit the site again. 
8.4.1 
Physical examination 
Physical examination will be performed according to Table 8-2. 
At Screening and Cycle 1 Day 1 prior to treatment, a complete physical examination will be 
performed and will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and 
neurological. 
After Cycle 1 Day 1 onwards, a short physical examination will be performed (it will include 
the examination of general appearance, vital signs). 
Clinically relevant findings that were present prior to signing informed consent must be 
recorded on the appropriate eCRF that captures medical history. Significant new findings that 
begin or worsen after informed consent which meet the definition of an AE must be recorded 
as an AE. 


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For Japan only: oxygen saturation (SpO2) will be measured by pulse oximetry for Japanese 
participants every time physical examination is performed as indicated in Table 8-2. The results 
of SpO2 will be recorded only in the source documentation. 
8.4.2 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature. 
Vital signs assessments will be performed as per schedule in Table 8-2. 
8.4.3 
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 timepoints as specified in Table 8-2. 
8.4.4 
Performance status 
The performance status will be assessed according to the Eastern Cooperative Oncology Group 
(ECOG) Performance Status Scale as specified in Table 8-2 following the schedule given in 
Table 8-4. 
Table 8-4 
ECOG performance status 
Grade 
ECOG status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory< and able to carry out 
work of a light or sedentary nature e.g., light house work, office work 
2 
Ambulatory and capable of all 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 
Death 
8.4.5 
Laboratory evaluations 
All laboratory parameters assessed for safety purposes described in Table 8-5 Laboratory 
assessment will be evaluated locally as per Table 8-2. Unscheduled assessment can be 
performed if clinically indicated. 
The results of the laboratory tests performed locally will be recorded in the eCRF, unless 
differently specified in Table 8-2. Novartis must be provided with a copy of the normal ranges 
and certification of the all laboratories used to assess participants’ safety during study conduct, 
when possible. The Investigator is responsible for reviewing all laboratory reports for 
participants in the study and evaluating any abnormalities for clinical significance. 


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At any time during the study up to safety follow-up, abnormal laboratory parameters which are 
clinically relevant and require an action to be taken with study treatment (e.g., require dose 
modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the adverse event eCRF page. The severity of laboratory data will be graded using 
the Common Terminology Criteria for Adverse events (CTCAE) v5.0. Additional analyses are 
left to the discretion of the Investigator. 
Table 8-5 
Laboratory assessment 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells, Differential 
(Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, 
Other (absolute value preferred , %s are acceptable) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase (LDH), 
Calcium, Magnesium, Phosphorus, Sodium, Potassium, Creatinine, Direct 
Bilirubin, Indirect Bilirubin, Total Bilirubin, Blood Urea Nitrogen (BUN) or 
Urea, Uric Acid, Amylase, Lipase, non-fasting Glucose 
Urinalysis 
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
Thyroid 
T4 [free], TSH 
Virology 
HBV, HCV, HIV 
Additional tests 
CA 19-9, Troponin I and NTproBNP 
Pregnancy Test 
Serum / Urine pregnancy test  
8.4.5.1 
Hematology 
Please refer to Table 8-5 Laboratory assessment for a list of tests to be performed and  
Table 8-2 for timing of assessments. 
8.4.5.2 
Chemistry 
Please refer to Table 8-5 Laboratory assessment for a list of tests to be performed and  
Table 8-2 for timing of assessments. 
At Day 1 of each cycle, full chemistry will be assessed. 
At Day 8 and Day 15 of each cycle, alleviated chemistry tests will be done. Only Alkaline 
phosphatase, ALT, AST, Creatinine, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, and 
BUN or Urea will be assessed. 
8.4.5.3 
Urinalysis 
Please refer to Table 8-5 Laboratory assessment for a list of tests to be performed and  
Table 8-2 for timing of assessments. 
8.4.5.4 
Thyroid 
Thyroid panel outlined in Table 8-5 Laboratory assessment will be performed in the Safety 
Run-in part and in Randomized part in the NIS793 with and without spartalizumab (Arms 1 
and 2) as per the assessment schedule in Table 8-2. 


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8.4.5.5 
Virology 
Virology panel outlined in Table 8-5 Laboratory assessment will be performed as per the 
assessment schedule in Table 8-2. 
8.4.5.6 
Additional tests 
Carbohydrate antigen 19-9 (CA 19-9) outlined in Table 8-5 Laboratory assessment will be 
performed as per the assessment schedule in Table 8-2. 
8.4.6 
Electrocardiogram (ECG) 
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position to 
ensure a stable baseline. The preferred sequence of cardiovascular data collection during study 
visits is ECG collection first, followed by vital signs, and blood sampling. The individual ECGs 
should be recorded approximately 2 minutes apart.  
Standard 12 lead ECGs are to be performed with ECG machines available at the site at screening 
and as clinically indicated. 
On day and timepoints coinciding with blood sample collection, the ECG should be taken prior 
to blood collection. 
For any ECGs with participant safety concerns, two additional ECGs must be performed to 
confirm the safety finding. In that case, the mean QTcF value will be calculated from the 
triplicate ECGs for each participant. 
Any identifier details must be redacted e.g. participant initials, date of birth. 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or AEs as appropriate. 
Interpretation of the tracing must be made by a qualified physician and documented on the 
appropriate CRF. Each ECG tracing should be labeled with the study number, participant 
number, date, and kept in the source documents at the study site. Clinically significant 
abnormalities present at screening should be reported on the appropriate CRF. 
Clinically significant findings must be discussed with Novartis prior to enrolling the participant 
in the study. New or worsened clinically significant findings occurring after informed consent 
must be recorded as AEs. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the Investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the Investigator. 
8.4.6.1 
Cardiac imaging - echocardiogram or CT/MRI scan 
Cardiac imaging (either echocardiogram or CT/MRI), will be performed at screening to 
determine cardiac function and morphology at baseline. Thereafter, echocardiogram will be 
performed if clinically indicated and/or if cardiac enzymes are elevated: 
≥ 2x ULN (if normal at screening), or ≥ 2x baseline (if baseline value was elevated). 


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8.4.6.2 
Cardiac enzymes 
Cardiac specific enzyme Troponin I and NTproBNP will be performed at screening, C3D1 and 
day 1 of every third cycle during treatment duration or as clinically indicated, and at EOT visit. 
8.4.7 
Pregnancy  
A condom is required for all sexually active male participants to prevent them from fathering a 
child and to prevent delivery of study treatment via seminal fluid to their partner. In addition, 
male participants should not donate sperm for the time period specified in Section 5.2. 
Pregnancy tests will be performed for women of childbearing potential. All pre-menopausal 
women who are not surgically sterile will have pregnancy testing. Additional pregnancy testing 
might be performed if requested by local requirements. 
At screening, a serum pregnancy test must be performed within 3 days before the first dose. 
During the study (Day 1 of each cycle starting with Cycle 2) and at End of Treatment, a serum 
pregnancy test must be performed. 
A urine or serum pregnancy test is to be performed every month during and at the end of the 
safety follow-up period. If the participant is not coming to the clinic during the safety follow-up 
period, a pregnancy test may be performed at home or at a local doctor’s office at each of the 
safety follow-up timepoints described above, and the results will be communicated to the site 
staff. These follow-up pregnancy tests will be recorded in the source documentation, not in the 
CRF.  
In case of a positive urine pregnancy test, additional tests must be performed to confirm 
pregnancy and if confirmed, it requires immediate discontinuation of study treatment. 
See Section 10.1.4 for pregnancy reporting. 
Local pregnancy test and associated results will not be collected on CRF. 
8.4.8 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. 
8.5 
Additional assessments 
8.5.1 
Pharmacokinetics 
To assess PK, 
and immunogenicity (IG) of NIS793, blood samples will be 
collected from all participants in Safety Run-in part and Randomized Arms 1 and 2 to 
determine serum level of NIS793, 
and anti-NIS793 antibody.  
To assess PK and IG of spartalizumab, blood samples will be collected from all participants in 
Safety Run-in part and Randomized Arm 1 of the study to determine free spartalizumab 
concentration in serum, and anti-spartalizumab antibody level in serum.  
To assess PK of gemcitabine and nab-paclitaxel, blood samples will be collected from all 
participants in Safety Run-in part and all three Randomized arms of the study. PK of 
gemcitabine, dFdU (2',2'-difluoro-deoxyuridine, the primary metabolite of gemcitabine), and 
total nab-paclitaxel will be determined in plasma.  




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Table 8-6 
Pharmacokinetic blood collection log - NIS793 and spartalizumab in 
Safety Run-in part and Randomized Arms 1 & 2 
Cycle 
Day 
Scheduled 
Timepoint (h) 
NIS793 
analytes 
Spartalizumab 
analytes 
1 
1 
Predose a 
PK and IG 
PK and IG 
1 
1 
1h post dose (± 5min) 
PK 
PK 
1 
2 
24h post dose (+ 24h) 
PK 
PK 
1 
8 
168h post dose (± 8h) 
PK 
PK 
1 
15 
336h (± 24h post 
dose)  
(pre-NIS793 dose) 
PK 
- 
2 
1 
Predose a 
PK and IG 
PK and IG 
3 
1 
Predose a 
PK and IG 
PK and IG 
3 
1 
1h post dose§ (± 
5min) 
PK 
PK 
3 
2 
24h post dose (+ 48h) 
PK 
PK 
3 
8 
168h post dose (± 8h) 
PK 
- 
3 
15 
336h (± 24h post 
dose)  
(pre-NIS793 dose) 
PK 
- 
4 
1 
Predose a 
PK and IG 
PK and IG 
5 
1 
Predose a 
PK and IG 
PK and IG 
6 
1 
Predose a 
PK and IG 
PK and IG 
7 
1 
Predose a 
PK and IG 
PK and IG 
8 
1 
Predose a 
PK and IG 
PK and IG 
EOT 
  
- 
PK and IG 
PK and IG 
End of safety 
follow-upc 
 
- 
PK and IG 
PK and IG 
Unscheduledb 
  
- 
PK and IG 
PK and IG 
IG, immunogenicity 
a Pre-dose blood samples should be collected prior to start of NIS793 and spartalizumab infusion 
b Unscheduled PK and IG samples will be collected in the event of a clinically significant AE (such 
as infusion reaction/anaphylaxis/DILI) or if immunogenicity is suspected. 
c Samples will not be collected if end of safety follow up may be performed via phone call 












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Study treatment must be discontinued under the following circumstances: 
• Participant/guardian decision 
• Any situation in which study participation might result in a safety risk to the participant 
• Death 
If discontinuation of study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should not be considered withdrawn from the study unless they withdraw their 
consent (see Section 9.1.2). Where possible, they should return for the assessments indicated in 
the Assessment Schedule. If they fail to return for these assessments for unknown reasons, every 
effort (e.g. telephone, e-mail, letter) should be made to contact the participant/pre-designated 
contact as specified in the lost to follow-up Section 9.1.3. This contact should preferably be 
done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• AEs / SAEs 
The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
For participants who discontinue treatment for reasons other than documented disease 
progression, death, lost to follow-up, or withdrawal of consent as applicable, tumor assessments 
must continue to be performed every 8 weeks until 52 weeks then every 12 weeks until 
documented disease progression per Investigator, death, lost to follow-up, or withdrawal of 
consent as applicable. 
In some circumstances, participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST 1.1 criteria (refer to Section 6.1.4.1 for detail). 
These participants will continue assessments as outlined in Section 8, and will complete the 
EOT visit only after permanent discontinuation of study treatment. 
9.1.1.1 
Replacement policy 
Participants of the Randomized part will not be replaced on study. All treated participants will 
contribute to the final analyses. During Safety Run-in part, if a participant is considered to be 
non-evaluable for the Dose Determining Set (Section 12.1.3), enrollment of a new participant 
to the current cohort will be considered. Enrollment of new participants may be considered until 
six evaluable participants within a cohort are achieved.   


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9.1.2 
Withdrawal of informed consent/Opposition to use data//biological 
samples 
Withdrawal of consent/opposition to use data occurs when a participant: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required in a certain country’s legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection or use of personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the Investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed. 


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9.1.4 
Early study termination by the sponsor 
The study can be stopped by Novartis at any time. 
Reasons for early termination  
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. The Investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the participant’s interests. The Investigator or sponsor depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.  
9.2 
Study completion and post-study treatment 
Study completion is defined as when the end of study criteria are met, or, in the event of an 
early study termination decision, the date of that decision. 
9.2.1 
End of study 
The end of study is defined as one of the following: 
• All participants have discontinued study treatment and completed the safety follow-up and 
at least 80% of the participants have died, withdrawn consent or are lost to follow-up.  
• Another study becomes available that can continue to provide participants’ study treatment, 
and all participants ongoing are transferred to that clinical study and all discontinued 
participants have completed the safety follow-up period. Transfer of participants will only 
be allowed after primary endpoints (refer to Table 2-1) have been reached. 
• The study is terminated early (Section 9.1.4). In such case the end of study will be when all 
participants have completed the treatment period and the safety follow-up period. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside the study through an alternative treatment option to subjects (or patients) who, in the 
opinion of the Investigator, are still deriving clinical benefit. 
For participants who transfer to another clinical study or an alternative treatment option to 
continue provision of study treatment, the follow-up for safety, disease progression and survival 
will not be performed. 
See Section 12 Data Analysis and statistical methods for details of timing of the primary 
analysis and final reporting of data. 


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9.2.2 
Post-treatment follow-up 
After treatment discontinuation, all participants will be followed for safety and survival, as 
described in Section 9.2.3 and Section 9.2.4. 
Participants who discontinue study treatment for any reason other than death, disease 
progression per RECIST 1.1 while on treatment, clinical deterioration, lost to follow-up, 
consent withdrawal, study termination, also should return for tumor evaluation assessments. 
If participants refuse to return for these visits or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone to determine if the participant had 
disease progression. Once the Follow up for Disease progression period ended, the End of Post 
treatment Phase disposition CRF should be completed. 
In addition, participants who discontinue study treatment for any reason other than death, 
disease progression (radiological or clinical deterioration), lost to follow-up, withdrawal of 
consent or study termination should return for tumor evaluation assessments every 8 weeks until 
52 weeks then every 12 weeks until confirmation of disease progression per RECIST 1.1, death, 
lost to follow-up, or withdrawal of consent. If a participant starts a new anti-neoplastic therapy 
prior to progression, tumor assessments should continue per the planned visit schedule  
(Table 8-2) until disease progression is documented. In addition, all new antineoplastic 
therapies given after the last dose of study treatment, will be recorded in the eCRF. 
If participants refuse to return for these visits or are unable to do so, every effort should be made 
to contact them or a knowledgeable informant by telephone to determine if the participant had 
disease progression. 
9.2.3 
Safety follow-up 
All participants must have safety evaluations for 90 days after the last dose of NIS793, 150 days 
after the last dose of spartalizumab and 30 days after the last dose of gemcitabine and nab-
paclitaxel, whichever is longer. The evaluations can be done by telephone call or visit for the 
30-, 90-, and 150-day safety follow-up visits. Concomitant medications will be collected until 
the 30-day safety follow-up has been completed or the start of a new antineoplastic therapy, 
whichever occurs first. A PK and immunogenicity sample should be collected at the end of 
safety follow-up as described in Section 8.5.1. If the safety evaluation is conducted by phone, 
samples do not need to be collected. 
Data collected should be added to the relevant CRF. For female participants of childbearing 
potential, pregnancy tests will be performed as outlined in Section 8.4.7. 
9.2.4 
Survival follow-up 
After completion of the safety follow-up, participants will enter the survival follow-up period. 
Participants will be contacted by telephone every 12 weeks to follow-up their survival status. 
Any new antineoplastic therapies that have been started since the last contact date will also be 
collected during these phone calls. 


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10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g. any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a clinical 
investigation participant after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The Investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
• AEs will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. Grade 1 to 5 will be used to characterize the severity 
of the AE. 
• Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
• Its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported 
• Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
• Action taken regarding with study treatment. 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
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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 AEs 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. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 
AE monitoring should be continued for at least 30 days for all participants, 90 days for 
participants treated with NIS793 and 150 days for participants treated with spartalizumab, 
following the last dose of study treatment. 
Following the completion of the 30 days safety follow-up period, if a new post-treatment 
antineoplastic therapy is initiated, only AEs suspected to be related to study treatment will be 
collected in the Adverse Events CRF. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Progression of maligna
ing fatal outcomes), if documented by use of appropriate 
method (as per RECIST
criteria for solid tumors), should not be reported as a SAE, 
except if the Investigator considers that progression of malignancy is related to study treatment. 
AEs separate from the progression of malignancy (i.e. 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. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. 


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10.1.2 
Serious adverse events 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred. 


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10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days for all participants, 90 days for participants 
treated with NIS793 and 150 days for participants treated with spartalizumab, following the last 
administration of study treatment, must be reported to Novartis safety immediately, without 
undue delay, but no later than within 24 hours of obtaining knowledge of the events (Note: If 
more stringent, local regulations regarding reporting timelines prevail). Detailed instructions 
regarding the submission process and requirements are to be found in the Investigator folder 
provided to each site. Information about all SAEs is collected and recorded on the electronic 
with paper back-up Serious Adverse Event Report Form; all applicable sections of the form 
must be completed in order to provide a clinically thorough report. 
Any SAEs experienced after the end of the safety follow-up should only be reported to Novartis 
Safety if the Investigator suspects a causal relationship to study treatment.  
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the Investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
Investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
SAE collection starts at time of main study informed consent whether the participant is a screen 
failure or not. 
After the completion of the 30 days safety follow-up period, if a participant starts a 
post-treatment antineoplastic therapy, then only SAEs suspected to be related to study treatment 
will be reported. 
Any SAEs experienced after the end of the safety follow-up should only be reported to Novartis 
Safety if the Investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting  
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 


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Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy should be recorded and reported by the Investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1 and Section 10.1.2). 


