Clinical trial NCT03207867
Conditions: NSCLC, Non Small Cell Lung Cancer RCC, Renal Cell Cancer Pancreatic Cancer Urothelial Cancer Head and Neck Cancer DLBCL, Diffused Large B Cell Lymphoma MSS, Microsatellite Stable Colon Cancer TNBC, Triple Negative Breast Cancer Melanoma mCRPC, Metastatic Castration Resistant Prostate Cancer
Keywords: Immunotherapy A2aR PDR001 NIR178 NSCLC solid tumors
Sponsor: Novartis Pharmaceuticals
Start date: 2017-08-28; Completion date: 2023-02-14
Enrollment: 315 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this phase 2 study is to evaluate the efficacy and safety of NIR178 in combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma (DLBCL) and further explore schedule variations of NIR178 to optimize immune activation through inhibition of A2aR.

Detailed description:
This is an open-label multi-part, phase II study evaluating the combination of NIR178 and PDR001 in patients with advanced solid tumors and diffuse large B cell lymphoma (DLBCL).

The study has three parts:

* Part 1: Multi-arm Bayesian adaptive signal finding design in solid tumors and diffuse large B cell lymphoma (DLBCL) with continuous dosing of NIR178 in combination with PDR001.
* Part 2: Exploration of continuous and intermittent NIR178 schedules in combination with PDR001 in patients with advanced non-small cell lung cancer (NSCLC).
* Part 3: Further evaluation of optimal intermittent or continuous schedule of NIR178 in combination with PDR001 (if selected based on results of Part 2). As of protocol amendment 6, Part 3 explored the safety and pharmacokinetics of the film-coated tablet (FCT) formulation of NIR178 continuous dosing in combination with PDR001 in tiple negative breast cancer (TNBC) patients.

In addition, a separate safety run-in part was conducted in Japan in order to adequately characterize the safety and pharmacokinetic profiles of NIR178 as a single-agent and in combination with PDR001.

Patients enrolled in this study received NIR178 either twice daily (BID) continuously or based on the assigned intermittent schedule within 60 minutes prior to PDR001 infusion. PDR001 400 mg was administered via IV infusion over 30 minutes once every 4 weeks. Each treatment cycle was 28 days. Patients enrolled in the Japanese safety run-in part received NIR178 as single agent for the first cycle (28 days). If the patients completed Cycle 1 without experiencing dose limiting toxicities (DLTs), they initiated combination therapy with PDR001 starting Cycle 2 onwards, and continued at the same dose of NIR178. An additional cohort in the Japanese safety run-in part of the study received NIR178 in combination with PDR001 starting with Cycle 1. If the patients complete Cycle 1 without experiencing DLTs, they continued to receive combination treatment.

Patients received treatment with the combination until disease progression (assessed by investigator per immune-related response criteria (iRECIST) or Cheson 2014), unacceptable toxicity, death or discontinuation from study treatment for any other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator), otherwise known as End of Treatment.

Arms: arm 1: Part 1: NIR178 continuously in combination with PDR001 400mg every 4 weeks. The part 1 enrolled 9 different tumor types. arm 2: Part 2: Three different dosing schedules of NIR178 twice daily (BID) including continuous and two intermittent in combination with PDR001 arm 3: Further evaluation of optimal intermittent or continuous schedule of NIR178 in combination with PDR001 (if selected based on results of Part 2). A film-coated tablet of NIR178 was assessed. arm 4: Different dosing schedules of NIR178 were explored.
Interventions: intervention 1: NIR178 intervention 2: PDR001
Intervention descriptions: intervention 1: NIR178, a new, non-xanthine based compound, is a potent oral adenosine A2a receptor against antagonist being developed by Novartis.

NIR178 was administered orally twice daily (BID) as a capsule (Part 1, Part 2 and Japanese safety run-in) and as a film-coated table (Part 3). There were up to 3 dose levels assessed: 80, 160 and 240 mg. Three alternative dosing schedules were evaluated: continuous (Part 1, Part 2, Part 3, Japanese safety run-in), 2 weeks on/2 weeks off (Part 2) and 1 week on/1 week off (Part 2).

Each cycle consisted of 28 days. intervention 2: PDR001 is a human monoclonal antibody (MAb) administered on Day 1 of each cycle. PDR001 400 mg was administered via intravenous (i.v.) infusion over 30 minutes every 4 weeks (Q4W).

Protocol documents:
Prot_000.pdf: 
Clinical Development
NIR178, PDR001
Oncology Clinical Trial Protocol CNIR178X2201 / NCT03207867
A Phase II, multi-center, open label study of NIR178 in 
combination with PDR001 in patients with selected 
advanced solid tumors and non-Hodgkin lymphoma
Document type
Amended Protocol Version
EUDRACT number
2017-000241-49
Version number
v06 (Clean)
Development phase
II
Document status
Final
Release date
22-Oct-2020
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 15-Jan-2017


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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................7
List of figures ......................................................................................................................7
List of tables ........................................................................................................................8
List of abbreviations..........................................................................................................10
Glossary of terms...............................................................................................................13
Amendment 06 (22-Oct-2020) ..........................................................................................15
Amendment 05 (November 2019).....................................................................................21
Amendment 4 (29-Oct-2018) ............................................................................................25
Amendment 3 (02-Jul-2018) .............................................................................................29
Amendment 2 (29-Aug-2017)...........................................................................................30
Amendment 1 (26-May-2017)...........................................................................................33
Protocol summary:.............................................................................................................35
1
Background........................................................................................................................40
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............41
1.1.1
Adenosine A2a Receptor (A2aR) overview..........................................41
1.1.2
PD-1 overview ......................................................................................42
1.2
Introduction to investigational treatment(s) and other study treatment(s).............43
1.2.1
Overview of NIR178.............................................................................43
1.2.2
Overview of PDR001............................................................................48
2
Rationale............................................................................................................................50
2.1
Study rationale and purpose...................................................................................50
2.2
Rationale for the study design ...............................................................................51
2.3
Rationale for dose and regimen selection..............................................................53
2.4
Rationale for choice of combination drugs............................................................55
2.4.1
Potential for drug interactions...............................................................55
2.5
Rationale for choice of comparators drugs............................................................55
2.6
Risks and benefits..................................................................................................56
3
Objectives and endpoints...................................................................................................57
4
Study design ......................................................................................................................59
4.1
Description of study design ...................................................................................59
4.1.1
Part 1: Bayesian adaptive signal finding in solid tumors and 
DLBCL..................................................................................................61
4.1.2
Part 2: NIR178+PDR001 schedule optimization..................................61
4.1.3
Part 3: NIR178+PDR001 additional exploration in selected tumor 
types ......................................................................................................62


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4.1.4
Japanese safety run-in part....................................................................63
4.2
Timing of interim analyses and design adaptations...............................................65
4.2.1
Part 1: Bayesian adaptive signal finding in solid tumors and 
DLBCL..................................................................................................65
4.3
Definition of end of study......................................................................................66
4.4
Early study termination..........................................................................................66
5
Population..........................................................................................................................66
5.1
Patient population..................................................................................................66
5.2
Inclusion criteria ....................................................................................................67
5.3
Exclusion criteria...................................................................................................70
6
Treatment...........................................................................................................................73
6.1
Study treatment......................................................................................................73
6.1.1
Dosing regimen.....................................................................................75
6.1.2
Ancillary treatments..............................................................................76
6.1.3
Treatment duration................................................................................76
6.2
Dose modifications................................................................................................77
6.2.1
Dose modification and dose delay ........................................................77
6.2.2
Follow-up for toxicities.........................................................................88
6.2.3
Dose reduction steps for NIR178..........................................................90
6.3
Concomitant medications ......................................................................................90
6.3.1
Permitted concomitant therapy .............................................................91
6.3.2
Permitted concomitant therapy requiring caution and/or action...........91
6.3.3
Prohibited concomitant therapy ............................................................91
6.4
Patient numbering, treatment assignment or randomization .................................92
6.4.1
Patient numbering .................................................................................92
6.4.2
Treatment assignment or randomization...............................................92
6.4.3
Treatment blinding................................................................................93
6.5
Study drug preparation and dispensation...............................................................93
6.5.1
Study treatment packaging and labeling ...............................................93
6.5.2
Drug supply and storage........................................................................94
6.5.3
Study drug compliance and accountability ...........................................94
6.5.4
Disposal and destruction .......................................................................94
7
Visit schedule and assessments .........................................................................................95
7.1
Study flow and visit schedule................................................................................95
7.1.1
Screening.............................................................................................105
7.1.2
Treatment period.................................................................................106


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7.1.3
Discontinuation of study treatment .....................................................107
7.1.4
Withdrawal of consent ........................................................................108
7.1.5
Follow up for safety evaluations.........................................................108
7.1.6
Follow-up for disease progression ......................................................109
7.1.7
Follow-up for survival.........................................................................109
7.1.8
Lost to follow-up.................................................................................110
7.2
Assessment types.................................................................................................110
7.2.1
Efficacy assessments...........................................................................110
7.2.2
Safety and tolerability assessments.....................................................113
7.2.3
Pharmacokinetics and immunogenicity assessments..........................118
122
8
Safety monitoring and reporting......................................................................................124
8.1
Adverse events.....................................................................................................124
8.1.1
Definitions and reporting ....................................................................124
8.1.2
Laboratory test abnormalities..............................................................126
8.2
Serious adverse events.........................................................................................126
8.2.1
Definitions...........................................................................................126
8.2.2
Reporting.............................................................................................127
8.3
Emergency unblinding of treatment assignment .................................................128
8.4
Pregnancies..........................................................................................................128
8.5
Warnings and precautions....................................................................................128
8.6
Data Monitoring Committee................................................................................128
9
Data collection and management.....................................................................................129
9.1
Data confidentiality .............................................................................................129
9.2
Site monitoring ....................................................................................................129
9.3
Data collection.....................................................................................................130
9.4
Database management and quality control..........................................................130
10 Statistical methods and data analysis ..............................................................................131
10.1
Analysis sets ........................................................................................................131
10.1.1
Full Analysis Set .................................................................................131
10.1.2
Safety set .............................................................................................132
10.1.3
Pharmacokinetic analysis set...............................................................132
10.2
Patient demographics/other baseline characteristics ...........................................132
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................132
10.4
Primary objective.................................................................................................133
10.4.1
Variable...............................................................................................133


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10.4.2
Statistical hypothesis, model, and method of analysis........................133
10.4.3
Handling of missing values/censoring/ discontinuations....................136
137
10.5
Secondary objectives ...........................................................................................137
10.5.1
Efficacy objectives..............................................................................137
10.5.2
Safety objectives .................................................................................138
139
10.5.4
Pharmacokinetics ................................................................................140
10.5.5
Resource utilization.............................................................................141
10.5.6
Patient-reported outcomes...................................................................142
142
10.7
Interim analysis....................................................................................................142
10.8
Sample size calculation........................................................................................143
10.9
Power for analysis of key secondary variables....................................................147
11 Ethical considerations and administrative procedures ....................................................147
11.1
Regulatory and ethical compliance......................................................................147
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................147
11.3
Informed consent procedures...............................................................................147
11.4
Discontinuation of the study................................................................................148
11.5
Publication of study protocol and results.............................................................148
11.6
Study documentation, record keeping and retention of documents.....................149
11.7
Confidentiality of study documents and patient records .....................................149
11.8
Audits and inspections.........................................................................................150
11.9
Financial disclosures............................................................................................150
12 Protocol adherence ..........................................................................................................150
12.1
Amendments to the protocol................................................................................150
13 References (available upon request)................................................................................151
14 Appendices ......................................................................................................................156
14.1
Appendix 1: Concomitant medications ...............................................................156
14.2
Appendix 2: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free and Overall Survival (based on RECIST 1.1)................158
14.2.1
Introduction.........................................................................................160
14.2.2
Efficacy assessments...........................................................................160
14.2.3
Definitions...........................................................................................160
14.2.4
Disease measurability..........................................................................160
14.2.5
Eligibility based on measurable disease..............................................161


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14.2.6
Methods of tumor measurement - general guidelines.........................161
14.2.7
Baseline documentation of target and non-target lesions ...................163
14.2.8
Follow-up evaluation of target and non-target lesions........................164
14.2.9
Follow-up and recording of lesions.....................................................164
14.2.10
Non-nodal lesions................................................................................164
14.2.11
Nodal lesions.......................................................................................164
14.2.12
Determination of target lesion response..............................................165
14.2.13
Determination of non-target lesion response ......................................167
14.2.14
New lesions .........................................................................................168
14.2.15
Evaluation of overall lesion response .................................................168
14.2.16
Efficacy definitions .............................................................................169
14.2.17
Best overall response...........................................................................169
14.2.18
Time to event variables .......................................................................172
14.2.19
Progression-free survival ....................................................................172
14.2.20
Overall survival...................................................................................172
14.2.21
Time to progression.............................................................................172
14.2.22
Time to treatment failure.....................................................................172
14.2.23
Duration of response ...........................................................................173
14.2.24
Time to response .................................................................................173
14.2.25
Definition of start and end dates for time to event variables ..............174
14.2.26
Handling of patients with non-measurable disease only at baseline...175
14.2.27
Sensitivity analysis..............................................................................176
14.2.28
Data handling and programming rules................................................178
14.2.29
Study/project specific decisions..........................................................178
14.2.30
End of treatment phase completion.....................................................178
14.2.31
End of post-treatment follow-up (study phase completion)................179
14.2.32
Medical validation of programmed overall lesion response ...............179
14.2.33
Programming rules..............................................................................180
14.2.34
Calculation of ‘time to event’ variables..............................................180
14.2.35
Incomplete assessment dates...............................................................180
14.2.36
Incomplete dates for last known date patient alive or death ...............180
14.2.37
Non-target lesion response..................................................................180
14.2.38
Study/project specific programming...................................................181
14.2.39
Censoring reason.................................................................................181
14.2.40
References (available upon request) ...................................................182


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14.3
Appendix 3: iRECIST Guidelines for response in trials testing 
immunotherapeutics.............................................................................................183
14.3.1
Introduction.........................................................................................183
14.3.2
iRECIST response assessment............................................................184
14.3.3
References (available upon request) ...................................................186
14.4
Appendix 4: Details of statistical methodology...................................................187
14.4.1
Prior specification of model parameters .............................................187
14.4.2
Hypothetic scenario testing.................................................................188
14.4.3
Operating characteristics.....................................................................193
14.4.4
Hypothetical scenario testing after addition of new groups................196
14.4.5
Addition of RCC naive, RCC pretreated group and mCRPC group 
at NIR178 240 mg BID.......................................................................201
14.5
Appendix 5: Efficacy guideline for prostate cancer (based on PCWG3)............205
14.6
Appendix 6: Calculation - Cockcroft-Gault formula for GFR estimate..............207
List of appendices
Appendix 1: Concomitant medications
Appendix 2: Guidelines for Response, Duration of Overall Response, TTF, TTP, 
Progression-Free Survival and Overall Survival (based on RECIST v1.1).
Appendix 3: iRECIST: Guidelines for response in trials testing immunotherapeutics
Appendix 4: Details of statistical methodology
Appendix 5: Efficacy guideline for prostate cancer (based on PCWG3)
Appendix 6: Calculation – Cockcroft-Gault formula for GFR estimate 
List of figures
Figure 1-1
Adenosine A2a Receptor (A2aR) signaling..........................................42
Figure 1-2
Effect of NIR178 chronic treatment in the MC38 syngeneic mouse 
model.....................................................................................................44
Figure 1-3
Blockade of PD-1/PD-L1 interaction by PDR001................................49
Figure 4-1
Study design..........................................................................................60
Figure 4-2
Study design- Japanese run-in part (NIR178 Single Agent and 
NIR178 +PDR001) ...............................................................................60
Figure 4-3
Alternate NIR178 dosing schedules within one cycle ..........................62
Figure 6-1
Management of toxicity requiring dose interruptions...........................78


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List of tables
Table 1-1
Relative bioavailability of a film-coated tablet (FCT) formulation 
variant of NIR178 compared to the existing capsule formulation 
(hard gelatin capsule) in Beagle dog.....................................................46
Table 3-1
Objectives and related endpoints ..........................................................57
Table 6-1
Dose and treatment schedule.................................................................73
Table 6-2
Criteria for dose reduction / interruption and re-initiation of 
NIR178 and PDR001 treatment for adverse drug reactions..................79
Table 6-3
Criteria for defining dose limiting toxicities for the Japanese safety 
run-in part..............................................................................................87
Table 6-4
Clinical and Diagnostic assessments to rule out possible causes of 
LFT abnormalities.................................................................................89
Table 6-5
Dose reduction steps for NIR178..........................................................90
Table 7-1
Visit evaluation schedule for patients in Part 1, Part 2 NIR178 S1 
(NIR178 Schedule 1-BID continuous dosing), Part 3 and Japanese 
safety run-in ..........................................................................................96
Table 7-2
Visit evaluation schedule for patients in Part 2 NIR178 S 2 
(NIR178 Schedule 2 regimen-two weeks on two weeks off dosing)....99
Table 7-3
Visit evaluation schedule for patients in Part 2 NIR178 S3 
(NIR178 Schedule 3-one week on, one week of dosing)....................102
Table 7-4
Imaging/Disease Assessment Collection Plan ....................................113
Table 7-5
ECOG performance status...................................................................115
Table 7-6
Local clinical laboratory parameters collection plan ..........................116
Table 7-7
Central ECG collection plan ...............................................................118
Table 7-8
Pharmacokinetic blood collection log for PDR001 and ADA (all 
study parts and schedules, including Japanese safety run-in and 
Part 3)..................................................................................................119
Table 7-9
Pharmacokinetic blood collection log for NIR178: Part 1, Part 2, 
Part 3 (NIR178 Schedule 1), and Japanese safety run-in....................120
Table 7-10
Pharmacokinetic blood collection log for NIR178 Part 2 (NIR178 
Schedule 2)..........................................................................................121
Table 7-11
Pharmacokinetic blood collection log for NIR178 Part 2 (NIR178 
Schedule 3)..........................................................................................122
123
Table 10-1
Type of tumors of interest with definition of being clinically 
meaningful...........................................................................................135
Table 10-2
Noncompartmental pharmacokinetic parameters................................141
Table 10-3
Posterior summaries for given number of responses (ORR) ..............144
Table 10-4
Posterior probability that schedule 1 (S1) has higher ORR than 
schedule 2 (S2)....................................................................................145


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Table 10-5
Posterior probability that schedule 1 (S1) has higher ORR than 
both schedule 2 (S2) and schedule 3 (S3) ...........................................145
Table 10-6
Probability of detecting adverse events with specified incidence 
rate based on N=10 patients................................................................146
Table 10-7
Posterior mean and 95% credible intervals for given ORR rates........146
Table 14-1
List of prohibited medications ............................................................157
Table 14-2
List of medications to be used with caution........................................157
Table 14-3
Response criteria for target lesions .....................................................165
Table 14-4
Response criteria for non-target lesions..............................................167
Table 14-5
Overall lesion response at each assessment ........................................168
Table 14-6
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................176
Table 14-7
Options for event dates used in PFS, TTP, duration of response........177
Table 14-8
Time Point (TP) iResponse.................................................................186
Table 14-9
Specifications for model parameters, and prior median (95 percent 
credible intervals) for ORR.................................................................188
Table 14-10
Hypothetical data scenarios and decision at interim...........................189
Table 14-11
Hypothetical data scenarios and decision at final ...............................191
Table 14-12
True underlying ORR (percent) in the four scenarios.........................193
Table 14-13
Simulation results for Scenario 1 (NIR178 and PDR001 
combination inactive for all tumor types) ...........................................194
Table 14-14
Simulation results for Scenario 2a (all tumor types active) and 
Scenario 2b (one single tumor type [T4-Bladder] inactive, all other 
active)..................................................................................................195
Table 14-15
Simulation results for scenario 3 (four tumor types active while 
other four inactive)..............................................................................195
Table 14-16
Hypothetical data scenarios and decision at interim...........................197
Table 14-17
Hypothetical data scenarios and decision at final ...............................199
Table 14-18
Hypothetical data scenarios and decision at interim...........................201
Table 14-19
Hypothetical data scenarios and decision at final ...............................203
Table 14-20
PCWG3 criteria of progression by disease manifestation...................205


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List of abbreviations
A2aR
Adenosine A2a Receptor
ACTH
Adrenocorticotropic hormone
ADA
Anti-drug antibody
AE
Adverse Event
AhR
Arylhydrocarbon receptor
ALK
Anaplastic lymphoma receptor tyrosine kinase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AMP
Adenosine monophosphate
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area under the concentration-time curve
BCRP
Breast cancer resistance protein
BID
bis in diem/twice a day
BOR
Best overall response
CI
Confidence interval
Cmax
Maximum concentration
CMO&PS
Chief Medical Office and Patient safety
CMV
Cytomegalovirus
COPD
Chronic Obstructive Pulmonary Disease
CR
Complete response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CRS
Cytokine Release Syndrome
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
CYP
Cytochrome P450
DBL
Database lock
DC
Dendritic cell
DCR
Disease control rate
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLBCL
Diffuse large B cell lymphoma
DLT
Dose Limiting Toxicity
DOR
Duration of response
EBV
Epstein-Barr virus
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FAS
FCT
Full analysis set
Film-coated Tablet
FDA
Food and drug administration
FDG-PET
Fluorodeoxyglucose positron emission tomography
G-CSF
Granulocyte-colony stimulating factor
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal


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GM-CSF
HGC
Granulocyte-macrophage colony-stimulating factor
Hard gelatin capsule 
HIV
Human immunodeficiency virus (HIV)
HNSCC
Head and neck squamous cell carcinoma
HSV
Herpes simplex virus
IA
IC
Interim analysis
Non-tumor immune cell staining score
IFNγ
Interferon gamma
ILD
Interstitial lung disease
IL-6
Interleukin-6
INR
International Normalized Ratio
irAEs
Immune-related adverse events
iRECIST
Immune-related response evaluation criteria for solid tumors (RECIST)
IRT
Interactive Response Technology (Interactive Web Response System)
IUD
Intrauterine device
IUS
Intrauterine system
IV
Intravenous(ly)
LFT
Liver function test
LLOQ
Lower Limit of Quantification
mCRPC
Metastatic Castration Resistant Prostate Cancer
M-CSF
Macrophage colony-stimulating factor
MRI
Magnetic resonance imaging
MSS
MTD
Microsatellite stable
Maximum tolerated dose
NGS
Next-generation sequencing
NK
Natural killer cell
NSCLC
Non-small cell lung cancer
OATP
Organic anion transporting polypeptide
ORR
Overall response rate
OS
Overall survival
PAS
Pharmacokinetic analysis set
PBMC
Peripheral blood mononuclear cell
PCWG3
Prostate Cancer Working Group 3
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression free survival
P-gp
P-glycoprotein
PK
Pharmacokinetic
PR
Partial response
PSA
Prostate-specific antigen
PT
Prothrombin time
PxR
Pregnane X Receptor
Q2W
Every two weeks
Q4W
Every 4 weeks
RCC
Renal cell carcinoma


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RDE
Recommended dose for expansion
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RoW
Rest of the world
RP2D
Recommended phase II dose
S1
Schedule 1
S2
Schedule 2
S3
Schedule 3
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable disease
SJS
Stevens-Johnson syndrome
TBIL
Increased total bilirubin
TCGA
Tumor Cell Genome Atlas
Teffs
Effector T cells
TEN
Toxic epidermal necrolysis
TIL
Tumor infiltrating lymphocytes
TKI
Tyrosine-kinase inhibitor
Tmax
Time to reach maximum (peak) drug concentration
TNBC
Triple Negative Breast Cancer
Tregs
Regulator T cells
TTF
Time to treatment failure
TTP
Time to progression
ULN
Upper Limit of Normal


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen (i.e. 
treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.)
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not 
include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked 
to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study procedures 
that was not included in the investigational treatment
Personal data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject/healthy volunteer 
who enrolls in the study
Period
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc.
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of the 
tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when study 
treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to the 
patient (subject) as part of the required study procedures, including placebo and 
active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason


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Treatment group
A treatment group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. Cohorts are not expanded, new cohorts are 
enrolled.
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.
Withdrawal of study consent
(WoC)
Withdrawal of consent occurs only when a patient does not want to participate 
in the study any longer, and does not allow any further collection of personal 
data.


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Amendment 06 (22-Oct-2020)
Amendment rationale
The primary purposes of this protocol amendment are:
1) To open Part 3 of the study to explore the clinical activity of treatment with PDR001 + 
NIR178 in patients with TNBC whose disease does not express PD-L1 IC=0 (<1%) as 
determined by VENTANA PD-L1 SP142 Assay. Additionally, to assure a more 
homogenous patient population, patients must not have received more than 2 prior lines 
of chemotherapy for advanced or metastatic disease. Evidence of clinical activity was 
observed in heavily pretreated TNBC patients in Part 1 of this study, with an ORR of 
11% in 27 evaluable patients who received  NIR178 160 mg BID plus PDR001 400 mg 
Q4W. In a subset of patients, we observed the 2 PR and 1 SD in 4 patients with a PD-
L1 SP-142 IC=0. With the recent approval of PD-(L)1 inhibitors in combination with 
nab-paclitaxel for patients with advanced or metastatic TNBC, whose tumors express 
PD-L1 (IC≥1) (Schmid et al 2018, Narayan et al 2020), an effective treatment for 
patients with immunologically cold tumors is needed.
2) To introduce a new film-coated tablet (FCT) formulation of NIR178 into Part 3 of the 
study only. The available PK data from this study, using a hard gelatin capsule 
formulation of NIR178 consistently shows large variability in drug exposure in patients. 
Based on preclinical PK studies for formulation conducted in Beagle dogs, the
alternative FCT formulation is expected to enhance the oral bioavailability of NIR178 
in humans and reduce variability in PK. Furthermore, the new FCT offers more 
favorable biopharmaceutical properties compared to the existing capsule formulation,
including smaller pill size, presence of a film coat, and availability of a higher dosage 
strength (240 mg) of NIR178 to reduce pill burden. The other parts of the study will 
continue to use the hard gelatin capsule formulation of NIR178.
Additional changes include: 
Reduction in the ECG collection plan to safety monitoring levels. As of 03 Aug 2020, extensive 
ECG sampling, with time-matched PK data, was performed in 257 patients in the 
CNIR178X2201 study including 244 patients at NIR178 160mg BID, and 13 patients at NIR178 
240mg BID; both in combination with PDR001 400mg Q4W. Two out of 257 (<1.0%) patients
experienced QTc prolongation (one G1 and one G2) suspected to be related to study treatment. 
Formal PK-QTc analysis is currently ongoing.
Amendment of the safety run-in to assess NIR178 240mg BID in combination with PDR001 
400mg Q4W starting at Cycle 1 in Japanese patients. No obvious ethnic differences in safety 
and PK were observed between Japanese versus non-Japanese patients and no DDI between 
NIR178 and PDR001 was observed. Therefore, patients in the Japanese safety run-in will 
receive this investigational combination therapy starting at Cycle 1. 
Revision in the definition of end of study to include the option for patients on study treatment 
and who, in the opinion of the investigator, are still deriving clinical benefit at the time of end 
of study, to transfer to another study or to an alternative treatment option to continue providing 
study treatment to these patients.


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Addition of potential drug-induced liver injury (DILI) follow-up guidance based on a Health 
Authority request. Further recommendations for dose reduction and follow up for DILI and 
pneumonitis have been added. To date, no Hy’s law cases or death cases due to hepatic adverse 
events have been reported.
Study Status
As of August 3rd, 2020 a total of 266 patients were treated in the study. In Part 1, 198 patients 
were treated: RCC, mCRPC, TNBC, DLBCL, HNSCC, Melanoma, MSS Colorectal Cancer, 
Pancreatic, Urothelial. In Part 2, 62 NSCLC patients were treated: Schedule 1 (22), Schedule 2 
(20) and Schedule 3 (20). Part 2 of the study is now closed to enrollment. In the Japanese safety 
run-in, 6 patients were treated: NIR178 single agent 80mg (3) and NIR178 single agent 160mg 
(3) during Cycle 1.
Changes in the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions:

Protocol summary: Updated to indicate that Part 3 will be opened in parallel with Part 1 to 
further assess TNBC patients with PD-L1 SP142 IC score of 0 using NIR178 continuous 
dosing schedule in combination with PDR001. Clarified that a second tumor group will be 
considered for Part 3 after completion of Part 1. Additional updates to this section include 
the following: all newly enrolled Japanese patients beginning with this amendment will 
receive 240mg of NIR178 (in combination with PDR001 400mg Q4W) as part of the safety 
run-in, the addition of a new FCT formulation of NIR178 to evaluate the pharmacokinetics 
and safety in comparison to the current capsule formulation and the addition of TNBC to 
one of the selected tumor types in Part 3. 

Section 1.2.1.3 Biopharmaceutics: A section was added to provide relative bioavailability 
data in Beagle dogs for NIR178 existing capsule formulation versus NIR178 film-coated 
tablet and suspension formulation. Table 1-1 added to provide aforementioned data. 

Section 1.2.1.4 Clinical experience: Updated the cut-off date to align with the latest NIR178 
(PBF-509) Investigator’s Brochure edition 4. Removed a DLT that was inadvertently 
included. Added study status update in regards to CNIR178X2201. 

Section 2.2 Rationale for the study design: Updated to reflect that Part 3 will be opened in 
parallel with Part 1 and will enroll TNBC patients with PD-L1 SP-142 IC score of 0 (<1%) 
as part of one of the selected tumor groups. Additionally, Part 3 will assess the safety and 
pharmacokinetics of a new FCT formulation of NIR178 at the dose of 160 mg BID using a 
continuous dosing schedule. Additional clarifications include the use of NIR178 240mg 
BID in combination with PDR001 in Japanese patients as part of the safety run-in part. 

Section 2.3 Rationale for dose regimen selection: Updated the dosing regimen of the 
Japanese safety run-in to NIR178 240mg BID in combination with PDR001 starting at 
Cycle 1 Day 1. Additional updates include clarifying Part 3 enrollment dose with the FCT 
formulation of NIR178 as well as rationale for why the formulation was selected. 


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
Section 2.6 Risks and Benefits: A statement was added to note that no new safety risks due 
to the SARS-CoV-2 virus and the COVID-19 pandemic have been identified at this time 
and therefore the benefit risk of study treatment remains unchanged. 

Table 3-1 Objectives and endpoint: Updated to include PDR001 plasma concentrations and 
PK parameters as a secondary objective for the Japanese safety run-in part of the study. 

Section 4.1 Description of study design: Updated to clarify that Part 3 will be opened in 
parallel with Part 1 and will assess TNBC patients with a known PD-L1 SP-142 status of 
IC=0 (<1 %) using the FCT formulation of NIR178. Additionally, explanation was added 
that Part 3 will explore the safety and pharmacokinetics of the FCT formulation of NIR178. 

Figure 4-1 Study design: Added TNBC with PD-L1 SP142 status of IC=0 (<1 %) as one of 
the selected tumor groups of Part 3. Additionally, updated Part 3 study design and included
language for NIR178 240mg in combination with PDR001 in the Japanese safety run-in. 

Figure 4-2 Study Design Japanese run-in part: Updated figure to reflect current Japanese 
safety run-in design

Section 4.1.3 Part 3: NIR178+PDR001 additional exploration in selected tumor types: 
Updated to clarify that one of the tumor groups selected for Part 3 will include TNBC. 
Additionally, dose increment criteria for Part 3 was added.

Section 4.1.4 Japanese safety run-in part: Revised language to state that as of Amendment 
6 patients enrolled in the Japanese safety run-in will receive NIR178 240mg BID in 
combination with PDR001. Additional updates include adding the 240mg dose level to the 
DLT period language. 

Section 4.3 Definition of end of study: Added language for post-trial access programs or 
roll over protocols which would allow all ongoing patients to transfer to that clinical study 
as applicable. 

Section 5.2 Inclusion criteria: Added TNBC with PD-L1 status of IC=0 (<1%) as 
determined by Ventana PD-L1 SP-142 assay as one of the selected tumor groups of Part 3. 
Additionally, inclusion criteria for Part 3 TNBC tumor group has been added. 

Section 5.3 Exclusion criteria: Added reference to Appendix 6 which contains the 
Cockcroft-Gault formula.  

Section 6.1 Study treatment: Updated to note the formulation for Part 3 as NIR178 FCT. 

Table 6-1 Dose and Treatment schedule: Table updated to include a new row for the NIR178 
FCT formulation. 

Section 6.1.1 Dosing Regimen: Updated to change the formulation of NIR178 to FCT in 
Part 3 of the study and clarified that as of Amendment 6, Japanese safety run-in patients 
will enroll in NIR178 240mg in combination with PDR001. Additional updates include 
adding language around dose escalation to NIR178 240mg BID FCT.


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
Table 6-2 Criteria for dose reduction/interruption and re-initiation of NIR178 and PDR001 
treatment for adverse drug reactions: Revised to include recommended dose modifications 
for DILI. Additional updates for pneumonitis section include recommending to seek 
consultation with pulmonologist and managing toxicity per institutional practice. 
Additionally, updated recommendations were added for AST/ALT elevation management. 
Guidance provided if suspicion of autoimmune hepatitis due to AST/ALT elevation is noted. 

Section 6.2.2.1 Follow up on potential drug-induced liver injury (DILI) cases: Included 
additional guidance on DILI follow-up.

Table 6-4 Clinical and Diagnostic assessments to rule out possible causes of LFT 
abnormalities: Added table to provide guidance on specific assessments that can be 
performed in the event of LFT abnormalities. 

Table 6-5 Dose reduction steps for NIR178: Additional table added to note dose reduction 
steps for patients receiving NIR178 FCT in Part 3 of the study. Additionally, the dose 
reduction table for NIR178 160mg BID was removed as dose reduction steps are outlined 
in the NIR178 capsule formulation (hard gelatin capsule) respective table. 

Section 6.3.2 Permitted concomitant therapy requiring caution and/or action: Added 
language that BCRP substrates in combination with NIR178 should be used with caution.

Section 7.1 Study flow and visit schedule: Clarified that Part 3 will follow the continuous 
BID visit schedule. Additional clarification was added that allows the implementation of 
alternative care if the COVID-19 pandemic limits or prevents on-site study visits. 

Table 7-1: Visit evaluation schedule for patients in Part 1, Part 2 NIR178 S1 (NIR178 
Schedule 1-BID continuous dosing), Part 3 and Japanese safety run-in: Added row to note 
that baseline tumor molecular characteristics for patients will be collected at screening. 

Section 7.1.1.3 Patient demographics and other baseline characteristics: Added clarification 
that baseline tumor molecular characteristics may be collected to determine eligibility of 
inclusion in the study.

Section 7.1.3 Discontinuation of study treatment: Language added that end of treatment 
procedures will be performed for patients who transfer into another study or alternative 
treatment. 

Section 7.1.5.1 Follow-up period: Section added to clarify that patients enrolled to another 
clinical study or alternate treatment as described in Section 4.3 will not have follow-up for 
safety, disease progression and survival assessments performed. 

Section 7.2.2 Safety and tolerability assessments: Language added that regular phone or 
virtual calls will occur every 4 weeks or more frequently if needed for safety monitoring 
during the COVID-19 pandemic if on-site study visits are limited/prohibited. 

Table 7-6 Local clinical laboratory parameters collection plan: Added activated partial 
thromboplastin time (aPTT) test name to the coagulation test category.

Section 7.2.2.5.7 Pregnancy and assessments of fertility: Language added to state if during 
the COVID-19 pandemic the patient cannot visit the site to have serum pregnancy tests, 
local urine pregnancy test kits may be used. 


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
Table 7-7 Central ECG collection plan: Reduced the ECG collection plan at selected visits 
to safety monitoring levels. 

Section 7.2.3 Pharmacokinetics and immunogenicity assessments: Statement added to note 
that if during COVID-19 visits are limited, the collection of samples may be modified by 
Novartis. 

Table 7-8 Pharmacokinetic blood collection log for PDR001 and ADA (all study parts and 
schedules, including Japanese safety run-in and Part 3): clarification added for patients 
enrolled in the Japanese safety run-in part as of amendment 6 will receive NIR178 in 
combination with PDR001 starting at cycle 1 and PDR001/ADA PK sample collections will 
also begin at Cycle 1. 

Table 7-9 Pharmacokinetic blood collection log for NIR178: Part 1, Part 2, Part 3 (NIR178 
Schedule 1), and Japanese safety run-in: clarification added to table header to include Part 
3 into NIR178 PK collection log table. 

Section 9.4 Database management and quality control: Removed language noting a CD-
ROM of patient data would be given to Investigators after final database lock. 

Section 10.4.1 Variable: Minor typographical error was removed and included in 
appropriate Section 10.5.2.

Section 10.4.2 Statistical hypothesis, model, and method of analysis: Updated to indicate 
that Part 3 will enroll TNBC as one of the selected tumor groups and how TNBC data will 
be analyzed. 

Section 10.8 sample size calculation: Updated to clarify that 20-30 patients will be enrolled 
in Part 3. Table 10-6 and Table 10-7 added for further clarification. Additional updates 
include adding NIR178 in combination with PDR001 to the Japanese safety run-in part. 
Section 11.3 Informed Consent procedures: Language was added that if challenges arise 
during the COVID-19 pandemic and limit obtained written informed consent, informed 
consent discussion may occur remotely based on local guidance. 

Section 13 References: Updated to reflect new references 

Appendix 1: Concomitant Medications: Updated the concomitant medication reference and 
Table 14-1 List of Prohibited Medications and Table 14-2 List of Medications to be used 
with caution.

Section 14.2.30 End of treatment phase completion: Updated the end of treatment visit and 
its associated assessments to occur within 14 days of last study treatment.

Appendix 6 Calculation – Cockcroft-Gault formula for GFR estimate: Calculation guidance 
added


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IRBs/ECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The other changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised informed consent that takes into account the changes described in this 
protocol amendment.


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Amendment 05 (November 2019)
Amendment rationale
The primary purpose of this protocol amendment is to increase the dose of NIR178 to 240 mg 
twice daily from 160 mg twice daily for all newly enrolled patients, as well as to allow the 
enrollment of patients with metastatic castration resistant prostate cancer (mCRPC) and IO 
pretreated RCC patients in Part 1 of the study.
The rationale to increase the dose of NIR178 to 240 mg twice daily is based on:
1. Data from the Phase I/Ib clinical trial, CNIR178X2103J, where the maximum tolerated 
dose (MTD) of NIR178 was determined to be 240 mg BID in combination with PDR001 
400 mg Q4W. In the current study, as of May 24, 2019, 224 patients have been treated 
safely with NIR178 160 mg twice daily in combination with PDR001 400 mg Q4W 
(please refer to Section 2.3 for details) to support increasing the NIR178 dose to 240 mg 
BID.  
2. Preliminary exposure response data 
 analysis from available paired biopsies 
in patients treated with NIR178 in the CNIR178X2201 study demonstrated that post-
treatment increases in CD8 T cell tumor infiltration relative to baseline (measured by IHC) 
were associated with improved anti-tumor activity. The extent of CD8 infiltration in the 
tumor also correlates with systemic exposure. Therefore, increasing the dose of NIR178 to 
240 mg BID would be expected to translate into improvement in clinical response rates
(please refer to Section 2.3 for details). The dose of the combination partner PDR001 
remains unchanged (400 mg every 4 weeks).
A new tumor type will be added to Part 1 to allow enrollment of patients with mCRPC based 
on emerging clinical data supporting a potential role for adenosine pathway immune modulation 
in this setting. Anti-CD73 monoclonal antibody treatment suppressed growth of prostate tumors 
and inhibited lung metastases in mice inoculated with TRAMP-C1 tumor cells 
(Stagg et al 2012). Emerging clinical data support a potential role for adenosine pathway 
immune modulation in patients with mCRPC (Siu et al 2018, Bendell et al 2019,
Luke et al 2019).
A new tumor group of IO pretreated RCC patients will now be enrolled into the RCC arm of 
Part 1 of the study since immune checkpoint inhibitors are now routinely used in the treatment 
of advanced/metastatic RCC and have resulted in significantly longer overall survival. 
Nevertheless, disease progression is still observed in a large proportion of patients who develop 
resistance to checkpoint inhibitors. In order to test the hypothesis that immunosuppression due 
to activation of the adenosine pathway leads to resistance to anti-PD-(L)1 therapy and treatment 
with NIR178 may reverse this resistance, the inclusion criteria will be amended to include RCC 
patients who have been previously treated with anti-PD-(L)1 therapy.
Since the use of checkpoint inhibitors has become first line standard of care treatment for 
indications, (such as NSCLC, RCC) the design of Part 3 of the protocol will be modified to 
allow for further evaluation of one or two tumor groups (from Part 1 and Part 2). Once the 
recommended dose and dosing schedule (Part 2) is determined, Part 3 may be initiated after
agreement among Novartis and investigators. 


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There has not been much hypothesis or evidence either from this trial (or in the literature) 
regarding changes in tumor mutational burden over the course of the few months on therapy. 
The on treatment cfDNA collections have been of value in the case of trials (usually for targeted 
therapies) with a goal of monitoring the timing of specific acquired resistance mutations. 
 
Study Status
At the time of this amendment, November 14, 2019, a total of 243 patients have been enrolled 
on the study. In Part 1, 174 patients have been enrolled: RCC (11), TNBC (30), DLBCL (9), 
HNSCC (23, including 4 non-HNSCC), Melanoma (16), MSS Colorectal Cancer (58), 
Pancreatic (14), Urothelial (14). In Part 2, 62 NSCLC patients were enrolled: Schedule 1 (22), 
Schedule 2 (20) and Schedule 3 (20). In Japanese safety run-in, there were 6 patients enrolled: 
NIR178 80mg (3) and NIR178 160mg (3).
Changes in the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions:

Protocol Summary: updated to allow Part 3 to enroll patients in any one or two tumor 
groups based on emerging clinical data from Part 1 and Part 2. Additional updates to this 
section include the following: all newly enrolled patients beginning with this amendment 
will receive 240 mg of NIR178 (in combination with PDR001 400 mg Q4W), the addition 
of mCRPC and IO pretreated RCC to the tumor types in Part 1 and the removal of
language requiring a protocol amendment to open Part 3 for enrollment.

Section 1.2.1.3 Clinical experience: updated to reflect that the MTD of the 
CNIR178X2103J study for NIR178 as a single agent was declared as 480 mg BID and the 
MTD for NIR178 in combination with PDR001 400 mg Q4W was declared as 240 mg 
BID.

Section 2.2 Rationale for the study design: updated to reflect that Part 3 will include any 
one or two tumor groups based on emerging clinical data from Part 1 and Part 2, as well 
clarify that if NSCLC is selected as a tumor group for Part 3, this group will enroll 
patients previously exposed to immunotherapy. Additional clarifications include that the 
terms “tumor groups” and “tumor types” are used interchangeably throughout the 
protocol.

Section 2.3 Rationale for dose regimen selection: updated the starting dose of NIR178 to 
240mg BID for all newly enrolled patients beginning with this amendment as well as the 
rationale for the dose change, which is based on combined PK 
 data along 
with exposure-response analysis and data from the ongoing CNIR178X2103J study.

Table 3-1 Objectives and endpoints: revised to include PCWG3 criteria as a primary 
endpoint in Parts 1 and 3 as well as PSA as a secondary endpoint for mCRPC. 
 

Section 4.1 Rationale for study design: updated to clarify that Part 3 will open for 
enrollment after data from Parts 1 and 2 are available


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
Figure 4-1 Study design: Added IO pretreated RCC and mCRPC as additional tumor 
groups to Part 1 of the study. Additionally, updated Part 3 study design

Section 4.1.1 Part 1: Bayesian adaptive signal finding in solid tumors and DLBCL: added 
RCC to the IO pre-treated groups as well as mCRPC in Part 1.

Section 4.1.3 Part 3: NIR178+PDR001 schedule exploration in additional tumor types: 
updated to clarify that the tumor groups selected for Part 3 will be based on emerging 
clinical data from Parts 1 and 2. If NSCLC is selected as a tumor group for Part 3, this 
group will enroll patients previously exposed to immunotherapy.

Section 4.1.4 Japanese Safety Run-In Part: Added Japanese safety run-in results for the 
80 mg and 160 mg doses of NIR178

Section 4.4 Early Study Termination: updated template language for early termination of 
the trial

Section 5.2 Inclusion criteria: updated Part 3 inclusion criteria to clarify that the tumor 
groups selected for Part 3 will be based on emerging data from Parts 1 and 2, latest 
scientific literature as well as a discussion between Novartis and study investigators. 
Additionally, if NSCLC is selected as a tumor group for Part 3, patients who have been 
exposed to prior immunotherapy will be enrolled. Other updates to this section include the 
addition of prior lines of therapy requirements for RCC (IO pretreated) and mCRPC.

Section 5.3 Exclusion Criteria: Added language to allow GnRH therapy for mCRPC 
patients.

Section 6.1 Study treatment: updated to change the dose of NIR178 to 240 mg BID for all 
newly enrolled patients.

Section 6.1.1 Dosing regimen: updated to change the dose of NIR178 to 240 mg BID for 
all newly enrolled patients.

Section 6.1.3 Treatment duration: Added language regarding PCWG3 guidance for 
mCRPC

Table 6-4 Dose reduction steps for NIR178: revised to include an additional table 
indicating the dose reduction steps for newly enrolled patients starting on the study at the 
240 mg dose.

Table 7-1, Table 7-2 and Table 7-3 Visit schedule and assessments: revised to only require 
CrCl calculation at Screening and Cycle 1 Day 1, included aPTT for coagulation testing 
and only required a pregnancy test for women of child-bearing potential.
 
 
 

Section 7.1.2 Treatment period: Added PCWG3 guidance for mCRPC

Section 7.1.3 Discontinuation of study treatment: Added PCWG3 guidance for mCRPC

Section 7.1.6 Follow-up for disease progression: Added PCWG3 guidance for mCRPC

Section 7.2.1 Efficacy assessments: Added PCWG3 guidance for mCRPC

Table 7-4 Imaging/Disease assessment collection plan: Added language for additional 
imaging bone scans for mCRPC


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
Section 10.4 Primary objective: updated to reflect that Part 3 will enroll one or two tumor 
groups based on emerging data from Parts 1 and 2 as well as remove the requirement of a 
protocol amendment in order to open Part 3

Section 10.4.2 Statistical hypothesis, model, and method of analysis: updated to indicate 
that Part 1 will enroll patients in 13 different groups. Additional updates include clarifying
that the tumor groups selected for Part 3 will be based on emerging data from Parts 1 and 
2 and if NSCLC is selected as a tumor group for Part 3, patients who have been exposed to 
prior immunotherapy will be enrolled

Section 10.5.1 Efficacy objectives: PSA was added for mCRPC patients

Table 10-1 Type of tumors of interest with definition of being clinically meaningful: 
updated to include IO pretreated RCC as a tumor group in Part 1 as well as mCRPC.

Section 10.8 Sample size calculation: updated the sample size for all tumor types. 
Additionally updated to include that the tumor groups selected for Part 3 will be based on 
emerging data from Parts 1 and 2 and if NSCLC is selected as a tumor group for Part 3, 
patients who have been exposed to prior immunotherapy will be enrolled.

Section 13 References: Updated to reflect new references 

Section 14.4.1.1: Corrected variance parameter typo

Section 14.4.5: Added RCC IO pretreated group as well as mCRPC group to the statistical 
section regarding modeling

Appendix 5 Efficacy guideline for prostate cancer: Section Added – PCWG3 guidance
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 other changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised informed consent that takes into account the changes described in this 
protocol amendment.


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Amendment 4 (29-Oct-2018)
Amendment rationale
The primary purpose of this amendment is to update the protocol eligibility criteria and related 
statistical analysis sections for select indications from Part 1 based on preliminary evidence of
anti-tumor activity and changes in the standard of care, specifically: 
MSS CRC:

Based on the available clinical data in this indication (1 patient with a partial response and 
3 with stable disease out of 14 evaluable patients), patients with microsatellite stable 
colorectal cancer (MSS CRC) will continue to be enrolled. However, in order to evaluate 
efficacy and safety for patients with different RAS genotypes, enrollment will continue in 
two sub-groups (RAS wild-type & RAS mutant) based on locally available laboratory 
data. Moreover, RAS status will be collected, including for patients that have already been 
enrolled, as per standard local clinical practices.   
Head & Neck:

Based on the available clinical data in this indication (2 patients with partial responses and 
3 with stable disease out of 11 evaluable patients), patients with Head and Neck group
cancer will continue to be enrolled. However, enrollment will be restricted to Head and 
Neck Squamous Cell Carcinoma (HNSCC), thus creating a more homogenous patient 
population. 

Recent publications points towards a role of the A2aR/CD73 axis during cancer 
progression and overall survival in HNSCC (Vogt et al 2018). In order to explore if the 
adenosine pathway is critical in the acquired resistance to an anti-PD1/L1therapy, a new 
treatment group with HNSCC who were previously treated with an anti-PD1/L1 antibody 
as a single agent or in combination will be included.
Cutaneous Melanoma:

In order to evaluate a homogenous melanoma patient population, only cutaneous 
melanoma patients will be enrolled. Checkpoint (anti PD-1) and BRAF V600 inhibitors 
have become the standard of care for cutaneous melanoma. To test the hypothesis that 
adenosine pathway inhibition could help bypass acquired resistance to anti-PD(L)1 
therapy, the inclusion criteria will be amended to require patients have been treated with 
prior anti-PD(L)1 therapy and BRAF V600 inhibitor therapy (for BRAF V600 mutant 
patients). The BRAF status will be determined per standard local laboratory testing. 
Other updates to the protocol:

The contraception language has been updated to align with the latest version of the 
PDR001 and NIR178 Investigator Brochures. A condom is not required to be used while 
receiving monoclonal antibodies (e.g. PDR001 in this case only) as they are not genotoxic 
and they have a low distribution to the semen with a relatively small quantity of semen 
delivered to the vagina (low absorption). Hence, sexually active males should still use a 
condom during intercourse while on study treatment and 30 days after stopping NIR178. 
Patients should not father a child during this period. 


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
To facilitate the work flow of the participating sites and offer more flexibility particularly 
on days with extensive PK draws for both, NIR178 and PDR001, and ECG assessments 
(e.g. Cycle 1 Day 1), the 60 minutes window between NIR178 morning dose and start of 
PDR001 infusion has been lifted since this is not anticipated to affect PK property 
determination for either drug. 

An optimized LC-MS/MS assay permits measurement NIR178 and its metabolite NJI765 
simultaneously using a single plasma sample, therefore the collection of separate blood 
aliquots to assess PK of the metabolite has been removed. The metabolite will continue to 
be monitored in participating patients using NIR178 PK sample aliquots.