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10.2 
Additional Safety Monitoring 
10.2.1 
Data Monitoring Committee   
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
Investigators participating in the study.  
The DMC will assess at defined intervals the progress of a clinical trial, safety data (aggregated 
data and by treatment data), and critical efficacy variables and recommend to the sponsor 
whether to continue, modify, or terminate a trial. 
Specific details regarding composition, responsibilities, data monitoring, and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC. 
11 
Data Collection and Database management  
11.1 
Data collection  
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the Investigator staff. 
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control  
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 


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Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the Investigators and their staff. During the study, 
Novartis employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The field monitor will visit the site to check the completeness 
of participant records, the accuracy of data capture / data entry, the adherence to the protocol 
and to Good Clinical Practice, the progress of enrollment, and to ensure that study treatment is 
being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the field monitor during these visits. Continuous remote monitoring 
of each site’s data may be performed by a centralized Novartis/delegated CRO/CRA 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis clinical teams to assist 
with trial oversight. 
The Investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
participant's file. The Investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 


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12 
Data analysis and statistical methods 
Data from participating centers in this protocol will be combined, so that an adequate number 
of participants will be available for analysis. 
The primary analysis may be conducted and results may be reported in a primary CSR when 
both or either of the following criteria are met: 
• Approximately 60 participants (who comply with the FAS criteria) have experienced a PFS 
event (documented progression as per RECIST 1.1 or death due to any cause) in the NIS793 
with spartalizumab and gemcitabine/nab-paclitaxel (Arm 1) and gemcitabine/nab-
paclitaxel (Arm 3) arms.  
• Approximately 60 participants (who comply with the FAS criteria) have experienced a PFS 
event (documented progression as per RECIST 1.1 or death due to any cause) in the NIS793 
with gemcitabine/nab-paclitaxel (Arm 2) and gemcitabine/nab-paclitaxel (Arm 3) arms. 
In case of primary CSR, any additional data for participants continuing to receive study 
treatment past the data cutoff date for the primary CSR, as allowed by the protocol, will be 
reported at completion of the study in a final CSR. 
All summaries, listings, figures and analyses will be performed for all participants in the Safety 
Run-in part and by treatment arm for the Randomized part, unless otherwise specified. 
Additional summaries by participant subgroups may be produced as relevant for selected 
endpoints. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, distributions (e.g., 25th and 75th percentiles) may also be presented. 
Screen failure participants, as described in Section 8.1, and the reasons for not starting the study 
treatment will be reported in a listing, but will not be included in any analyses. 
Details of the statistical analysis and data reporting will be provided in the Statistical Analysis 
Plan (SAP). Any data analysis carried out independently by the Investigator should be 
submitted to Novartis before publication or presentation. 


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12.1 
Analysis sets 
12.1.1 
Full Analysis Set 
Randomized Part 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, participants will be 
analyzed according to the treatment they have been assigned to during the randomization 
procedure. 
Safety Run-in and Randomized parts 
The Complete Full Analysis Set (C-FAS) comprises all participants from FAS and participants 
to whom study treatment has been assigned during the Safety Run-in part and who received 
at least one dose of study treatment (i.e. at least one dose of any drug of the study treatment 
(including incomplete infusion)).  
12.1.2 
Safety Set 
Safety Run-in part 
The Safety set 1 includes all participants who received at least one dose of study treatment 
(i.e. at least one dose of any drug of the study treatment (including incomplete infusion)).  
Randomized part 
The Safety set 2 includes all participants who received at least one dose of study treatment 
(i.e. at least one dose of any drug of the study treatment (including incomplete infusion)). 
Participants in the Randomized part will be analyzed according to treatment received, where 
treatment received is defined as: 
• the randomized treatment assigned if it was received at least once, or 
• the first treatment received if the randomized treatment was never received.  
All safety endpoints will be analyzed based on the safety sets. 
12.1.3 
Dose-Determining Set 
Safety Run-In part 
The Dose Determining Set (DDS) consists of all participants in the Safety Run-in part who 
met the minimum exposure criterion and have sufficient safety evaluations after 4 weeks of 
treatment or experienced a DLT during the first 4 weeks of treatment.  
A participant is considered to have met the minimum exposure criterion if the participant has 
received 2 doses of NIS793 (2100 mg Q2W or 1400 mg Q2W (only applicable in case of second 
cohort in Safety Run-in part)), 1 dose of spartalizumab (400 mg Q4W), 3 doses of gemcitabine 
(1000 mg/m2 Days 1, 8, and 15), and 3 doses of nab-paclitaxel (125 mg/m2 Days 1, 8, and 15).  
Participants who do not experience a DLT during the first 4 weeks of treatment are considered 
to have sufficient safety evaluations if they have been observed for 4 weeks following the first 
dose and are considered by both the Sponsor and Investigators to have enough safety data to 
conclude a DLT did not occur. 


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12.1.4 
Pharmacokinetic Analysis Set 
Randomized part 
Five separate Pharmacokinetic analysis sets (PAS) will be considered. One for NIS793 
(NIS-PAS), one for spartalizumab (PDR-PAS), one for gemcitabine (GEM-PAS), one for 
dFdU, the primary metabolite of gemcitabine (dFdU-PAS), and one for nab-paclitaxel 
(PAC-PAS). Each of the PAS includes all participants who provide an evaluable PK profile for 
this specific PAS. A profile is considered to be evaluable if all of the following conditions are 
satisfied: 
• Participant receives one dose (complete infusion) of the planned treatments 
• Participant provides at least one valid primary PK parameter  
• For pre-dose samples, have the sample collected before the next dose administration 
Participants may be removed from PK analysis on an individual basis depending on the number 
of available blood samples. These participants will be identified at the time of analysis. 
12.1.5 
Immunogenicity Analysis Set 
Randomized part 
The immunogenicity (IG) set includes two parts: IG prevalence set and IG incidence set: 
• The IG prevalence set includes all participants in the FAS with a determinant baseline IG 
sample or at least one determinant post-baseline IG sample. 
• The IG incidence set includes all participants in the IG prevalence set with a determinant 
baseline IG sample and at least one determinant post-baseline IG sample. 
The definition of a determinant sample will be specified in the SAP. 
12.2 
Participant demographics and other baseline characteristics  
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for participants in the Safety Run-in part using the C-FAS and by 
treatment arm for participants in the Randomized part using the FAS. 
Relevant medical histories and current medical conditions at baseline will be summarized and 
listed by system organ class, preferred term, and treatment arm. 
12.3 
Treatments 
Safety sets 1 and 2 will be used for the analyses below. 
The duration of exposure in weeks of NIS793, spartalizumab, gemcitabine, and nab-paclitaxel 
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. 
The duration of exposure will also be presented for each study drug. 


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The number of participants with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment arm 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 by participant and summarized by anatomical therapeutic 
classification system (ATC) term and treatment arm. 
12.4 
Analysis of the primary endpoints/estimands 
12.4.1 
Safety endpoints 
Safety Run-in part 
The primary safety objective is to characterize the safety and tolerability of NIS793 with 
spartalizumab and gemcitabine/nab-paclitaxel and to identify the dose to be tested in 
Randomized part and in future studies of NIS793 with spartalizumab and 
gemcitabine/nab-paclitaxel. 
12.4.1.1 Definition of primary endpoints 
The primary endpoints will be evaluated based on the following criteria: 
• Incidence of DLTs 
• Incidence of AEs and SAEs 
• Changes in laboratory values, vital signs, and ECGs 
• Dose interruptions, reductions, and dose intensity 
12.4.1.2 Statistical hypothesis, model, and method of analysis 
For all safety analyses, safety set 1 will be used.  
The overall observation period will be divided into three mutually exclusive segments: 
Pre-treatment period 
• From day of participant’s first informed consent to the day before first administration of 
any study drug. 
On-treatment period 
• From date of first administration of any study drug to 30 days after date of last actual 
administration of any study drug (including start and stop date). 
Post-treatment period 
• Starting at day 30+1 after the last administration of study treatment in the combination arm. 
Safety summaries will primarily be based on all data from the on-treatment period.  
Following last administration of study treatment, AEs (including SAEs) will be collected for 
30 days from last dose of gemcitabine/nab-paclitaxel, 90 days from the last dose of NIS793, 
and 150 days from the last dose of spartalizumab. New anti-cancer therapies will be collected 
until participant’s death or lost to follow-up.  Following start of new anti-cancer therapy, only 


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study treatment related AEs will be collected.  Select summaries of related AEs will be produced 
for the combined on-treatment and post-treatment periods. Details will be specified in the SAP. 
Dose-limiting toxicities 
The dose to be tested in Randomized part will be decided based upon the percentage of DLTs 
during the first 4 weeks of treatment for participants in the DDS, along with the evaluation of 
additional safety, clinical, PK, 
data. 
Algorithmic based approach 
For a dose to be declared safe, the targeted DLT rate should be below 33%. Occurrence of two 
or more DLTs out of six evaluable participants would trigger dose de-escalation or the end of 
study. For more details on the safety criteria refer to Section 6.5 and Appendix 4. 
Reporting 
DLTs will be listed and their incidence will be summarized by primary system organ class and 
worst grade (CTCAE version 5.0), using the DDS. 
Adverse events 
The number (and percentage) of participants with treatment emergent AEs (events started after 
the first dose of study medication or events present prior to start of treatment but increased in 
severity based on preferred term) will be summarized in the following ways: 
• by primary system organ class and preferred term 
• by primary system organ class, preferred term, and maximum severity 
• by Standardized MedDRA Query (SMQ) and preferred term 
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation, and AEs leading to dose adjustment.  
The number (and percentage) of participants with AEs of special interest (AESIs) will be 
summarized. A participant with multiple AEs within a primary system organ class is only 
counted once towards the total of the primary system organ class. 
SAEs, non-serious AEs, and AESIs during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths, and SAEs (including those from the pre and post-treatment periods) will be 
listed and those collected during the pre-treatment and post-treatment period will be flagged. 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. 
The following parameters will be collected: height (cm), weight (kg), body temperature (°C), 
heart rate (beats per minute), systolic and diastolic blood pressure (mmHg). 
Vital signs collected during on-treatment will be summarized. The number and percentage of 
participants with notable vital sign values will be presented for the safety set 1. A listing of 
participants with notable vital signs will be provided and values measured during the 


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post-treatment follow up will be flagged in the listing. Notable vital sign values criteria will be 
specified in the SAP. 
12-lead ECG 
12-lead ECGs including PR, QRS, QT and QTcF intervals and heart rate will be obtained for 
each participant during the study. ECG data will be read and interpreted locally. The average 
of the ECG parameters at each assessment should be used in the analyses.  
ECGs collected during on-treatment will be summarized. The number and percentage of 
participants with notable ECG values will be presented. A listing of participants with notable 
ECGs will be provided and values measured during the post-treatment follow-up will be flagged 
in the listing. Notable ECG values criteria will be specified in the SAP. 
Clinical Laboratory Evaluations 
All laboratory data will be listed by participant and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time. Shift tables 
using the low/normal/high/ (low and high) classification will be used to compare baseline to the 
worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 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 used. 
For laboratory tests where grades are not defined by CTCAE v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges. 
For laboratory tests where grades are defined by CTCAE v5.0: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant will 
be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value. 
For laboratory tests where grades are not defined by CTCAE v5.0: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value. 
Tolerability 
Tolerability of study drug will be assessed by summarizing the number of and reasons for dose 
delays/interruptions and dose reductions. Dose intensity will also be tabulated for each 
component of the study treatment. 


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12.4.1.3 Handling of missing values/censoring/discontinuations 
Participant safety data will be reported up to the cut-off date, end of post-treatment 
(if discontinued), death, lost to follow-up, or withdrawal of consent as applicable, whichever 
happened first. Missing values will not be imputed and will be reported as such. 
12.4.1.4 Sensitivity and Supportive analyses 
Not applicable. 
12.4.2 
Efficacy estimands 
Randomized part 
The primary efficacy objective of this study is to characterize the difference in anti-tumor 
activity of:   
a) NIS793 
with 
spartalizumab 
and 
gemcitabine/nab-paclitaxel 
versus 
gemcitabine/nab-paclitaxel and  
b) NIS793 with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel,  
by estimating the progression-free survival (PFS). Estimation of the hazard ratios (HRs) of the 
PFS and the corresponding credible intervals will be used to detect the magnitude of such 
anti-tumor activity difference. 
12.4.2.1 Definition of primary estimand 
PFS is defined as the time from the date of randomization to the date of the first documented 
progression or death due to any cause. PFS will be assessed via local review according to 
RECIST 1.1 (see Appendix 1 for further details). In the primary analysis, PFS will be censored 
at the date of the last adequate tumor assessment if no PFS event is observed prior to the analysis 
cut-off date. Handling of missing data (e.g., due to administrative censoring) is provided in 
Section 12.4.2.4. 
12.4.2.2 Statistical hypothesis, model, and method of analysis 
The same Bayesian model will be used to estimate and provide inferential summaries for both 
PFS HRs a) NIS793 with spartalizumab and gemcitabine/nab-paclitaxel (Arm 1) versus 
gemcitabine/nab-paclitaxel (Arm 3) and b) NIS793 with gemcitabine/nab-paclitaxel (Arm 2) 
versus gemcitabine/nab-paclitaxel (Arm 3). For each comparison, the PFS will be modeled 
using a two-piece hazard model, which allows specifying different hazard rates before and after 
the possible delayed effect for Arms 1 and 2 and constant hazard rate for Arm 3. Models are 
presented for the first comparison (Arm 1 vs Arm 3). The same assumptions apply to the 
second comparison (Arm 2 vs Arm 3). 
                        𝜆𝜆𝑡𝑡(𝑡𝑡) = 𝜆𝜆1 + (𝜆𝜆2 −𝜆𝜆1) ቀ
1
2 +
1
2 tanh൫𝑠𝑠(𝑡𝑡−𝜈𝜈)൯ቁ and ൜𝜆𝜆1 = 𝜇𝜇∗𝜂𝜂
𝜆𝜆2 = 𝜇𝜇/𝜂𝜂 
                                                           𝜆𝜆𝑐𝑐(𝑡𝑡) = −
log൫PFS(t)൯
t
, 




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More details will be provided in the SAP. 
12.4.2.5 Sensitivity analysis for primary estimand 
As a sensitivity efficacy analysis, PFS will be analyzed using a Cox model, without considering 
delayed effects, based on the FAS with the same analysis conventions as for the primary 
estimand. The treatment effect for each of the two comparisons will be summarized by the 
overall HR with its one-sided 90% confidence interval. Kaplan-Meier curves for PFS as well 
as medians along with their two-sided 95% confidence intervals will be presented for each 
treatment arm. 
12.4.2.6 Supplementary analyses 
A supplementary clinical question of interest is: 
• What is the effect of NIS793 and gemcitabine/nab-paclitaxel with and without 
spartalizumab relative to gemcitabine/nab-paclitaxel in prolonging time to death or 
radiological progression in first line mPDAC, had a new anti-cancer therapy not been 
available or had participants not discontinued treatment due to COVID-19?  
The justification for targeting these treatment effects is that we wish to estimate the relative 
effects of the treatment strategies in the absence of potentially a) a confounding effect of any 
new anti-cancer therapy that is not a part of the assigned treatment strategy or b) a treatment 
discontinuation due to COVID-19.  
In this supplementary estimand, all four attributes, that is population, primary variable, 
treatments of interest, and summary measure will be the same as for the primary estimand. 
Handling of intercurrent events: 
• New anti-cancer therapy initiated before observing PFS event will be handled using the 
hypothetical strategy.  
• Treatment discontinuation related to COVID-19 will be handled using the hypothetical 
strategy; 
• Treatment discontinuation for any reason not related to new anti-cancer therapy or COVID-
19 will be handled using the treatment policy strategy, as for the primary estimand. 
Start of a new anti-cancer therapy prior to disease progression or death and treatment 
discontinuation due to COVID-19 will be analyzed considering two different options: 
Option 1 
PFS will be censored at the last adequate disease assessment before the start of new anti-
neoplastic therapy or before discontinuing treatment due to COVID-19.  
Option 2 
Data from participants who switched to a new anti-cancer therapy or discontinued treatment 
due to COVID-19 will be imputed, simulating PFS times from a different model than the one 
described in Section 12.4.2.2. For the imputation, we will take into account the hazard rate of 
participants who remained into the study. 


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12.4.2.7 Supportive analyses 
As a supportive efficacy analysis of the study, PFS will be analyzed for the first comparison 
(Arm 1 vs Arm 3), based on the C-FAS, using the same analysis conventions as for the primary 
estimand. Participants from the Safety Run-in part will be analyzed together with Arm 1. For 
each arm separately, the Bayesian posterior estimate of median and one-sided 90% credible 
interval of HR will be presented using C-FAS. Similarly, for each arm separately, the median 
PFS per local review and the one-sided 90% confidence interval for HR of PFS will be 
presented, using C-FAS. The same analysis conventions as in the primary efficacy analysis will 
be applied.  
12.5 
Analysis of secondary endpoints/estimands  
Randomized part  
12.5.1 
Efficacy estimands 
The secondary efficacy objectives of this study are to assess the following:  
• Anti-tumor activity of NIS793 with and without spartalizumab in combination with 
gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel, based on overall response 
rate (ORR), duration of response (DOR), and time to progression (TTP)  
• Overall survival (OS) of NIS793 with and without spartalizumab in combination with 
gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel. 
Overall response rate (ORR)  
ORR is defined as the proportion of participants with a best overall response (BOR) of 
confirmed complete response (CR) or partial response (PR) as per Investigator assessment as 
per RECIST 1.1 (see Appendix 1).  
ORR will be calculated based on the data from the FAS and the corresponding 95% confidence 
intervals based on the exact binomial distribution (Clopper and Pearson 1934) will be presented. 
Duration of response (DOR) 
DOR is defined as the time from the date of first documented response (CR or PR) to the first 
documented progression per RECIST 1.1 or death due to any cause. If a participant with a CR 
or PR has no progression or death, the participant is censored at the date of last adequate tumor 
assessment. Definition of last adequate tumor assessment is provided in Appendix 1.  
DOR will be analyzed based on FAS for participants with confirmed BOR of CR or PR. Median 
DOR, 
with 
corresponding 
95% 
CI, 
and 
25th 
and 
75th 
percentiles 
(Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) will be presented. Kaplan-
Meier estimates for DOR proportions at specific timepoints, along with 95% CI (Greenwood’s 
formula, Kalbfleisch and Prentice 2002) will also be provided. 


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Time to progression (TTP) 
TTP is the time from the date of randomization to the date of event defined as the first 
documented progression per RECIST 1.1 or death due to underlying cancer. If a participant has 
no progression or death, the participant is censored at the date of last adequate tumor 
assessment. Definition of last adequate tumor assessment is provided in Appendix 1.  
TTP will be summarized using the Kaplan-Meier method, based on FAS. Median TTP, with 
corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein 
and Moeschberger 1997) will be presented. Kaplan-Meier estimates for TTP proportions at 
specific timepoints, along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002) 
will also be provided. 
Overall survival (OS) 
OS is defined as the time from the date of randomization to date of death due to any cause. If a 
participant is not known to have died by the date of the cut-off, OS will be censored at the last 
date the participant was known to be alive.  
OS will be summarized using the Kaplan-Meier method, based on FAS. Median OS, with 
corresponding 95% CI, and 25th and 75th percentiles (Brookmeyer and Crowley 1982, 
Klein and Moeschberger 1997) will be presented. Kaplan-Meier estimates for OS proportions 
at specific timepoints, along with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 
2002) will also be provided. 
12.5.1.1 Handling of intercurrent events of secondary estimands 
The secondary analyses will account for three intercurrent events as explained in the following: 
• Start of a new anti-cancer therapy prior to disease progression or death: Tumor 
assessment data collected after discontinuation of study treatment and start of new anti-
cancer therapy will be used to derive the secondary variables. 
• Treatment discontinuation related to COVID-19: Tumor assessment data collected after 
discontinuation of study treatment due to COVID-19 will be used to derive the secondary 
variables. 
• Treatment discontinuation for any reason not related to new anti-cancer therapy or 
COVID-19: Tumor assessment data collected after discontinuation of study treatment will 
be used to derive the secondary variables. 
12.5.1.2 Handling of missing values not related to intercurrent events 
For handling of missing values, censoring, and discontinuations refer to Section 12.4.2.4. 
12.5.2 
Safety endpoints 
Randomized part 
For all safety analyses, safety set 2 will be used. Results will be presented by treatment arm 
following the analyses as presented in Section 12.4.1. 


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12.5.3 
Immunogenicity 
Immunogenicity will be characterized descriptively by tabulating ADA prevalence at baseline 
and ADA incidence on-treatment. The impact of immunogenicity on PK, safety, and efficacy 
will be explored. Further details will be specified in the SAP. 
12.5.4 
Pharmacokinetics 
All PK data analysis and PK summary statistics will be based on the NIS-PAS, PDR-PAS, 
GEM-PAS, dFdU-PAS, and PAC-PAS. PK parameters will be determined using non-
compartmental method(s) for NIS793, spartalizumab, gemcitabine, dFdU, and nab-paclitaxel. 
NIS793, spartalizumab, gemcitabine, dFdU, and nab-paclitaxel concentration data will be listed 
by treatment, participant, and visit/sampling timepoint. Descriptive summary statistics will be 
provided by treatment and visit/sampling timepoint, including the frequency (n, %) of 
concentrations below the LLOQ and reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. Concentrations below LLOQ will be treated as 
zero in summary statistics and for PK parameter calculations.   
The PK parameters in the Table 12-1 will be estimated and reported, when applicable. 
Descriptive summary statistics, for the PK parameters, will include: mean (arithmetic and 
geometric), SD, and CV (arithmetic and geometric), median, minimum, and maximum. An 
exception to this is Tmax where median, minimum, and maximum will be presented. Missing 
data will not be imputed and will be treated as missing. 
Table 12-1 
Non-compartmental pharmacokinetic parameters  
AUClast 
 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) 
AUCtau 
 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time 
x volume-1) 
Cmax 
 
The maximum (peak) observed serum/plasma drug concentration after dose 
administration (mass x volume-1) 
Tmax 
 
The time to reach maximum (peak) serum/plasma drug concentration after dose 
administration (time) 
Ctrough 
 
The lowest serum/plasma drug concentration reached by a drug before the next dose 
is administered (mass x volume-1) 
T1/2 
 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration time curve (time). Use qualifier for other half-lives 
CL 
 
The total body clearance of drug from the serum/plasma (volume x time-1) 
Vz 
 
The volume of distribution during terminal phase (associated with λz) (volume) 
12.5.4.1 Handling of missing values/censoring/discontinuations 
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%. 


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12.5.4.2 Population pharmacokinetic analysis 
If data permit, a non-linear mixed-effects model may be applied to the NIS793 and/or 
spartalizumab and/or gemcitabine and/or dFdU and/or nab-paclitaxel concentration-time data 
to generate post hoc estimates of pharmacokinetic parameters to characterize the NIS793 and/or 
spartalizumab and/or gemcitabine and/or dFdU and/or nab-paclitaxel exposure. If there is 
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. 
Data generated on hypothesis-free platforms will be reported separately (e.g. CSR addendum). 


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12.7 
Interim analyses 
Safety Run-in part 
No formal IA is planned. However, the dose evaluation from the Safety Run-in part for 
NIS793 with spartalizumab and gemcitabine/nab-paclitaxel allows that decisions are taken 
based on the current data. More precisely, after each cohort in the dose evaluation, the decision 
to proceed with the Randomized part, de-escalate, or end the study will be based on review, 
by Novartis study personnel and Investigators, of available safety and tolerability information 
(including the DLT risk assessment) along with PK 
data. Details of this procedure and 
the process for communication with Investigators are provided in Section 6.5.  
Randomized part 
IA of efficacy data may be conducted to support decision making concerning the Sponsor’s 
clinical development projects. Additional supportive analyses of available clinical data may be 
considered if appropriate. Details on the IA may be provided in the CSR SAP or in a stand-
alone SAP.  
However, this IA is not planned to support formal design adaptations in the current phase II 
study. 
The safety data will be monitored on a regular basis by the DMC (as defined in Section 10.2.1). 


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Further details will be provided in DMC charter and DMC SAP. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoints 
Safety Run-in part  
No formal statistical power calculations to determine sample size were performed for this part 
of the study.  
At least six participants will be enrolled in order to have six evaluable participants. Table 16-8 
in Appendix 4 presents the probability of observing zero, one, or more than two DLTs out of 
six participants for different true DLT rates. In case of dose de-escalation to dose level -1 
(Table 6-2), a second cohort will open and at least six more participants will be enrolled in order 
to have six evaluable participants. 
Randomized part 
Sample size calculation was based on simulations for various scenarios on treatment outcome, 
number of participants included, and number of events at the timepoint of the analysis using the 
Bayesian model defined in Section 12.4.2.2. 
The evaluation of the success criteria was based on the HR of the PFS (NIS793 with 
spartalizumab and gemcitabine/nab-paclitaxel vs gemcitabine/nab-paclitaxel) after the 
timepoint of risk change in the assumed two-piece hazard model (HR2) used in the Bayesian 
model (in order to account for potential delayed effects). The same success criteria apply for 
the HR of the PFS of NIS793 with gemcitabine/nab-paclitaxel vs gemcitabine/nab-paclitaxel. 
The success criteria used for the evaluation of the efficacy of the simulation samples are the 
following: 
• At least 50% confidence level that HR2 ≤ 0.7 
• At least 90% confidence level that HR2 < 1 
Approximately 150 participants are expected to be treated in the study (additionally to those 
from the Safety Run-in part), randomized with ratio 1:1:1 (NIS793 with spartalizumab and 
gemcitabine/nab-paclitaxel (Arm 1): NIS793 with gemcitabine/nab-paclitaxel (Arm 2): 
gemcitabine/nab-paclitaxel (Arm 3)). In this calculation a 10% risk of dropout per participant 
year has been taken into consideration. 
Regarding the enrolment plan of the study, we assume that 15 participants will be accrued per 
month in all three arms, until a total of 150 participants are treated in the study. 
The reported median PFS for gemcitabine/nab-paclitaxel as first-line therapy for PDAC 
participants was 5.5 months in Von Hoff study (Von Hoff et al 2013). It was, therefore, assumed 
that the median PFS of gemcitabine/nab-paclitaxel ranged between 5 and 6 months. For the 
NIS793 treated arms, we expect an approximately 3-month delayed onset of clinical benefit due 
to immunotherapeutic compounds that will be referred to as delayed effect. Additionally, we 
expect around 50% reduction in the hazard rate of PFS, after the timepoint of risk change in the 
assumed two-piece hazard model.  


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For both comparisons, the same model assumptions are considered. Therefore, sample size 
calculations will be presented only for the first comparison and the same calculations will be 
applicable to the second comparison. Table 12-2 presents the operating characteristics of the 
Bayesian model with different outcome scenarios keeping stable the total sample size to 
100 participants (for Arms 1 and 3), the number of total PFS events to 60 required at the 
timepoint of the analysis, and assuming a 3-month delayed effect for Arm 1. With this 
combination, reasonable operating characteristics can be achieved. Description of operating 
characteristics of alternative sample size and delayed effect assumptions can be found in 
Appendix 5. 
Table 12-2 
Operating characteristics for scenarios with 100 participants, 
60 events, and a 3-month delayed effect 
Scenarios  
Median PFS in months 
Arm 1 vs Arm 3 (Hazard ratio)  
Probability of Success 
Median follow-up 
period since FPFV 
(months)† 
5.5 vs 5.5 (HR2=1) 
0.151 
14.1 
5.0 vs 5.0 (HR2=1) 
0.124 
13.3 
6.0 vs 6.0 (HR2=1) 
0.137 
14.8 
8.0 vs 6.0 (HR2=0.600) 
0.697 
16.2 
7.5 vs 5.5 (HR2=0.557) 
0.735 
15.5 
6.6 vs 5.0 (HR2=0.557) 
0.709 
15.5 
9.0 vs 6.0 (HR2=0.500) 
0.864 
16.8 
8.5 vs 5.5 (HR2=0.456) 
0.914 
16.1 
HR2: Hazard ratio after the risk change in the two-piece hazard model. 
† FPFV of the Randomized part. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the Investigator and IRB/IEC 
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures 
(e.g., advertisements) and any other written information to be provided to participants. Prior to 
study start, the Investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the instructions 
and procedures found in this protocol and to give access to all relevant data and records 
to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated agents 
of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical 


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site is requested by a regulatory authority, the Investigator must inform Novartis immediately 
that this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (see Section 9.2.1) and finalization 
of the study report the results of this trial will be submitted for publication and posted in a 
publicly accessible database of clinical trial results, such as the Novartis clinical trial results 
website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial Investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of Investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes. 
14 
Protocol adherence  
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and Health Authorities, where required, it cannot be 
implemented. 


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14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
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NCCN Guidelines (2019) Available from: https://www.nccn.org/professionals/physician_gls/.  
Neesse A, Michl P, Frese KK, et al (2011) Stromal biology and therapy in pancreatic cancer. 
Gut; 60(6):861-8.  
Neuzillet C, de Gramont A, Tijeras-Raballand A, et al (2014) Perspectives of TGF-β 
inhibition in pancreatic and hepatocellular carcinomas. Oncotarget; 5(1):78-94. 
O’Reilly EM, Oh DY, Dhani N, et al (2019) Durvalumab with or without tremelimumab for 
patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. 
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Pickup M, Novitskiy S and Moses HL (2013) The roles of TGFβ in the tumour 
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Provenzano PP, Cuevas C, Chang AE, et al (2012) Enzymatic targeting of the stroma ablates 
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Renton KW (2005) Regulation of drug metabolism and disposition during inflammation and 
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Schutte M, Hruban RH, Hedrick L, et al (1996) DPC4 gene in various tumor types. Cancer 
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16 
Appendices 
16.1 
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1) 
16.1.1 
Introduction 
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009). 
The efficacy assessments described in Section 16.1.2 and the definition of best response in 
Section 16.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.1.3.2 is summarizing the “time to 
event” variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 16.1.4 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. 
16.1.2 
Efficacy assessments 
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247. 
16.1.2.1 Definitions 
16.1.2.1.1 
Disease measurability 
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions. 
• Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
For patients without measurable disease see Section 16.1.3.2.8 
• Measurable lesions (both nodal and non-nodal) 
Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm. 
Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft tissue 
component meets the definition of measurability. 


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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. 
16.1.2.1.2 
Eligibility based on measurable disease 
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 16.1.3.2.8. 
16.1.2.2 Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 


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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. 
16.1.2.3 Baseline documentation of target and non-target lesions 
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions: 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the 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 16.1.2.1.1. 
• Nodal target: See Section 16.1.2.1.1. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF. 


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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. 
16.1.2.4 Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions will be calculated 
(at baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 16-1) and non-target lesions (Table 16-2) identified at baseline. 
These evaluations are then used to calculate the overall lesion response considering both the 
target and non-target lesions together (Table 16-3) as well as the presence or absence of new 
lesions. 
16.1.2.4.1 
Follow-up and recording of lesions 
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number. 
Non-nodal lesions 
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size). 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement.  This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval. 
In other cases where the lesion cannot be reliably measured for reasons other than its size 
(e.g., borders of the lesion are confounded by neighboring anatomical structures), no 
measurement should be entered and the lesion cannot be evaluated. 


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Nodal lesions 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist. 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval. 
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. 
16.1.2.4.2 
Determination of target lesion response 
Table 16-1 
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 
• SOD for CR may not be zero when nodal lesions are part of target lesions 
• 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 
• 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 16.1.2.2). 


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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 16-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). 
Proper documentation should be available to support this decision. This 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 


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for target lesions. On the case report form, the diameter of the “merged lesion” should be 
recorded for the size of one of the original lesions while a size of “0”mm should be entered 
for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response should 
be assigned when all nodal target lesions shrink to less than 10 mm and all non-nodal target 
lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if either 
a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm and 
there is at least 20% increase in sum of the diameters of all nodal target lesions relative to 
nadir with at least 5 mm increase in the absolute sum of the diameters.  
• 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. 
16.1.2.4.3 
Determination of non-target lesion response 
Table 16-2 
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) 


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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 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 16.1.2.4.2 for assigning PD following a CR for the non-target lesion response in the 
presence of non-target lesions nodal lesions should be applied. 
16.1.2.4.4 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion 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 16.1.2.5). 


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• 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 16.1.2.2. 
16.1.2.5 Evaluation of overall lesion response 
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in  
Table 16-3. 
Table 16-3 
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 
This overall lesion response also applies when there are no non-target lesions identified at baseline. 
Once confirmed PR was achieved, all these assessments are considered PR. 
As defined in Section 16.1.2.4. 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
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. 
16.1.3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
16.1.3.1 Best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria. 


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The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol. 
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met. 
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed. 
• For non-randomized trials where response is the primary endpoint, confirmation is needed. 
• For trials intended to support accelerated approval, confirmation is needed 
• For all other trials, confirmation of response may be considered optional. 
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules: 
• CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required 
• PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR prior 
to progression where confirmation not required 
• SD = at least one SD assessment (or better) > 6 weeks after randomization/start of treatment 
(and not qualifying for CR or PR). 
• PD = progression ≤ 12 weeks after randomization/ start of treatment (and not qualifying for 
CR, PR or SD). 
• 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 


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PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD. 
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (≥30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ≥20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable. 
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments. 
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response. 
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates. 
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources: 
• Investigator overall lesion response 
• Central Blinded Review overall lesion response 
• Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review) 
The primary analysis of the best overall response will be based on the sequence of 
investigator/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” 
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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. 
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). 
16.1.3.2 Time to event variables 
16.1.3.2.1 
Progression-free survival 
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint. 
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment. 
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.  
16.1.3.2.2 
Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 


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16.1.3.2.3 
Time to progression 
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer. 
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment. 
16.1.3.2.4 
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. 
16.1.3.2.5 
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. 


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16.1.3.2.6 
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). 
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. 
16.1.3.2.7 
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. 


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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 16.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options. 
• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the worst 
possible outcome as it means the patient cannot subsequently respond. Since the statistical 
analysis usually makes use of the ranking of times to response it is sufficient to assign the 
worst possible censoring time which could be observed in the study which is equal to the 
maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise.  In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
16.1.3.2.8 
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. 


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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 16.1.3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. 
This corresponds to the latest date for either the visit date, lab sample date or tumor 
assessment date. If available, the last known date patient alive from the survival follow-up 
page is used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
16.1.3.2.9 
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 16-5.  


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Table 16-4 
Overall lesion response at each assessment: patients with non-target 
disease only 
Non-target lesions 
New Lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD1 
No 
Non-CR/non-PD 
UNK 
No 
UNK 
PD 
Yes or No 
PD 
Any 
Yes 
PD 
1 As defined in Section 16.1.2.4. 
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category. 
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account. 
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”.  
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
16.1.3.2.10 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 16.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 
April 2005) as a reference, the following analyses can be considered: 


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Table 16-5 
Options for event dates used in PFS, TTP, duration of response 
Situation 
Options for end-date (progression or 
censoring)1 
(1) = default unless specified differently in 
the protocol or RAP 
Outcome 
A 
No baseline assessment 
(1) Date of randomization/start of treatment3 Censored 
B 
Progression at or before next 
scheduled assessment 
(1) Date of progression 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C1 Progression or death after exactly 
one missing assessment 
(1) Date of progression (or death) 
(2) Date of next scheduled assessment2 
Progressed 
Progressed 
C2 Progression or death after two or 
more missing assessments 
(1) Date of last adequate assessment2 
(2) Date of next scheduled assessment2 
(3) Date of progression (or death) 
Censored 
Progressed 
Progressed 
D 
No progression 
(1) Date of last adequate assessment 
Censored 
E 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator 
claim 
(1) 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 
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 16.1.3.2.7. 
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in  
Section 16.1.3.2.7. 
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death. 
The primary analysis and the sensitivity analyses must be specified in the protocol. 
Clearly define if and why options (1) are not used for situations C, E and (if applicable) F. 
Situations C (C1 and C2): Progression or death after one or more missing assessments: 
The primary analysis is usually using options (1) for situations C1 and C2, i.e. 
• (C1) taking the actual progression or death date, in the case of only one missing assessment. 
• (C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments. 


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In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2. 
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration. 
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1) (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, 
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 16-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment 
(from baseline)”, with the following definition: 
• Date of previous scheduled assessment (from baseline) is the date when a 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. 


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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. 
16.1.4 
Data handling and programming rules 
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates). 
16.1.4.1 Study/project specific decisions 
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation. 
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock). 
16.1.4.2 End of treatment phase completion 
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
The end of treatment visit and its associated assessments should occur within 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.  


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16.1.4.3 End of post-treatment follow-up (study phase completion) 
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up. 
Patients may provide study phase completion information for one of the following reasons: 
• Adverse event 
• Lost to follow-up 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Technical problems 
• Subject/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
16.1.4.4 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 
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 
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16.1.4.5 Programming rules 
The following should be used for programming of efficacy results: 
16.1.4.5.1 
Calculation of ‘time to event’ variables 
Time to event = end date - start date + 1 (in days) 
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative. 
16.1.4.5.2 
Incomplete assessment dates 
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year. 
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date 
(and assessment date is calculated as outlined in Section 16.1.3.2.7). If all measurement dates 
have no day recorded, the 1st of the month is used. 
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation. 
16.1.4.5.3 
Incomplete dates for last known date patient alive or death 
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact. 
16.1.4.5.4 
Non-target lesion response 
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’. 
16.1.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.1.4.5.6 
Censoring reason 
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page. 
For survival the following censoring reasons are possible: 
• Alive 
• Lost to follow-up 


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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 16-4) 
• 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 16.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted: 
• 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-
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. 
16.1.5 
References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791. 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47. 
Ellis S, Carroll KJ, Pemberton K (2008) Analysis of duration of response in oncology trials. 
Contemp Clin Trials 2008; 29: 456-465. 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man. 
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18. 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16. 