Scan assessments post discontinuation of study treatment will no longer be collected when 
the patient starts a new antineoplastic therapy

An optional biopsy may be collected for patients that continue study treatment beyond 
disease progression due to overall clinical benefit.

Minor updates to the permitted and prohibited concomitant therapy tables to ensure that 
the same drug does not appear in both tables of the protocol. In addition, update to the list 
of drugs with known risk of QT prolongation/TdP under prohibited medications table 
based most recent database from CredibleMeds®.

Removal of the blood sample collection for the assessment of serum cytokines used for 
retrospective analysis of a cytokine release syndrome adverse event. Blood samples for 
serum cytokines were included due to the unknown risk of CRS with IO agents alone and 
in combination, and to allow an assessment of any association between cytokines and 
clinical events. These samples have been drawn at baseline and at the time of a potential 
CRS event, stored, and analyzed retrospectively. Due to this, results are not intended to be 
used to support clinical decision-making for patients with possible CRS. There were no 
unexpected clinically assessed events of CRS observed across 19 studies including more 
than 2200 patients. The risk of CRS in the current study is deemed to be low, thus 
supporting the removal of this blood sample collection.
Study status
At the time of this amendment, a total of 115 patients have been enrolled on the study.
Changes in the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions:

Section 1.2.1.3 Clinical experience has been updated based on available data for the 
CNI178X2103J trial.

Section 2.1 Study rationale and purpose: revised based on updated data available for 
CNIR178X2103J trial.

Section 4.1 Description of study design: revised to add a sentence on optional biopsy may 
be collected at disease progression for patients continuing on study treatment due to 
overall clinical benefit.

Figure 4-1 Study Design: was updated based on the new template and addition of new 
tumor types


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
Section 4.1.1 Part 1: Bayesian adaptive signal finding in solid tumors and DLBCL: revised 
to include the additional tumor types

Section 4.2.1 Part 1: Bayesian adaptive signal finding in solid tumors and DLBCL: revised 
to include 40 MSS CRC patients

Section 5.2 Inclusion Criteria #4:

RAS mutant: Up to three prior lines of therapy for metastatic disease including prior 
therapy with fluoropyrimidine- oxaliplatin- and irinotecan- based regimens.

RAS wild type: Up to three prior lines of therapy for metastatic disease including 
prior therapy with fluropyrmidine-oxaliplatin- and irinotecan-based regimens along 
with prior treatment with an antibody targeting EGFR (e.g. cetuximab or 
panitumumab). 

Section 5.2 Inclusion Criteria #4:

IO Naive HNSCC: Patients with squamous cell carcinoma of head and neck 
(HNSCC) with no more than 3 prior lines of therapy. Patient must have received a 
prior platinum-containing regimen and have not been previously treated with any 
anti-PD1/L1 agents in single agent/combinations.

IO pre-treated HNSCC: Patients with HNSCC with no more than 2 prior lines of 
therapy. Patient must have received a prior platinum-containing regimen and have 
been pretreated with an anti-PD-1/PD-L1 as a single agent or in combinations

Section 5.2 Inclusion Criteria #4:

BRAF V600 wild type patients: anti-PD-1/PD-L1 single-agent, or in combination 
with anti-CTLA-4 therapy 

BRAF V600 mutant patients: anti-PD-1/PD-L1 single-agent, or in combination with 
anti-CTLA-4 therapy. In addition, subjects must have received prior BRAF V600 
inhibitor therapy, either single-agent or in combination with a MEK inhibitor

Section 5.2 Exclusion criteria #9: revised prior lines of therapy based on each tumor type

Section 5.3 Exclusion Criteria #32: The contraception language has been updated to align 
with the latest version of the PDR001 and NIR178 Investigator Brochures.

Section 6.1 Study Treatment: The start time of PDR001 infusion on dosing days can occur 
at any given time regardless of the dose administration schedule of NIR178.  The 
requirement for 60 minute window between NIR178 morning dose and start of PDR001 
infusion in inpatient visits in which the two study drugs are administered on the same day 
(e.g., Cycle 1 Day 1, Cycle 2 Day 1, etc) has been removed to facilitate the work flow of 
the participating sites, since this is not predicted to affect the PK properties of either drug.

Section 6.2.2 Follow-up for toxicities: removal of safety cytokine analysis assessment

Section 7.1 Study flow and visit schedule: Tables 7-1, 7-2, and 7-3 have been updated to 
reflect that the safety cytokine assessments are no longer required.

Section 7.1.4 Withdrawal of Consent language has been updated

Section 7.1.6 Follow-up for Disease Progression: Once patients start on new antineoplastic 
therapy post discontinuation of study treatment, patient does not need to be followed for 
disease progression.


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
Section 7.1.7 Survival Follow-Up: Clarified that survival follow-up will start upon 
completion of the 150-day safety follow-up or disease progression follow-up 

Section 7.2 Pharmacokinetics and Immunogenicity: An update on the PK sample 
collection plan has be done, removing the collection of separate blood samples to measure 
NJI765 (NIR178 metabolite), since a new assay allows to measure both molecules 
(NIR178 and NJI765) from the same blood sample.
 

Section 7.2.2.7.1 Electrocardiogram (ECG): The interval for ECG collection has been 
updated from 5-10min to 1-2min to ensure consistency throughout the protocol

Section 7.2.3 Pharmacokinetics and immunogenicity assessments: revised to include 
language regarding if PDR001 is stopped or temporally paused, the events should be 
captured in the DAR PK eCRF pages.

Table 7-9 Pharmacokinetics blood collection log for NIR178 Part 1: have been revised 
stated that the same blood samples collected to asses PK of NIR178 will be used to 
measure its metabolite NJI765 

Table 7-10 Pharmacokinetics blood collection log for NIR178 Part 2: have been revised 
stated that the same blood samples collected to asses PK of NIR178 will be used to 
measure its metabolite NJI765 

Table 7-11 Pharmacokinetics blood collection log for NIR178 Part 3:  have been revised 
stated that the same blood samples collected to asses PK of NIR178 will be used to 
measure its metabolite NJI765 

Section 7.2.31 Analytic methods: revised text regarding quantification of PK collection or 
NIR178 and NJI765 samples
 
 

Section 8.4 Pregnancies: Pregnancy outcomes should be collected for the female partners 
of any males who took study treatment in this study and the newborn will be followed up 
to 12 months (instead of 3 months) after delivery date.

Section 10 Statistical Methods & Data Analysis: Section has been updated accordingly

Section 14.1 Appendix 1 Concomitant Medications:  The permitted and prohibited 
concomitant therapy tables has been updated to ensure that the same drug is not listed in 
both tables of the protocol

Section 14.4 Appendix 4 Details regarding the statistical methodology: section has been 
updated accordingly


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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 other changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised informed consent that takes into account the changes described in this 
protocol amendment.
Amendment 3 (02-Jul-2018)
Amendment rationale
The primary purpose of this amendment is to incorporate health authority-requested language
requiring study treatment discontinuation in the event of Stevens-Johnson syndrome (SJS)/
toxic epidermal necrolysis (TEN) in response to the occurrence of a case of Stevens Johnson 
Syndrome in the current study. This change has already been implemented as part of an urgent 
safety measure released on 15 June 2018. 
This protocol amendment is now formalizing these changes in the table describing the criteria 
for dose reduction/interruption and re-initiation of treatment for adverse drug reactions and, in 
addition, aligning with the recently published guidelines on the clinical management of 
suspected immune-related toxicities. 
Study status
At the time of this amendment, a total of 110 patients have been enrolled on the study.
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 2.6: Risk-benefit section was updated to reflect the overall safety risk including 
cutaneous toxicity. In addition, reference to the dose modification guidelines was added

Table 6-2 The criteria for dose reduction/interruption and re-initiation of treatment for 
adverse drug reactions: language has been added to mandate permanent study treatment 
discontinuation for SJS/TEN (USM related)

Table 6-2 The criteria for dose reduction/interruption and re-initiation of treatment for 
adverse drug reactions were updated to include latest toxicity management guidelines per 
ASCO, NCCN and ESMO. Moreover, the AST and ALT exclusion criteria has been 
revised to align with the updated toxicity management guidelines

Appendix 5- Recommended management algorithms for suspected toxicities and all 
references to Appendix 5 have been removed as the information is now incorporated in 
Table 6-2 for dose reduction/interruption and re-initiation of treatment for adverse drug 
reaction 


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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 in this amendment identified above as being related to the USM have already been 
implemented by a USM letter issued on 18 May 2018. These changes are required for patient 
safety (i.e. necessary to eliminate immediate hazards to the trial subjects ICH GCP 3.3.8). 
Therefore they were required to have been implemented prior to IRB/IEC approval of this 
amendment.
The other changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised informed consent that takes into account the changes described in this 
protocol amendment.
Amendment 2 (29-Aug-2017)
Amendment rationale
The primary purpose of this amendment is to implement the following changes:

Inclusion of Japanese patients via safety run-in part in order to evaluate safety and 
pharmacokinetic properties of NIR178 as a single agent prior to their participation in 
different parts of this study, as recommended by the Japanese Health Authority. The
Japanese safety run-in part will enroll separately from the phase II study in the rest of the 
world (RoW).
Since there were no differences in the safety and PK profiles of PDR001 between 
Japanese and non-Japanese patients treated at the RDE of 400mg IV Q4weeks in study 
CPDR001X1101, and given the low likelihood of drug-drug interaction (DDI) between 
NIR178 and PDR001 (Section 2.4.1), the safety and PK profile of single agent NIR178 in 
Japanese patients compared to that for patients treated in the ongoing phase 1b dose 
escalation study in NSCLC (CNIR178X2103J), will be the primary determinant of 
whether or not Japanese patients can join the phase II part of this study. If the dose of 
NIR178 used in Parts 1-3 (160mg BID continuously) is declared to be tolerable and safe in 
Japanese patients, then Japanese patients may subsequently be enrolled into all parts of the 
phase II study. Additional changes specifically applying to Japanese patients in the safety 
run-in are:

added language for Japanese patients that written consent is necessary from both the 
patient and his/her legal representative if he/she is under the age of 20 years

added chest x-rays at screening and during cycle 1 and oxygen saturation during 
physical exam in order to monitor drug-induced interstitial lung disease (ILD) per 
Japanese standards

For Japanese patients, added the requirement for hospitalization during the first cycle 
of therapy


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
Based on recent Health Authority recommendation, overall response assessment by 
iRECIST has been added as a secondary endpoint, following the iRECIST definitions and 
rules for response assessment in cancer immunotherapy trials (Seymour et al 2017)

irRC criteria has been replaced by iRECIST criteria for guiding decisions on treatment 
duration and/or discontinuation due to disease progression. Accordingly, patients will 
receive treatment with the combination of NIR178+PDR001 until disease progression 
(assessed by investigator per iRECIST)

Based on the availability of a new capsule strength (40 mg) for NIR178, the first dose 
reduction step from 160mg (dose level -1) for patients requiring dose reduction due to 
adverse events has been changed from 80mg (50% dose reduction) to 120mg BID (25% 
dose reduction), in order to minimize the impact on benefit to the patient. The dose of 
80mg NIR178 has been changed to dose level -2

In order to account for patients who cannot obtain biopsies in cycle 3 due either to early 
disease progression or early response with loss of accessible residual lesions, the on-
treatment biopsy and blood sample collection time point has been moved from C3D15 ± 
15 days and C2D1, respectively, to C2D1 +15 days

Minor inconsistencies and typographical errors have been corrected throughout the 
document
Study status
At the time of this amendment, the study has not been opened for recruitment.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Protocol Summary, Table 3-1 Objectives and related endpoints, Section 6.1.3 Treatment 
duration, Section 7.1.2 Treatment period and Visit evaluation schedule Tables 7-1, Table 
7-2, Table 7-3, Section 10.5.1, Appendix 14.3 has been updated to replace irRC with 
iRECIST published in March 2017. The corresponding term “irRC” was replaced with 
“iRECIST”.

Protocol Summary, Section 2.2 Rationale for study design, Table 3-1 Objectives and 
related endpoints, Section 4.1 Description of study design was updated to include 
language regarding Japanese safety run-in part. In addition, a new Section 4.1. and a 
corresponding Figure 4-2 Study design-Japanese run-in part was added to give an 
overview of the safety in Japanese patients in the run-in part

Section 5.2 Inclusion criteria: Revised inclusion criteria # 1 to specify consent requirement 
for Japan

Section 5.2 Inclusion criteria: Revised inclusion criteria # 2 to specify that the Japanese 
safety run-in part can enroll in any tumor type included in Part 1 and Part 2

Section 5.2 Inclusion criteria: Revised inclusion criteria # 3 to exempt patients in the 
Japanese safety run-in from biopsy requirement as the main purpose of the safety run-in is 
to evaluate safety and pharmacokinetic property of the study treatment


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
Section 5.2 Inclusion criteria: Revised inclusion criteria # 6 to specify that the patients in 
Japanese safety run-in part may have received prior immunotherapy

Section 5.3 Exclusion criteria: Revised exclusion criteria # 9 to clarify that the patients in 
Japanese safety run-in part may have received more than 3 prior lines of therapy

Section 5.3 Exclusion Criteria: Revised exclusion criteria # 15 to replace QTcB to QTcF

Section 5.3 Exclusion Criteria: Revised exclusion criteria # 17 to specify history severe 
hypersensitivity due to ingredients of the study drug(s) another other monoclonal 
antibodies.

Section 5.3 Exclusion Criteria: Revised exclusion criteria # 31 to specify women who are 
considered post-menopausal and not of child bearing potential.

Section 6.1 Study treatment: Added a new capsule strength (40 mg) for NIR178 in Table 
in 6-1

Section 6.1.1 Dosing regimen: Revised to include treatment regimen for Japanese safety 
run-in part

Table 6-3 Definitions of dose limiting toxicities for Japanese safety run-in part: Added to 
include DLT definitions for Japanese safety run-in part

Table 6-4 Dose reduction steps for NIR178: Revised to add a new dose level -1 (120 mg) 
for NIR178

Section 6.4.1 and Section 6.4.2: Updated to clarify that the IRT will not be used for 
Japanese Safety run-in part.

Table 7-1 Visit evaluation schedule: Updated to include additional assessments required 
for Japan (Physical exam at Cycle 2 Day 15, and Chest X-ray at screening, Cycle 1 Day 
15, Cycle 2 Day 1 and Cycle 2 Day 15).

Section 7.1.1 Screening: Updated to revise the biopsy collection window for screening

Table 7-4 Imaging/Disease assessment collection plan: Updated to add FDG-PET/CT 
requirement for lymphoma patients with known bone marrow involvement and FDG-avid 
tumors

Section 7.2.2.1 Physical examination: Updated to include Japan specific assessments 
(pulse oximetry)

Section 7.2.2.6 [For Japan only] Radiological examinations: Added to include Japan 
specific requirement for Chest X-ray

Section 7.2.2.7.1 Electrocardiogram (ECG): Clarified that the ECG evaluations will done 
centrally

Table 7-8 and Table 7-9 Pharmacokinetic blood collection log for PDR001 and NIR178: 
Title was updated to include Japanese safety run-in part
 

Section 10 Statistical methods and data analysis, Section 10.5.2.2 Adverse events (AEs): 
Revised to include analysis plan for Japanese safety run-in part

Section 10 Statistical methods and data analysis, Section 10.5.1 Efficacy analysis: 
Updated to include iRECIST as a secondary efficacy endpoint


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. The changes herein 
affect the Informed Consent. Sites are required to update and submit for approval a revised 
informed consent that takes into account the changes described in this protocol amendment.
Amendment 1 (26-May-2017)
Amendment rationale
The primary purpose of this amendment is to address the following health authority requests:

Clarify that the additional tumor type to be selected in Part 3, based on emerging data 
from Part 1, may only begin enrollment via implementation by formal protocol 
amendment

Update inclusion criteria to require specific prior standard therapies for tumor types in part 
1

Add exclusion criteria for patients with a history of non-infectious pneumonitis or 
interstitial lung disease

Add inclusion criteria for DLBCL to ensure that the enrollment of patients with DLBCL is 
limited to patients with no available therapies of proven clinical benefit

Provide case definitions for treatment-emergent immune-mediated adverse drug reactions 
in the protocol and guidance on assessment and management of immune related adverse 
events

Include specific criteria for continuing study treatment beyond RECIST-defined 
radiological progression

Update risk-benefit section to indicate potential for overlapping toxicities of combination 
immunotherapies

Clarify that the primary efficacy analysis will be based on RECIST v1.1 for solid tumors 
and Cheson 2014 for Lymphoma and that irRC criteria will be used only for decisions 
around treatment discontinuation due to disease progression
Study status
At the time of this amendment, the study has not been opened for recruitment.


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Protocol summary, Section 2.2, Section 4.1.3, Section 10.4, Section 10.8 : Language 
regarding the “additional tumor type from Part 1” has been modified for Part 3 to specify 
that the additional tumor type in Part 3 will be selected based on emerging data from Part
1 and enrollment into this tumor group will only occur via a formal protocol amendment.

Section 2.6 Risks and benefits: Revised to indicate risks of overlapping toxicities for 
combination immunotherapies

Section 5.2 Inclusion criteria: Revised inclusion criteria #4 to specify prior lines of 
systemic therapy for specific tumor type and added inclusion criteria # 5 for patients with 
DLBCL

Section 5.3 Exclusion criteria: Added exclusion criteria #5 to exclude patients with history 
of interstitial lung disease or non-infectious pneumonitis

Section 6.2.2: Added Section 6.2.2. to define immune related adverse events and 
management of irAEs

Section 7.1.2: Updated to clarify criteria for study treatment continuation beyond disease 
progression

Section 7.2.1: Clarified that RECIST 1.1 and Cheson (2014) (for DLBCL) will be used for 
analysis of response. irRC will be used only for treatment decision making around study 
discontinuation due to progressive disease.

Section 10.4.1: Updated to clarify that the primary analysis will be based on RECIST v1.1 
for solid tumors and Cheson 2014 for DLBCL.

Section 14.5: Appendix 5 was added to provide recommendation on the management for 
suspected immune related toxicities
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. The changes herein 
affect the Informed Consent. Sites are required to update and submit for approval a revised 
informed consent that takes into account the changes described in this protocol amendment.


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Protocol summary:
Title
A Phase II, multi-center, open label study of NIR178 in combination with PDR001 in 
patients with selected advanced solid tumors and non-Hodgkin lymphoma
Brief title
Study of efficacy and safety of NIR178 and PDR001 combination in patients with 
selected solid tumors and non-Hodgkin lymphoma
Sponsor and
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this phase II study is to evaluate the efficacy and safety of NIR178 in 
combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma 
(DLBCL) and further explore schedule variations of NIR178 to optimize immune 
activation through inhibition of A2aR.
Primary Objective(s) 
and Key Secondary 
Objective
The study is divided into 3 parts. The primary objective of each part is as follows:

Part 1:To evaluate the efficacy of NIR178 and PDR001 combination in patients 
with selected advanced solid tumors and diffuse large B cell lymphoma (DLBCL)

Part 2: To assess the efficacy of several intermittent dosing schedules of 
NIR178 in combination with PDR001 in NSCLC

Part 3: To further evaluate efficacy of the best performing dosing schedule of 
NIR178 in one or two tumor groups selected from Part 1 and Part 2. The
additional tumor groups will be selected based on the emerging data from Part 1
and Part 2.
Secondary 
Objectives

To assess the efficacy of NIR178+PDR001 in select advanced solid tumors and 
lymphoma

To assess the safety and tolerability of the NIR178 and PDR001 combination

To characterize changes in the immune infiltrate in tumors

To characterize the pharmacokinetics (PK) of NIR178, its metabolite NJI765 and 
PDR001 in combination

To assess immunogenicity of PDR001

Japanese safety run-in part: To assess the safety and pharmacokinetic profiles 
of NIR178 single-agent and in combination with PDR001 in Japanese patients 
Study design
This is a multi-center, open label, phase II study to evaluate efficacy of the NIR178 
and PDR001 combination in NSCLC, other solid tumors, and diffuse large B-cell 
lymphoma (DLBCL).
The study has three parts: Part 1: Multi-arm Bayesian adaptive signal finding design 
in solid tumors and diffuse large B cell lymphoma (DLBCL); Part 2: NIR178 schedule 
exploration in NSCLC; Part 3: Further evaluation of intermittent dosing schedules of 
NIR178 in combination with PDR001 in additional tumor types, if Part 2 identifies an 
intermittent dosing schedule of NIR178 as warranting further exploration.
In addition, a separate safety run-in part will be conducted for patients in Japan in 
order to evaluate safety and pharmacokinetics of NIR178 as a single agent and 
NIR178 in combination with PDR001 prior to their participation in different parts of 
this phase II study, as recommended by the Japanese Health Authority. This 
Japanese safety run-in part will enroll separately from the phase II study in the rest of 
the world (RoW).
Patients enrolled in this study will receive NIR178 160 mg either BID continuously or 
based on the assigned intermittent dosing schedule. All newly enrolled patients 
under Amendment 5 will receive NIR178 240 mg BID. PDR001 will be administered 
via IV infusion over 30 minutes once every 4 weeks. Each treatment cycle is 28 days.
As of protocol amendment 6, Part 3 will be opened in parallel with Part 1 to further 
assess TNBC patients with a PD-L1 SP-142 IC score of 0 (<1%) using the NIR178 
continuous dosing schedule in combination with PDR001. A second tumor group will 
be considered for Part 3 after completion of Part 1. Patients will receive treatment 
with the combination until disease progression (assessed by investigator per 
immune-related response criteria (iRECIST) (Appendix 3 or Cheson et al (2014)), 


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unacceptable toxicity, death or discontinuation from study treatment for any other 
reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the 
discretion of the investigator), otherwise known as End of Treatment.
Population
Adult patients with histologically documented advanced or metastatic solid tumors 
(e.g. non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), pancreatic 
cancer, urothelial cancer, head and neck squamous cell carcinoma (HNSCC), 
diffuse large B-cell lymphoma (DLBCL), microsatellite stable colorectal cancer (MSS 
CRC), triple negative breast cancer (TNBC), cutaneous melanoma and metastatic 
castration resistant prostate cancer (mCRPC) will be enrolled.
All patients must have disease amenable to biopsy and must be willing to undergo 
biopsy at screening/baseline, and during the course of study treatment as per 
protocol requirement. For Parts 1 and 2, patients must not have received prior 
immunotherapy (with the exception of the following IO pretreated groups: cutaneous 
melanoma, HNSCC and RCC). Prior immunotherapy status for Part 3 will depend on 
the tumor groups selected and their standard of care treatments at the time. As of 
protocol amendment 6, Part 3 will be opened to further assess TNBC patients with a
PD-L1 SP-142 IC score of 0 (<1%). A second tumor group will be considered for Part
3 after completion of Part 1.Japanese safety run-in part can enroll any tumor type 
included in Parts 1,2 and 3.
Inclusion criteria

Male or female patients ≥18 years of age.
For Japan only: written consent is necessary both from the patient and 
his/her legal representative if he/she is under the age of 20 years.

Histologically documented advanced or metastatic solid tumors or 
lymphomas

Part 1: histologically confirmed renal cell carcinoma (RCC), pancreatic 
cancer, urothelial cancer, head and neck squamous cell carcinoma 
(HNSCC), diffuse large B-cell lymphoma (DLBCL), microsatellite stable 
colorectal cancer (MSS CRC), triple negative breast cancer (TNBC),
cutaneous melanoma or mCRPC

Patients with colorectal cancer must have microsatellite stable (MSS) 
disease as detected by PCR-based assay or mismatch repair proficient 
as detected by immunohistochemistry and confirmed RAS status 
(KRAS and NRAS) by standard testing of tumor specimen based on 
local available laboratory data.

Patients with unresectable or metastatic cutaneous melanoma must
have confirmed BRAF V600E status by standard testing of tumor 
specimen, based on local available laboratory data.

Part 2: histologically confirmed diagnosis of advanced/metastatic NSCLC. 
For those with mixed histology, there must be a predominant histology

Patients should have confirmed EGFR and ALK status when clinically 
indicated and performed per standard testing of tumor specimen based 
on local available laboratory data.

Part 3: histologically confirmed diagnosis of selected advanced/metastatic 
malignancies. Based on emerging data from Part 1, Part 2 and latest 
scientific literature along with discussion between Novartis and study 
investigators, one or two tumor groups will be further explored in Part 3. As 
of protocol amendment 6, Part 3 will be opened to further assess TNBC 
patients with a PD-L1 SP-142 IC score of 0 (<1%). A second tumor group 
will be considered for Part 3 after completion of Part 1.

Safety run-in part in Japanese patients can enroll any tumor type included in 
Parts 1 2, and 3.

Patient (except for those participating in Japanese safety run-in) must have 
a site of disease amenable to biopsy, and be a candidate for tumor biopsy 
according to the treating institution’s guidelines. Patient must be willing to 
undergo a new tumor biopsy at screening, and again during therapy on this 
study. The use of recent sample is permitted under the following conditions 
(both must be met):


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
Biopsy was collected ≤ 6 months before 1st dose of study treatment and 
available at the site.

No antineoplastic therapy was given to the patient since collection of biopsy
(with the exception of IO pretreated cutaneous melanoma, HNSCC and
RCC).

Part 1 – 3 only: Patients (other than those with DLBCL) must previously 
have received at least 1 and no more than 3 prior lines of therapy (with the 
exception of IO pretreated cutaneous melanoma, HNSCC and RCC) for 
their disease, specifically including the following, unless considered 
inappropriate for the patient (e.g. safety concern, label contraindication):

MSS CRC:

Patients with MSS colorectal cancer must have received (or be 
intolerant to) prior therapy with fluoropyrimidine-oxaliplatin- and 
irinotecan- based regimens.

Patient with wild type RAS must have received prior treatment with an 
antibody targeting EGFR (e.g. cetuximab or panitumumab)

TNBC:

Part 1: Patients with triple negative breast cancer must have   
received a prior taxane containing regimen.

Part 3: 

Patients should have documented disease progression 
following, or intolerance to, no more than 2 prior lines of
chemotherapy for advanced or metastatic disease.
Neoadjuvant and/or adjuvant chemotherapy administered with 
curative intent will count as one prior line of therapy, if disease 
recurred within 12 months of the last treatment. 

Patients must have received prior systemic treatment that 
included taxane-based chemotherapy for (neo) adjuvant or 
metastatic disease. 

Patients should have a known PD-L1 status as per local 
available testing determined by VENTANA PD-L1 SP142
Assay with IC score of 0 (<1%) 

Urothelial Cancer:

Patients with urothelial cancer must have received a prior platinum-
containing regimen or be ineligible for cisplatin.

RCC:

IO naive RCC: Patients with renal cell carcinoma must have received a 
prior VEGF tyrosine kinase inhibitor (TKI).

IO pretreated RCC: Patients with RCC with no more than 2 prior lines 
of therapy. Patient must have received a prior VEGF TKI and have 
been pretreated with an anti-PD-1/PD-L1 as a single agent or in 
combinations

HNSCC:

IO Naive HNSCC: Patients with squamous cell carcinoma of head and 
neck (HNSCC) with no more than 3 prior lines of therapy. Patient must 
have received a prior platinum-containing regimen and have not been 
previously treated with any anti-PD1/L1 agents in single 
agent/combinations.

IO pre-treated HNSCC: Patients with HNSCC with no more than 2 prior 
lines of therapy. Patient must have received a prior platinum-containing 
regimen and have been pretreated with an anti-PD-1/PD-L1 as a single 
agent or in combinations

Cutaneous Melanoma:

Patients must previously have received at least 1 and no more than 2 
prior lines of therapy.


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
BRAF V600E wild type patients: must have received anti-PD-1/PD-L1 
single-agent, or in combination with anti-CTLA-4 therapy

BRAF V600E mutant patients: must have received prior anti-PD-1/PD-
L1 single-agent, or in combination with anti-CTLA-4 therapy. In 
addition, subjects must have received prior BRAF V600E inhibitor 
therapy, either single-agent or in combination with a MEK inhibitor

Metastatic castration resistant prostate cancer (mCRPC):

Of the 1-3 prior lines of therapy that the patient has received, patients 
must have received and failed at least one line of treatment after 
emergence of castration resistant disease

DLBCL:

Patients with DLBCL should be limited to those with no available 
therapies of proven clinical benefit.

Patient should have had prior autologous hematopoietic stem cell 
transplantation (auto-HSCT) or determined to be ineligible for auto-
HSCT.

NSCLC:

Patients with NSCLC must have received a prior platinum-based 
combination.

For patients with NSCLC, EGFR mutation with exon 19 deletion or 
L858R mutation (Exon 21) or anaplastic lymphoma receptor tyrosine 
kinase (ALK) rearrangement positive must have failed prior Tyrosine-
kinase inhibitor (TKI) therapy.

Patients with EGFR positive NSCLC with a T790M mutation must have 
progressed on osimertinib or discontinued due to toxicity

Patients should have had prior autologous hematopoietic stem cell 
transplantation (auto-HSCT) or determined to be ineligible for auto-HSCT.

Patients must not have received prior immunotherapy (previous immune 
checkpoint inhibitors; single agent and/or combination therapy with anti-
CTLA-4, anti-PD-1, anti-PD-L1), with the exception of groups: IO pretreated
cutaneous melanoma, HNSCC and RCC in Part 1, NSCLC patients enrolled 
in Part 3 and Japanese safety run-in part.

Patients must have measurable disease, defined as at least one lesion that 
can be accurately measured in at least one dimension (longest diameter to 
be recorded for non-nodal lesions and short axis for nodal lesions) as >20 
mm with conventional techniques or as >10 mm with spiral computer 
tomography (CT) scan, Magnetic Resonance Imaging (MRI), or calipers by 
clinical exam.
Exclusion criteria

Ongoing or prior treatment with A2aR inhibitors. Patients previously treated with 
A2aR inhibitors for non-oncologic indications (e.g. Parkinson’s disease) may be 
considered for enrollment on a case by case basis.

Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. 
For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and 
nitrosoureas, 6 weeks is indicated as washout period. For patients receiving 
anticancer immunotherapies, 4 weeks is indicated as the washout period.
Gonadotropin-releasing hormone (GnRH) therapy to maintain effective 
testosterone suppression levels is allowed for mCRPC patients. 

Current or prior use of immunosuppressive medication within 28 days before the 
first dose of PDR001, with the exception of intranasal/inhaled corticosteroids or 
systemic corticosteroids at physiological doses (not exceeding equivalent of 10 
mg/day of prednisone)

History of interstitial lung disease or non-infectious pneumonitis

History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active 
disease ≥2 years before the first dose of study drug and of low potential 
risk for recurrence


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
Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease

Adequately treated carcinoma in situ without evidence of disease

Active or prior documented autoimmune disease within the past 2 years. 
Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded.

More than 2 or 3 prior lines of therapy (as indicated above for each tumor 
group), except for Japanese safety run-in part.
Investigational and 
reference therapy
NIR178 and PRD001 administered as a combination
Efficacy 
assessments
Tumor response according to RECIST Version 1.1 and iRECIST (for solid tumors), or 
Cheson et al (2014) (for lymphoma) assessed by investigator. For mCRPC, tumor 
assessments will also include the recommendations from the PCWG3.
To characterize changes in the immune infiltrate in tumors
Safety assessments
Frequency, severity and seriousness of AEs, laboratory abnormalities and other 
safety parameters. Dose interruptions, reductions and dose intensity.
Other assessments
 
 
 
 
 
 
 
 
 
Data analysis
It is planned that the data from participating centers in this protocol will be combined, 
so that an adequate number of patients will be available for analysis. Data will be 
summarized using descriptive statistics (continuous data) and/or contingency table 
(categorical data) for demographic and baseline characteristics, efficacy 
measurements, safety measurements and all relevant PK and PD measurements. 
Categorical data will be presented as frequencies and percentages. For continuous 
data, mean, standard deviation, median, minimum, and maximum will be presented.
Key words
Immunotherapy, A2aR, PDR001, NIR178, NSCLC, solid tumors


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1
Background
The immune system is a critical regulator of tumor biology with the capacity to support or 
inhibit tumor development, growth, invasion and metastasis. However, over time and under 
pressure from immune attacks, tumors have developed strategies to successfully evade the host 
immune system. Various molecular and cellular mechanisms responsible for tumor evasion 
have been identified. Strategies designed to harness the immune system (immunotherapy) are 
the focus of several recent promising therapeutic approaches for cancer patients. 
Immunotherapy has demonstrated impressive outcomes for some patients with cancer 
(Ohta et al 2006, Pardoll 2012, Sitkovsky et al 2014, Zarek et al 2008). The success of 
checkpoint blockade in recent clinical trials has been a major step forward in the development 
of immunotherapy for the treatment of cancer, confirming the clinical importance of tumor 
immune evasion through usurping fundamental pathways of immune regulation.
In March 2015, nivolumab was approved by the Food and Drug Administration (FDA) for the 
treatment of metastatic squamous non-small cell lung cancer (NSCLC) that has failed 
chemotherapy, based on results of the pivotal phase III CheckMate-017 trial 
(Brahmer et al 2015), which showed improved overall survival (OS) compared to docetaxel in 
NSCLC patients with squamous cell histology (9.2 vs 6.0 months; HR = 0.59; 95% CI, 0.44-
0.79; P = 0.00025). More recently, the phase III CheckMate-057 trial met the primary endpoint 
of improved OS (meetinglibrary.asco.org).
With the success of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed 
death-1 (PD-1) and programmed death ligand-1 (PD-L1) inhibition in clinical trials, significant 
effort has focused on uncovering other targetable checkpoint pathways active in the tumor 
microenvironment. In this regard, adenosine signaling through the A2a receptor has been found 
to function as one such promising negative feedback loop.
Like CTLA-4, PD-1 and PD-L1, adenosine signaling in the inflammatory setting serves to 
dampen immunologic response and protect tissues from associated injury. While extracellular 
adenosine levels are typically very low, tissue breakdown and hypoxia (common to 
inflammatory and tumor microenvironments) generate high levels of extracellular adenosine
(Dubyak et al 1993, Blay et al 1997). Extracellular adenosine can signal through a set of four 
G-protein-coupled receptors: A1, A2a, A2b, and A3 (Robeva et al 1996). Adenosine signaling 
through A2a and A2b receptors expressed on a variety of immune cell subsets and endothelial 
cells has been established as having an important role in protecting tissues during inflammatory 
responses (Zarek et al 2007, Fishman et al 2009, Young et al 2014). Because of its distribution 
and dynamic expression pattern on a broader array of immune cells, most of this protective 
effect is thought to be secondary to signaling through the high-affinity A2a adenosine receptor. 
A2a receptor blockade represents the potential next generation of immune checkpoint inhibition 
in cancer immunotherapy.


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1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
Adenosine A2a Receptor (A2aR) overview
Adenosine in the tumor microenvironment inhibits T cells. Adenosine is a potential mediator 
of immunotherapy resistance based on the knowledge that the extracellular tumor 
microenvironment contains high levels of adenosine as a consequence of anaerobic glycolysis 
in hypoxic regions; preferential utilization of aerobic glycolysis for energy metabolism in non-
hypoxic regions (the Warburg effect); and tumor cell expression of the ectonucleotidase CD73 
that catabolizes Adenosine monophosphate (AMP) to produce adenosine. It had been known 
that adenosine produced within the hypoxic microenvironment of inflamed tissue functions to 
limit the exuberance of the inflammatory response to reduce collateral damage of normal tissue 
by inflammatory cells and cytokines. This is due to a direct inhibitory effect on T cells that 
express A2aRs52, leading to discovery that adenosine in the tumor microenvironment interferes 
with anti-tumor immunity.
Expression of A2a adenosine receptor (A2aR) has been reported on monocytes/macrophages, 
mast cells, granulocytes, lymphocytes, Dendritic cell (DC), natural killer (NK) cells, endothelial 
cells, and airway epithelial cells (Ahmad et al 2009, Fredholm 2007). Nutrient deprivation and 
accumulation of metabolites in the tumor microenvironment (TME) like adenosine have been 
identified as a new regulatory node to target to re-establish anti-tumor immunity. Of the four 
known types of adenosine receptors, A2aR is the predominantly expressed subtype in most 
immune cells (Antonioli et al 2013, Fredholm et al 2001, Sitkovsky and Ohta 2013) Beyond the 
induction of regulator T cell (Treg) with stronger immunosuppressive phenotype 
(Ohta et al 2012), the stimulation of A2aR results in inhibition of proliferation, cytokine production 
and cytotoxicity of T cells and NK cells as well as decreased antigen presentation by 
macrophages/dendritic cells (Antonioli et al 2013, Fredhold et al 2001, Sitkovsky and Ohta 2013) 
(Figure 1-1). The combination of an adenosine antagonist (SCH58261 or ZM241365) with T 
cell checkpoint blockade (an anti-PD1 or anti-CTLA4 agent) resulted in a reduction of 
metastasis in the B16F10 melanoma model (Mittal et al 2014, Iannone et al 2014). This finding 
supports the non-redundant role for adenosine and checkpoints molecules in the immune 
response in cancer and provides a rationale for testing this combination in the clinic.
In vivo studies using mice with global knockout of A2aR have demonstrated enhanced rejection 
of highly immunogenic tumors including melanoma and lymphoma in a CD8 T cell dependent 
manner (Ohta et al 2006, Waickman et al 2012). However, in these same mice models, global 
deletion of A2aR did not impact growth rates of other immunogenic tumors including B16F10 
melanoma and MB49 bladder carcinomas (Ohta et al 2006). Others have reported shortened 
survival of infiltrating T cells and impaired anti-tumor immunity with both global, and 
lymphoid specific genetic depletion of A2aR (Cekic et al 2013). A genetically modified strain 
of C57Bl6 mice engineered to have A2aR depleted only in lymphoid cells displayed enhanced 
growth rates of ectopically implanted B16F10 melanoma and MB49 bladder tumors, reduced 
effector-memory differentiation, and reduced expression of anti-apoptotic IL7Ra in memory 
T cells (Cekic and Linden 2014). Together, these data show that while A2aR deletion leads to 
robust immune activation in vivo, global and persistent A2aR deletion can have deleterious 
effects on anti-tumor immunity and promote tumor growth in some in vivo models. 


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Therefore, pharmacologic inhibition of A2aR in the clinic may require careful exploration of 
both continuous and intermittent inhibition in order to optimize both the intensity and duration 
of A2aR blockade to achieve maximal anti-tumor effect (Figure 1-1).
Figure 1-1
Adenosine A2a Receptor (A2aR) signaling
Figure adapted from Leone et al (2015).
1.1.2
PD-1 overview
PD-1 is a critical checkpoint receptor that is expressed by effector T cells (Teffs) upon 
activation (Okazaki et al 2013). It is also expressed by B cells, NK T cells, CD4+ Treg cells, 
and some DC subsets upon activation (Francisco et al 2010). Its ligands, PD-L1 and 
programmed death-ligand 2 (PD-L2) are expressed by dendritic cells, macrophages and 
monocytes, and can be induced on virus-infected cells and many types of tumors 
(Keir et al 2008). Engagement of PD-1 with its ligands PD-L1 and PD-L2 negatively regulates
effector T cell signaling and function and protects the tumor cells from the induction of 
apoptosis by Teffs.


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The PD-1/PD-L1 axis is exploited by many tumor types to avoid detection by the adaptive 
immune system (Murphy 2011). Blockade of the PD-1 pathway has been shown to lead to 
increased numbers of Teffs through induction or expansion and improved cytolytic activity 
towards tumors. Additionally, PD-1 blockade is associated with accumulation of Teffs and a 
reduced numbers of Tregs at the tumor site (Wang et al 2009, Mangsbo et al 2010, 
Mkrtichyan et al 2011, Rosenblatt et al 2011).
Both preclinical and clinical studies have demonstrated that anti-PD-1 blockade restores activity 
of “exhausted” Teffs and results in robust anti-tumor response. Clinical data with other anti-
PD-1 antibodies have demonstrated that PD-1 checkpoint inhibition results in clinically relevant 
anti-tumor activity in a variety of solid tumors, including melanoma, NSCLC, renal cell 
carcinoma (RCC) and head and neck squamous cell carcinoma (HNSCC) with an acceptable 
and manageable safety profile (Topalian et al 2012, Hamid et al 2013, Lyford-Pike et al 2013, 
Powles et al 2014, Topalian et al 2014, Ansell et al 2015, Homet Moreno and Ribas 2015, 
Michel Ortega and Drabkin 2015, Sunshine and Taube 2015).
Despite these successes, many patients do not respond to/or relapse following treatment with 
PD1 inhibitors. Additional strategies employing combination of PD-1 inhibition with other 
immune checkpoints are hypothesized to improve the response rates seen with PD-1 inhibitors 
alone. Combined inhibition of the PD-1 pathway and A2aR has been shown to enhance CD8 T 
and NK cell anti-tumor activity and reduce metastatic burden in preclinical models 
(Young et al 2014, Waickman et al 2012), supporting evaluation of this combination in the 
clinic.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of NIR178
NIR178 [5-bromo-2,6-di(1H-pyrazol-1-yl)pyrimidin-4-amine], a new, non-xanthine-based 
compound, is a potent oral adenosine A2a receptor antagonist being developed by Novartis. 
NIR178 has been profiled in binding assays against the four known adenosine receptors 
demonstrating selectivity for A2A compared to the other adenosine receptors (A1, A2b, and 
A3). The inhibition constants (Ki) were 12nM against A2A and over 1uM for the other 
adenosine receptors. Furthermore, the compound was able to inhibit the increase of cyclic 
adenosine monophosphate (cAMP) induced by an adenosine A2A agonist with a Ki of 25nM.
As NIR178 was in-licensed by Novartis from Palobiofarma, pre-clinical and clinical data 
generated with this compound prior to this study and detailed in the Investigator’s Brochure (IB) 
uses the Palobiofarma designation, PBF-509. For further information, please refer to the 
[NIR178 (PBF-509) Investigator’s Brochure].
1.2.1.1
Non-clinical experience
Initial evaluation of the anti-tumor activity of NIR178 was done with ex vivo experiments using 
lung cancer cells from patient biopsies and in vivo experiments in syngeneic mice using 
B16-CD73+ and MCA205 cells. The ex vivo experiments studied the effect of NIR178 on the 
secretion of interferon gamma (IFNγ) in tumor cells and tumor infiltrating lymphocytes (TIL) 
arising from treatment resistant tumors from patients with lung cancer. NIR178 alone was able 


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to increase secretion of IFNγ in tumors enriched with TIL of patient donors. In four out of six
human lung tumors assayed, NIR178 (1µM) was able to stimulate the secretion of IFNγ and
some other interleukins into the medium, demonstrating robust immune stimulation of the 
infiltrating lymphocytes present within the tumors.
The combination of NIR178 (1µM) with either an anti PD-L1 or an anti-PD1 antibody appears 
to increase interferon gamma secretion of those tumors synergistically. The synergism of anti-
PD1 antibody and NIR178 has been assessed in MC38 syngeneic tumor models. Of note, the 
anti-PD1 antibody used in this experiment was not PDR001 (which is not mouse cross-reactive) 
but a surrogate antibody (clone 5D1).
In order to understand whether different schedules of administration of NIR178 could affect the 
outcome of the combination, continuous and intermittent schedules of NIR178 in the presence 
or absence of anti-PD1 antibody were compared.
A cohort of 90 C57Bl/6 mice were subcutaneously implanted with 1 x 106 MC38 cells and 
randomized at day 5 when tumors were palpable. Tumor bearing mice were distributed in six 
groups of treatment as described below:
1. Vehicle control (0.5% SLS; 0.5% MC)
2. NIR178 50 mg/kg BID, continuous schedule
3. NIR178 50 mg/kg BID, for 4 consecutive days followed by 3 days off
4. Anti-PD1 (10mg/kg) once a week + vehicle
5. NIR178 50 mg/kg BID, continuous schedule + anti-PD1 once a week
6. NIR178 50 mg/kg BID for 4 consecutive days followed by 3 days off + anti-PD1 (10 
mg/kg)
Mice were treated for 9 days with vehicle control or PBF-509 alone or together with anti- PD1 
antibody at the above indicated doses and schedules by oral gavage from day 5. Tumor volume 
was measured twice a week as illustrated in Figure 1-2. P values were calculated using Mann-
Whitney test.
Figure 1-2
Effect of NIR178 chronic treatment in the MC38 syngeneic mouse 
model


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Intermittent dosing of NIR178 demonstrated a trend towards better control of tumor growth 
than chronic continuous dosing schedules in mice (Figure 1-2). Furthermore it was observed 
that the statistical significance of the response of the combination group (NIR178 and anti-PD1) 
was stronger when three days of drug holiday was introduced into the dosing schedule. 
These subtle, but statistically significant differences in tumor growth rates between continuous 
and intermittent schedules lend support to further exploring intermittent scheduling of NIR178 
in the clinical setting.
1.2.1.2
Non-clinical pharmacokinetics and drug metabolism for NIR178
The non-clinical pharmacokinetics of NIR178 has been investigated in mouse, rat, and dog 
in vivo models. The clearance and volume of distribution determined for NIR178 were high in 
both the rat and the dog. The apparent half-life was short to moderate in rat and dog. NIR178 
was orally available in mouse, rat, and dog with the bioavailability in rat determined to be 
moderate (~44%).
In vitro plasma protein binding assessment of NIR178 showed low to moderate protein binding 
(low, 0-50% bound; moderate 50-90% bound) across species.
Hydroxylation and subsequent glucuronidation, sulfonation, or pyrazole ring-opening were the 
metabolic pathways observed in incubates of NIR178 with rat, dog, and human cryopreserved 
hepatocytes. None of the NIR178 metabolites characterized were determined to be unique to 
human. A hydroxylated metabolite of NIR178 named NJI765 (M1 or PBF-849) was observed 
circulating in both rat and dog from toxicology studies at exposures less than the parent 
exposure. The cytochrome P450 (CYP) enzyme 1A2 was found to be the primary enzyme 
responsible for the clearance of NIR178 in human liver microsomes.
NIR178 was determined in vitro to be a potent reversible inhibitor of human (h) CYP1A2 and 
a weak inhibitor of hCYP2D6 and hCYP2C19. Based on a mechanistic static model of 
drug-drug interactions (DDIs), NIR178 has the potential to cause increased exposures for 
hCYP1A2 substrates.
Results from in vitro luciferase assays demonstrate that NIR178 is unable to activate Pregnane 
X Receptor (PxR) and aryl hydrocarbon receptor (AhR), suggesting that NIR178 is not likely 
to be an inducer of drug metabolizing enzymes.
NIR178 was tested as an inhibitor of the human organic anion-transporting polypeptide (OATP) 
proteins 1B1 and 1B3 using in vitro cell lines expressing OATP1B1 and OATP1B3. NIR178 
inhibited the transport activity of OATP1B1 with a maximum observed inhibition of 33% at 
50 µM, and had no effect on OATP1B3 activity.
NIR178 was tested in in vitro cell lines as an efflux inhibitor of the human breast cancer 
resistance protein (BCRP) and P-glycoprotein (P-gp). NIR178 showed no inhibition of a P-gp 
human ortholog. NIR178 maximally inhibited BCRP in vitro by 73.9% at 50 µM with an 
estimated IC50 of 14.2 µM. NIR178 may cause an increase in the systemic exposure of 
co-medications whose clearance is significantly mediated by BCRP, but not P-gp, provided that 
sufficiently high concentrations of NIR178 are achieved in vivo.
Please refer to [NIR178 (PBF-509) Investigator’s Brochure] for further details.


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1.2.1.3
Biopharmaceutics
A crossover relative bioavailability study [Study DMPK R1701376] in Beagle dog was 
conducted to screen the in vivo pharmacokinetic performance of a film-coated tablet (FCT) 
formulation prototype of NIR178 in comparison to the existing hard gelatin capsule (HGC) 
formulation used in current clinical trials. In this study, both formulations were administered as 
intact dosage form and as a suspension in water. When administered orally at a dose of 80 mg
as intact dosage forms, the average bioavailability of NIR178 in FCT increased by 17% 
compared to the HGC. However, when both formulations were administered after making a 
suspension in water, the average bioavailability of NIR178 in FCT increased by 44%  compared 
to the HGC existing formulation. The study also seems to suggest less variability in PK of 
NIR178 with the FCT formulation (Table 1-1).
Data from this dog PK study guided the selection of the proposed film-coated tablet which will 
be introduced in the current clinical study. The proposed film-coated tablet led to reduced 
variation in PK and improved bioavailability of NIR178.
Table 1-1
Relative bioavailability of a film-coated tablet (FCT) formulation 
variant of NIR178 compared to the existing capsule formulation (hard 
gelatin capsule) in Beagle dog 
Dosage form
Dose
Median Tmax 
(hr)
Mean Cmax, 
ng/mL (CV%)
Mean AUClast, 
ng*hr/mL 
(CV%)
AUClast fold 
change vs. 
reference
Hard gelatin 
capsule 
(intact) 
[reference]
80 mg PO
1.0
3,410 (69)
6,940 (69)
Film-coated 
tablet (intact)
80 mg PO
2.0
4,770 (34)
8,110 (41)
1.17
Hard gelatin 
capsule 
(suspension1)
[reference]
80 mg PO
(Suspension 
in water)
1.0
6,090 (53)
10,000 (64)
Film-coated 
tablet 
(suspension1)
80 mg PO
(Suspension 
in water)
1.0
7,880 (25)
14,400 (25)
1.44
Source: Study DMPK R1701376
Study used a crossover design with N=6 dogs per dosing period; 
150 mL water was used to bring the capsule or tablet drug product to a suspension prior to oral 
administration via gavage.
Abbreviations: PO, orally; Cmax, maximum observed plasma concentration; AUClast, area under the 
plasma concentration-time curve from time zero to the time of the last quantifiable concentration.
[...]
1.2.1.4
Clinical experience
Two healthy volunteer studies were conducted with single agent NIR178 and there is one 
ongoing Phase I/Ib trial (CNIR178X2103J) of NIR178 as single agent and in combination with 
PDR001 in patients with advanced non-small cell lung cancer (NSCLC).