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16.3 
Appendix 3: List of concomitant medications 
In general, the use of any concomitant medication deemed necessary for the care of the 
participant is permitted in this study, except as specifically prohibited below. 
Concomitant administration of study treatments could result in DDIs that could potentially lead 
to reduced activity or enhanced toxicity of the concomitant medications and/or gemcitabine 
and/or nab-paclitaxel. Please note that all lists in Appendix 3 are not comprehensive. 
Please refer to regular update online sources and the label of the concomitant drug to decide 
whether a drug is permitted (with caution) or prohibited based on Section 6.2.2 
(prohibited Medications). In case of doubt, please contact the medical monitor with any 
questions. 
16.3.1 
Permitted medication to be used with caution 
The list of CYP450 substrates and list of CYP450 inhibitors / inducers was compiled from the 
University of Washington’s Drug Interaction Database (updated January 2020) 
(https://www.druginteractionsolutions.org/). This list is only meant to be used as a guidance. 
Table 16-7 
List of CYP substrates, inhibitors and inducers of CYP3A4, and 
inhibitors of CYP2C8 to be used with caution 
Category 
Drug name 
CYP3A4 substrates which are known or 
potential auto-perpetrators 
clarithromycin, conivaptan, encorafenib, 
erythromysin, diltiazem, mifepriston, ribociclib, 
telthromycin, troleandomycin, verapamil 
Strong CYP3A4 inhibitors 
ceritinib, clarithromysin, conivaptan, grapefruit juice 
(citrus paradisi fruit juice, 240 mL TID), idealisib, 
itraconazole, ketoconazole, mibefradil, mifepristone, 
nefazodone, posaconazole, ribociclib, telithromycin, 
troleandomycin, voriconazole 
Strong CYP3A4 inducers 
apalutamide, avasimibe1, carbamazepine, 
enzalutamide, ivosidenib, lumacaftor, mitotane, 
phenobarbital, phenytoin, rifabutin, rifapentine, 
rifampin (rifampicin), St John’s wort (Hypericum 
perforatum)1 
Strong and moderate CYP2C8 inhibitors 
clopidogrel (strong), deferasirox (moderate), 
gemfibrozil (strong), letermovir (moderate), 
teriflunomide (moderate) 
1Herbal product 
This list of CYP450 inhibitors and inducers was compiled from the University of Washington’s Drug 
Interaction Database (updated January 2020) 
 


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16.4 
Appendix 4: Statistical considerations – Algorithmic based 
approach for Safety Run-in part 
Dose evaluation for NIS793 with spartalizumab and gemcitabine/nab-paclitaxel will follow the 
algorithm specified in Section 6.5. 
In particular, Table 16-8 below specifies the probability of potential confirmation of dose to be 
tested in Randomized part, or switching to a different dose and regimen (if not tested yet), or 
dropping the study treatment, based on observation of number of DLTs out of six evaluable 
participants for different true DLT rates. 
Table 16-8 
Dose evaluation scenarios (NIS793 with spartalizumab and 
gemcitabine/nab-paclitaxel) 
 
Probability of observing 0,1 or ≥ 2 DLTs out of 6 participants: 
True probability of DLT 
0 or 1 * 
≥2** 
5% 
0.97 
0.03 
15% 
0.78 
0.22 
25% 
0.53 
0.47 
35% 
0.32 
0.68 
45% 
0.17 
0.83 
*declaration of dose to be tested in Randomized part allowed 
**dose and regimen not considered safe. Either switch to a different dose and regimen (if not tested 
yet) or drop the study treatment 


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16.5 
Appendix 5: Bayesian model set-up and prior specifications 
16.5.1 
Statistical model 
For each comparison, the underlying PFS time (in years) will be modeled using a two-piece 
hazard model. This model allows the specification of different hazard rates before/after the 
possible delayed effect for NIS793 with spartalizumab and gemcitabine/nab-paclitaxel (Arm 1) 
and for NIS793 with gemcitabine/nab-paclitaxel (Arm 2) and constant hazard rate for 
gemcitabine/nab-paclitaxel (Arm 3). Models, below, present the first comparison (Arm 1 vs 
Arm 3) and the same assumptions apply to the second comparison (Arm 2 vs Arm 3). The 
hazard function for each arm is given by   
                        𝜆𝜆𝑡𝑡(𝑡𝑡) = 𝜆𝜆1 + (𝜆𝜆2 −𝜆𝜆1) ቀ
1
2 +
1
2 tanh൫𝑠𝑠(𝑡𝑡−𝜈𝜈)൯ቁ and ൜𝜆𝜆1 = 𝜇𝜇∗𝜂𝜂
𝜆𝜆2 = 𝜇𝜇/𝜂𝜂 
𝜆𝜆𝑐𝑐(𝑡𝑡) = −log൫PFS(t)൯
t
,   
where 𝜆𝜆𝑡𝑡 and  𝜆𝜆𝑐𝑐 are the hazard rates for Arms 1 and 3, respectively. Parameters 𝜆𝜆1 and 𝜆𝜆2 are 
the respective hazard rates before/after the delayed effect for Arm 1, 𝜇𝜇 is a type of average 
hazard and 𝜂𝜂 is the divergence from this average in each period. The study year is depicted by 
𝑡𝑡, 𝑠𝑠= 15 is a fixed slope parameter that dictates the speed with which the hazard changes from 
period 1 to period 2 and 𝜈𝜈 is the risk changing timepoint (i.e., the time to the delayed effect). 
The corresponding HR between Arm 1 and Arm 3 after the delayed effect is 𝜆𝜆2/𝜆𝜆c. 
In a clinical trial, the time to progression may lie between the assessment at which the event is 
observed and day of the previous assessment+1 when participants have an event of progression. 
It is assumed the time to the event has a uniform distribution within this period. 
16.5.2 
Prior specifications 
Prior for the risk change-point 
A Gamma prior is used for the time of the risk change-point 𝜈𝜈. For Arms 1 and 2 the prior is 
selected such that the mode is 0.25 years (i.e. three months) and the variance is 0.015. 
The resulting priors for 𝜈𝜈 is Gamma(6, 20). 
Prior for Arm 3 PFS 
For Arm 3, a two component mixture of gamma distributions is used for the prior for 𝜆𝜆𝑐𝑐. 
These components correspond to a median PFS of 0.46 years (i.e. 5.5 months) as reported in 
the Von Hoff trial and an 80% credible interval of (0.32, 0.72) years (3.8, 8.6 months)  
(Figure 16-1). 
The resulting mixture Gamma distribution is: 0.2*Gamma(2.0, 1.1) + 0.8*Gamma(15.5, 10.0) 
with median PFS of 0.46 years.  


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Figure 16-1 
Prior distribution for Arm 3 PFS 
 
Prior for Arms 1 and 2 
The same Gamma priors will be assumed for both Arms 1 and 2 for the hazard before and after 
the delayed effect. Gamma priors for 𝜇𝜇 and 𝜂𝜂 are selected such that the resulted median PFS is 
at least 2 months higher than the median PFS of Arm 3 (5.5 months) with a wide credible 
interval. The resulting priors for 𝜇𝜇 and 𝜂𝜂 are Gamma(4.6, 4.2) and Gamma(5, 4), respectively.  
Full prior 
Combining the priors for 𝜈𝜈, 𝜇𝜇, and 𝜂𝜂 gives the complete specification of the prior of PFS for 
Arms 1 and 2 (Figure 16-2). This is a weakly informative prior with median PFS of 0.63 years 
(i.e. 7.6 months) and a wide 80% credible interval of (0.29, 1.45) years (3.5, 17.4 months). 


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Figure 16-2 
Full prior distribution for Arms 1 and 2 PFS 
 
Operating characteristics 
The operating characteristics for the Bayesian analysis described in Section 12.4.2.2 are 
obtained by performing extensive simulations.  
16.5.2.1 Generating hypothetical datasets 
Let ni denote the sample size for each treatment group, and a𝑗𝑗 denote the accrual rate in the jth 
accrual month.  
For each treatment group different possible values for the underlying median PFS are specified. 
For each scenario with one of the specified value for the underlying median PFS, the 
hypothetical PFS dataset is generated by the following steps: 
1. Set accrual waiting time to 0 for the first participant. Generate accrual waiting times for the 
remaining participants based on equidistance enrollment within each month with the accrual 
rate being a𝑗𝑗= 10 participants/month.  
2. Generate a random sample of ni PFS times in unit of year following the two-piece hazard 
model with the timepoint of risk change being at 0.25 years.  
3. Take a sample of ni × 𝑟𝑟𝑒𝑒  participants from the ni participants without replacement, where 
𝑟𝑟𝑒𝑒 is the early dropout rate before the first assessment and is pre-specified as 6.25% in this 
study. Set the corresponding censoring time as 1 day. 


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4. Generate a random sample of ni-ni ∗𝑟𝑟𝑒𝑒  censoring times, based on the assumption of an 
exponential distribution corresponding to a dropout risk of 𝑟𝑟𝑑𝑑= 0.1 per participant year. 
Where censoring time is earlier than event time, the participant follow up time is set to the 
censoring time and the participant is treated as censored in the subsequent analysis. 
5.  For each participant an assessment schedule is generated, based on tumor assessments 
occurring every 8 weeks during the first year and every 12 weeks thereafter. A +/- 1 week 
window is assumed for each assessment, with the timing of the assessment distributed 
uniformly within this window. For each participant with an event it is assumed the event is 
observed at the next assessment on or after the day of the event. For censored participants, 
the day of censoring is the last assessment on or before the day of censoring.   
6. Calculate accrual calendar time (i.e., the cumulative sum of the accrual waiting times before 
the participant enrolled) and scheduled PFS calendar time (i.e., the sum of accrual calendar 
time and the event/censoring occurred time time). Rank the non-censored scheduled PFS 
calendar time from the shortest to the longest. Since the primary analysis will be performed 
after 60 events are observed, the 60th non-censored scheduled PFS calendar time will be 
considered as the day of analysis.  
7. For participants with progression events after the day of analysis, and hence censored in that 
analysis, the censoring time is set to be the day of last assessment on or before the day of 
analysis cut-off. 
The steps 1-7 above are repeated to generate a total of 1000 hypothetical datasets for each 
scenario. 
16.5.2.2 Posterior analysis 
Given the prior distributions and parameter values specified above, the corresponding posterior 
distributions for each of the 1000 hypothetical datasets are obtained by performing extensive 
MCMC simulations using Stan with 5000 iterations plus a burn-in length of 3000 for each of 
four chains. For each pair of posterior values of 𝜆𝜆2 and 𝜆𝜆c the HR after the timepoint of risk 
change HR2 is calculated as 𝜆𝜆2/𝜆𝜆c. The calculated HR from the iterations form the posterior 
distribution for the primary endpoint. The mean, median, standard deviation, and 90%-quantile 
will be calculated from this posterior distribution. The operating characteristics in terms of 
probability of success among 1000 hypothetical datasets for the above mentioned Bayesian 
study design under different true median PFS for each arm are summarized in the following 
table. 


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Table 16-9 
Probabilities to declare a success under various scenarios, assuming 
a 3-month delayed effect  
Scenarios  
Median PFS in months 
Arm 1 vs Arm 3 (Hazard ratio) 
 
Sample size and analysis timing 
N=100, when 
60 events 
were 
observed 
N=110, 
when 70 
events 
were 
observed 
N=110, when 
75 events 
were 
observed 
N=120, when 
80 events 
were 
observed 
5.5 vs 5.5 (HR2=1) 
0.151 
0.117 
0.115 
0.123 
5.0 vs 5.0 (HR2=1) 
0.124 
0.138 
0.124 
0.115 
6.0 vs 6.0 (HR2=1) 
0.137 
0.155 
0.147 
0.131 
8.0 vs 6.0 (HR2=0.600) 
0.697 
0.735 
0.751 
0.762 
7.5 vs 5.5 (HR2=0.557) 
0.735 
0.801 
0.825 
0.840 
6.6 vs 5.0 (HR2=0.557) 
0.709 
0.774 
0.808 
0.821 
9.0 vs 6.0 (HR2=0.500) 
0.864 
0.906 
0.920 
0.921 
8.5 vs 5.5 (HR2=0.456) 
0.914 
0.919 
0.938 
0.950 
HR2: Hazard ratio after the risk change in the two-piece hazard model. 
Note: The success criteria are defined as at least 50% confidence level that HR2≤ 0.7 and at least 90% 
confidence level that HR2<1. 
The sample size of 100 participants with the analysis timing of 60 events is selected. It is the 
minimum sample size and minimum number of events that ensures approximately 70% 
probability to declare success if the underlying HR2<0.6, while controlling the probability to 
declare success at approximately 15% if the underlying HR2=1. 
Additional sensitivity analyses for 100 participants and 60 events, while varying the underlying 
assumption of delayed effect in the NIS793 based arm, are presented in Table 16-10 and 
Table 16-11. The results imply that the Bayesian model is robust.  


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Table 16-10 
Operating characteristics for scenarios with 100 participants, 
60 events, and a 2-month delayed effect 
Scenarios  
Median PFS in months 
Arm 1 vs Arm 3 (Hazard ratio)  
Probability of Success 
Median follow-up 
period since FPFV 
(months)† 
5.5 vs 5.5 (HR2=1) 
0.151 
14.1 
6.0 vs 6.0 (HR2=1) 
0.137 
14.8 
8.0 vs 6.0 (HR2=0.666) 
0.607 
16.1 
7.5 vs 5.5 (HR2=0.636) 
0.650 
15.5 
8.5 vs 5.5 (HR2=0.538) 
0.821 
14.4 
8.0 vs 5.0 (HR2=0.500) 
0.866 
15.2 
HR2: Hazard ratio after the risk change in the two-piece hazard model. 
† FPFV of the Randomized part. 
Table 16-11 
Operating characteristics for scenarios with 100 participants, 
60 events, and no delayed effect 
Scenarios  
Median PFS in months 
Arm 1 vs Arm 3 (Hazard ratio)  
Probability of Success 
Median follow-up 
period since FPFV 
(months)† 
5.5 vs 5.5 (HR2=1) 
0.151 
14.1 
6.0 vs 6.0 (HR2=1) 
0.137 
14.8 
8.0 vs 6.0 (HR2=0.750) 
0.430 
16.1 
7.5 vs 5.5 (HR2=0.733) 
0.448 
15.2 
8.5 vs 5.5 (HR2=0.647) 
0.614 
16.0 
8.0 vs 5.0 (HR2=0.625) 
0.646 
15.1 
HR2: Hazard ratio after the risk change in the two-piece hazard model. 
† FPFV of the Randomized part. 
 

SAP_001.pdf: 
Clinical Development 
NIS793 
CNIS793B12201 / NCT04390763
A phase II, open label, randomized, parallel arm study of 
NIS793 (with and without spartalizumab) in combination 
with SOC chemotherapy gemcitabine/nab-paclitaxel, and 
gemcitabine/nab-paclitaxel alone in first-line metastatic 
pancreatic ductal adenocarcinoma (mPDAC)  
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Amendment 1 
Release date: 
11-June-2024
Number of pages: 
56 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 3.0, Effective from 01-Jul-2020 






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Table of contents 
Table of contents ................................................................................................................. 4 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design ............................................................................................................ 9 
1.2 
Study objectives and endpoints ............................................................................. 12 
2 
Statistical methods ............................................................................................................. 13 
2.1 
Data analysis general information ......................................................................... 13 
2.1.1 
General definitions ................................................................................ 14 
2.2 
Analysis sets .......................................................................................................... 18 
2.2.1 
Full Analysis Set ................................................................................... 18 
2.2.2 
Safety Set .............................................................................................. 19 
2.2.3 
Dose-Determining Set ........................................................................... 19 
2.2.4 
Pharmacokinetic Analysis Set ............................................................... 19 
2.2.5 
Immunogenicity Analysis Set ............................................................... 20 
2.2.6 
Subgroup of interest .............................................................................. 21 
2.3 
Participant disposition, demographics and other baseline characteristics ............. 21 
2.3.1 
Participant disposition ........................................................................... 21 
2.3.2 
Demographic data ................................................................................. 22 
2.3.3 
Medical history...................................................................................... 22 
2.3.4 
Diagnosis and extent of cancer ............................................................. 22 
2.3.5 
Protocol deviations ................................................................................ 22 
2.3.6 
Analysis sets .......................................................................................... 22 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 22 
2.4.1 
Study treatment / compliance ................................................................ 22 
2.4.2 
Dose reductions, interruptions, or permanent discontinuations ............ 25 
2.4.3 
Prior, concomitant and post therapies ................................................... 26 
2.5 
Analysis of the primary objectives ........................................................................ 26 
2.5.1 
Safety objective ..................................................................................... 26 
2.5.2 
Efficacy objective .................................................................................. 28 
2.6 
Analysis of the key secondary objective ............................................................... 30 
2.7 
Analysis of secondary efficacy objectives ............................................................. 30 
2.7.1 
Secondary estimands ............................................................................. 31 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 31 


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2.7.3 
Handling of intercurrent events of secondary estimands ...................... 32 
2.7.4 
Handling of missing values/censoring/discontinuations ....................... 33 
2.8 
Safety analyses....................................................................................................... 33 
2.8.1 
Adverse events (AEs) ............................................................................ 33 
2.8.2 
Deaths .................................................................................................... 35 
2.8.3 
Laboratory data ..................................................................................... 35 
2.8.4 
Other safety data ................................................................................... 36 
2.9 
Pharmacokinetic endpoints .................................................................................... 37 
2.10 
Immunogenicity ..................................................................................................... 39 
2.10.1 
Sample ADA status ............................................................................... 39 
2.10.2 
Participant ADA status .......................................................................... 40 
2.10.3 
Transient and persistent ADA responses .............................................. 40 
2.11 
Patient-reported outcomes ..................................................................................... 41 
 
 ............................................................................................................. 41 
 
 .............................................................................................. 42 
2.14 
Interim analysis ...................................................................................................... 42 
3 
Sample size calculation ..................................................................................................... 42 
3.1 
Primary endpoints .................................................................................................. 42 
4 
Change to protocol specified analyses .............................................................................. 44 
5 
Appendix ........................................................................................................................... 46 
5.1 
Imputation rules ..................................................................................................... 46 
5.1.1 
Study drug ............................................................................................. 46 
5.1.2 
AE date imputation ............................................................................... 47 
5.1.3 
Concomitant medication date imputation ............................................. 47 
5.1.4 
Handling missing month/day in date of death/last known 
participant alive from survival eCRF page ........................................... 48 
5.2 
AEs coding/grading ............................................................................................... 48 
5.3 
Laboratory parameters derivations ........................................................................ 48 
6 
Reference ........................................................................................................................... 56 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 12 
Table 2-1 
Time windows for ECOG performance status assessments .................. 17 
Table 2-2 
Last contact date data sources ............................................................... 18 
Table 2-3 
Participant classification based on protocol deviations and non-
protocol deviation criteria ..................................................................... 21 


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Table 2-4 
Definition of last date of exposure to study drug .................................. 23 
Table 2-5 
Clinically notable changes in vital signs ............................................... 37 
Table 2-6 
Non-compartmental PK parameters ...................................................... 37 
 