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In the first in human trial in healthy volunteers conducted by Palobiofarma (using compound 
designation PBF-509), seven single ascending doses (10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 
320 mg, and 480 mg) were evaluated. NIR178 was found to be safe and well tolerated with no 
dose-limiting toxicity (DLT) reported at all administered dose levels. No clinically relevant 
changes related with the NIR178 administration were found in the safety parameters evaluated 
(ECG, vital signs, blood chemistry, and hematology) in any of the healthy volunteers 
participating in the study.
In a subsequent multiple ascending dose clinical trial, the safety, tolerability of two doses 
(80 and 160 mg) of NIR178 were evaluated administering the compound once daily for 8 days. 
Similar to the single dose administration trial, NIR178 was found to be safe and well tolerated 
at both doses tested with no DLTs reported.
CNIR178X2103J is an ongoing phase I/Ib study evaluating the safety, tolerability, and anti-
tumor activity of NIR178 as single agent and in combination with PDR001 in patients with 
advanced/metastatic NSCLC. The study design utilizes a modified 3+3 dose escalation 
algorithm.
Dosing began on 15 October, 2015 with PBF-509 (NIR178) given orally twice daily in 28 day 
cycles. As of January 15, 2020, the single agent NIR178 dose escalation part has enrolled 25 
patients across five dose levels: 80mg BID (n=3), 160mg BID (n=3), 320mg BID (n=7), 480mg 
BID (n=6) and 640mg (n=6). In general, NIR178 has been well tolerated as single agent and 24
out of 25 patients (96%) have discontinued treatment. Two patients died on treatment due to 
underlying disease. There were two DLTs reported: Grade 3 nausea and Grade 3 ALT/AST 
increased, both at the 640mg dose level.  The maximum tolerated dose of oral single agent of 
NIR178 was declared at 480mg BID. No grade 4 adverse events were reported. Four patients
out of 25 experienced grade 3 treatment related toxicity which include nausea, pneumonitis, 
AST/ALT increase and lipase increase. Among 19 evaluable patients (out of 25 dosed on single 
agent NIR178), best overall responses include 1 patient with complete response (CR), 1 patient 
with partial response (PR) and 7 patients with stable disease (SD). The maximum tolerated dose 
(MTD) for single agent NIR178 was declared as NIR178 480 mg BID (Chiappori et al 2018).
The combination of NIR178 with PDR001 has been evaluated in the phase I/Ib study 
CNIR178X2103J as a parallel dose escalation in patients with advanced NSCLC. Dose 
escalation followed a modified 3+3 algorithm, in which PDR001 was dosed at the RDE of 
400mg IV Q28 days and NIR178 was escalated from a starting dose of 160mg BID. Dosing with 
the combination began on August 11, 2016. As of January 15, 2020, 25 patients have been
treated with NIR178 in combination with PDR001. There were four dose-limiting toxicities 
reported: 2 patients with grade 3 pneumonitis, one patient with grade 3 fatigue and one patient 
with grade 3 ALT/AST increase. The most frequent (≥10%) drug-related AEs were nausea 
(24%), AST/ALT increase (both 20%), fatigue (16%), and lipase increase (12%). The most 
frequent (≥5%) Gr 3 drug-related AEs were AST increase (12%), ALT increase, lipase increase 
and pneumonitis (all 8%). At the time of data cutoff, there was 1 complete response (CR) and 
1 partial response (PR) and 12 stable disease (SD) reported. The MTD for  NIR178 in 
combination with PDR001 400 mg Q4W was declared as 240 mg BID (Chiappori et al 2018).
Please refer to [NIR178 (PBF-509) Investigator’s Brochure] for further details.


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In the ongoing CNIR178X2201 trial, as of August 3, 2020, 13 patients were treated with the 
NIR178 240mg dose in combination with PDR001 400mg Q4W with available safety data. The 
first 10 patients enrolled at the NIR178 240mg dose, have completed at least one cycle of 
treatment with G3 AEs suspected to be related to study drug occurring in two patients. Less 
than 33% of the first 10 patients enrolled in this regimen experienced a G3/G4 AE suspected to 
be related to study drug, which is below the defined threshold as outlined in Section 6.2.3. To 
date, the dose of NIR178 240mg BID in combination with PDR001 400mg Q4W has shown to 
be safe and well tolerated. 
1.2.1.4.1 Clinical pharmacokinetics of NIR178
The pharmacokinetics of NIR178 both single and repeat dose of NIR178 has been characterized 
in healthy volunteers in prior studies as well as in NSCLC patients in an ongoing Phase I/Ib 
study (CNIR178X2103J). A mono-oxygenated metabolite (NJI765) was also monitored in 
healthy volunteer studies. In healthy volunteers, (single ascending dose levels of 10, 20, 40, 80, 
160, 320 and 480 mg) NIR178 demonstrated rapid absorption and elimination with a Tmax of 
0.17-4 hrs and a terminal elimination half-life of 1.06-3.83 hrs. Concentrations in the systemic 
circulation were generally below the lower limit of detection at 10 and 20 mg.
Systemic exposure (Cmax and AUC) over the dose range of 40 to 480 mg generally increased 
more than proportionally with dose; inter-subject variability was moderate to high.
In the Phase I/Ib study in advanced NSCLC, patients were dosed NIR178 orally twice daily 
(BID) as a single agent 80, 160, 320, 480, and 640mg. NIR178 was rapidly absorbed with a 
median Tmax occurring at 2 hours post-dose.  NIR178 featured nonlinear pharmacokinetics, 
both dose- and time-dependent. Similarly to healthy volunteers, NIR178 systemic exposure 
increased more than proportionally with dose following single and repeated BID dosing of 80 
to 640 mg. Despite of its short terminal half-life, the accumulation ratio of NIR178 was 
approximately 3-fold after one week of multiple daily dosing compared to a single dose. 
Inter-subject variability in Cmax and AUC was moderate to high. The pharmacokinetics of 
NIR178 (160, 240, and 320 mg BID) when given in combination with PDR001 (400 mg every 
4 weeks) in patients with advanced NSCLC is largely similar to that of NIR178 alone, 
suggesting no clinically relevant interaction between the two drugs.
Please refer to the [NIR178 (PBF-509) Investigator’s Brochure] for further details.
1.2.2
Overview of PDR001
PDR001 is a high-affinity, ligand-blocking, humanized anti-programmed death-1 (PD-1) IgG4 
antibody that blocks the binding of Programmed death-ligand 1 (PD-L1) and programmed 
death-ligand 2 (PD-L2) to PD-1. PDR001 recognizes PD-1 in cynomolgus monkeys and shows 
functional activity in vitro/ex vivo.
For further details, please refer to the [PDR001 Investigator’s Brochure].


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Figure 1-3
Blockade of PD-1/PD-L1 interaction by PDR001
APC: Antigen Presenting Cell; MHC: Major Histocompatibility; TCR: T cell Receptor
1.2.2.1
Non-clinical experience
PDR001 binds specifically and with high affinity to human PD-1. In Biacore assays, the 
constant of dissociation of PDR001 on human PD-1 is 0.827 nM. In lymphocyte stimulation 
assays using human blood ex vivo, PDR001 enhances interleukin-2 (IL-2) production by 
approximately 2 fold in response to super antigen stimulation with Staphylococcal enterotoxin 
B. PDR001 does not cross-react with rodent PD-1, and cannot be evaluated in murine tumor 
models. It does cross-react with cynomolgus monkey PD-1, and is functionally active, making 
cynomolgus monkey a relevant species for toxicology studies. The affinity of PDR001 for 
cynomolgus PD-1 is 0.929 nM, nearly the same for human PD-1, as noted above.
The non-clinical toxicology of PDR001 was evaluated in a five week good laboratory practice 
toxicology study in cynomolgus monkeys with safety pharmacology endpoints and an eight 
week recovery. Doses as high as 100 mg/kg/week were evaluated without drug-related in-life, 
mortality, organ weight changes, or macroscopic findings noted. At the highest doses tested, 
macrophage infiltrates in the spleen and limited mononuclear infiltrates in the vascular and 
perivascular space were noted.
For further details, please refer to the [PDR001 Investigator’s Brochure].
1.2.2.2
Clinical experience
The first in human phase I/II study CPDR001X2101 started enrollment on 27 April 2015 and 
is ongoing in patients with advanced malignancies. The dose escalation part of the study was 
completed with a total of 58 patients treated at the dose levels of 1, 3 and 10 mg/kg every two 
weeks (Q2W) and 3 and 5 mg/kg every 4 weeks (Q4W). No patient experienced a 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 
PDR001 of 400 mg Q4W or 300 mg Q3W. The expected PDR001 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 


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safety data, the recommended phase II doses (RP2D) of PDR001 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.
PDR001 is currently being studied alone or in combination with other agents in ongoing phase 
I/Ib/II clinical trials. The preliminary 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 adverse events. As observed with other PD-1 inhibitors, immune-mediated toxicities 
observed with PDR001 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. Based on the preliminary 
data, PDR001 was well tolerated with a safety profile similar to those of other marketed anti-
PD-1 antibodies.
For further details, please refer to the [PDR001 Investigator’s Brochure].
2
Rationale
2.1
Study rationale and purpose
The purpose of this phase II study is to evaluate the efficacy and safety of NIR178 in 
combination with PDR001 in multiple solid tumors and diffuse large B-cell lymphoma 
(DLBCL) and further explore schedule variations of NIR178 to optimize immune activation 
through inhibition of A2aR.
Combination therapies using multiple inhibitors of immune function can significantly improve 
response rates. For example, a nivolumab/ipilimumab combination providing blockade of the 
PD-1 and CTLA-4 immune checkpoints significantly improved responses for patients with 
advanced melanoma (Larkin et al 2015). Expanding the depth, breadth and durability of 
responses to treatment is now an important focus of clinical oncology research. These efforts 
include targeting different steps in the anti-tumor immune response to stimulate T lymphocyte 
activity in tumors, reduce suppressive effects of Tregs and myeloid cells, and engender 
long-lasting immunity through vaccines and enhancers of dendritic cell function 
(Mellman et al 2011).
The biological mechanisms and the preclinical evidence indicate that adenosine signaling 
through A2aR is an important immunosuppressive component within the tumor 
microenvironment, which may limit and possibly mediate resistance to immune checkpoint 
blockade with PD1 inhibitors. Therefore, pharmacological inhibition of A2aR in combination 
with PD1 mAb, PDR001, may be an effective way to alleviate immune-suppression, reduce 
tumor growth, and increase anti-tumor activity of PDR001.
In an ongoing phase Ib dose escalation trial in NSCLC (CNIR178X2103J), NIR178 has 
demonstrated an overall favorable safety profile as a single agent in dose escalation, with two
DLTs observed to date across five dose levels. Early data from dose escalation in combination 
with PDR001 also shows an overall manageable safety profile. Importantly, encouraging 
preliminary anti-tumor activity has been observed in a heavily pre-treated NSCLC population 
(one complete response (CR), one partial response (PR) and twelve stable disease (SD) seen 


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with single agent NIR178 out of 25 patients treated; 1 CR, 1 PR and 6 SD in combination with 
PDR001 out of 25 patients treated).
Based on encouraging early clinical activity in NSCLC and tolerability of the combination of 
NIR178 with PDR001, this phase II study will further explore the efficacy and safety of the 
combination of NIR178 and PDR001 in multiple tumor types. Intermittent dosing schedules of 
NIR178 in combination with PDR001 will also be explored in this study as preclinical data
shows a trend towards improved control of tumor growth using intermittent dosing of NIR178 
in syngeneic mouse models.
For further details, please refer to the [NIR178 (PBF-509) Investigator’s Brochure].
2.2
Rationale for the study design
This open label phase II study has three parts: Part 1: Multi-arm Bayesian adaptive signal 
finding design of NIR178 (dosed continuously) in combination with PDR001 in solid tumors 
and diffuse large B cell lymphoma (DLBCL); Part 2: Exploration of continuous and intermittent 
schedules of NIR178 in combination with PDR001 in patients with advanced NSCLC; Part 3: 
Further evaluation of efficacy of the best performing dosing schedule of NIR178 in combination 
with PDR001 in one or two tumor groups selected from Parts 1 and 2. The tumor group(s)
selected for Part 3 will be based on emerging data from Part 1, Part 2 and latest scientific 
literature. Parts 1 and 2 will enroll in parallel. As of protocol amendment 6, enrollment in Part 
2 has been completed, and the continuous dosing schedule of NIR178 has been selected as the 
preferred dose regimen as clinical efficacy results do not support the hypothesis that intermittent 
dosing improves NIR178 + PDR001 antitumor activity. Part 3 will be opened in parallel with 
Part 1, and will further assess TNBC patients with an IC score of 0 using NIR178 continuous 
dosing schedule in combination with PDR001. A second tumor group may be considered for 
Part 3 after completion of Part 1. Additionally, Part 3 will assess the safety and 
pharmacokinetics of a new FCT formulation of NIR178. The terms tumor types and groups are 
used interchangeably.
The purpose of Part 1 is to broadly evaluate the efficacy of NIR178 and PDR001 in 11 selected 
solid tumors and diffuse large B cell lymphoma (DLBCL) using a Bayesian adaptive signal 
finding design that utilizes predetermined futility/expansion thresholds to best identify tumor 
types that warrant further study with the combination. Tumor types were selected based on 
presence of features thought to be associated with adenosine mediated immunosuppression 
including, but not limited to, gene expression levels of CD73 and A2aR based on data from the 
Tumor Cell Genome Atlas (TCGA).
In order to effectively screen for efficacy signals across multiple tumor types, a Bayesian 
adaptive design will be used to identify those tumors in which the combination of 
NIR178+PDR001 demonstrates superior response rates in relation to that of current standard of 
care therapies. Based on observed overall response rate (ORR) for the first 10 patients in each 
tumor type in relation to established historical controls, a Bayesian model employing a 
hierarchical borrowing algorithm will determine which tumors warrant further expansion to a 
maximum of 30 patients, using pre-specified futility criteria. The advantages of such Bayesian 
approaches as opposed to traditional frequentist approaches have been previously described 
(Berry 2011, Zhen et al 2012). Please see Section 4.1.


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The purpose of Part 2 will be to explore the safety, efficacy, 
 of
continuous and several intermittent dosing schedules of NIR178 in combination with PDR001, 
in light of preclinical data showing slightly decreased rates of tumor growth in vivo with 
intermittent dosing schedules of NIR178. In order to control for confounding variables and 
precisely assess the effect of altering the NIR178 schedule, only patients with advanced NSCLC 
who are naïve to prior immunotherapy will be enrolled to this part. In order to further balance 
covariates across the 3 groups, patients will be randomized in a 1:1:1 fashion to one of 3 arms, 
each evaluating a different dosing schedule of NIR178 within a 28 day cycle. The decision to 
further explore the intermittent or continuous dosing schedule will be based on the integrated 
analysis of efficacy, safety 
. Please see Section 4.2.
If Part 2 identifies an intermittent or a continuous dosing schedule of NIR178 in combination 
with PDR001 as warranting further study, Part 3 will initiate in order to further evaluate the 
safety and efficacy of the intermittent or continuous NIR178 schedule using a new FCT 
formulation of NIR178, with two parallel groups of 20 to 30 patients each. One or two tumor 
groups from Part 1 and/or Part 2 will be further explored in Part 3 with the intermittent or 
continuous NIR178 schedule based on clinical efficacy 
 emerging data. If one of 
the tumor groups selected for Part 3 is advanced NSCLC, this group will enroll patients 
previously exposed to checkpoint inhibitors. As of protocol amendment 6, Part 3 will be opened 
in parallel with Part 1 to further assess the clinical activity in TNBC patients with a PD-L1 SP-
142 status of IC=0 using an NIR178 continuous dosing schedule in combination with PDR001. 
A second tumor group may be considered for Part 3 after completion of Part 1.
Additionally, as per recommendation of the Japanese Health Authority, a safety run-in part will 
be conducted in Japanese patients dosed at either 80mg or 160mg BID of NIR178 for the first 
cycle of treatment. The data generated from the safety run-in is considered adequate to evaluate 
the safety and pharmacokinetic (PK) profiles of single agent NIR178. Since there were no 
differences in the safety and PK profiles of PDR001 between Japanese and non-Japanese 
patients treated at the RDE of 400mg IV Q4 weeks in study CPDR001X1101, and given the 
low likelihood of DDI between NIR178 and PDR001 (Section 2.4.1), following the first cycle
safety run-in patients who receive single-agent NIR178 will be treated with the combination of 
NIR178+PDR001 starting cycle 2 onwards (Section 4.1.4). While the final analysis of safety 
will use all available safety and pharmacokinetic data (including combination phase with 
PDR001), the safety of single agent NIR178 in Japanese patients in relation to that of non-
Japanese patients treated at the same dose levels in the phase I study CNIR178X2103J, will be 
the primary determinant of whether or not Japanese patients can join the phase II study. As of 
Protocol Amendment 6, patients enrolled in the Japanese safety run-in part of the study will be 
treated with NIR178 240mg hard gelatin capsules BID in combination with PDR001 400mg 
Q4W starting at Cycle 1 Day 1. Based on the data from the Japanese safety run-in at the 80mg 
and 160mg, there were  no obvious ethnic differences on safety and PK observed between 
Japanese versus non-Japanese patients. In addition, no DDI has been observed between NIR178 
and PDR001. This design also allows Novartis to assess DLT in combination therapy in 
Japanese patients at the recommended dose.


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2.3
Rationale for dose and regimen selection
In this study the selection of dosing regimen is based on the currently available preclinical and 
clinical safety, efficacy, PK and PK/PD information for the NIR178 and PDR001 combination. 
Based on currently available data from the ongoing phase 1b study (CNIR178X2103J), NIR178 
160mg BID will be administered (continuous or intermittent dosing schedule) in combination 
with PDR001 at 400 mg every 4 weeks in this phase II study. All newly enrolled patients under 
Amendment 5 will receive NIR178 240 mg BID in combination with PDR001 400 mg every 4 
weeks. Patients enrolled in Part 3 of the study will receive the new FCT formulation of NIR178, 
starting with a dose of 160 mg BID in combination with PDR001 400 mg every 4 weeks. After 
the initial 10 patients complete at least the first cycle of treatment, safety and available PK data 
will be analyzed to determine if an increase of the NIR178 dose to 240 mg BID is warranted,
see Section 4.1.3. For the Japanese safety run-in three dose levels of NIR178 will be evaluated 
(80mg,160mg and 240mg). As of protocol amendment 6, patients enrolled in the Japanese 
safety run-in will be administered NIR178 240mg hard gelatin capsules BID in combination 
with PDR001 400mg every 4 weeks starting at Cycle 1 Day 1. 
A starting dose of NIR178 160 mg BID in combination with PDR001 using the new FCT 
formulation was selected based on the following considerations:

NIR178 240 mg BID in combination with PDR001 400 mg QW4 was declared as MTD,
based on clinical data with the existing formulation;

FCT (administration as intact tablet) increased the bioavailability of NIR178 in dog 
relative to existing capsule formulation (administered as intact capsule) by 17% (refer 
to Table 1-1);

Decrease in variability of PK parameters of FCT (CV% of AUClast decreased from 69 
to 41 and CV% of Cmax decreased from 69 to 34);

Cumulative safety data of NIR178 at the dose 240 mg BID + PDR001 in other tumor 
indications (e.g., RCC, mCRPC) using existing capsule formulation is not yet available.  
Preliminary evidence, based on emerging data from the current phase 2 study CNIR178X2201,
shows that patients may derive more clinical benefit from a higher starting dose of NIR178, 
more specifically:

Combined 
 pharmacokinetic, and efficacy data show a trend for patients 
with increases in CD8 T-cell infiltration in on-treatment biopsies to demonstrate 
greater anti-tumor efficacy. Further, there is evidence of a correlation between 
exposure, T cell infiltration, and response to provide further support for the higher 
dose exploration.


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
Of the 165 patients (Part I only) treated with NIR178 160mg twice daily continuously 
in combination with PDR001 400mg every 4 weeks, 99 patients (60.0%) experienced 
AEs (all grades) suspected to be related to study treatment. The most commonly 
reported AEs were fatigue (29 patients, 17.6%), increased AST (20 patients, 12.1%), 
decreased appetite (17 patients, 10.3%), increased ALT (16 patients, 9.7%), nausea 
(15 patients, 9.1%), vomiting (10 patients, 6.1%), pruritus (9 patients, 5.5%). 
For further details, please refer to the [NIR178 (PBF-509) Investigator’s Brochure].

Exposure-response analysis for safety indicates that the steady-state pharmacokinetic 
exposure of NIR178 at 240 mg BID combined with PDR001 400 mg Q4W is below 
the select 33% probability threshold for patients to develop Grade 3-4 AST and/or 
ALT elevation. Further, preliminary analysis revealed a concentration-dependency in 
hepatotoxicity AEs across the clinically relevant exposure range of NIR178. 
Despite the positive trend of AST/ALT elevations with exposure, elevation of 
transaminases was in general reversible and manageable upon dose reduction or 
interruption based on clinical observation. Therefore, existing guidelines in the 
protocol for dose reduction and/or interruption for NIR178 are considered to be 
effective in managing transaminase elevations by decreasing drug exposure 
(refer to Table 6-2).

NIR178 240 mg BID + PDR001 400 mg Q4W was determined to be the maximum 
tolerated dose (MTD) for the double combination and was well tolerated in patients 
with advanced NSCLC.  Increasing the dose of NIR178 to 240 mg BID from 160 mg 
BID will add one additional dose reduction step if needed, as follows: 240 mg 
(starting dose), 160 mg (dose level -1, 33% reduction), 120 mg (dose level -2, 25% 
reduction), and 80 mg (dose level -3, 33% reduction). Dose reduction below 80 mg 
BID is not allowed (refer to Table 6-5).

The capsule formulation of NIR178 used in CNIR178X2103J study to establish the 
maximum tolerated dose (MTD) of NIR178 + PDR001 combination in advanced NSCLC 
patients differs from that used in CNIR178X2201 study with regards to excipients and their
quantitative composition as well as manufacturing. The relative bioavailability between 
Novartis’ capsule formulation (used in the present clinical study) and the one used in the 
first-in-human study CNIR178X2103J has not been determined. Preliminary analysis based 
on cross-study comparison of patient-level pharmacokinetic data did not show apparent 
differences in drug exposure following repeated dosing of NIR178 160 mg BID using these 
two formulations, therefore it is considered that the pharmacokinetic and safety profile of 
NIR178 240 mg BID + PDR001 in the current study will be consistent to that observed 
earlier in CNIR178X2103J study with the 240 mg BID dose.
PDR001 is being tested in an ongoing, multicenter, open-label study CPDR001X2101 with a 
phase I dose escalation part followed by a phase II part. The recommended phase II dose was 
declared as 400 mg every 4 weeks.
For further information, please refer to Section 1.2.2.2.


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2.4
Rationale for choice of combination drugs
In preclinical studies, NIR178 combination with either an anti PD-L1 or an anti-PD-1 antibody 
increases interferon gamma secretion of selected tumors synergistically. The synergism of 
anti-PD1 antibody and NIR178 has been assessed in MC38 syngeneic tumor models. 
Furthermore, NIR178 as a single agent and in combination with PDR001 appears to have a 
manageable safety profile and preliminary signs of clinical activity, based on data from an 
ongoing phase Ib study in patients with advanced NSCLC, supporting further evaluation of this 
combination clinically in other tumor types.
2.4.1
Potential for drug interactions
Drug-drug interaction (DDI) between NIR178 and PDR001 are not expected although specific 
studies have not been conducted.
As an antibody, PDR001 is eliminated through protein catabolism and target-mediated 
disposition. Therefore, PDR001 is not anticipated to be directly eliminated through 
hepatic/renal metabolism and excretion or to compete with the elimination of NIR178, which 
is likely eliminated through metabolism. However, immunomodulatory drugs may induce 
systemic cytokines that alter CYP-mediated metabolism and affect the clearance of small 
molecules (Harvey et al 2014, Girish et al 2011). Therefore, the risk of DDI between PDR001 
and the NIR178 cannot be totally excluded. For nivolumab, the Clinical Pharmacology and 
Biopharmaceutics Review (Nivolumab FDA application (2014)) states that nivolumab did not 
affect CYP enzyme-related cytokine modulation at doses as high as 10 mg/kg in patients. 
Nevertheless, concentration measurements of NIR178 in the presence of PDR001 are evaluated 
in CNIR178X2103J study and will be evaluated in this study to explore a possible 
pharmacokinetic drug interaction between PDR001 and combined drugs.
2.5
Rationale for choice of comparators drugs
Not applicable.


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2.6
Risks and benefits
Appropriate eligibility criteria, as well as specific dose modification and stopping rules, are 
included in this protocol. Recommended guidelines for prophylactic or supportive management 
of study-drug induced adverse events are provided in Section 6.2 and Section 6.3. The risk to 
patients in this study may be minimized by compliance with the eligibility criteria and study 
procedures, as well as close clinical monitoring, and stopping rules.
While the incidence of immune related adverse events with single agent PD-1 inhibitors has 
been well characterized, there may be a higher incidence of immune related adverse events with 
combination immune therapies, including the combination of NIR178 + PDR001. 
These immune-mediated adverse events may be serious and may include, but are not limited to, 
pneumonitis, hepatitis, severe cutaneous adverse reactions, endocrine disorders and other 
autoimmune disorders. Given that responses to single agent PD-1/PDL-1 inhibitors can be 
improved upon with combinations of IO therapies, the combination of NIR178 and PDR001 is 
hypothesized to improve the response to existing standard of care therapies in the tumors being 
evaluated in this study. The encouraging tolerability and response rates observed in the ongoing 
phase Ib study of NIR178+PDR001 in advanced NSCLC in both immunotherapy exposed and 
naive patients lends support to this hypothesis. Therefore, the benefit of the combination of 
NIR178 + PDR001 is thought to outweigh the risk in patients with advanced malignancies being 
evaluated in this study.
No substantial additional risk for patients' safety due to the SARS-CoV-2 virus and the COVID-
19 pandemic has been identified at this time and therefore the benefit risk remains unchanged. 
In case of active COVID-19 infection, a careful benefit risk evaluation will be performed to 
determine whether patients can remain on study treatment or not.
For additional information on risk-benefit assessment, please refer to [NIR178 (PBF-509)
Investigator’s Brochure] and [PDR001 Investigator’s Brochure].