 ......................................................... 42 
Table 3-1 
Operating characteristics for scenarios with 100 participants and 60 
events .................................................................................................... 43 
Table 5-1 
Imputation rules for a partially missing AE start date .......................... 47 
Table 5-2 
Imputation legend and AE/treatment start date relationship ................. 47 
Table 5-3 
CTC grades for laboratory values in Novartis Oncology ...................... 50 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 10 
Figure 1-2 
Study flow in Safety Run-in part .......................................................... 11 
Figure 1-3 
Study flow in Randomized part............................................................. 12 
Figure 4-1 
Prior distribution for Gemcitabine/Nab-paclitaxel arm ........................ 44 
Figure 4-2 
Prior distribution for NIS793-based arms ............................................. 45 
 


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List of abbreviations 
ADA 
Anti-drug Antibody 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALP 
Alanine Phosphatase  
ALT 
Alkaline Aminotransferase 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BOR 
Best Overall Response 
BSA 
Body Surface Area 
CD8 
Cluster of Differentiation 8 
C-FAS 
Complete Full Analysis Set 
CI 
Confidence Interval 
CR 
Complete Response 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DDS 
Dose Determining Set 
DI 
Dose Intensity 
DMC 
Data Monitoring Committee  
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Co-operative Oncology Group 
eCRF 
Electronic Case Report Form 
EOT 
End of Treatment 
FAR 
First Available Report 
FAS 
Full Analysis Set 
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
IG 
Immunogenicity 
 
 
K-M 
Kaplan-Meier 
LLOQ 
Lower Limit of Quantitation 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
mPDAC 
metastatic Pancreatic Ductal Adenocarcinoma 
NMQ 
Novartis MedDRA Queries 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PAS 
Pharmacokinetic Analysis Set 
PD 
Pharmacodynamics 
PDI 
Planned Dose Intensity 
PD-L1 
Programmed Death-Ligand 1 
PDS 
Programming Datasets Specifications 
PFS 
Progression-Free Survival 


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PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
RDI 
Relative Dose Intensity 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD  
Stable Disease 
SD 
Standard Deviation 
SMQ 
Standardized MedDRA Queries 
SOC 
Standard of Care 
SOC 
System Organ Class 
TBL 
Total Bilirubin Level 
TFLs 
Tables, Figures, Listings 
TGF-β 
Transforming Growth Factor-Beta 
TTP  
Time-to-Progression 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cells 
WHO 
World Health Organization 


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1 
Introduction 
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CNIS793B12201 that will be presented in the Clinical Study Report (CSR).  
The output shells (in-text and post-text) accompanying this document can be found in the Tables, 
Figures and Listings (TFL) shells document. The specifications for derived variables and 
datasets can be found in the Programming Datasets Specifications (PDS) document. The content 
of this SAP is based on protocol amendment version 04 dated 18-April-2022. All decisions 
regarding analyses, as defined in the SAP document, have been made prior to database lock of 
the study data. 
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend. 
The SAP, TFL shells, and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., IB updates, abstracts, posters, presentations, 
manuscripts, and management updates. Data used for these analyses will have a status aligned 
to the database lock guidance. 
1.1 
Study design 
This is a randomized, parallel arms, open-label, multi-center, Phase II study to evaluate the 
efficacy and safety of NIS793 with and without spartalizumab in combination with 
gemcitabine/nab-paclitaxel in participants with first-line metastatic pancreatic ductal 
adenocarcinoma (mPDAC). 
The study is expected to enroll at least 156 participants. An overview of the study design is 
depicted in Figure 1-1. 


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Figure 1-1 
Study design 
 
Safety Run-in part 
The study will start with a Safety Run-in part to assess the safety and tolerability of NIS793 
in combination with spartalizumab and standard of care (SOC) gemcitabine/nab-paclitaxel. 
Doses defined for each study treatment, as part of this quadruplet will be administered in the 
Randomized part in the quadruplet/triplet/doublet-based treatment arms. At least six 
participants will be enrolled in the Safety Run-in part. 
NIS793 will be administered at a flat dose of 2100 mg every 2 weeks and spartalizumab at a 
flat dose of 400 mg every 4 weeks. Gemcitabine (1000 mg/m² on Days 1, 8, and 15) and nab-
paclitaxel (125 mg/m² on Days 1, 8, and 15) will be given as per label.  
A safety review meeting, as described in the CSP Section 6.5.2.1, will take place when six 
enrolled participants have completed 4 weeks of treatment or discontinued earlier due to dose 
limiting toxicity (DLT). The dose decision will be guided by an algorithm specified in CSP 
Section 6.5.2. If a decision to modify the dosing regimen is made at this time, an additional 
safety review of a new dosing regimen will take place after six additional participants have been 
enrolled and completed 4 weeks of treatment or have discontinued earlier due to DLT.  
Refer to Figure 1-2 for an overview of the Safety Run-in part study flow. 


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Figure 1-2 
Study flow in Safety Run-in part 
 
EOT: end of treatment; FU: follow-up 
Randomized part 
After the Safety Run-in part has been completed, the randomization part will open and 
approximately 150 participants will be randomized in a 1:1:1 ratio to one of the three treatment 
arms:  
• Arm 1: NIS793 with spartalizumab and gemcitabine/nab-paclitaxel 
• Arm 2: NIS793 with gemcitabine/nab-paclitaxel 
• Arm 3: gemcitabine/nab-paclitaxel 
Randomization will not be stratified.  
Participants in any randomized arm will be treated according to each study treatment dose, 
including gemcitabine/nab-paclitaxel (dose label), declared to be safe in the Safety Run-in part.  
An independent Data Monitoring Committee (DMC) will monitor safety and efficacy data 
during the trial. A separate DMC SAP will specify the analyses to be performed for the DMC 
reviews. No formal interim efficacy analysis is planned in this study.  
Progression free survival (PFS) as per local Investigator’s review of tumor response based on 
RECIST 1.1 criteria is the primary endpoint in the Randomized part of the study. 
The primary efficacy and primary safety analyses, as well as the overall survival analysis may 
be performed once both the following criteria are met: 
• At least 60 participants have experienced a PFS event (documented progression as per 
RECIST 1.1 or death due to any cause) in Arms 1 and 3 and  
• at least 60 participants have experienced a PFS event (documented progression as per 
RECIST 1.1 or death due to any cause) in Arms 2 and 3. 
The final analysis will be performed after the completion of the study. 
Refer to Figure 1-3 for an overview of the study flow in Randomized part. 


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Figure 1-3 
Study flow in Randomized part 
 
R: randomization; EOT: end of treatment; FU: follow-up 
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(s) 
Endpoint(s) 
Primary Objective(s) 
Endpoint(s) for primary objective(s)  
Safety Run-in part: 
• To assess the safety and tolerability of 
NIS793 + spartalizumab in combination with 
gemcitabine/nab-paclitaxel 
• 
Incidence of DLTs during the first 4 weeks of 
treatment 
• Safety: Incidence and severity of treatment 
emergent AEs and SAEs, changes between 
baseline and post-baseline laboratory 
parameters, vital signs, and ECG 
parameters 
• Tolerability: Dose interruptions, reductions 
and dose intensity 
Randomized part: 
• 
To evaluate the progression-free survival (PFS) of 
NIS793 with spartalizumab in combination with 
gemcitabine/nab-paclitaxel versus 
gemcitabine/nab-paclitaxel  
• 
To evaluate the PFS of NIS793 with 
gemcitabine/nab-paclitaxel versus 
gemcitabine/nab-paclitaxel 
 
• 
Progression-free survival based on Response 
Evaluation Criteria in Solid Tumors (RECIST1.1) 
as per local Investigator’s review 
Secondary Objective(s) 
Endpoint(s) for secondary objective(s) 
Randomized part 
 
• 
To evaluate the safety and tolerability of NIS793 
with and without spartalizumab in combination 
with gemcitabine/nab-paclitaxel versus 
gemcitabine/nab-paclitaxel 
• 
Incidence and severity of AEs and SAEs, including 
changes in laboratory values, vital signs and 
ECGs, dose interruptions, reductions, and dose 
intensity 
• 
To assess the preliminary anti-tumor activity of 
NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel 
versus gemcitabine/nab-paclitaxel 
• 
Overall response rate (ORR), Duration of 
response (DOR), Time to Progression (TTP) 
RECIST 1.1 as per local Investigator’s review 


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Objective(s) 
Endpoint(s) 
• 
To assess Overall Survival (OS) of NIS793 with 
and without spartalizumab in combination with 
gemcitabine/nab-paclitaxel versus 
gemcitabine/nab-paclitaxel 
• 
Overall Survival (OS) 
• 
To assess the CD8 and PD-L1 status of the 
participants at screening and on treatment versus 
gemcitabine/nab-paclitaxel 
• 
Change from baseline in CD8 and PD-L1 IHC 
related markers 
• 
To characterize the incidence of immunogenicity 
of NIS793 and spartalizumab in combination with 
gemcitabine/nab-paclitaxel 
• 
Antidrug antibodies (ADA) prevalence at baseline 
and ADA incidence on-treatment (anti-NIS793 
and anti-spartalizumab) 
• 
To characterize the pharmacokinetics (PK) of 
NIS793, spartalizumab, gemcitabine/nab-
paclitaxel in combination treatment or alone 
(gemcitabine/nab-paclitaxel) 
• 
Pharmacokinetic parameters (e.g. Ctrough, Cmax, 
AUClast) 
• 
PK concentration time profiles 
2 
Statistical methods 
2.1 
Data analysis general information 
Novartis will perform the analysis specified in this SAP for the CSR. SAS version 9.4 or later 
and R version 3.4.3 or later will be used to perform all data analyses and to generate tables, 
figures, and listings. 
At the time of the primary analysis, clinical data obtained from the treatment arms of the 
randomized part suggested that there was no evidence of clinical benefit when combining 
NIS793 with spartalizumab and gemcitabine/nab-paclitaxel and, NIS793 with gemcitabine/nab-
paclitaxel compared to gemcitabine/nab-paclitaxel alone. In light of these data, the 


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administration of NIS793 was stopped. Therefore, the reported CSR will be abbreviated. The 
abbreviated CSR will include at least one output for each primary and secondary endpoint. 
The primary efficacy and primary safety analyses, as well as the overall survival analysis may 
be presented in a First Available Report (FAR) document, if deemed necessary, when at least 
60 participants have experienced a PFS event (documented progression as per RECIST 1.1 or 
death due to any cause) in Arms 1 and 3 and at least 60 participants have experienced a PFS 
event in Arms 2 and 3. The FAR will include outputs planned within the TFL shells document 
related to the previously mentioned analyses.  
All events with a 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 a documented end date. The cut-off date for the primary analysis will 
be the date the last of the required events is documented.  
All primary and secondary analyses will be reported in the full CSR at the end of the study. The 
end of study is defined as one of the following: 
• All participants have discontinued study treatment and completed the safety follow-up and 
at least 80% of the participants have died, withdrawn consent or are lost to follow-up;  
• Another study becomes available that can continue to provide participants’ study 
treatment and all ongoing participants are transferred to that clinical study and all 
discontinued participants have completed the safety follow-up period. Transfer of 
participants will only be allowed after primary endpoints have been reached; 
• The study is terminated early. In such case, the end of study will be when all participants 
have completed the treatment period and the safety follow-up period. 
General analysis conventions 
Pooling of centers: Unless specified, data from all study centers will be pooled for the analysis. 
Due to the expected small number of participants enrolled at centers, no center effect will be 
assessed. 
 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
overall participants in the Safety Run-in part and by treatment arm for participants in the 
Randomized part; a missing category will be included as applicable. Percentages will be 
calculated using the number of participants 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) overall participants 
in the Safety Run-in part and by treatment arm for participants in the Randomized part. 
2.1.1 
General definitions  
Definitions below apply for each part of the study. A participant included in the Safety Run-in 
part will not enter in the Randomized part. 


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2.1.1.1 
Investigational drug and investigational treatment 
Investigational drug will refer to NIS793 and spartalizumab. Control drug will refer to 
gemcitabine and nab-paclitaxel.  
The terms investigational and control drug may also be referred to as study drug. 
Safety Run-in part 
Investigational treatment will refer to: 
• Arm 1: NIS793 + spartalizumab + gemcitabine + nab-paclitaxel. 
Randomized part 
Investigational treatment will refer to: 
• Arm 1: NIS793 + spartalizumab + gemcitabine + nab-paclitaxel; 
• Arm 2: NIS793 + gemcitabine + nab-paclitaxel. 
Control treatment will refer to: 
• Arm 3: gemcitabine + nab-paclitaxel. 
The terms investigational and control treatment may also be referred to as study treatment.  
2.1.1.2 
Date of first administration of study drug  
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug is administered and recorded on the treatment page eCRF. The date of first 
administration of study drug will also be referred as start of investigational drug. 
2.1.1.3 
Date of last administration of study drug  
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug is administered and recorded on the treatment page eCRF. The date of last 
administration of study drug will also be referred as end of investigational drug.  
2.1.1.4 
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment was administered as per treatment page eCRF. The 
date of first administration of study treatment will also be referred as start of study treatment. 
For example, if the first dose of NIS793 with spartalizumab and gemcitabine/nab-paclitaxel is 
taken on 13Oct2020, 25Dec2020, 13Oct2020, and 13Sep2020 respectively, then the date of first 
administration of study treatment is on 13Sep2020 
2.1.1.5 
Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a non-zero 
dose of any component of study treatment was administered as per treatment page eCRF. The 
date of last administration of study treatment will also be referred as end of study treatment. 


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For example, if the last dose of NIS793 with spartalizumab and gemcitabine/nab-paclitaxel is 
taken on 13Oct2020, 25Dec2020, 13Oct2020, and 13Sep2020 respectively, then the date of last 
administration of study treatment is on 25Dec2020. 
2.1.1.6 
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. 
In the Safety Run-in part, the reference start date for all assessments is the start of study 
treatment. In the Randomized part, the reference start date for safety assessments (e.g., 
adverse event onset, laboratory abnormality occurrence, vital sign measurement, dose 
adjustments, etc.) is the start of study treatment. The reference start date for all other non-
safety assessments (i.e., tumor assessment, survival time, disease progression, tumor response, 
and ECOG performance status) is the date of randomization.  
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. 
2.1.1.7 
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. 
2.1.1.8 
Baseline 
In the Safety Run-in part, the last available assessment on or before the date of start of study 
treatment is defined as “baseline” assessment for both safety and efficacy. 
In the Randomized part, for efficacy evaluations, the last non-missing assessment, including 
unscheduled assessments on or before the date of randomization is taken as “baseline” value or 
“baseline” assessment.  
In the context of baseline definition, the efficacy evaluations also include 
ECOG performance status. For safety evaluations, the last available assessment on or before 
the date of start of study treatment is taken as ‘‘baseline” assessment. For safety parameters 
(e.g., ECGs or vital signs), where study requires multiple replicates per timepoint, the average 
of these measurements would be calculated for baseline (if not already available in the database). 
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
multiple values are from the same laboratory or collected for ECGs or vital signs, then the last 
value should be considered as baseline. 
If participants have no value as defined above, the baseline result will be missing.  


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2.1.1.9 
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 participant’s informed consent to the day before first 
administration of study treatment; 
2. on-treatment period: from date of first administration of study treatment up 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 30+1 after last administration of study treatment. 
Safety summaries (tables, figures) and summaries of on-treatment deaths 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, all deaths which 
occurred during the study (i.e., during the on-treatment and post-treatment periods) will be 
summarized.  
An on-treatment adverse event (or treatment-emergent AEs) is defined as any adverse event 
reported in the on-treatment period.   
An on-treatment assessment is defined as any assessment performed after the date of first 
administration of any study drug i.e., assessments performed in the following time interval 
(including the lower and upper limits): from date of first administration of any study drug +1 
up to 30 days after the date of last administration of study treatment. 
Data listings will include all assessments/events, flagging those, which are not on-treatment 
assessment/event (i.e., pre-treatment and post-treatment period). 
2.1.1.10 Window for multiple assessments 
In order to summarize ECOG performance status collected over time (including unscheduled 
visits), the assessments will be time slotted. The following general rule will be applied in 
creating the assessment windows: If more than one assessment is available in the same time 
window, the assessment closest to the planned date will be considered. If 2 assessments within 
a time window are equidistant from the target date, then the earlier of the 2 assessments will be 
used. If multiple assessments on the same date then the average will be used.   
Table 2-1 
Time windows for ECOG performance status assessments 
Time Window 
Planned Visit Timing  
Time Window Definition 
On treatment 
 
 
Baseline (screening) 
Before study Day 1 
< Day 1 
Cycle 1 Day 1 
Study Day 1* 
Study Day 1 
Cycle 1 Day 8 
Cycle 1 Day 15 
Cycle 2 Day 1 
Cycle 2 Day 8 
Cycle 2 Day 15 
Study Day 8 
Study Day 15 
Study Day 29 
Study Day 36 
Study Day 43 
Study Day 8-11 
Study Day 15-18 
Study Day 29-32 
Study Day 36-39 
Study Day 43-46 
Every cycle thereafter 
Cycle k Day 1 
Study Day d = (k - 1) * 28 + 1 
Study Day d-(d+3) 


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Time Window 
Planned Visit Timing  
Time Window Definition 
On treatment 
 
 
Cycle k Day 8 
Cycle k Day 15 
Study Day d = (k - 1) * 28 + 8 
Study Day d = (k - 1) * 28 + 15 
Note: EOT data will be included if 
obtained within 14 days of last dose 
of study treatment OR  
within 14 days of the decision of 
discontinuation of study treatment 
*Study Day 1 = First study treatment 
2.1.1.11 Last contact date 
The last contact date will be derived for participants not known to have died at the analysis cut-
off using the last complete date among the following: 
Table 2-2 
Last contact date data sources  
Source data 
Conditions 
Date of Randomization  
No condition 
Last date participant was known to be alive from 
Survival Follow-up page  
Participant 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 treatment page  
Non-missing dose. Doses of 0 are allowed 
End of treatment date from end of treatment page 
No condition 
Imaging assessment date 
Imaging marked as done 
Laboratory/PK collection dates 
Sample collection marked as ‘done’ 
Vital signs date 
At least one non-missing parameter value 
Performance Status date 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
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 participant 
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 treatment page) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring, if coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of participants in the analysis of time-to-event 
endpoints. 
2.2 
Analysis sets 
2.2.1 
Full Analysis Set 
Randomized Part 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, participants will be 
analyzed according to the treatment they have been assigned to during the randomization 
procedure. 
Safety Run-in and Randomized parts 