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Part 1:To evaluate the efficacy of NIR178 and 
PDR001 combination in patients with selected 
advanced solid tumors and diffuse large B cell 
lymphoma (DLBCL)
Overall Response Rate (ORR) by RECIST v1.1 (for solid tumors) or 
Cheson (for DLBCL) or PCWG3 criteria for mCRPC (Appendix 5)
Refer to Section 10.4.
Part 2: To assess the efficacy of continuous and 
several intermittent dosing schedules of NIR178 in 
combination with PDR001 in NSCLC
Overall Response Rate (ORR) by RECIST v1.1 (for solid tumors)
Part 3: To evaluate efficacy of intermittent or 
continuous dosing schedule of NIR178 in one or two 
selected tumor types
Overall Response Rate (ORR) by RECIST v1.1 (for solid tumors) or 
Cheson (for DLBCL) or PCWG3 criteria for mCRPC (Appendix 5)
Secondary
Refer to Section 10.5 and 
Appendix 3.
To assess efficacy of NIR178+PDR001 in select 
advanced solid tumors and lymphoma
Overall Response rate (ORR) by iRECIST and in addition, for 
mCRPC, best PSA change from baseline.
To assess efficacy of NIR178+PDR001 in select 
advanced solid tumors and lymphoma
Disease Control Rate (DCR), duration of response (DoR), 
Progression Free Survival (PFS), 2 year Overall Survival (OS) rate by 
RECIST v1.1 and iRECIST (for solid tumors), Cheson (for DLBCL), 
and PCWG3 criteria for mCRPC (Appendix 5)
To assess the safety and tolerability of the NIR178 
and PDR001 combination using NIR178 hard gelatin 
capsule and FCT formulation 
Frequency, severity and seriousness of AEs, laboratory abnormalities 
and other safety parameters. Dose interruptions, reductions and dose 
intensity.
To characterize changes in the immune infiltrate in 
tumors
Change from baseline in TILs by immunohistochemistry (IHC) (such 
as CD8)


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Objective
Endpoint
Analysis
To characterize the pharmacokinetics (PK) of 
NIR178, its metabolite NJI765 and PDR001 in 
combination using hard gelatin capsule and FCT 
formulation
Plasma concentration time profiles of NIR178, NJI765 and PK 
parameters.
Serum concentration time profiles of PDR001 and PK parameters
To assess immunogenicity of PDR001
Presence and/or concentration of anti-PDR001 antibodies
Japanese Safety Run-in:To assess the preliminary 
safety, and PK of single agent NIR178 and in 
combination with PDR001 in Japanese patients
Frequency, severity and seriousness of DLTs, AEs, laboratory 
abnormalities and other safety parameters (ECG, physical exams 
etc).
Plasma concentration time profiles of NIR178/PDR001 and PK 
parameters.


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4
Study design
4.1
Description of study design
This is an open-label multi-part, phase II study evaluating the combination of NIR178 and 
PDR001 in patients with advanced solid tumors and diffuse large B cell lymphoma (DLBCL). 
Patients will receive treatment with the combination until disease progression (assessed by 
investigator per iRECIST (Appendix 3) or Cheson et al (2014) for DLBCL), unacceptable 
toxicity, start of a new anti-neoplastic therapy, or discontinuation at the discretion of the 
investigator or patient, lost to follow-up, death or study is terminated by the sponsor. All patients 
who discontinue from study treatment due to disease progression must have their progression 
clearly documented. All disease assessments will be performed locally by the investigator.
Submission of a pre-treatment and on-study tumor sample is mandated for all patients enrolled. 
The timing of the sample collection will be: 1) A pre-treatment biopsy (defined as obtained after 
most recent therapy and within 6 months preceding first dose of study treatment 2) on-treatment 
tumor biopsy taken on C2D15 (+15 days). Exceptions may be made on a case by case basis 
after discussion between Novartis and the Investigator. An optional biopsy may be collected at 
end of treatment and at disease progression when patients continue on study treatment due to 
overall clinical benefit.
This phase II study has 3 parts (Figure 4-1). Parts 1 and 2 will enroll in parallel, and Part 3 will 
open once results from Parts 1 and 2 are available. As of protocol amendment 6, Part 3 will be 
opened in parallel with Part 1, using the NIR178 continuous dosing schedule, which was 
identified as the preferred dosing schedule in Part 2 of the study.

Part 1: Multi-arm Bayesian adaptive signal finding design in 13 groups (some of which in
subgroups based on mutation status or prior treatment), and diffuse large B cell lymphoma 
(DLBCL) with continuous dosing of NIR178 in combination with PDR001.

Part 2: Exploration of continuous and intermittent NIR178 schedules in combination with 
PDR001 in patients with advanced non-small cell lung cancer (NSCLC).

Part 3: Further evaluation of optimal intermittent or continuous schedule of NIR178 in 
combination with PDR001 (if selected based on results of Part 2). As of protocol 
amendment 6, Part 3 will explore the safety and pharmacokinetics of the FCT formulation 
of NIR178 continuous dosing in combination with PDR001 in TNBC patients. A second 
tumor group may be considered for Part 3 following analysis of data from Part 1. 

In addition, a safety run-in part will be conducted in Japanese patients with tumor types 
specified in parts 1,2 and 3, in order to evaluate the safety and pharmacokinetic profiles of 
NIR178 as a single-agent or in combination with PDR001(Section 4.1.4 and Figure 4-2).


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Figure 4-1
Study design
Figure 4-2
Study design- Japanese run-in part (NIR178 Single Agent and NIR178 
+PDR001) 


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4.1.1
Part 1: Bayesian adaptive signal finding in solid tumors and DLBCL
Part 1 of the study will enroll patients in
the following tumor groups: renal cell carcinoma 
(RCC) (IO naive and IO pretreated), pancreatic cancer, urothelial cancer, squamous cell 
carcinoma of head and neck cancer (HNSCC) (IO naive and IO pretreated),, diffuse large B-cell 
lymphoma (DLBCL), microsatellite stable colorectal cancer (MSS CRC) (RAS wildtype and
RAS mutant), triple negative breast cancer (TNBC), cutaneous melanoma (BRAF V600E) and 
metastatic castration resistant prostate cancer (mCRPC). Each tumor type will initially enroll at 
least 10 patients (with minimum requirements described in Section 4.2). Depending on whether 
or not pre-specified criteria for futility are met, each tumor group may enroll up to a maximum 
of 30 patients with the exception of the MSS CRC RAS mutant and RAS wildtype groups, in 
which 20 additional patients will be enrolled per group. Therefore, this part will enroll a 
minimum of 130 patients and may enroll a maximum possible total of 310 patients.
Accrual to each tumor type in Part 1 will based on futility analyses of observed ORR rates via 
interim analyses (for details of timing on interim analysis, see Section 4.2). These analyses will 
allow borrowing of information across tumor types with a hierarchical model (see Section 10). 
The hierarchical model allows dynamic borrowing of information between groups such that 
more borrowing occurs across the groups that have similar ORR and less borrowing between 
groups which differ. In this way, the model is a compromise between the two alternate extremes 
of either a completely pooled analysis or a separate analysis in each group.
4.1.2
Part 2: NIR178+PDR001 schedule optimization
Part 2 of the study will enroll only patients with advanced/metastatic NSCLC who are naïve to 
prior immunotherapy. Eligible patients will be randomized in a 1:1:1 fashion to one of 3 groups, 
each evaluating a different dosing schedule of NIR178 within a 28 day cycle (Figure 4-3). 
The dosing schedule of PDR001 will be the same in each group (400mg IV every 28 days). 
Randomization will be done in order to balance covariates across the three different groups. 
Given the known correlation between PD-L1 expression and response to PD-1 inhibitors in 
NSCLC, the treatment groups will be analyzed retrospectively according to baseline PD-L1 
expression 
(present/absent) 
defined 
by 
expression 
levels 
<1% 
or 
> 
1%
by 
immunohistochemistry (IHC).


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Three schedules of NIR178 will be evaluated in parallel in combination with PDR001 
(Figure 4-3):

NIR178 S1: BID continuous

NIR178 S2: BID 14 days on/14 days off

NIR178 S3: BID 7 days on/7 days off
Figure 4-3
Alternate NIR178 dosing schedules within one cycle
Each NIR178 dosing group will enroll 20 patients (total 60 patients). The safety, tumor response 
rates, and tumor immune modulation of the intermittent NIR178 schedules (NIR178 S2 and S3) 
will be compared to that in the continuous schedule (NIR178 S1). Based on cumulative data 
(including safety, tolerability, preliminary anti-tumor activity, PK, and PD) across the three 
schedules, an intermittent dosing schedule may be selected by Novartis for further evaluation 
in Part 3 of the study after documented discussion with study investigators.
4.1.3
Part 3: NIR178+PDR001 additional exploration in selected tumor types
Part 3 of the study will be an expansion of an intermittent or continuous NIR178 dosing 
schedule (if selected) and further evaluation of safety, efficacy, and immune modulation of the 
alternate NIR178 schedule in combination with PDR001 in one or two tumor groups of 
20 patients each. If Part 3 is initiated, a total of 50 patients would be enrolled to this part. 
The one or two tumor groups in Part 3 will be selected based on the emerging data from Part 1
and Part 2. If one of the tumor groups selected for Part 3 is NSCLC, this group will enroll 
patients previously exposed to immunotherapy. 
Novartis may decide to not open Part 3 for enrollment based on emerging data from Part 1 and 
Part 2.
As of Protocol Amendment 6, TNBC is one of the selected tumor groups and will enroll patients 
with a known PD-L1 SP142 status of IC=0 (<1%). Part 3 of the study will evaluate continuous 
BID NIR178 dosing schedule using the FCT NIR178 formulation. In specific, evaluation of 
safety, efficacy, and immune modulation of the continuous NIR178 schedule in combination 
with PDR001 will be performed in the TNBC tumor group which will consist of 20-30 patients. 
An additional tumor group may be considered for Part 3 which may enroll 20 patients. 
Part 3 of the study will start with the FCT formulation of NIR178 at 160mg BID in combination 
with PDR001 400mg Q4W as a PK/safety run-in part. After the first 10 patients complete at 
least 1 cycle, a safety analysis will be conducted to decide whether to increase the NIR178 dose 


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to 240mg BID or complete Part 3 with NIR178 160mg BID. The dose increment criteria is as 
follows:

If < 2 patients of the 10 evaluable patients have Grade 3/4 AEs suspected to be related study 
drug with 1 cycle of study treatment, dose escalate to 240 mg BID and enroll 20 additional 
patients 

If 2 or 3 patients of the 10 evaluable patients have Grade 3/4 AEs suspected to be related 
study drug with 1 cycle of study treatment, 10 more patients will be enrolled at 160 mg BID

If > 3 patients of the 10 evaluable patients have Grade 3/4 AEs suspected to be related study 
drug with 1 cycle of study treatment, no additional patients will be enrolled and 
development of the FCT formulation will be reassessed.
Cumulative data (including safety, tolerability, preliminary anti-tumor activity, PK, and PD) 
will be reviewed on an ongoing basis by Novartis and study investigators via teleconferences.
4.1.4
Japanese safety run-in part
A separate safety run-in part will be conducted in Japan in order to adequately characterize the 
safety and pharmacokinetic profiles of NIR178 as a single-agent (Figure 4-2). Patients enrolled 
in this part will be excluded from the primary analysis for efficacy and will also be exempt from 
the mandatory paired biopsy requirement.
Patients enrolled in the safety run-in part must be hospitalized for the first cycle of therapy for 
safety monitoring. Patients will receive NIR178 as single agent for the first cycle (28 days). 
If the patients complete cycle 1 without experiencing DLTs (see Table 6-3), they will initiate 
combination therapy with PDR001 400mg IV q4weeks starting cycle 2 onwards, and continue 
at the same dose of NIR178. Patients who experience a DLT in cycle 1 will be permanently 
discontinued from the study treatment and will not proceed to combination therapy. Patients 
will continue on combination therapy until they experience unacceptable toxicity, confirmed 
disease progression per iRECIST or Cheson et al (2014) for DLBCL and/or treatment is 
discontinued at the discretion of the investigator or the patient.
As of Amendment 6, newly enrolled patients in the Japanese safety run-in will receive NIR178 
240mg BID in combination with PDR001 400mg IV Q4W starting Cycle 1 day 1. If the patients 
complete cycle 1 without experiencing DLTs, they will continue on the same combination 
therapy of NIR178 and PDR001.
In the CPDR001X1101 study of single agent PDR001 in Japanese patients, the safety and PK 
of PDR001 for Japanese patients were similar between Japanese and non-Japanese patients and 
the recommended dose determined for PDR001 in non-Japanese patients was found to be 
acceptable for Japanese patients. Therefore, the dose for PDR001 in the safety run-in part will 
be 400 mg IV Q4 weeks.
The period for evaluating DLTs will be cycle 1 (i.e. the first 28 days of treatment with single 
agent NIR178). Patients must complete a minimum of 80% of planned therapy during cycle 
1 with the minimum safety evaluation and drug exposure or have had a DLT within the 
first cycle of treatment to be considered evaluable for dose escalation decisions. 
Dose escalation decisions will occur when the cohort of patients has met these criteria. 
Upon comprehensive review of all available safety, PK, and PD data (including that of the 


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combination therapy phase), Novartis in conjunction with the Japanese study investigators will 
determine if additional patients in Japan can join the phase II study. The safety run-in will 
evaluate two NIR178 dose levels sequentially. Each dose level may consist of 3 to 6 newly 
enrolled patients who have tumor histologies specified in Section 5, and meet all other 
inclusion/exclusion criteria.
1. NIR178 80mg BID continuously (-1 dose level)
2. NIR178 160mg BID continuously
The first three patients enrolled to the NIR178 80mg dose level will be observed for a full cycle 
of treatment with NIR178 before additional patients are enrolled. All patients will have 
enrollment staggered by at least 24 hours.

If one patient experiences a DLT at the NIR178 80mg dose level, the safety run-in part 
will be terminated and Japanese patients will not join the phase II study.

If 0/3 patients at 80mg experience a DLT in cycle 1, evaluation of the 80 mg dose level 
will be complete and the next dose level (160mg BID) with single agent NIR178 or (160 
mg BID) or NIR178 240 mg in combination with PDR001will be initiated with 3 new 
patients.

If 0/3 patients at 160mg NIR178 experience a DLT in cycle 1, NIR178 160mg dose in 
combination with PDR001 may be declared safe in Japanese patients upon review of all 
available safety, PK, and PD data, and Japanese patients may join the phase II part of the 
study.

If 1 out of 3 patients experience a DLT at 160mg NIR178 during cycle 1, 3 additional 
patients will be enrolled to this dose level. If no more than 1 out of 6 patients experience 
DLT during cycle 1 at the 160mg dose, NIR178 in combination with PDR001 may be 
declared safe upon comprehensive review of the all available safety, PK, and PD data, and 
new Japanese patients may directly join the phase II part of the study.

If more than 1 DLT occurs at the 160mg dose level of single agent NIR178 during cycle 1, 
the safety-run-in part will be terminated and Japanese patients will not join the phase II
part of the study.
Patients who do not complete at least 80% of planned therapy during cycle 1 for reasons other 
than interruption/discontinuation due to AEs (e.g. Due to disease, progression or withdrawal of 
consent) will be replaced. If the 160mg dose of NIR178 in combination with PDR001 is 
declared well-tolerated (based on the observed DLTs and other available safety data), patients 
at the 80mg dose level who have completed at least 2 cycles of combination therapy with 
PDR001 without grade 2 or higher treatment related toxicity, may be allowed to escalate the 
NIR178 dose to 160mg after documented discussion with Novartis.
Based on the data from the Japanese safety run-in at the 80 mg and 160 mg NIR178 doses, no 
obvious ethnic differences on safety and pharmacokinetics were observed as compared with the 
data from non-Japanese patients who were enrolled in CNIR178X2103J and CNIR178X2201.
Therefore, Japanese patients can join other parts of this study. 
As of Amendment 6, Japanese patients in safety run-in will receive NIR178 240mg BID in 
combination with PDR001 starting cycle 1.


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
If 0/3 patients at NIR178 240mg in combination with PDR001 experience a DLT in cycle 
1, NIR178 240mg dose in combination with PDR001 may be declared safe in Japanese 
patients upon review of all available safety, PK, and PD data, and Japanese patients may 
join the other parts of the study.

If 1 out of 3 patients experience a DLT at 240mg NIR178 in combination with PDR001 
during cycle 1, 3 additional patients will be enrolled to this dose level. If no more than 1 
out of 6 patients experience DLT during cycle 1 at this dose, NIR178 in combination with 
PDR001 may be declared safe upon comprehensive review of all the available safety, PK, 
and PD data, and new Japanese patients may directly join the other parts of the study.

If more than 1 DLT occurs at the dose level of 240mg NIR178 in combination with 
PDR001 during cycle 1, the safety-run-in part will be terminated and Japanese patients 
will not join the rest of the study.
4.2
Timing of interim analyses and design adaptations
4.2.1
Part 1: Bayesian adaptive signal finding in solid tumors and DLBCL
Given the adaptive enrollment model and signal finding nature of this part, multiple interim 
analyses will be performed to either stop early for futility or enroll patients until the next Interim 
Analysis (IA) is performed or a maximum of 30 patients per group or 20 additional for each 
MSS CRC RAS wildtype and RAS mutant in that tumor type has been enrolled.
The first interim analysis (IA) will occur when at least one tumor type has accrued 10 patients 
who have at least one post-baseline disease assessment except for MSS-CRC RAS wildtype, 
MSS-CRC RAS mutant and RCC IO naive at 240 mg patients, in which no interim analysis will 
be done
Futility analyses at this and subsequent interim analyses will inform a “go/no-go" decision 
(to continue enrolling up to the maximum sample size allowed) for each tumor type based on 
dynamic borrowing of ORR data across tumor types (See Section 10).
For the purpose of the IA, if a patient is still on study and the last available efficacy assessment 
is a PR/CR which is yet to be confirmed by a subsequent scan, then this patient will be 
considered as a responder.
Subsequent IAs occur when one or more additional tumor types accrue 10 patients at the same 
dose level (with minimum requirements described before). While all available data will be used 
from all tumor types, the decision to stop early at the IA will be made only for tumor types with 
the minimum sample size requirement described above. Novartis will have the flexibility to 
choose IA time points if it appears that multiple tumor types may qualify for IA requirements 
within a reasonable time between them. The futility analysis will not be binding (even when the 
ORR-based early stopping criteria is met at an IA for a tumor type, Novartis along with 
investigators may decide to continue enrolling patients to that particular tumor type if 
comprehensive review of all available data suggests that the patients are receiving clinical 
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Japanese safety run-in:
No interim analysis is planned for this part. The decision for dose escalation and to allow 
participation in phase II part of the study will be based on all available safety data and the 
recommendation of participating investigators in Japan. Refer to Section 4.1.4.
4.3
Definition of end of study
The study will end when all patients have completed the treatment period and 150-day safety 
follow-up after the last dose of PDR001 or 30 days after the last dose of NIR178 whichever 
occurs later, and at least 80% of patients have completed at least 24 months of survival follow 
up from start of study therapy. Additionally, if another clinical study becomes available that 
can continue to provide study treatment in this patient population, all patients ongoing are 
transferred to that clinical study and all discontinued patients have completed the safety follow-
up period. The follow-up for disease progression and survival will not be performed or pursued 
(see Section 7.1.5.1) At the end of the study, every effort will be made to continue provision of 
study treatment to patients who in the opinion of the investigator are still deriving clinical 
benefit through designated post-trial access programs or roll-over protocols, provided patient 
meets all eligibility criteria.
Refer to Section 10 for details of timing of the primary analysis and final reporting of data.
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Reasons for early 
termination:

Unexpected, significant, or unacceptable safety risk to subjects 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 subject welfare and safety. 
Should early termination be necessary, the patient should be seen as soon as possible for 
End of Treatment (EoT) visit and the same assessments should be performed as described in 
Section 7.1.3 for a discontinued patient. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The investigator will be responsible for informing IRBs 
and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
Adult patients (≥18 years) with advanced or metastatic solid tumors or Diffuse Large B-cell
lymphomas will be enrolled in the study.
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. Patients who have completed the study may not be re-
enrolled for a second course of treatment. Patients who do not initially meet all of the inclusion 


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or exclusion criteria may be re-screened for consideration in the trial. If a patient is rescreened, 
the same patient ID number should be used.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Male or female patients ≥18 years of age.
For Japan only: written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years.
2. Histologically documented advanced or metastatic solid tumors or lymphomas
a. Part 1: histologically confirmed renal cell carcinoma (RCC), pancreatic cancer, 
urothelial cancer, head and neck squamous cell carcinoma (HNSCC), diffuse large 
B-cell lymphoma (DLBCL), microsatellite stable colorectal cancer (MSS CRC), triple 
negative breast cancer (TNBC), cutaneous melanoma or mCRPC
-
Patients with colorectal cancer must have microsatellite stable (MSS) disease as 
detected by PCR-based assay or loss of mismatch repair (MMR) protein 
expression by immunohistochemistry and confirmed RAS genotype by standard 
testing of tumor specimen based on local available laboratory data.
-
Patients with unresectable or metastatic cutaneous melanoma that have confirmed 
BRAF V600E status by standard testing of tumor specimen by local available
laboratory data.
b. Part 2: histologically confirmed diagnosis of advanced/metastatic NSCLC. For those 
with mixed histology, there must be a predominant histology
-
Patients should have confirmed EGFR and ALK genotype when clinically 
indicated and performed per standard testing of tumor specimen based on local 
laboratory data.
c. Part 3: histologically confirmed diagnosis of selected advanced/metastatic 
malignancies should Part 3 be opened to enrollment. As of protocol amendment 6, 
Part 3 will open and enroll TNBC patients with PD-L1 SP-142 IC=0. A second tumor 
group may be considered for Part 3 following analysis of data from Part 1.
d. Safety run-in part in Japanese patients can enroll any tumor type included in Parts 1, 
2 and 3.
3. Patient (except for those participating in Japanese safety run-in) must have a site of 
disease amenable to biopsy, and be a candidate for tumor biopsy according to the treating 
institution’s guidelines. Patient must be willing to undergo a new tumor biopsy at 
screening, and again during therapy on this study. The use of a recent sample is permitted 
under the following conditions (both must be met):
a. Biopsy was collected ≤ 6 months before 1st dose of study treatment
b. No immunotherapy was given to the patient since collection of biopsy.
4. Part 1 – 3 only: Patients (other than those with DLBCL) must previously have received at 
least 1 and no more than 3 prior lines of therapy for their disease (with the exception of IO 


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pre-treated cutaneous melanoma, HNSCC and RCC), unless considered inappropriate for 
the patient (e.g. safety concerns, label contraindications):

MSS Colorectal Cancer (MSS CRC):

Patients with MSS CRC must have received (or be intolerant to) prior therapy 
with fluoropyrimidine-oxaliplatin- and irinotecan- based regimens.

Patient with wild type RAS must have received prior treatment with an antibody 
targeting EGFR (e.g. cetuximab or panitumumab)

Triple Negative Breast Cancer (TNBC):

Part 1: Patients with TNBC must have received a prior taxane- containing 
regimen.

Part 3: 

Patients should have documented disease progression following, or 
intolerance to, no more than 2 prior lines of chemotherapy for advanced or 
metastatic disease. Neoadjuvant and/or adjuvant chemotherapy administered 
with curative intent will count as one prior line of therapy, if disease recurred 
within 12 months of the last treatment.

Patients must have received prior systemic treatment that included taxane-
based chemotherapy for (neo) adjuvant or metastatic disease. 

Patients should have a known PD-L1 status as per local available testing
determined by VENTANA PD-L1 SP142 Assay with IC score of 0 (<1%).

Urothelial Cancer: 

Patients with urothelial cancer must have received a prior platinum-containing 
regimen or be ineligible for cisplatin.

Renal Cell Carcinoma (RCC):

IO Naive RCC: Patients with RCC must have received a prior VEGF tyrosine 
kinase inhibitor (TKI).

IO pre-treated RCC: Patients with RCC with no more than 2 prior lines of 
therapy. Patient must have received a prior VEGF TKI and have been pretreated 
with an anti-PD-1/PD-L1 as a single agent or in combination

Head & Neck Squamous Cell Carcinoma (HNSCC):

IO Naive HNSCC: 

Patients with HNSCC with no more than 3 prior lines of therapy. 
Patient must have received a prior platinum-containing regimen and have not 
been previously treated with any anti-PD1/L1 agents in single 
agent/combinations.

IO pre-treated HNSCC: 

Patients with HNSCC with no more than 2 prior lines of therapy. Patient 
must have received a prior platinum-containing regimen and have been 
pretreated with an anti-PD-1/PD-L1 as a single agent or in combinations

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
Patients must previously have received at least 1 and no more than 2 prior lines 
of therapy.

BRAF V600E wild type patients: must have received anti-PD-1/PD-L1 single-
agent, or in combination with anti-CTLA-4 therapy

BRAF V600E mutant patients: must have received prior anti-PD-1/PD-L1 
single-agent, or in combination with anti-CTLA-4 therapy. In addition, subjects 
must have received prior BRAF V600E inhibitor therapy, either single-agent or 
in combination with a MEK inhibitor

Metastatic Castration Resistant Prostate Cancer (mCRPC):

Of the 1-3 prior lines of therapy, patients must have received and failed at least 
one line of treatment after emergence of castration resistant disease

Diffuse Large B-Cell Lymphoma (DLBCL):

Patients with DLBCL should be limited to those with no available therapies of 
proven clinical benefit.

Patient should have had prior autologous hematopoietic stem cell transplantation 
(auto-HSCT) or determined to be ineligible for auto-HSCT.

Non-Small Cell Lung Cancer (NSCLC):

Patients with NSCLC must have received a prior platinum-based 
combination.For patients with NSCLC, EGFR mutation with exon 19 deletion or 
L858R mutation (Exon 21) or anaplastic lymphoma receptor tyrosine kinase
(ALK) rearrangement positive must have failed prior Tyrosine-kinase inhibitor
(TKI) therapy

Patients with EGFR positive NSCLC with a T790M mutation must have 
progressed on osimertinib or discontinued due to toxicity.
5. If one of the tumor groups selected for Part 3 is NSCLC, this group will enroll patients 
previously exposed to immunotherapy. (In protocol amendment 4, this inclusion criteria 
has been incorporated as part of inclusion criteria #4.) Patients with DLBCL should be 
limited to those with no available therapies of proven clinical benefit

Patients should have had prior autologous hematopoietic stem cell transplantation 
(auto-HSCT) or determined to be ineligible for auto-HSCT.
6. Patients must not have received prior immunotherapy (previous immune checkpoint 
inhibitors; single agent and/or combination therapy with anti-CTLA-4, anti-PD-1, anti-
PD-L1), with the exception of cutaneous melanoma, IO pre-treated HNSCC and IO pre-
treated RCC in part 1, NSCLC patients enrolled in Part 3 and Japanese safety run-in part.
7. (In protocol amendment 4, this inclusion criteria has been incorporated as part of 
inclusion criteria #4.) For patients with NSCLC, EGFR mutation with exon 19 deletion or 
L858R mutation (Exon 21) or anaplastic lymphoma receptor tyrosine kinase (ALK)
rearrangement positive must have failed prior Tyrosine-kinase inhibitor (TKI) therapy.


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8. Patients must have measurable disease, defined as at least one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded for non-nodal lesions 
and short axis for nodal lesions) as >20 mm with conventional techniques or as >10 mm 
with spiral computer tomography (CT) scan, Magnetic Resonance Imaging (MRI), or 
calipers by clinical exam.
Note: If prior treatment was discontinued due to toxicity, patient must have continued 
evidence of measurable or evaluable disease.
9. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
10. Written informed consent must be obtained prior to any screening procedures. If consent 
cannot be expressed in writing, it must be formally documented and witnessed, ideally via 
an independent trusted witness.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of 
but not limited to surgery, radiation and/or corticosteroids.
2. History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease ≥2 years 
before the first dose of study drug and of low potential risk for recurrence

Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease

Adequately treated carcinoma in situ without evidence of disease
3. Active or prior documented autoimmune disease within the past 2 years
NOTE: Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded.
4. Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative 
colitis)
5. History of interstitial lung disease or non-infectious pneumonitis
6. History of primary immunodeficiency
7. History of allogeneic organ or stem cell transplant
8. Ongoing or prior treatment with A2aR inhibitors. Patients previously treated with A2aR 
inhibitors for non-oncologic indications (e.g. Parkinson’s disease) may be considered for 
enrollment on a case by case basis.
9. More than 2 or 3 prior lines of therapy (as indicated for each tumor type in the inclusion 
criteria 4), except for Japanese safety run-in part and DLBCL patients.
10. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. 
For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 
6 weeks is indicated as washout period. For patients receiving anticancer 
immunotherapies, 4 weeks is indicated as the washout period. GnRH therapy to maintain 
effective testosterone suppression levels is allowed for mCRPC patients. 


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11. Non-palliative radiotherapy within 2 weeks prior to the first dose of study drug. Palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful 
tumor mass is allowed. To allow for assessment of response to treatment, patients must 
have remaining measurable disease that has not been irradiated.
12. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, 
insertion of a central venous access device, and insertion of a feeding tube are not 
considered major surgery).
13. Current or prior use of immunosuppressive medication within 28 days before the first dose 
of PDR001, with the exception of intranasal/inhaled corticosteroids or systemic 
corticosteroids at physiological doses (not exceeding equivalent of 10 mg/day of 
prednisone)
14. Any of the following clinical laboratory results during screening (i.e., within 21 days 
before the first dose of study treatment):

Absolute Neutrophil Count <1.0 x 109/L

Platelets <100 x 109/L (for DLBCL patients platelets < 75 x 109/L)

Hemoglobin (Hgb) <9 g/dL (for DLBCL patients Hgb < 8g/dL)

Serum creatinine >1.5 mg/dL OR Creatinine Clearance < 45 mL/min using 
Cockcroft-Gault formula (Appendix 6)

Total bilirubin >1.5 x Upper limit of normal (ULN)

Aspartate transaminase (AST) > 3 x ULN

Alanine transaminase (ALT) > 3 x ULN
15. Mean QT interval corrected for heart rate (QTcF) ≥470 ms calculated from 3 
electrocardiograms (ECGs – in triplicate ≥1 minute apart)
16. Any unresolved toxicity (>Common Terminology Criteria for Adverse Events (CTCAE) 
grade 2) from previous anti-cancer therapy. Patients with irreversible toxicity that is not 
reasonably expected to be exacerbated by the investigational product may be included 
(e.g., hearing loss, peripherally neuropathy)
17. History of severe hypersensitivity to any ingredients of study drug(s) and other 
monoclonal antibodies and/or their excipients. Patients previously exposed to anti-
PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement 
therapy. Changes to the protocol for endocrinopathies should not be excluded
18. Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 
cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses 
including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C 
or human immunodeficiency virus (HIV), or psychiatric illness/social situations that in the 
investigator’s opinion would limit compliance with study requirements or compromise the 
ability of the subject to give written informed consent
19. Known history of previous clinical diagnosis of tuberculosis
20. History of leptomeningeal carcinomatosis
21. Receipt of any live vaccine within 4 weeks prior to study entry or within 4 weeks of 
receiving PDR001 or NIR178


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22. Pregnant or nursing (lactating) women
23. Any condition that, in the opinion of the investigator, would interfere with evaluation of 
study treatment or interpretation of patient safety or study results
24. Smoking (e.g. cigarettes, cigars and pipe) must be discontinued at least 7 days prior to 
initiating study drug administration; smoking cessation products (e.g transdermal nicotine 
patches or chewing gum) may be used.
25. Concurrent administration of strong inhibitors or moderate inducers of CYP1A2 is not 
permitted; administration must be discontinued at least 7 days prior to initiating study drug 
administration
26. Concurrent administration of sensitive and narrow therapeutic index substrates of 
CYP1A2 is not permitted; administration must be discontinued at least 7 days prior to 
initiating study drug administration
27. History of severe hypersensitivity reactions, which in the opinion of the investigator may 
pose an increased risk of serious infusion reaction.
28. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents ≤ 2 weeks prior to start of study 
treatment. If erythroid stimulating agents were initiated more than 2 weeks prior to the 
first dose of study treatment and the patient is on a stable dose, they can be maintained.
29. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease, 
including any of the following:

recent myocardial infarction (within last 6 months),

uncontrolled congestive heart failure,

unstable angina (within last 6 months),

clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker).
30. Specific underlying conditions for oral agents. For example: impairment of 
gastrointestinal (GI) function or GI disease that may significantly alter the absorption of 
oral NIR178 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, small bowel resection or presence of more than or equal to 
Grade 2 toxicity (except alopecia) due to prior therapy)
31. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 150 days after the last dose of PDR001 or 30 days after the last dose 
of NIR178, whichever occurs later. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. 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


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
Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate [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 ago. In the 
case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
32. Sexually active males unless they use a condom during intercourse while taking drug and 
30 days after stopping NIR178. Sexually active males should not father a child in this 
period. 
6
Treatment
6.1
Study treatment
For this study, the investigational drugs are NIR178 and PDR001. The study treatment is 
defined as NIR178 in combination with PDR001. Please note that additional dosage strengths 
for any of the study drugs may become available. They will be given as the following dose 
strength and forms:
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or Regimen
NIR178
40mg, 80mg and/or 160mg 
capsules for oral use
160mg, 
240mg*
Part 1
Part 2
Part 3
Continuous 
BID
Continuous and
intermittent BID 
per randomization
Continuous 
or intermittent 
BID based on 
Part 1 and 
Part 2 results
NIR178**
80mg, 240mg Film-coated tablet 
for oral use
160mg
240mg
Not 
applicable
Not applicable
Continuous 
BID 
PDR001
100mg powder for solution for 
infusion
400mg
Every 4 weeks
*All newly enrolled patients under Amendment 5 will receive NIR178 240mg BID
**As of Protocol Amendment 6, patients enrolled in Part 3 will receive continuous dosing of NIR178 FCT in 
combination with PDR001 


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NIR178
NIR178 will be administered at 160 mg orally twice daily (BID) either continuously or based 
on the assigned intermittent dosing schedule. As of Amendment 5, all newly enrolled patients 
will be treated with NIR178 240mg BID. As of amendment 6, in Part 3 of the study, NIR178 
FCT will be administered orally twice daily (BID) on a continuous dosing schedule starting 
with a dose of 160 mg BID, that may be increased to 240 mg BID based on safety and 
pharmacokinetic data available after the initial 10 patients are treated.
Patients should take NIR178 twice daily at approximately the same time each day in the 
morning and evening and should ensure there is an approximate 12-hour interval between each 
daily dose. On days that PK samples are obtained, the patient should take NIR178 during the 
clinic visit after the pre-dose PK samples and prior to post-dose PK samples, when instructed 
by the study staff. The patient should not take the morning dose of NIR178 at home during 
inpatient visits, particularly in those with PK assessments.
Patients should take NIR178 on an empty stomach (i.e. fast from food and drink, except water) 
at least 1 hour before or 2 hours after a meal. Each dose may be taken with a glass of water 
(approximately 8 ounces or approx. 235 mL). An ongoing clinical study (CNIR178X2103J) in 
NSCLC patients includes an investigation of the impact of food on NIR178 PK. If the results 
of this study indicate that NIR178 may be taken with or without regard to food, the fasting 
requirement may be removed and administration instructions will communicated in writing by 
Novartis.
Patients should be instructed to swallow whole capsules or tablets and not to chew or open them.
If vomiting occurs during the course of treatment, patients should not take the study drug 
(NIR178) again before the next scheduled dose.
Patients should be instructed not to make up missed doses. A missed dose is defined as a case 
when the full dose is not taken within 4 hours after the approximate time of the usual daily 
dosing. That day's dose should be omitted and the patient should continue treatment with the 
next scheduled dose.
PDR001
PDR001 will be administered via IV infusion over 30 minutes once every 4 weeks. Infusions 
of PDR001 can be extended to up to 2 hours if clinically indicated.
Further instructions for the preparation and dispensation of NIR178 and PDR001 are described 
in the CNIR178X2201 Pharmacy Manual.
Both study drugs will be administered on the same day. The first doses of the combination of 
NIR178 and PDR001 are administered at Cycle 1 Day 1, which defines the patient’s treatment 
cycles for the study. The start time of PDR001 infusion on dosing days can occur at any given 
time regardless of the dose administration schedule of NIR178.
All dosages prescribed and dispensed to patients and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
Dose modifications and reductions should be followed described in Section 6.2.1 and 
Section 6.2.2.


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6.1.1
Dosing regimen
Treatment cycle is defined as 28 days.
In Part 1 of the study, all patients will receive NIR178 240 mg twice daily continuously and 
400 mg of PDR001 administered every 28 days (prior to Amendment 5, all patients were treated 
with NIR178 160 mg BID).
In Part 2 of the study, all patients will be randomly assigned to one of the three NIR178 dosing 
schedules in combination with PDR001:
1. NIR178 S1: Patients will take NIR178 160mg twice daily continuously with PDR001 
400mg administered once on day 1, every 28 days.
2. NIR178 S2: Patients will take NIR178 160mg twice daily on days 1-14 of a 28 day cycle 
together with PDR001 400mg administered once on day 1 every 28 days.
3. NIR178 S3: Patients will take NIR178 160mg twice daily on days 1-7 and days 15-21 of a 
28 day cycle together with PDR001 400mg administered once on day 1 every 28 days.
In Part 3 of the study, one or two tumor groups may be selected based on emerging data from 
Part 1 and Part 2.
As of protocol amendment 6, Part 3 will be opened in parallel with Part 1 to further assess 
TNBC patients with a PD-L1 SP-142 status of IC=0 (<1%) using NIR178 FCT formulation 
continuous dosing schedule in combination with PDR001. A second tumor group may be 
considered for Part 3 after completion of Part 1. The first 10 patients enrolled in Part 3 will 
receive a NIR178 dose of 160 mg BID FCT, and after all patients complete at least 1 cycle of 
treatment, safety and PK analysis will be performed to decide whether the dose should be 
increased to NIR178 240 mg BID FCT. If there is unexpected toxicity due to formulation 
change the dose will not be escalated to NIR178 240mg BID FCT and an additional 10 
patients will be enrolled at NIR178 160mg BID FCT. If the NIR178 160mg BID FCT 
formulation is considered safe, dose escalation to NIR178 240 mg BID FCT will occur and an 
additional 20 patients will be enrolled.
In the Japanese safety run-in part, patients will take NIR178 at 80 or 160mg twice daily 
continuously during the Cycle 1, and then starting from Cycle 2D1, will receive NIR178 twice 
daily continuously in combination with PDR001 400mg administered once on day 1 every 
28 days. The starting dose of NIR178 80mg is 50% of the RoW starting dose at which no DLT 
was observed in the CNIR178X2103J phase I/Ib study in combination with PDR001. As of 
protocol amendment 6, patients enrolled in the Japanese safety run-in part will receive NIR178 
240mg twice daily in combination with PDR001 400 mg administered on day 1 of every 28 day 
cycles.   


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6.1.2
Ancillary treatments
Patients should not receive pre-medication to prevent an infusion reaction before the first 
infusion of study treatment, in order to determine if pre-medication is necessary. If a patient 
experiences an infusion reaction, he/she may receive pre-medication on subsequent dosing days. 
The pre-medication should be chosen per institutional standard of care, at the discretion of the 
treating physician.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a patient experiences a Grade 3 anaphylactic/anaphylactoid 
reaction, the patient will be discontinued from the study. The patient may resume study 
treatment following documented discussion with the Novartis medical monitor. Guidelines on 
management of infusion reactions are provided in Table 6-2 (Recommended Dose 
Modifications).
The CTCAE category of “Infusion related reaction” should be used to describe study treatment 
related infusion reactions, unless the investigator considers another category, such as “Allergic 
reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation.
6.1.3
Treatment duration
A patient may continue treatment with study treatment until the patient experiences 
unacceptable toxicity, confirmed disease progression per iRECIST or Cheson et al (2014) for 
DLBCL patients or as per PCWG3 guidance (Appendix 5) for mCRPC and/or treatment is 
discontinued at the discretion of the investigator or the patient. The patients should not be 
withdrawn from the study due to progressive disease per RECIST v1.1 or Cheson et al (2014)
only unless there is evidence suggesting lack of clinical benefit or clinical deterioration. If a 
patient has clinical or radiological evidence of disease progression but has evidence of clinical 
benefit and, in the opinion of the investigator, it is in the patient’s best interest to remain on 
study, then the patient may continue treatment after documented discussion with the Novartis 
medical monitor. In addition, treatment beyond disease progression should not jeopardize 
critical interventions to treat/prevent severe complications, or prevent patients from receiving 
adequate care (Section 7.1.2).
To account for possible late responses or responses with a prolonged immune-related tumor 
flare, patients with iRECIST or Cheson et al (2014) progression, ongoing during or at the end 
of treatment, may restart treatment if they experience a radiographic response following 
treatment discontinuation in the absence of interval treatment. Retreatment must begin within 
4 weeks of the documented response. The schedule will be the same as the schedule being used 
prior to treatment discontinuation.
Patients who continue treatment beyond initial disease progression will continue all study 
procedures as outlined in Section 7. In case of clinical deterioration or suspicion of disease 
progression, a follow-up imaging assessment should be performed promptly rather than waiting 
for the next scheduled assessment. Patients with evidence of further disease progression on an 
imaging assessment or who are no longer deriving clinical benefit will be discontinued.


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6.2
Dose modifications
6.2.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose or schedule 
adjustments are permitted in order to allow the patient to continue the study treatment. 
The following guidelines need to be applied:

For clinical management of suspected immune-related events, reference to consensus 
management guidelines is recommended such as those provided in the National 
Comprehensive Cancer Network (NCCN) Guidelines for the Management of 
Immunotherapy-Related Toxicities (available at : 
nccn.org/professionals/physician_gls/default.aspx#immunotherapy), the American Society 
for Clinical Oncology clinical practice guideline for Management of Immune-Related 
Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy 
(Brahmer et al 2018) or the European Society for Medical Oncology (ESMO) Clinical 
Practice Guidelines for Management of Toxicities from Immunotherapy 
(Haanen et al 2017).  Note that in general, study treatment should be interrupted for grade 
3 and 4 toxicities and for a subset of lower grade toxicities.

Consider early referral to specialists with expertise in the diagnosis and management of 
immune-related AEs to thoroughly investigate events of uncertain etiology

Events not included in the study protocol or the reference guidance documents should be 
managed per institutional preference
NIR178 dose may be interrupted and/or reduced for treatment related adverse events during the 
course of treatment. For NIR178, dose reduction steps should follow guidelines outlined in 
Table 6-5. Dose reductions are not permitted for PDR001. PDR001 may be delayed due to 
toxicities. A patient must discontinue treatment with NIR178 and PDR001 if the toxicity recurs 
with the same or worse severity after treatment is resumed at a lower dose. For Japanese safety 
run-in, dose reductions for NIR178 will not be allowed in the DLT observation period.
Dose modifications/delays of NIR178 and PDR001 for specific adverse events are summarized 
in Table 6-2. Deviations to mandatory dose interruptions and/or reductions are not allowed.
Permanent treatment discontinuation is mandatory for specific events and/or dose interruption 
periods as indicated in Table 6-2. However, in cases where a patient meeting criteria for 
permanent discontinuation due to a study treatment-related toxicity is experiencing clinical 
benefit and, in the opinion of the investigator it is in the patient’s best interest to remain on 
study, the patient may continue treatment after documented discussion with Novartis. All dose 
interruptions/reductions of NIR78 and dose delays of PDR001 must be recorded on the Dosage 
Administration Record CRF.
PDR001 and NIR178 dosing may resume once the adverse event has resolved to the specified 
grade or better (as outlined in Table 6-2) or baseline. Patients unable to resume combination 
therapy after resolution of an adverse event may continue with either NIR178 or PDR001 as 
single agent, if the Investigator considers it to be in the patient’s best interest to do so, following 
documented discussion with Novartis.


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After a dose interruption, patients who are able to resume study treatment within the same 
treatment cycle (i.e. within 28 days of the last PDR001 dose) should resume dosing with 
NIR178 at the next scheduled dose within the same cycle. For AEs that resolve more than 28 
days from the last dose of PDR001, both PDR001 and NIR178 must be restarted together with 
appropriate dose  as soon as patient is able, and re-initiation of therapy must constitute the 
beginning of the next treatment cycle. Disease assessments will continue to occur at the 
frequency specified within the protocol (See Section 7.2.1), even if no longer in sync with cycle 
clock.
Non-immune related AEs (non-irAEs), resulting in dose delay of PDR001 or NIR178 lasting 
longer than 14 days will necessitate discontinuation of study drug. Exceptions may be made if 
the Investigator considers it to be in the patient’s best interest to resume therapy, following 
documented discussion with Novartis. In the event of immune related AEs (irAEs) requiring 
treatment interruption, combination therapy with NIR178 and PDR001 can resume only when 
the specific irAE has resolved as outlined in Table 6-2, patient requires no more than 
physiologic dose of steroids (steroid equivalent of ≤ 10mg/day of prednisone), and patient has 
discontinued any other immunosuppressive drugs that were initiated for the irAE. Overall, for 
irAEs that do not recover to ≤ Grade 1 or baseline at a dose of immunosuppression of
≤10 mg/day prednisone or equivalent within 12 weeks after initiation of immunosuppressive 
therapy, and/or requiring continuation of other immunosuppressive drugs, PDR001 and NIR178 
must be permanently discontinued (Figure 6-1).
Figure 6-1
Management of toxicity requiring dose interruptions


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Table 6-2
Criteria for dose reduction / interruption and re-initiation of NIR178 and PDR001 treatment for adverse drug 
reactions
The instructions provided in this table and the criteria for dose reduction / interruption are used to determine a 
protocol deviation.
Worst toxicity CTCAEa grade
Recommended Dose Modification
Infusion reaction or hypersensitivity reaction
Grade 1
Decrease infusion rate until recovery of the symptoms.
Grade 2
Stop infusion immediately, and keep line open. 
Follow institutional guidelines for the management and follow-up of infusion reaction.
Restart infusion at 50% of previous rate under continuous observation. Ensure that there is a minimum observation period of 
1 hour prior to restarting the infusion.
If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-medication, then permanently discontinue study 
treatment.
Grade 3 and Grade 4
Discontinue infusion immediately, and discontinue study treatment.
Provide supplemental oxygen, fluids, and other resuscitative measures as needed. Monitor vital signs (e.g. blood pressure, 
pulse, respiration, and temperature) every 15 ± 5 minutes until resolution.
Cytokine Release Syndrome (CRS)
Grade 2
See instructions for Grade 2 Infusion Reaction above.
Grade 3 or Grade 4
Discontinue study treatment.
Follow-up CRS as per institutional guidelines.
Ocular (uveitis, eye pain, blurred vision)
Grade 1
Continue study treatment without dose modification.
Ophthalmology consultation.
Grade 2
Hold study treatment.
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.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
Pulmonary (pneumonitis)
Grade 1
Consider study treatment hold.
Manage per institutional practice, consultation with pulmonologist is recommended.
Consider resuming study treatment upon radiographic evidence of improvement.
Grade 2
Hold study treatment.
Pulmonary and infection workup, consultation with pulmonologist is recommended.
Upon resolution to ≤ Grade 1, may resume study treatment without dose modification.
Grade 3 or Grade 4
Discontinue study treatment.
Manage per institutional practice, consultation with pulmonologist is recommended.
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.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
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.
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.
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. After resuming 
treatment with NIR178, close monitoring with at least weekly LFTs is recommended for 1 cycle of treatment.
If suspicion of autoimmune hepatitis, the following confirmatory diagnostic serological markers are recommended: Serum 
autoantibodies including antinuclear (ANA), smooth muscle antibody (SMA) or antibody to liver-kidney microsomes (anti-
LKM), Immunoglobulin levels, total globulins, and when possible liver biopsy. 
Grade 3 AST and/or ALT
ALT or AST >3 x ULN and TBL >2 x 
ULN (or international normalized ratio 
[INR] >1.5)
ALT or AST >3 x ULN and symptoms 
of hepatitis (eg, fatigue, nausea, 
vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or 
eosinophilia [>5%])
Hold study treatment.
Manage per institutional practices.
Upon resolution to ≤ Grade 1 or baseline within 7 days, consider resuming PDR001 at the same dose and NIR178 at a lower 
dose after discussion with the Novartis Medical Monitor. After resuming treatment with NIR178, close monitoring with at least 
weekly LFTs is recommended for 1 cycle of treatment.
Otherwise, discontinue study treatment.
If suspicion of autoimmune hepatitis, the following confirmatory diagnostic serological markers are recommended: Serum 
autoantibodies including antinuclear (ANA), smooth muscle antibody (SMA) or antibody to liver-kidney microsomes (anti-
LKM), Immunoglobulin levels, total globulins, and when possible liver biopsy. 
Grade 4 AST and/or ALT
Discontinue study treatment.
Isolated total bilirubin elevation**


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Worst toxicity CTCAEa grade
Recommended Dose Modification
Grade 2
Hold study treatment. 
Upon resolution to ≤ Grade 1 or baseline, may continue study treatment without dose modification.
Grade 3
Hold study treatment.
Upon resolution to ≤ Grade 1 or baseline, may consider resuming study treatment after discussion with the Novartis Medical 
Monitor.  
Grade 4
See footnote**.  Otherwise, discontinue study treatment.
Combined elevations of AST or ALT   
and total bilirubin 
For participants with normal baseline 
ALT and AST and total bilirubin value:
AST or ALT >3.0 x ULN combined with 
total bilirubin >2.0 x ULN without 
evidence of cholestasis
OR
[AST or ALT >3x baseline OR > 8.0 
xULN], whichever is lower, combined 
with [total bilirubin >2x baseline 
AND >2.0 x ULN]
**Note: For participants with Gilbert’s 
syndrome, at least 2-fold increase in 
direct bilirubin.
Mandatory: Interrupt treatment and adjudicate for DILI:
Repeat as soon as possible, preferably within 48 hours from awareness of the abnormal results, then with weekly monitoring 
of LFTs, or as clinically indicated, until AST, ALT, or total bilirubin have resolved ≤ ULN or to baseline. (Refer to the 
Section 6.2.2.1 for additional follow-up evaluations as applicable.)
If causality assessment indicates that DILI is probable: Permanently discontinue participant from treatment.
If not DILI: Treat the identified cause according to institutional guidelines. Once resolved, reduce by one dose level.
Asymptomatic amylase and/or lipase elevation***
Grade 3 or Grade 4, 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.