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The Complete Full Analysis Set (C-FAS) comprises all participants from FAS and participants 
to whom study treatment has been assigned during the Safety Run-in part and who received 
at least one dose of study treatment (i.e., at least one dose of any study drug of the study 
treatment (including incomplete infusion)).  
2.2.2 
Safety Set 
Safety Run-in part 
The Safety set 1 includes all participants who received at least one dose of study treatment (i.e., 
at least one dose of any study drug of the study treatment (including incomplete infusion)).  
Randomized part 
The Safety set 2 includes all participants who received at least one dose of study treatment (i.e., 
at least one dose of any study drug of the study treatment (including incomplete infusion)). 
Participants in the Randomized part will be analyzed according to the treatment received, 
where treatment received is defined as: 
• the randomized treatment assigned if it was received at least once, or 
• the first treatment received if the randomized treatment was never received.  
All safety endpoints will be analyzed based on the safety sets. 
2.2.3 
Dose-Determining Set 
Safety Run-In part 
The Dose Determining Set (DDS) consists of all participants in the Safety Run-in part who 
met the minimum exposure criterion and have sufficient safety evaluations after 4 weeks of 
treatment or experienced a DLT during the first 4 weeks of treatment.  
A participant is considered to have met the minimum exposure criterion if the participant has 
received 2 doses of NIS793 (2100 mg Q2W or 1400 mg Q2W (only applicable in case of second 
cohort in Safety Run-in part)), 1 dose of spartalizumab (400 mg Q4W), 3 doses of gemcitabine 
(1000 mg/m2 Days 1, 8, and 15), and 3 doses of nab-paclitaxel (125 mg/m2 Days 1, 8, and 15).  
Participants who do not experience a DLT during the first 4 weeks of treatment are considered 
to have sufficient safety evaluations if they have been observed for 4 weeks following the first 
dose and are considered by both the Sponsor and Investigators to have enough safety data to 
conclude a DLT did not occur. 
2.2.4 
Pharmacokinetic Analysis Set 
Randomized part 
Five separate Pharmacokinetic analysis sets (PAS) will be considered. One for NIS793 (NIS-
PAS), one for spartalizumab (PDR-PAS), one for gemcitabine (GEM-PAS), one for dFdU, the 
primary metabolite of gemcitabine (dFdU-PAS), and one for nab-paclitaxel (PAC-PAS). Each 
of the PAS includes all participants who provide an evaluable PK profile for this specific PAS. 
A profile is considered to be evaluable if all of the following conditions are satisfied: 
• Participant receives one dose (complete infusion) of the planned treatments; 


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• Participant provides at least one valid primary PK parameter; 
• For pre-dose samples, have the sample collected before the next dose administration. 
Participants may be removed from PK analysis on an individual basis depending on the number 
of available blood samples. These participants will be identified at the time of analysis. 
2.2.5 
Immunogenicity Analysis Set 
Randomized part 
The immunogenicity (IG) set includes two parts: IG prevalence set and IG incidence set: 
• The IG prevalence set includes all participants in the Safety set 2 with a non-missing 
baseline anti-drug anti-body (ADA) sample or at least one non-missing post-baseline ADA 
sample; 
• The IG incidence set includes all participants in the IG prevalence set with a non-missing 
baseline ADA sample and at least one non-missing post-baseline ADA sample. 
Participant Classification  
Participants may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific participant classification rules defined in 
Table 2-3. Participants that were randomized by error and did not receive any study drug will 
not be included in any analysis set. 


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Table 2-3 
Participant classification based on protocol deviations and non-
protocol deviation criteria 
Analysis set 
Protocol deviations leading to 
exclusion 
Non protocol deviation leading 
to exclusion 
FAS 
No written informed consent 
Not applicable 
C-FAS 
No written informed consent 
Safety Run-in part: No dose of 
any component of study treatment 
Randomized part: Not applicable 
Safety Set 1 and 2 
No written informed consent 
No dose of any component of 
study treatment 
DDS  
No written informed consent 
See definition of DDS 
NIS-PAS, PDR-PAS, GEM-PAS, 
dFdU-PAS, and PAC-PAS 
No written informed consent 
See definitions of NIS-PAS, PDR-
PAS, GEM-PAS, dFdU-PAS, and 
PAC-PAS 
Immunogenicity prevalence set 
No written informed consent 
See definition of IG prevalence set 
Immunogenicity incidence set  
No written informed consent 
See definition of IG incidence set 
Withdrawal of inform consent 
Any data collected in the clinical database after a participant withdraws informed consent from 
all further participation in the trial will not be included in the analysis. The date on which a 
participant withdraws full consent is recorded in the eCRF.  
Additional data, for which there is a separate informed consent, collected in the clinical database 
without having obtained that consent will not be included in the analysis. These data will be 
excluded by the presence of the appropriate protocol deviation criterion. 
2.2.6 
Subgroup of interest 
Not applicable.  
2.3 
Participant disposition, demographics and other baseline 
characteristics 
Summaries and listings described in this section will be based on the C-FAS, separately for 
participants in the Safety Run-in part and in the Randomized part. Summaries will be 
reported overall participants in the Safety Run-in part and by treatment arm for participants in 
the Randomized part.  
No inferential statistics will be provided. 
2.3.1 
Participant disposition 
The number (%) of treated (randomized) participants will be presented for the Safety Run-in 
part (Randomized part). The number (%) of participants treated/untreated, no. of participants 
(%) who are still on treatment at the time of cut-off, the no. of participants (%) who discontinued 
the study phases, and the primary reason for discontinuation, number (%) of patients who 
discontinued from post treatment follow-up and reasons for discontinuation will be presented. 
Screen failure and not-treated (not-randomized) participants and the reasons for screening 
failure and not starting the study treatment will be reported in a listing. 


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2.3.2 
Demographic data 
Demographic data including age, sex, race, ethnicity, height, baseline weight, BMI, and ECOG 
performance status will be listed and summarized. In addition, the following age categories will 
be summarized: 18- <65 years, 65- < 85 years, and ≥ 85 years. 
2.3.3 
Medical history 
Medical history and current medical conditions, including cancer-related conditions and 
symptoms entered on eCRF will be summarized and listed. Separate summaries will be 
presented for ongoing and historical medical conditions.  The summaries will be presented by 
primary system organ class (SOC) and preferred term (PT), using the latest Medical Dictionary 
for Regulatory Activities (MedDRA) terminology available at the time of reporting. The 
MedDRA version will be specified in the CSR as a footnote in the applicable tables/listings. 
2.3.4 
Diagnosis and extent of cancer 
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer, details of tumor histology/cytology, histologic grade, stage at initial diagnosis 
with time since initial diagnosis, stage at time of study entry, number and type of metastatic 
sites.  Metastatic sites will be based on diagnosis page.  
Imputation rules for partially missing dates are provided in Section 5.1.  
2.3.5 
Protocol deviations 
The number (%) of participants in the C-FAS with any protocol deviation, including Covid-19 
related protocol deviations, will be tabulated by deviation category. All protocol deviations will 
be listed. 
2.3.6 
Analysis sets 
The number (%) of participants in each analysis set (defined in Section 2.2) will be summarized 
and listed. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Cumulative dose, dose intensity (DI), and relative dose intensity (RDI) will be summarized 
separately for each component of study treatment, overall participants in the Safety Run-in 
part and additionally, by treatment arm for participants in the Randomized part. Duration of 
exposure will be calculated for each component of study treatment. Duration of exposure will 
be categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of participants in each interval. The number (%) of participants who have dose 
reductions or interruptions, and the reasons, will be summarized by treatment .  
Participant level listings of all doses administered on treatment along with dose change reasons 
will be produced. 


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Safety sets 1 and 2 will be used for all summaries and listings of study treatment. 
2.4.1.1 
Duration of exposure to study treatment 
The duration of exposure to study treatment is defined considering the duration of exposure of 
each study drug as:  
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1.  
Summary of duration of exposure of study treatment will include categorical summaries (<6 
weeks, 6-<12 weeks, 12-<18 weeks, 18-<24 weeks, 24-<48 weeks, 48-<72 weeks, +72 weeks) 
and continuous summaries (i.e., mean, standard deviation etc) using weeks as time units. 
2.4.1.2 
Duration of exposure to investigational/control drug 
Duration of exposure (days) = (last date of exposure to study drug – date of first administration 
of study drug + 1). 
Duration of exposure to NIS793 (days) = (last date of exposure to NIS793 – date of first 
administration of NIS793 + 13). 
Duration of exposure to spartalizumab (days) = (last date of exposure to spartalizumab – date 
of first administration of spartalizumab + 27). 
Duration of exposure to gemcitabine (days) = (last date of exposure to gemcitabine – date of 
first administration of gemcitabine + 6 or 13). 
Duration of exposure to nab-paclitaxel (days) = (last date of exposure to nab-paclitaxel) – (date 
of first administration of nab-paclitaxel + 6 or 13). 
Table 2-4 
Definition of last date of exposure to study drug 
Scenario 
Definition of last date of exposure to 
study drug  
Example 
NIS793: Study drug 
with a Q2W regimen   
The planned end date of the last cycle in 
which the last non-zero dose of the study 
drug was last administered. 
In a 28 day cycle with a Q2W 
regimen, the last date of exposure is 
the date of first infusion in the last 
cycle + 13 days. 
Spartalizumab: Study 
drug with a Q4W 
regimen   
The planned end date of the last cycle in 
which the last non-zero dose of the study 
drug was last administered. 
In a 28 day cycle with a Q4W 
regimen, the last date of exposure is 
the date of first infusion in the last 
cycle + 27 days. 
Gemcitabine / Nab-
paclitaxel: Study drug 
with a Day 1, 8, and 15 
regimen   
The planned end date of the last cycle in 
which the last non-zero dose of the study 
drug was last administered. 
 
In a 28 day cycle with a Day 1, 8, 
and 15 regimen, the last date of 
exposure is the date of infusion in 
the last cycle + 
• 
6 days if infusion is at Day 1 or 
8; 
• 
13 days if infusion is at Day 15. 
Note: If the participant died or was lost to follow-up before the derived last date, the last date of exposure to 
study drug is the date of death or the date of last contact, respectively.  
If the derived last date of exposure goes beyond the data cut-off date, it should be truncated to the date of data 
cut-off. 


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2.4.1.3 
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 each of the study treatment components, 
respectively.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration.  
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the participant is on the study treatment as documented in the treatment page eCRF.  
For participants who did not take any drug, the actual cumulative dose is by definition equal to 
zero for that drug. 
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the participant is assumed to have taken a non-zero dose during dosing periods.  
NIS793 / Spartalizumab 
For NIS793 and spartalizumab the planned cumulative dose is the planned starting dose 
summed over the number of expected infusions during the treatment period (e.g, a participant 
treated for 60 days is expected to have two infusions). 
Gemcitabine / Nab-paclitaxel 
For gemcitabine and nab-paclitaxel the dose in mg/m2 at cycle N is equal to the dose 
administered (mg) at cycle N divided by the body surface area (BSA) at the beginning of cycle 
N using the weight measured before the infusion. For gemcitabine (nab-paclitaxel), the dose in 
mg/m2 at cycle N will be the sum of the 3 doses planned to be received at Days 1, 8, and 15 of 
cycle N. The dose in mg/m2 will be calculated using the BSA at the beginning of the cycle (i.e., 
Day 1). 
BSA (m2) at cycle N = ඥ𝑊𝑊𝑊𝑊 (𝑘𝑘𝑘𝑘) ∗𝐻𝐻𝐻𝐻(𝑐𝑐𝑐𝑐)/3600 (Mosteller formula), 
where Wt=weight at the beginning of cycle N (usually this is the weight taken before the 
infusion of cycle N or last weight available if this is missing) and Ht=Height at the beginning 
of the study.  
2.4.1.4 
Dose intensity and relative dose intensity 
DI is defined for participants with non-zero duration of exposure. For participants who did not 
take the drug, the DI is by definition equal to zero. 
DI (dosing unit/unit of time) = cumulative dose (dosing unit) / duration of exposure (unit of 
time) 
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
participants as per protocol in the same dose unit and unit of time as that of the dose intensity.  
DI, PDI, and RDI are defined as: 
For NIS793 and spartalizumab: 
• DI (mg/cycle) = [cumulative dose (mg) / duration of exposure (days)]*28 


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• PDI is the planned dose as per protocol in mg (i.e., for NIS793 2100 mg Q2W and for 
spartalizumab 400 mg Q4W) 
• RDI (%) = DI (mg/cycle) / PDI (mg/cycle) * 100 
For gemcitabine and nab-paclitaxel 
• DI (mg/m2/cycle) = [cumulative dose (mg/m2) / duration of exposure (days)]*28 
• PDI is the planned dose as per protocol in mg/m2 (i.e., for gemcitabine 1000 mg/m2 and 
for nab-paclitaxel 125 mg/m2, Days 1, 8, and 15) 
• RDI (%) = DI (mg/m2/cycle) / PDI (mg/m2/cycle) * 100 
The DI and the RDI will be summarized for each study drug component tested within the groups 
as defined for the cumulative dose above by descriptive statistics. RDI will be summarized in 
percentage. Summary of RDI includes categorical summaries. The RDI categories are < 50%, 
≥ 50% - < 75%, ≥ 75% - < 90%, ≥ 90% - < 110%, and ≥ 110%. 
2.4.2 
Dose reductions, interruptions, or permanent discontinuations 
The number of participants who have dose reductions, permanent discontinuations or 
interruptions, and the reasons, will be summarized overall participants in the Safety Run-in 
part and by treatment arm for participants in the Randomized part, for each of the study drug 
components. All dosing data will be listed. 
‘Dose interrupted’ and ‘Dose permanently discontinued’ fields from the treatment page eCRF 
pages will be used to determine the dose reductions, dose interruptions, and permanent 
discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’ 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 are entered on consecutive days with different reasons, they will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption.  
Dose reduction: A dose change where the prescribed dose level is lower than the previous 
prescribed dose level 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 eCRF. 
Number of reductions will be derived programmatically based on the change and the direction 
of the change.  
NIS793 / Spartalizumab 
No dose reductions are allowed for NIS793/spartalizumab in the Randomized part and beyond 
the first 28 days period of the Safety Run-in part. 
Gemcitabine / nab-paclitaxel 


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Dose reductions are allowed for gemcitabine/nab-paclitaxel and should follow the dose 
reduction steps described in CSP Table 6-4. For each participant, a maximum of two dose level 
reductions for gemcitabine/nab-paclitaxel is allowed, after which the participant must be 
discontinued.  
Dose interruption: Actual dose administered equal to zero, between the first and last non-zero 
doses, following a non-zero actual dose administered. Number of dose interruptions and 
corresponding reason will be summarized. 
2.4.3 
Prior, concomitant and post therapies 
Prior anti-neoplastic therapy 
Prior anti-neoplastic therapies are not allowed. 
Post treatment anti-neoplastic therapy 
Anti-neoplastic therapies since discontinuation of study treatment will be listed by Anatomical 
Therapeutic Classification (ATC) and PT.  
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a participant coinciding with the study treatment 
period. Concomitant therapy includes 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 dictionary that employs the WHO-ATC classification system and 
summarized by lowest ATC class and PT using frequency counts and percentages. Surgical and 
medical procedures will be coded using MedDRA and summarized by SOC and PT. 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. 
All concomitant medications will be listed. Any concomitant therapies starting and ending 
prior to the start of study treatment or starting more than 30 days after the last date of study 
treatment will be flagged in the listing. 
2.5 
Analysis of the primary objectives 
2.5.1 
Safety objective 
Safety Run-in part 
The primary safety objective is to characterize the safety and tolerability of NIS793 with 
spartalizumab and gemcitabine/nab-paclitaxel and to identify the dose to be tested in the 


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Randomized part and in future studies of NIS793 with spartalizumab and gemcitabine/nab-
paclitaxel. 
2.5.1.1 
Primary endpoints 
The primary endpoints will be evaluated based on the following criteria: 
• Incidence of DLTs; 
• Incidence of AEs and SAEs; 
• Changes in laboratory values, vital signs, and ECGs; 
• Dose interruptions, reductions, and dose intensity. 
In order to assess tolerability, dose interruptions, reductions, and RDI will be considered.  
2.5.1.2 
Statistical hypothesis, model, and method of analysis 
DLT evaluation will be based on participants included in the DDS and will be guided by an 
algorithmic-based design. For a dose to be declared safe for the Randomized part, DLT rate 
should be below 33%, as described below. 
A cohort of at least six participants will be treated in the higher dose regimen (NIS793 2100 mg 
Q2W, spartalizumab 400 mg Q4W, gemcitabine 1000 mg/m2, and nab-paclitaxel 125 mg/m2). 
To be evaluable, participants must complete 4 weeks of treatment with the minimum safety 
evaluation and drug exposure or have a DLT within these 4 weeks. Refer to  
Section 2.2.3 for more details on evaluable participants. 
Dose confirmation will occur if the following conditions are met: 
• Six evaluable participants treated at this dose regimen; 
• No more than one DLT has been observed out of six evaluable participants; 
• It is the dose recommended for participants after review of all clinical, PK, and laboratory 
data by Novartis and Investigators in a safety review meeting. 
If one of the conditions specified above is not satisfied, dose confirmation cannot be declared 
and a second cohort may be treated at a lower dose regimen (NIS793 1400 mg Q2W, 
spartalizumab 400 mg Q4W, gemcitabine 1000 mg/m2, and nab-paclitaxel 125 mg/m2). The 
same criteria are applied for this new dose regimen. If dose confirmation cannot be declared on 
this lower dose, the Randomized part cannot start and the study will end. 
Dose evaluation scenarios based on the algorithmic-based design are given in CSP  
Appendix 4.  
DLTs 
DLTs will be listed and their incidence will be summarized by PT and by SOC, PT, and worst 
grade based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, 
using the DDS.  


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Safety and Tolerability 
Refer to Section 2.8 for details on safety analysis. For details on tolerability analysis, dose 
interruptions, reductions, and dose intensity refer to Section 2.4. 
2.5.1.3 
Handling of missing values/censoring/discontinuations 
Participants in the Safety Run-in part who are ineligible for the DDS will be excluded from 
the primary analysis. However, their data will be used for all remaining analyses.  
2.5.2 
Efficacy objective 
Randomized part 
The primary efficacy objective of this study is to characterize the difference in anti-tumor 
activity of:  
a. NIS793 with spartalizumab and gemcitabine/nab-paclitaxel versus gemcitabine/nab-
paclitaxel and  
b. NIS793 with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel, 
in prolonging time to death or radiological progression in first line mPDAC. The primary 
analysis may be performed once both the following criteria are met: 
• Approximately 60 participants have experienced a PFS event (documented progression as 
per RECIST 1.1 or death due to any cause) in Arms 1 and 3 and  
• Approximately 60 participants have experienced a PFS event (documented progression as 
per RECIST 1.1 or death due to any cause) in Arms 2 and 3. 
2.5.2.1 
Primary estimands 
The primary clinical question of interest is: 
• What is the effect of NIS793 plus gemcitabine/nab-paclitaxel with and without 
spartalizumab relative to gemcitabine/nab-paclitaxel in prolonging time to death or 
radiological progression in first line mPDAC, 
• regardless of whether participants switched to a new anti-cancer therapy that is not part of 
their assigned treatment strategy or/and 
• regardless of whether participants discontinued treatment (due to Covid-19 or any reason 
not related to new anti-cancer therapy)?  
The justification for targeting these treatment effects is that we wish to estimate the two relative 
effects of the treatment strategies in the presence of a) a potentially new anti-cancer therapy that 
is not a part of the assigned treatment strategy or/and b) in the presence of treatment 
discontinuation (due to Covid-19 or any reason not related to new anti-cancer therapy).  
The primary population is adult participants with mPDAC who have not received any systemic 
treatment for metastatic disease. Further details about the population are provided in CSP 
Section 5.  
The primary variable of the study is PFS, defined as the time from the date of randomization to 
the date of the first documented progression or death due to any cause. For the primary efficacy 
analysis, PFS will be based on local review of tumor assessments, using RECIST 1.1 criteria 




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• Start of a new anti-cancer therapy prior to disease progression or death will be handled 
using the treatment policy strategy: Tumor assessment data collected after discontinuation 
of study treatment and start of new anti-cancer therapy will be used to derive PFS. 
• Treatment discontinuation related to Covid-19 will be handled using the treatment policy 
strategy: Tumor assessment data collected after discontinuation of study treatment due to 
Covid-19 will be used to derive PFS. 
• Treatment discontinuation for any reason not related to new anti-cancer therapy or 
Covid-19 will be handled using the treatment policy strategy: Tumor assessment data 
collected after discontinuation of study treatment will be used to derive PFS. 
2.5.2.4 
Handling of missing values/censoring/discontinuations 
In the primary analysis, if a participant 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. 
If a PFS event is observed after two or more missing or non-adequate tumor assessments, then 
PFS will be censored at the last adequate tumor assessment before the PFS event. If a PFS event 
is observed after a single missing or non-adequate tumor assessment, the actual date of event 
will be used [CSP Appendix 1].  
The date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of complete response (CR), partial response (PR), or stable disease (SD) before 
an event or a censoring reason has occurred. If no post-baseline assessments are available 
(before an event or a censoring reason occurred), the date of treatment randomization will be 
used. 
2.5.2.5 
Sensitivity analysis  
As a sensitivity efficacy analysis, PFS will be analyzed using a Cox model, without considering 
delayed effects, based on the FAS with the same analysis conventions as for the primary 
estimand. The treatment effect for each of the two comparisons (Arm 1 versus Arm 3 and Arm 
2 versus Arm 3) will be summarized by the overall HR with its one-sided 90% confidence 
interval (CI). Kaplan-Meier (K-M) estimates for PFS as well as medians along with their two-
sided 95% CI will be presented for each treatment arm. The corresponding K-M curves will be 
presented.  
2.6 
Analysis of the key secondary objective 
There is no key secondary objective.  
2.7 
Analysis of secondary efficacy objectives 
Randomized part 
The secondary efficacy objectives are to: 
• Assess the preliminary anti-tumor activity of NIS793 with and without spartalizumab in 
combination with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel; 


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• Assess the Overall Survival (OS) of NIS793 with and without spartalizumab in combination 
with gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel. 
2.7.1 
Secondary estimands 
The secondary clinical questions of interest are: 
• What is the preliminary anti-tumor activity of NIS793 plus gemcitabine/nab-paclitaxel with 
and without spartalizumab relative to gemcitabine/nab-paclitaxel in first line mPDAC,  
• regardless of whether participants switched to a new anti-cancer therapy that is not 
part of their assigned treatment strategy or/and 
• regardless of whether participants discontinued treatment (due to Covid-19 or any 
reason not related to new anti-cancer therapy)?  
• What is the overall survival (OS) of NIS793 plus gemcitabine/nab-paclitaxel with and 
without spartalizumab relative to gemcitabine/nab-paclitaxel in first line mPDAC,  
• regardless of whether participants switched to a new anti-cancer therapy that is not 
part of their assigned treatment strategy or/and 
• regardless of whether participants discontinued treatment (due to Covid-19 or any 
reason not related to new anti-cancer therapy)?  
The justification for targeting these treatment effects is that we wish to estimate the two relative 
effects of the treatment strategies in the presence of a) a potentially new anti-cancer therapy that 
is not a part of the assigned treatment strategy or/and b) in the presence of treatment 
discontinuation (due to Covid-19 or any reason not related to new anti-cancer therapy).  
The same population as for the primary estimand will be considered. 
The secondary variables of the study are overall response rate (ORR), duration of response 
(DOR), time to progression (TTP), and OS.  
2.7.2 
Statistical hypothesis, model, and method of analysis 
All secondary estimands will be analyzed based on the FAS.  
Overall response rate 
ORR is defined as the proportion of participants with a best overall response (BOR) of 
confirmed complete response (CR) or partial response (PR) as per Investigator assessment as 
per RECIST 1.1 [CSP Appendix 1].  
ORR and the corresponding 95% CI based on the exact binomial distribution (Clopper and 
Pearson 1934) will be presented. Overall response will be listed by treatment arm. 
Duration of response 
DOR only applies to participants whose BOR is CR or PR by Investigator assessment as per 
RECIST 1.1. 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. Participants continuing without progression 
or death will be censored at the date of their last adequate tumor assessment. Definition of last 
adequate tumor assessment is provided in CSP Appendix 1. 


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DOR will be analyzed for participants with confirmed BOR of CR or PR. If there are at least 8 
participants per arm with a confirmed BOR of CR and PR the following analyses will be 
conducted:  
• Unadjusted Cox model for the overall HR and the 95% CI; 
• Median DOR, with corresponding 95% CI and 25th and 75th percentiles (Brookmeyer and 
Crowley 1982, Klein and Moeschberger 1997); 
• K-M estimates for DOR proportions at specific timepoints (3, 6, 12, and 18 months), along 
with 95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002); 
• Summary of number (%) of events and censored participants. 
Time to progression 
TTP is the time from the date of randomization to the date of event defined as the first 
documented progression per RECIST 1.1 or death due to underlying cancer. If a participant has 
no progression or death, the participant is censored at the date of last adequate tumor assessment. 
Definition of last adequate tumor assessment is provided in CSP Appendix 1. 
The following analyses will be conducted:  
• Unadjusted Cox model for the overall HR and the 95% CI; 
• Median TTP, with corresponding 95% CI and 25th and 75th percentiles (Brookmeyer and 
Crowley 1982, Klein and Moeschberger 1997); 
• K-M estimates for TTP rate at specific timepoints (3, 6, 12, and 18 months), along with 95% 
CI (Greenwood’s formula, Kalbfleisch and Prentice 2002); 
• Summary of number (%) of events and censored participants. 
Overall survival 
OS is defined as the time from the date of randomization to the date of death due to any cause. 
If a participant is not known to have died by the cut-off date, OS will be censored at the last 
date the participant was known to be alive.  
The following analyses will be conducted:  
• Unadjusted Cox model for the overall HR and the 95% CI; 
• Median OS, with corresponding 95% CI and 25th and 75th percentiles (Brookmeyer and 
Crowley 1982, Klein and Moeschberger 1997); 
• K-M estimates for OS rate at specific timepoints (3, 6, 12, and 18 months), along with 
95% CI (Greenwood’s formula, Kalbfleisch and Prentice 2002); 
• Summary of number (%) of deaths and censored participants. 
The corresponding K-M curves will be presented. 
2.7.3 
Handling of intercurrent events of secondary estimands 
The secondary analyses will account for three intercurrent events as explained in the following: 
• Start of a new anti-cancer therapy prior to disease progression or death will be handled 
using the treatment policy strategy: Tumor assessment data collected after discontinuation 


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of study treatment and start of new anti-cancer therapy will be used to derive the secondary 
variables. 
• Treatment discontinuation related to Covid-19 will be handled using the treatment policy 
strategy: Tumor assessment data collected after discontinuation of study treatment due to 
Covid-19 will be used to derive the secondary variables. 
• Treatment discontinuation for any reason not related to new anti-cancer therapy or 
Covid-19 will be handled using the treatment policy strategy: Tumor assessment data 
collected after discontinuation of study treatment will be used to derive the secondary 
variables. 
2.7.4 
Handling of missing values/censoring/discontinuations 
For handling of missing values, censoring, and discontinuations refer to Section 2.5.2.4. 
2.8 
Safety analyses 
All safety analyses will be based on the Safety sets 1 and 2. Summaries and listings described 
in this section will be presented, separately, overall participants in the Safety Run-in part and 
by treatment arm for participants in the Randomized part.  
2.8.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE eCRF page will be listed along with the information collected on those AEs e.g., AE 
relationship to study drug, AE outcome etc. AEs will be collected for 30 days from last dose of 
gemcitabine/nab-paclitaxel, 90 days from last dose of NIS793, and 150 days from last dose of 
spartalizumab. AEs with start date outside of the on-treatment period will be flagged in the 
listings. 
AEs will be summarized by number and percentage of participants having at least one AE, 
having at least one AE in each primary SOC, and for each PT using MedDRA coding. A 
participant with multiple occurrences of an AE will be counted only once in the respective AE 
category. A participant with multiple CTCAE grades for the same PT 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 SOC will be presented alphabetically, and the PTs will be sorted 
within primary SOC in descending frequency. The sort order for the PT will be based on their 
frequency in the investigational arm.  
The following AE summaries will be produced: 
• Overview of adverse events (number and % of participants with any AE, any SAE, any fatal 
SAE, any dose change/interruptions, AE leading to discontinuation, requiring additional 
therapy) and death; 
• AEs suspected to be study drug related by PT and severity; 
• AEs suspected to be study drug related leading to discontinuation of study drug 
• AEs leading to study drug discontinuation regardless of study drug relationship by PT and 
severity; 


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• AEs suspected to be study drug related by primary SOC, PT, and severity; 
• AEs leading to study drug discontinuation regardless of study drug relationship by 
primary SOC, PT, and severity; 
• AEs regardless of relationship to study drug by SOC, PT, and severity 
• AEs regardless of relationship to study drug by SOC and severity 
• AEs regardless of relationship to study drug by PT and severity 
In addition, a summary of  serious adverse events (SAEs) with number of occurrences will be 
produced (an occurrence is defined as >1 day between start and prior end date of record of same 
PT). 
The following SAE summaries will be produced: 
• SAEs regardless of relationship to study drug by SOC, PT, and severity 
• SAEs regardless of relationship to study drug by PT and severity 
The following listings will be produced: 
• All AEs. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
An adverse event of special interest (AESI) is a grouping of AEs that are of scientific and 
medical concern specific to compound NIS793 and/or spartalizumab and/or gemcitabine and/or 
nab-paclitaxel. These groupings are defined using MedDRA terms, SMQs (standardized 
MedDRA queries), high level group terms, high level terms, and PTs. Customized SMQs 
(Novartis MedDRA queries, NMQ) may also be used. An 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 
participants with at least one event of the AESI occurring during on-treatment period will be 
summarized. 
A non-exhaustive list of AESI is provided below for each investigational drug. 
NIS793 / spartalizumab 
• Renal toxicity/serum creatinine ≥ Grade 2 
• Neutropenia ≥ Grade 3 
• Febrile Neutropenia 
• Immunogenicity/Hypersensitivity reactions ≥ Grade 3 
• Infusion reactions ≥ Grade 3   
• Diarrhea  ≥ Grade3 
• Hypertension ≥ Grade 3 
• Hemorrhage ≥ Grade 3 
• Cardiac disorders (valvulopathy, cardiomyopathy) 
• Skin reactions ≥ Grade 3 
• Eyelid abnormality ≥ Grade 2 


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A Case Retrieval Sheet (CRS) with the exact composition of the AE groupings is to be used to 
map reported AEs to the AESI groupings.  
The most up-to-date version of NIS793 and spartalizumab specific eCRS will be used. 
Summaries of these AESI will be provided. A listing of all grouping levels down to the 
MedDRA PTs used to define each AESI will be generated. 
2.8.2 
Deaths 
Separate summaries for on-treatment deaths by PT and all deaths (including post-treatment 
deaths) by primary SOC and PT will be produced.  
All deaths will be listed and those from post-treatment periods will be flagged. A separate listing 
of deaths prior to starting treatment will be provided for all screened participants. 
EudraCT and clinicaltrials.gov requirements for AEs and deaths summaries 
For the legal requirements of clinicaltrials.gov and EudraCT, two tables are required.  
• All deaths (all-cause mortality) from the pre-, on-, and post-treatment periods by SOC and 
PT;  
• AEs/SAEs regardless of study drug relationship, from on- and post-treatment periods by 
SOC and PT.  
For these tables, respective follow-up periods after the last dose of corresponding study 
treatments as mentioned in Section 2.8.1 will be considered.  
If for the same participant, several consecutive AEs (irrespectively 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 AEs 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. 
2.8.3 
Laboratory data 
Summaries will include all assessments available for the lab parameters collected no later than 
30 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): 
• 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. 


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The following listings will be produced for the laboratory data: 
• Listings of all laboratory data, with CTC grades and classification relative to the laboratory 
normal range. Lab data collected during the post-treatment period will be flagged.   
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST, and alkaline 
phosphatase (ALP). The number (%) of participants with worst post-baseline values as per 
Novartis Liver Toxicity guidelines will be summarized: 
• ALT or AST > 3xULN  
• ALT or AST > 5xULN  
• ALT or AST > 8xULN  
• ALT or AST > 10xULN  
• ALT or AST > 20xULN  
• TBL > 2xULN  
• TBL > 3xULN  
• AST and ALT =< ULN at baseline 
• ALT or AST >3x ULN & BILI >2x ULN 
• ALT or AST >3x ULN & BILI >2x ULN & ALP >=2x ULN 
• ALT or AST >3x ULN & BILI >2x ULN & ALP <2x ULN 
• AST and ALT > ULN at baseline 
• Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) 
• Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP >=2x ULN 
• Elevated ALT or AST (*) & BILI (>2x Bsl and 2x ULN) & ALP <2x ULN 
* Elevated AST or ALT defined as: >3x ULN if =< ULN at baseline, or (>3x Bsl or 8x ULN) 
if > ULN at baseline 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
In case the study requires ECG replicates, the average of the ECG parameters should be used. 
A listing of ECG assessments will be produced and notable values will be flagged. A listing of 
cardiac imaging data will be produced for participants in the Randomized part. 
2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters will be collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg). 
For analysis of vital signs the clinically notable vital sign criteria are provided in  
Table 2-5  
Clinically notable changes in vital signs below. 


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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 °C 
- 
The number and percentage of participants with notable vital sign values (high/low) in the on-
treatment period will be presented.  
A listing of all vital sign assessments will be produced and notable values will be flagged. 
Assessments collected outside the on-treatment period will be flagged.  
2.9 
Pharmacokinetic endpoints  
Randomized part 
The PK parameters that will be determined are shown in Table 2-6 PK parameters are derived 
based on non-compartmental methods using Phoenix WinNonlin® software version 8.0 or 
higher. 
Table 2-6 
Non-compartmental PK parameters  
AUClast 
 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x 
volume-1) 
AUCtau 
 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-
1) 
Cmax 
 
The maximum (peak) observed serum/plasma drug concentration after dose administration 
(mass x volume-1) 
Tmax 
 
The time to reach maximum (peak) serum/plasma drug concentration after dose administration 
(time) 
Ctrough 
 
The lowest serum/plasma drug concentration reached by a drug before the next dose is 
administered (mass x volume-1) 
T1/2 
 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration time curve (time). Use qualifier for other half-lives 
CL 
 
The total body clearance of drug from the serum/plasma (volume x time-1) 
Vz 
 
The volume of distribution during terminal phase (associated with λz) (volume) 
Descriptive statistics (n, arithmetic mean, coefficient of variation% (CV%) mean, standard 
deviation (SD), median, geometric mean, CV% geo-mean, minimum, and maximum) will be 
presented by study drug and treatment arm for NIS-PAS, PDR-PAS, GEM-PAS, dFdU-PAS, 
and PAC-PAS for all PK parameters defined in Table 2-6 except Tmax. For Tmax only n, 
median, minimum, and maximum will be presented.  


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All individual PK parameters will be listed by study drug and treatment arm using the FAS. 
PK concentrations  
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, 
SD, median, geometric mean, CV% geo-mean, minimum, and maximum) for PK concentration 
will be presented at each scheduled timepoint by study drug and treatment arm for NIS-PAS, 
PDR-PAS, GEM-PAS, dFdU-PAS, and PAC-PAS. 
Handling of PK data below LLOQ or missing 
All concentration values below the lower limit of quantitation (LLOQ) 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%. The number of non-zero concentrations will also be 
reported in the summary statistics. 
At the time of analysis, concentration data from participants may be removed from the 
estimation of certain PK parameters depending on the number of available blood samples, 
concomitant medications, vomiting, etc. Specific timepoints might be removed from the 
analysis set if technical issues with the sample are reported (e.g., sampling issues, missing 
information). These participants and concentration data points will be identified at the time of 
analysis. 
Missing values for any PK data will not be imputed and will be treated as missing. 


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2.10 
Immunogenicity 
Randomized part 
Immunogenicity analysis is applicable to Arms 1 and 2.  
2.10.1 
Sample ADA status 
Each ADA sample is assessed in a three-tiered ADA testing approach. All ADA 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 can test negative in either the screening or confirmatory assay but for statistical 
analysis purposes they are not differentiated. The following properties of each sample will be 
provided in the source data (i.e., the third party data output (e.g., WLIMS) processed by 
PreAdvance):  
• Result of assay according to pre-specified confirmatory cut point: ‘POSITIVE’, 
‘NEGATIVE’, or ‘NOT REPORTABLE’; 
• Titer: numerical representation of the magnitude of ADA response; 
• Presence of NAb (for positive samples, if NAb assay results are available): ‘POSITIVE’ 
or ‘NEGATIVE’; 
• Threshold for determining treatment-boosted (titer fold change (i.e., x-fold)).  
The following definitions apply only to non-missing samples: 
• ADA-negative sample: Sample where assay result is ‘NEGATIVE’   
• ADA-positive sample: Sample where assay result is ‘POSITIVE’ 
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding non-missing baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing. 
• Treatment-induced ADA-positive sample: ADA-positive sample post-baseline with ADA-
negative sample at baseline; 
• Treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with titer 
that is at least the titer fold (i.e., x-fold) change greater than the ADA-positive baseline 
titer; 
• Treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with titer 
that is less than the titer fold (i.e., x-fold) change greater than the ADA-positive baseline 
titer. 
The following summaries of ADA sample status (n and %) will be provided using the 
Immunogenicity prevalence set:  
• ADA-positive samples (i.e., ADA prevalence), both overall and by time point (including 
baseline). For summaries by time point, the denominator is the number of participants at 
that time point with a non-missing sample. 


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Listings will be provided of ADA sample status together with the corresponding PK 
concentration. 
2.10.2 
Participant ADA status 
Any ADA sample collected after more than 90 days of the last dose of NIS793 and 150 days of 
the last dose of PDR001 will not be used for summaries or derivations and will only be included 
in the listing. 
Participant ADA status is defined as follows: 
• Treatment-induced ADA-positive participant: participant with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample; 
• Treatment-boosted ADA-positive participant: participant with ADA-positive sample at 
baseline and at least one treatment-boosted ADA-positive sample;  
• Treatment-unaffected ADA-positive participant: participant with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-unaffected 
ADA-positive sample; 
• Treatment-reduced ADA-positive participant: participant with ADA-positive sample at 
baseline and at least one non-missing post baseline sample, all of which are ADA-negative 
samples;  
• ADA-negative participant: participant with ADA-negative sample at baseline and at least 
one non-missing post baseline sample, all of which are ADA-negative samples;   
• Inconclusive participant: participant who does not qualify for any of the above definitions 
or a participant for which the baseline sample is missing.   
The following summaries of ADA participant status (n and %) will be provided using 
Immunogenicity incidence set (for % the denominator is the number of participants in the 
Immunogenicity incidence set unless otherwise specified):  
• Participants with ADA-negative sample at baseline; 
• Participants with ADA-positive sample at baseline; 
• ADA-negative participants; 
• Treatment-induced ADA-positive participants; for % the denominator is the number of 
participants with ADA-negative sample at baseline; 
• Treatment-boosted ADA-positive participants; for % the denominator is the number of 
participants with ADA-positive sample at baseline; 
• ADA-positive participants (i.e., ADA incidence): calculated as the number of 
treatment-boosted ADA-positive and treatment-induced ADA-positive participants;  
2.10.3 
Transient and persistent ADA responses 
Treatment-induced ADA-positive participants will be analyzed for transient and persistent 
ADA responses 
Transient ADA response is defined as follows:  
• Treatment-induced ADA detected only at one sampling time point during the 
treatment or follow-up observation period (excluding the last sampling time point) 


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and that sampling time point is 16 weeks or more before an ADA-negative last 
sample  
OR 
• Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the participant’s last sampling time point is ADA-negative. 
Persistent ADA response is defined as follows: 
• Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
of 16 weeks or longer  
OR 
• Treatment-induced ADA incidence at the last sampling time point of the treatment or 
follow-up observation period, or at a sampling time point within less than 16 weeks 
before an ADA-negative last sample. 
2.11 
Patient-reported outcomes 
Not applicable.  
2.12 
Biomarkers 
Randomized part 
As a project standard, Novartis Oncology Biometrics and Data Management will analyze only 
biomarkers collected in the clinical database. There may be circumstances when a decision 
is made to stop sample collection, or not perform, or discontinue their analysis due to either 
practical or strategic reasons. Under such circumstances, the number of samples may be 
inadequate to perform a rigorous data analysis and the available data will only be listed and 
potentially summarized.  
The FAS will be used for all biomarker analyses. Unless otherwise specified, all statistical 
analyses of biomarker data will be performed on participants with biomarker data. 
The expression levels of PD-L1 and CD8 will be listed and summarized by treatment arm, 
participant and visit/timepoint (Table 2-7). Table with descriptive statistics at baseline, one or 
several post-baseline timepoints and change from baseline to this/these post-baseline timepoints 
will be provided. 
 




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cohort will open and at least six more participants will be enrolled in order to have six evaluable 
participants. 
Randomized part 
Sample size calculation was based on simulations for various scenarios on treatment outcome, 
number of participants included, and number of events at the timepoint of the analysis using the 
Bayesian model defined in Section 2.5.2.2. 
The evaluation of the success criteria was based on the HR of the PFS (NIS793 with 
spartalizumab and gemcitabine/nab-paclitaxel versus gemcitabine/nab-paclitaxel) after the 
timepoint of risk change in the assumed two-piece hazard model (HR2) used in the Bayesian 
model (in order to account for potential delayed effects). The same success criteria apply for 
the HR of the PFS of NIS793 with gemcitabine/nab-paclitaxel versus gemcitabine/nab-
paclitaxel. 
The success criteria used for the evaluation of the efficacy of the simulation samples are the 
following: 
• At least 50% confidence level that HR2 ≤ 0.7 
• At least 90% confidence level that HR2 < 1 
Approximately 150 participants are expected to be treated in the study (additionally to those 
from the Safety Run-in part), randomized with ratio 1:1:1 (Arm 1: Arm 2: Arm 3). In this 
calculation, a 10% risk of drop-out per participant year has been taken into consideration. 
Regarding the enrolment plan of the study, we assume that 20 participants will be accrued per 
month until approximately a total of 156 participants are treated in the study. 
The reported median PFS for gemcitabine/nab-paclitaxel as first-line therapy for PDAC 
participants was 5.5 months in VonHoff study (Hoff et al., 2013). It was, therefore, assumed 
that the median PFS of gemcitabine/nab-paclitaxel ranged between 5 and 6 months. We expect 
around 50% reduction in the hazard rate of PFS in Arms 1 and 2 after the timepoint of risk 
change in the assumed two-piece hazard model. 
For both comparisons, the same model assumptions are considered. Therefore, sample size 
calculations will be presented only for the first comparison and the same calculations will be 
applicable to the second comparison. Table 3-1 presents the operating characteristics of the 
Bayesian model with different outcome scenarios, keeping stable the total sample size to 100 
participants (for Arms 1 and 3) and the number of total PFS events to 60 required at the 
timepoint of the analysis. With this combination, reasonable operating characteristics can be 
achieved. Description of operating characteristics of alternative sample size can be found in 
CSP Appendix 5. 
Table 3-1 
Operating characteristics for scenarios with 100 participants and 60 
events 
Scenarios  
(Arm 1 vs. Arm 3) 
PFS in months (Hazard ratio)  
Probability of 
Success 
6.2 vs. 5.5 months (HR2=1) 
0.104 
5.9 vs. 5.0 months (HR2=1) 
0.120 


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6.5 vs. 6.0 months (HR2=1) 
0.138 
8.4 vs. 5.5 months (HR2=0.600) 
0.684 
8.5 vs. 5.5 months (HR2=0.583) 
0.703 
9.0 vs  6.0 months (HR2=0.583) 
0.711 
8.8 vs  5.0 months (HR2=0.500) 
0.812 
9.4 vs. 5.5 months (HR2=0.500) 
0.846 
HR2: Hazard ratio after the risk change in the two-piece hazard model 
4 
Change to protocol specified analyses 
• An updated version, compared to the protocol, of the PFS priors is described below.  
Gemcitabine/Nab-paclitaxel arm (no delayed effect assumption) 
For the gemcitabine/nab-paclitaxel arm 8 historical studies that were investigating the drugs’ 
PFS in first line metastatic pancreatic ductal adenocarcinoma were used to inform the prior 
(references of the historical studies can be found in Section 6). Using the meta-analytic 
predictive approach, a 4-component mixture of gamma distributions (including a robustification 
factor) was derived. The resulting mixture Gamma distribution was: 0.68*Gamma(3.21, 1.69) 
+ 0.11*Gamma(4.71, 0.97) + 0.01*Gamma(1.33, 0.12)  + 0.2*Gamma(2.44, 1.00) with median 
PFS of 0.36 years (i.e.,  4.32 months).  
Figure 4-1 
Prior distribution for Gemcitabine/Nab-paclitaxel arm  
 
 




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HR of PFS will be presented, using C-FAS. The same analysis conventions as in the primary 
efficacy analysis will be applied.  
5 
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 participant is considered as on-going:  
The participant 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 
(prior to any death date or withdrawal of consent date, if available):  
Case 1: The dose end date is completely missing and the EOT visit 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 
Participants 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. 
However, if for a participant with a non-zero dose, the information on the participant visit panel 
is available, the date on this panel will be used to impute the first administration date. Before 
imputing the date, it will be checked that the date is not after the second administration or after 
the end date of the first record. 


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5.1.2 
AE date imputation 
A missing AE start date will be imputed using the logic matrix described in Table 5-1. 
Table 5-1 
Imputation rules for a partially missing AE start date 
 
AEM missing 
AEM<TRTM 
AEM=TRTM 
AEM>TRTM 
AEY missing 
Not imputation 
Not imputation 
Not imputation 
Not imputation 
AEY<TRTY 
(D) 
(C) 
(C) 
(C) 
AEY=TRTY 
(B) 
(C) 
(B) 
(A) 
AEY>TRTY 
(E) 
(A) 
(A) 
(A) 
AEM=Month AE started, AEY=Year AE started 
TRTM=Month treatment started, TRTY=Year treatment started 
Table 5-2 is the legend to the logic matrix shown in Table 5-1 and details the relationship of 
AE start date to study treatment start date. 
Table 5-2 
Imputation legend and AE/treatment start date relationship 
AE start date relationship 
Imputation 
(A) After treatment start or uncertain 
MAX(01MMMYYYY, TRTSDT+1) 
(B) Uncertain 
TRTSDT+1 
(C) Before treatment start 
15MMMYYYY 
(D) Before treatment start 
01JULYYYY 
(E) After treatment start 
01JANYYYY 
Before treatment start: Partial date indicates AE start date is prior to treatment start date. 
After treatment start: Partial date indicates AE start date is after treatment start date. 
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date. 
No imputation will be performed for missing/incomplete AE end dates. 
5.1.3 
Concomitant medication date imputation 
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 5.1.2). No imputation will be performed for concomitant 
medication end dates. 
5.1.3.1 
Prior therapies date imputation 
Not applicable.  
5.1.3.2 
Post therapies date imputation 
Start date 
Imputed date = max (End of Treatment date + 1, first day of the month), if day is missing. 
Imputed date = max (End of Treatment date + 1, 01JAN), if day and month are missing. 
Imputed date = End of treatment date +1 if the date is completely missing. 
End date 
No imputation 


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5.1.3.3 
Other imputations  
Diagnosis and extent of cancer 
When a date is recorded as a partial date, the missing day is imputed to the 15th of the month 
(e.g., DEC2007 imputed to 15DEC2007) and if the day and month are both missing then to 1st 
of January of that year (e.g., 2007 imputed to 01JAN2007). Such imputed data will be flagged 
in the listings. 
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. 
5.1.4 
Handling missing month/day in date of death/last known participant 
alive from survival eCRF page 
Partial date imputation is allowed for event (death)/censoring if coming from ‘Survival 
information’ or death eCRF. Here are the following imputation rules: 
• When only the day is missing, the last known participant alive date (from survival 
page) or date of death will be imputed to the maximum between 1st of the month and 
year available and any valid date used for last contact derivation + one day;  
• When the day and months are missing, the last known participant alive date (from 
survival page) or date of death will be imputed to the maximum between 1st of 
January of the year and any valid date used for last contact derivation + one day. 
5.2 
AEs coding/grading 
Adverse events are coded using the MedDRA terminology. AEs will be assessed according to 
the CTCAE version 5.0.  
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 National Cancer 
Institute CTCAE version 5.0. The calculation of CTCAE grades will be based on the observed 


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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 5.0 at the time of analysis will be used. For laboratory tests where grades are not defined 
by CTCAE version 5.0, 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. 
 


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Table 5-3 
CTC grades for laboratory values in Novartis Oncology 
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 ↓ 
WBC 
(Leukocytosis) 
109/L 
109/L 
WBC WBC 
3.9 – 10.7 x 109/L 
≥ LLN 
< LLN - 3.0 x 10
9 
/L 
- 
< 3.0 – 2.0 x 10
9 /L 
- 
< 2.0 – 1.0 x 109 /L 
> 100 x 10
9 /L 
< 1.0 x 10
9 /L 
- 
Hemoglobin 
(Anemia) 
Hemoglobin ↑ 
g/L 
g/L 
HGB 
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) 
(16.113 x mmol/L = g/L) 
≥ LLN 
< LLN - 100 g/L 
< LLN - 6.2 
mmol/L 
Increase >0-20 
g/L 
above ULN 
< 100 - 80 g/L 
< 6.2 - 4.9 mmol/L 
Increase >20-40 
g/L 
above ULN 
< 80 g/L 
< 4.9 mmol/L 
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 ↓ 
109/L 
NEUT 
≥2x109 /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 
Lymphocytes ↓ 
Lymphocytes ↑ 
109/L 
109/L 
LYM 
LYM 
≥1.5x109 
/L 
< 1.5 - 0.8 x 109 
/L 
- 
< 0.8 - 0.5 x 109 /L 
> 4 - 20 x 109 /L 
< 0.5 - 0.2 x 109 /L 
> 20 x 109 /L 
< 0.2 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 


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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 
Total bilirubin ↑ 
umol/L 
BILI 
5.1 – 20.5 umol/L or 0.3 – 1.2 
mg/dL 
≤ 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 ↑ 
umol/L 
CREAT 
61.9 - 115 umol/L or 0.7 – 1.3 
mg/dL 
≤ ULN 
> ULN - 1.5 x 
ULN 
> 1.5 - 3.0 x ULN 
> 3.0 - 6.0 x ULN 
> 6.0 x ULN 
 Creatinine kinase↑ 
 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 
(Hypoalbuminemia) 
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 
- 
 Total Cholesterol ↑  mmol/L  CHOL  
3.88 – 5.15 mmol/L or 150 - 199  
(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 
LIPASE 
<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 
AMYLASE 
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  
(Hyperuricemia)  
 mol/L  
 URATE  
150 - 470 umol/L or 2.5 – 8 mg/dL 
(59.48 x mg/dL = umol/L)  
Defined by clinical criteria only in CTCAE V5  
Phosphorus  
(Hypophosphatemia)  
mmol/L  PHOS  
0.97 – 1.45 mmol/L or 3.0 - 4.5 
mg/dL  
(0.32 x mg/dL = mmol/L)  
Defined by clinical criteria only in CTCAE V5  


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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 
Calcium (corrected) 
(Hypercalcemia) 
Calcium (corrected) 
(Hypocalcemia) 
mmol/L 
mmol/L 
CACALC 
CACALC 
2.2 - 2.6 mmol/L or 9 - 10.5 mg/dL 
(0.2495 x mg/dL = mmol/L) 
≤ ULN 
≥ LLN 
> ULN - 11.5 
mg/dL 
> ULN - 2.9 
mmol/L 
< LLN - 8.0 mg/dL 
< LLN - 2.0 
mmol/L 
> 11.5 - 12.5 
mg/dL 
> 2.9 - 3.1 mmol/L 
< 8.0 - 7.0 mg/dL 
< 2.0 - 1.75 
mmol/L 
> 12.5 - 13.5 
mg/dL 
> 3.1 - 3.4 mmol/L 
< 7.0 - 6.0 mg/dL 
< 1.75 - 1.5 
mmol/L 
> 13.5 mg/dL 
> 3.4 mmol/L 
< 6.0 mg/dL 
< 1.5 mmol/L 
Glucose (non-fasting) 
(Hyperglycemia)  
Glucose (fasting)  
(Hyperglycemia)  
mmol/L  
mmol/L  
GLUCSN  
GLUCSF  
<7.8 mmol/L or <140 mg/dL  
(0.05551 x mg/dL = mmol/L)  
3.9 – 5.8 mmol/L or 70 - 105 
mg/dL  
(0.05551 x mg/dL = mmol/L)  
Defined by clinical criteria only in CTCAE V5  
Glucose  
(Hypoglycemia)  
mmol/L  GLUCSN/GLUCSF 
≥ 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  
Magnesium  
(Hypermagnesemia) 
Magnesium  
(Hypomagnesemia) 
mmol/L 
mmol/L 
MG 
MG 
0.62 – 0.99 mmol/L or 1.5 – 2.4 
mg/dL 
(0.4114 x mg/dL = mmol/L) 
≤ ULN 
≥ LLN 
> ULN - 3.0 
mg/dL 
> ULN - 1.23 
mmol/L 
< LLN - 1.2 mg/dL 
< LLN - 0.5 
mmol/L 
- 
< 1.2 - 0.9 mg/dL 
< 0.5 - 0.4 mmol/L 
> 3.0 – 8.0 mg/dL 
> 1.23 – 3.3 
mmol/L 
< 0.9 - 0.7 mg/dL 
< 0.4 - 0.3 mmol/L 
> 8.0 mg/dL 
> 3.3 mmol/L 
< 0.7 mg/dL 
< 0.3 mmol/L 


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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 
Potassium 
(Hyperkalemia) 
Potassium 
(Hypokalemia) 
mmol/L 
mmol/L 
K 
K 
3.5 - 5.0 mmol/L 
(0.2558 x mg/dL = mEq/L = 
mmol/L) 
≤ ULN 
≥ LLN 
> ULN - 5.5 
mmol/L 
< LLN - 3.0 
mmol/L 
> 5.5 - 6.0 mmol/L 
- 
> 6.0 - 7.0 mmol/L 
< 3.0 - 2.5 mmol/L 
> 7.0 mmol/L 
< 2.5 mmol/L 
Triglyceride ↑  
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  
> 1000 mg/dL  
> 11.4 mmol/L  
Sodium 
(Hypernatremia) 
Sodium 
(Hyponatremia) 
mmol/L 
mmol/L 
SODIUM 
SODIUM 
136 - 145 mmol/L 
(0.435 x mg/dL = mEq/L = 
mmol/L) 
≤ ULN 
≥ LLN 
> ULN - 150 
mmol/L 
< LLN - 130 
mmol/L 
> 150 - 155 
mmol/L 
<129 - 125 mmol/L 
> 155 - 160 
mmol/L 
< 124 - 120 
mmol/L 
> 160 mmol/L 
< 120 mmol/L 
Coagulation 
INR ↑ 
1 
INR 
0.8 – 1.2 
≤ 1.2 
> 1.2- 1.5  
> 1.5- 2.5  
> 2.5  
-  
Activated partial 
thromboplastin time↑  
sec 
APTT 
25 - 35 sec  
≤ ULN  
> ULN - 1.5 x 
ULN  
> 1.5 - 2.5 x ULN  > 2.5 x ULN  
-  
Fibrinogen ↓  
g/L  
FIBRINO  
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  


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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 
ULN = Upper Limit of Normal range; LLN = Lower Limit of Normal range 
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.  
Clinical criteria such as ‘asymptomatic’ or ‘Life-threatening consequences’ are not considered for determination of LAB CTC grades. Concomitant usage of therapy is also 
not considered.  
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  


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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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6 
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Clopper CJ, Pearson ES (1934) The use of confidence or fiducial limits illustrated in the case 
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Hoff, D. D. Von et al. (2013) ‘Increased Survival in Pancreatic Cancer with nab-Paclitaxel 
plus Gemcitabine’, The New England journal of medicine, 369(18), pp. 1691–1703. doi: 
10.1056/NEJMoa1304369.   
Kalbfleisch JD, Prentice RL (2002) The Statistical Analysis of Failure Time Data. Wiley 
Series in Probability and Statistics. 
Klein JP, Moeschberger ML (1997) Survival analysis: techniques for censored and truncated 
data. Springer.