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Worst toxicity CTCAEa grade
Recommended Dose Modification
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 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
Grade 4
Hold study treatment. 
Upon resolution to Grade ≤ 1 with appropriate management, may resume study treatment without dose modification.
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


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Worst toxicity CTCAEa grade
Recommended Dose Modification
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.
Hematology
Neutropenia (ANC)
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


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Worst toxicity CTCAEa grade
Recommended Dose Modification
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
Hold study treatment. 
Upon resolution to ≤ Grade 1, resume study treatment without dose modification.
Grade 4
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)
*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: 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. 


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Table 6-3
Criteria for defining dose limiting toxicities for the Japanese safety run-in part
For the purpose of Japanese safety run-in part, DLT defined as follows:
Any Grade 4 AEs are DLTs with the exception of:
Neutropenia lasting ≤ 5 days that is not associated with fever or other clinical symptoms.
Lymphopenia or Leukopenia.
Electrolyte abnormalities that are not associated with clinical sequelae or deemed to be not clinically significant and are corrected with 
appropriate management or supplementation within 72 hours of the onset.
Any Grade 3 AEs are DLTs with the exception of:
Infusion reaction that resolves to ≤ Grade 1 within 6 hours.
Nausea and vomiting that resolves within 2 days after starting optimal anti-emetic therapy.
Thrombocytopenia without significant bleeding.
Anemia grade 3 that resolves within 7 days in the absence of transfusion
Diarrhea that resolves within 2 days after starting optimal anti-diarrhea treatment.
Hypertension that resolves within 7 days after starting treatment.
Infection or fever in the absence of neutropenia that resolves within < 5 days.
Rash or photosensitivity that resolves within 7 days after starting treatment.
Fatigue that resolves within 7 days.
Immune-related adverse events that resolve within 7 days after starting treatment with corticosteroids.
The following Grade 2 AEs are considered DLTs:
Newly emerging total bilirubin ≥ 2 x ULN with ≥ CTCAE Grade 3 AST/ALT.
Pneumonitis that does not resolve within 7 days after starting treatment with corticosteroids.
Eye pain or reduction of visual acuity that does not respond to topical therapy and does not improve to Grade 1 severity within 2 weeks of the 
initiation of topical therapy OR requires systemic treatment.
Other clinically significant toxicities, including a single event or multiple occurrences of the same event may be considered as DLTs.


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6.2.2
Follow-up for toxicities
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 adverse event 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 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 6.2.1 Dose modifications).
Patients whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first.
All patients must be followed up for irAEs, AEs and SAEs for up to 150 days following the last 
dose of PDR001 or up to 30 days following the last dose of NIR178.
6.2.2.1
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with total bilirubin increase may be indicative of 
potentially severe DILI, and should be considered as clinically important events 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 patient’s baseline AST/ALT and total 
bilirubin value; patients meeting any of the following criteria will require further follow-up as 
outlined below:

For patients 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 patients 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]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury.
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
GLDH, prothrombin time (PT)/INR, alkaline phosphatase, albumin, and creatine kinase.


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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, 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 patients without bone metastasis, or elevation of the liver-specific ALP 
isoenzyme in patients 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. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. 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 (https://livertox.nih.gov/rucam.html). 
Table 6-4 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities.
Table 6-4
Clinical and Diagnostic assessments to rule out possible causes of 
LFT abnormalities
Disease
Assesment
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

ANA & 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 CHF, 
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 patients’ medical history (hyperthyroidism 
/ thyrotoxic hepatitis – T3, T4, TSH; CVD / ischemic hepatitis – ECG, prior hypotensive 
episodes; T1D / glycogenic hepatitis).
Obtain PK sample to determine exposure to study treatment and metabolites.
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 


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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
6.2.3
Dose reduction steps for NIR178
Dose reduction steps for NIR178 are detailed in Table 6-5 based on the starting dose of 240 mg.
Of the first 10 patients enrolled at the NIR178 240mg dose across all tumor types, if more than 
33% of the patients experience grade 3 or higher suspected to be related adverse events, 
subsequent patients will start treatment at NIR178 160mg twice daily. Patients enrolled at the 
NIR178 240mg dose will be monitored on an ongoing basis for emerging toxicities.
Table 6-5
Dose reduction steps for NIR178
The following table should be used as a dose reduction guide for patients receiving NIR178 
capsule formulation (hard gelatin capsules):
Dose reduction*
Starting dose 
level
Dose level – 1
Dose level -2
Dose level – 3
NIR178
240 mg
160 mg
120 mg
80mg**
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
**Dose reduction below 80 mg is not allowed. Altering from initial dosing schedule for NIR178 is not allowed.
The following table should be used as a dose reduction guide for patients receiving NIR178 160 
mg or 240 mg BID film coated tablet (FCT) formulation: 
Dose reduction*
Starting dose level
Dose level – 1
Dose level – 2
NIR178
240 mg
160 mg***
80 mg**
*Dose reduction should be based on the worst toxicity demonstrated at the last dose.
**Dose reduction below 80 mg is not allowed. Altering from initial dosing schedule for NIR178 is not allowed.
***The first 10 patients enrolled in Part 3 of the study will be treated with the NIR178 160mg dose of the FCT 
formulation. A safety and PK analysis will be conducted to decide whether to increase the NIR178 dose to 240mg 
BID or complete Part 3 with NIR178 160mg BID. 
6.3
Concomitant medications
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the patient are allowed. The patient must 
be told to notify the investigational site about any new medications, herbal remedies and dietary 
supplements he/she takes after the start of the study treatment. All medications (other than study 
treatment) and significant non-drug therapies (including physical therapy, herbal/natural 
medications and blood transfusions) administered during the study must be listed on the Prior 
and 
Concomitant 
Medications 
or 
the 
Surgical
and 
Medical 
Procedures 
CRF. 


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Prior antineoplastic therapies including medications, radiotherapy, and surgery are to be 
recorded on the separate Prior Antineoplastic Therapy eCRF during screening.
6.3.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies CRF.
6.3.2
Permitted concomitant therapy requiring caution and/or action
NIR178 was demonstrated to be an inhibitor of CYP1A2 in vitro. Caffeine is a sensitive 
substrate of CYP1A2. Caution should be exercised if caffeine or caffeine containing food, 
beverages, or medications are consumed. Additionally, NIR178 was demonstrated to be a 
substrate of CYP1A2, therefore moderate and weak inhibitors of CYP1A2 should be used with 
caution.
NIR178 inhibited BCRP-mediated transport in vitro. Even though the risk of systemic inhibition 
of BCRP (e.g., liver, brain, and kidney) is predicted to be minimal to none, the potential risk of 
intestinal BCRP inhibition by NIR178 administered at clinically relevant doses cannot be ruled 
out. Therefore, concomitant administration of NIR178 with medications that are substrates of 
BCRP is permitted however caution should be exercised by the investigators (Table 14-2).
Anticoagulation is permitted if the patients are already at stable doses for >2 weeks at time of 
first dose and INR should be monitored as clinically indicated per investigator’s discretion. 
However, ongoing anticoagulant therapy should be temporarily discontinued to allow tumor 
biopsy according to institutional guidelines.
Anti-hypertensives are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with PDR001.
Please see Appendix 1 for further details.
6.3.3
Prohibited concomitant therapy
During the course of the study, patients must not receive other additional investigational drugs, 
agents, devices, chemotherapy, or any other therapies that may be active against cancer. 
However, limited-field palliative radiotherapy to non-target lesion(s) may be allowed as 
concomitant therapy following a documented discussion with Novartis. Such local therapies 
administrated during the study treatment must be listed on the Concomitant 
radiotherapy/surgery case report form (CRF) page. Additionally, other therapeutic monoclonal 
antibodies and immunosuppressive medications are prohibited.
GnRH therapy to maintain effective testosterone suppression levels is allowed for mCRPC 
patients.
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of an infusion reaction, irAEs, for prophylaxis against imaging contrast dye 


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allergy or replacement-dose steroids in the setting of adrenal insufficiency (providing this is 
≤10 mg/day prednisone or equivalent), or transient exacerbations of other underlying diseases 
such as chronic obstructive pulmonary disease (COPD) requiring treatment for < 3 weeks. 
Systemic corticosteroids required for the control of infusion reactions or irAEs must be tapered 
and be at non-immunosuppressive doses (≤ 10 mg/day of prednisone or equivalent) before the 
next study drug administration. If more than 10 mg/day prednisone is used, study treatment 
should be suspended. Topical, inhaled, nasal and ophthalmic steroids are allowed.
The use of live vaccines is not allowed through the entire duration of the study. Inactivated 
vaccines are allowed.
As previously discussed, NIR178 was found to be an inhibitor and substrate of CYP1A2 in vitro. 
Therefore, strong inhibitors and moderate inducers of CYP1A2 as well as sensitive 
(except caffeine) and narrow therapeutic index substrates of CYP1A2 are prohibited.
Additionally, medications known to cause Torsades de pointes and prolong the QT interval are 
prohibited.
Please see Appendix 1 for further details.
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the patient is assigned to the next sequential Subject 
No. available to the investigator through the Oracle Clinical RDC interface.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Disposition page.
IRT must be notified within 2 days that the patient was not randomized or did not start treatment.
For Japanese safety run-in part: Patients will be assigned by Novartis manually, outside IRT 
system.
6.4.2
Treatment assignment or randomization
Interactive Response Technology (IRT) will be used for treatment assignment, patient 
allocation and drug supply management for all patients.
In addition, in Part 2, patients will be randomized to one of the 3 treatment arms (Section 4.1
and Section 6.1) in a ratio of 1:1:1 through IRT.


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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the 
Interactive Response Technology (IRT) provider using a validated system that automates the 
random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication randomization list will be produced by or under the 
responsibility of Novartis Drug Supply Management using a validated system that automates 
the random assignment of medication numbers to medication packs containing each of the study 
treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to the 
IRT and confirm that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign 
a randomization number to the patient, which will be used to link the patient to a treatment arm 
and will specify a unique medication number for the first package of study treatment to be 
dispensed to the patient. The randomization number will not be communicated to the caller.
For Japanese safety run-in part: Patients will be assigned by Novartis manually, outside IRT 
system. IRT will not be used for this part.
6.4.3
Treatment blinding
This is an open-label study.
6.5
Study drug preparation and dispensation
NIR178
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF.
PDR001
PDR001 (100 mg powder for solution for infusion) will be administered intravenously as a 
30 minute infusion (up to 2 hours, if clinically indicated). Further instructions for the 
preparation and dispensation of PDR001 are described in the Pharmacy Manual.
6.5.1
Study treatment packaging and labeling
Study treatment, NIR178 and PDR001, will be provided as global clinical open-label patient 
specific supply and will be packed and labeled under the responsibility of Novartis, 
Drug Supply Management.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but will not supply information about 
the patient.
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Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength).
Site personnel will add the patient number on the label. If the label has 2-parts (base plus tear-off 
label), immediately before dispensing the package to the patient, site personnel will detach the 
outer part of the label from the package and affix it to the patient’s source document.
For patients that are assigned by the IRT system, responsible site personnel will identify the 
study treatment package(s) to dispense by the medication number(s) assigned by IRT to the 
patient.
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [NIR178 (PBF-509) Investigator’s Brochure] 
and [PDR001 Investigator’s Brochure].
6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Drug supply can be destroyed at the site if permitted by local 
regulations.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1, Table 7-2 and Table 7-3 lists all of the assessments and indicates with an “X”, the 
visits when they are performed. Japanese safety run-in part will be conducted in accordance 
with Table 7-1. Part 3 visit schedule will be followed by the continuous BID visit schedule
(Table 7-1).
All data obtained from these assessments must be supported in the patient’s source 
documentation. The table (“Category” column) indicates which assessments produce data to be 
entered into the clinical database (D) or remain in source documents only (S).
No CRF will be used as a source document.
Screening evaluations must be performed ≤ 21 days of Cycle 1 Day 1 (except for the pregnancy 
test which must be performed within 72 hours before day 1 of every cycle and baseline imaging 
assessment which should be performed ≤ 28 days of Cycle 1 Day 1). Assessments performed 
as part of the screening evaluations and within 3 days prior to the first dose of study treatment, 
are not required to be repeated on Cycle 1 Day 1. Laboratory and radiological assessments 
performed as part of standard of care prior to signing informed consent may be used if 
performed within the screening time window.
During the course of the study visits, tests and/or procedures should occur on schedule 
whenever possible. A visit window of +/- 3 days is allowed for assessments except Imaging and 
PK.
Imaging assessments have an on study visit window of ±1 week, regardless of dosing schedule 
or possible dose delays.
On PK collection days, the time windows are provided in Table 7-8 to Table 7-11. In situations 
when dosing is delayed, PK collections should also be delayed until the subsequent dose is 
given.
If the COVID-19 pandemic limits or prevents on-site study visits, alternative methods of 
providing continuing care may be implemented. Phone calls, virtual contacts (e.g. teleconsult) 
or visits by site staff/home nursing service to the patient’s home depending on local regulations 
and capabilities, can replace on-site study visits, for the duration of the pandemic until it is safe 
for the patient to visit the site again.


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Table 7-1
Visit evaluation schedule for patients in Part 1, Part 2 NIR178 S1 (NIR178 Schedule 1-BID continuous dosing), 
Part 3 and Japanese safety run-in
Visit Name
Category
Protocol 
Section
Screening
Cycle 1c
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of 
study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
8
15
22
28
1
15
1
15
Obtain Informed Consent
D
7.1.1.
X
IRT Registrationa
D
6.4, 
7.1.1.1.
X
Demography
D
7.1.1.3.
X
Inclusion/exclusion criteria
D
5.2, 5.3.
X
Medical History
D
7.1.1.3.
X
Diagnosis and extent of cancer
D
7.1.1.3.
X
Smoking History
D
7.1.1.3.
X
Prior antineoplastic therapy
D
7.1.1.3.
X
Prior/concomitant medications
D
7.1.1.3.
X
Throughout the study
X
X
Baseline tumor molecular 
characteristics 
D
7.1.1.3.
X
Antineoplastic therapies since 
discontinuation of study treatment
D
7.1.5, 
7.1.6, 
7.1.7.
X
X
IRT Randomizationa
6.4.
X
X
Physical examination
S
7.2.2.1.
X
X
X
X
X (for 
Japanese 
safety 
run-in 
only)
X
X
X
Performance status
D
7.2.2.4.
X
X
X
X
X
X
Height
D
7.2.2.3.
X
Weight
D
7.2.2.3.
X
X
X
X
X
X
This document (090095af8e09e1a8 in docbase CREDI_EH) has been digitally signed with external signatures using Entrust PKI.
Signatures manifested as of 10/29/2020 6:41:50 PM, signing status at this time:  Completed (1 of 1 signatures) 
Approved for report publication by Nesbitt Victoria in East Hanover at Thu, 29 Oct 2020 02:41:28 PM EDT


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1c
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of 
study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
8
15
22
28
1
15
1
15
Vital signs
D
7.2.2.2.
X
X
X
X
X
X
X
X
X
Hematology
D
7.2.2.5.1.
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2.
X
X
X
X
X
X
X
X
X
Thyroid Panel (TSH, free T4, T3)
D
7.2.2.5.4.
X
X
X
X
X
X
X
X
Coagulation (PTT/aPTT and PT or 
INR)
D
7.2.2.5.3.
X
If Clinically indicated
Creatinine clearance
D
7.2.2.5.2.
X
X
Hepatitis testing
D
7.2.2.5.5.
X
HIV testing
D
7.2.2.5.5.
X
Urinalysis
(microscopic or macroscopic)
D
7.2.2.5.8.
X
If Clinically indicated
Pregnancy test
D
7.2.2.5.7.
X
X
X
X
X
X
X
PSA (only for mCRPC patients)
D
7.2.2.5.8
X
X
X
X
X
X
Disease assessment/Tumor 
evaluation per iRECIST, RECIST 
v 1.1 or Cheson et al (2014) for 
lymphoma, color photography of 
visible lesion(s) and PCWG3
D
7.2.1.
X
Every 8 weeks from C1D1 
for 40 weeks and every 12 
weeks thereafter until 
progression of disease per 
iRECIST or Cheson et al 
(2014) or patient 
withdrawal
X (If not 
performed 
within 30 
days prior to 
EOT)
Bone marrow biopsy or aspirate in 
patients with known bone marrow 
involvement (for Lymphoma only)
D
7.2.1.
X
12 lead ECG
D
7.2.2.7.
X
X
X
X
X
X
X
Adverse events
D
8.
X
Throughout the study
X
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1c
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of 
study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
8
15
22
28
1
15
1
15
NIR178 dosing
D
6.1.
As per assigned schedule
PDR001 infusion
D
6.1.
Xa
X
X
X
PK sampling for NIR178, NJI765
and PDR001b
D
7.2.3.
X
X
X
X
X
X
X
X
X
X (up to 
cycle 6)
X
Chest X-ray
(For Japan only
D
7.2.2.6.
X
X
X
*Please refer to Section 7.1.5 for safety follow up, Section 7.1.6 for disease progression follow up, Section 7.1.7 for survival follow up and Section 7.1.8 for information 
on lost to follow-up patients.
a: Not applicable for Japanese safety run-in; An optional tumor sample may also be collected at disease progression when patients continue on study treatment due to 
overall clinical benefit
b: Please refer to Section 7.2.3. for Japanese safety run-in;
c: Patients will be hospitalized during first cycle for Japanese safety run-in.


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Table 7-2
Visit evaluation schedule for patients in Part 2 NIR178 S 2 (NIR178 Schedule 2 regimen-two weeks on two weeks 
off dosing)
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
8
14
15
22
1
15
1
15
Obtain Informed Consent
D
7.1.1.
X
IRT Registration
D
6.4, 
7.1.1.1.
X
Demography
D
7.1.1.3.
X
Inclusion/exclusion criteria
D
5.2, 5.3.
X
Medical History
D
7.1.1.3.
X
Smoking history
D
7.1.1.3.
X
Diagnosis and extent of cancer
D
7.1.1.3.
X
Prior antineoplastic therapy
D
7.1.1.3.
X
Prior/concomitant medications
D
7.1.1.3.
X
Throughout the study
X
X
Antineoplastic therapies since 
discontinuation of study treatment
D
7.1.5, 
7.1.6, 
7.1.7.
X
X
IRT Randomization
6.4.
X
X
Physical examination
S
7.2.2.1.
X
X
X
X
X
X
X
Performance status
D
7.2.2.4.
X
X
X
X
X
X
Height
D
7.2.2.3.
X
Weight
D
7.2.2.3.
X
X
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
X
X
X
X
Hematology
D
7.2.2.5.1.
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2.
X
X
X
X
X
X
X
X
X
Thyroid Panel (TSH, free T4, T3)
D
7.2.2.5.4.
X
X
X
X
X
X
X
X
Coagulation (PTT/aPTT and PT or 
INR)
D
7.2.2.5.3.
X
If Clinically indicated


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
8
14
15
22
1
15
1
15
Creatinine clearance
D
7.2.2.5.2.
X
X
Hepatitis testing
D
7.2.2.5.5.
X
HIV testing
D
7.2.2.5.5.
X
Urinalysis
(microscopic or macroscopic)
D
7.2.2.5.8.
X
If Clinically indicated
Pregnancy test
D
7.2.2.5.7.
X
X
X
X
X
X
X
Disease assessment/Tumor 
evaluation per iRECIST, RECIST v 
1.1 or Cheson et al (2014) for 
lymphoma, color photography of 
visible lesion(s)
D
7.2.1.
X
Every 8 weeks from 
C1D1 for 40 weeks and 
every 12 weeks 
thereafter until 
progression of disease 
per iRECIST or Cheson 
et al (2014) or patient 
withdrawal
X (If not 
performed 
within 30 
days prior to 
EOT)
12 lead ECG
D
7.2.2.7.
X
X
X
X
X
X
X
Adverse events
D
8.
X
Throughout the study
X
X
NIR178 dosing
D
6.1.
As per assigned schedule
PDR001 infusion
D
6.1.
X
X
X
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
8
14
15
22
1
15
1
15
PK sampling for NIR178, NJI765 and 
PDR001
D
7.2.3.
X
X
X
X
X
X
X
X
X
X (up to 
cycle 6)
X
*Please refer to Section 7.1.5 for safety follow up, Section 7.1.6 for disease progression follow up, Section 7.1.7 for survival follow up and Section 7.1.8 for information 
on lost to follow-up patients.
a: An optional tumor sample may be collected at disease progression when patients continue on study treatment due to overall clinical benefit.


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Table 7-3
Visit evaluation schedule for patients in Part 2 NIR178 S3 (NIR178 Schedule 3-one week on, one week of dosing)
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
7
8
15
22
1
15
1
15
Obtain Informed Consent
D
7.1.1.
X
IRT Registration
D
6.4, 
7.1.1.1.
X
Demography
D
7.1.1.3.
X
Inclusion/exclusion criteria
D
5.2, 5.3.
X
Medical History
D
7.1.1.3.
X
Smoking history
D
7.1.1.3.
Diagnosis and extent of cancer
D
7.1.1.3.
X
Prior antineoplastic therapy
D
7.1.1.3.
X
Prior/concomitant medications
D
7.1.1.3.
X
Throughout the study
X
X
Antineoplastic therapies since 
discontinuation of study treatment
D
7.1.5, 
7.1.6, 
7.1.7.
X
X
IRT Randomization
6.4.
X
X
Physical examination
S
7.2.2.1.
X
X
X
X
X
X
X
Performance status
D
7.2.2.4.
X
X
X
X
X
X
Height
D
7.2.2.3.
X
Weight
D
7.2.2.3.
X
X
X
X
X
X
Vital signs
D
7.2.2.2.
X
X
X
X
X
X
X
X
X
Hematology
D
7.2.2.5.1.
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5.2.
X
X
X
X
X
X
X
X
X
Thyroid Panel (TSH, free T4, T3)
D
7.2.2.5.4.
X
X
X
X
X
X
X
X
Coagulation (PTT/aPTT and PT or 
INR)
D
7.2.2.5.3.
X
If Clinically indicated
Creatinine clearance
D
7.2.2.5.2.
X
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
7
8
15
22
1
15
1
15
Hepatitis testing
D
7.2.2.5.5.
X
HIV testing
D
7.2.2.5.5.
X
Urinalysis
(microscopic or macroscopic)
D
7.2.2.5.8.
X
If Clinically indicated
Pregnancy test
D
7.2.2.5.7.
X
X
X
X
X
X
X
Disease assessment/Tumor evaluation 
per iRECIST, RECIST v 1.1 or Cheson
et al (2014) for lymphoma, color 
photography of visible lesion(s)
D
7.2.1.
X
Every 8 weeks from 
C1D1 for 40 weeks and 
every 12 weeks 
thereafter until 
progression of disease 
per iRECISTor Cheson et 
al (2014) or patient 
withdrawal
X (If not 
performed 
within 30 days 
prior to EOT)
12 lead ECG
D
7.2.2.7.
X
X
X
X
X
X
X
Adverse events
D
8.
X
Throughout the study
X
X
NIR178 dosing
D
6.1.
As per assigned schedule
PDR001 infusion
D
6.1.
X
X
X
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Day 1 of 
Subsequent 
cycles
End of study 
treatment 
(EoT)
Follow 
up *
Day of cycle
1
2
7
8
15
22
1
15
1
15
PK sampling for NIR178, NJI765 and 
PDR001
D
7.2.3.
X
X
X
X
X
X
X
X
X
X (up to 
cycle 6)
X
*Please refer to Section 7.1.5 for safety follow up, Section 7.1.6 for disease progression follow up, Section 7.1.7 for survival follow up and Section 7.1.8 for information 
on lost to follow-up patients.
a: An optional tumor sample may be collected at disease progression when patients continue on study treatment due to overall clinical benefit.


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7.1.1
Screening
The IRB/IEC study approved informed consent form (ICF) must be signed and dated before 
any study-specific screening procedure is performed. Procedures which are part of the clinical 
routine during the initial diagnostic work-up of the patient may be obtained before obtaining 
the ICF. A copy of the ICF must be given to the patient or to the person signing the form. 
The investigator or designee must record the date when the study informed consent was signed 
in the medical records of the patient.
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1, Table 7-2 and Table 7-3. Screening assessments 
must be completed within 21 days prior to the first dose of treatment except for the radiological 
tumor assessment which should be performed within 28 days prior to the first dose. 
Screening assessments must be repeated if outside of screening windows. Patients are allowed 
to re-screen after abnormal labs or symptoms are corrected or treated.
Submission of a newly obtained tumor sample (formalin fixed, in ethanol) is required from all 
patients (except for patients in Japanese safety run-in part) at screening, unless the patient has 
a recently obtained tumor sample that meets the following criteria (both criteria must be met):

Biopsy sample was collected ≤ 6 months before 1st dose of study medication and the 
sample is available at the site.

No immunotherapy was given to the patient since collection of biopsy sample.
For details refer to Section 7.2.4.
7.1.1.1
Eligibility screening
Following registering in the IRT (except for Japanese safety run-in patients) for screening, 
patient eligibility will be checked once all screening procedures are completed. Please refer and 
comply with detailed guidelines in the IRT manual.
7.1.1.2
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). If the patient fails to be randomized, the IRT must be notified within 2 days 
of the screen fail that the patient was not randomized.
7.1.1.3
Patient demographics and other baseline characteristics
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, smoking history, diagnosis and extent of cancer, details of prior 
anti-neoplastic treatments, prior medication, procedures, significant non-drug therapies, 
baseline tumor molecular characteristics and any other assessments that are done for the purpose 
of determining eligibility for inclusion in the study.


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7.1.2
Treatment period
The treatment period commences on the first day of the first cycle of NIR178 and PDR001 
combination.
During the study treatment period, patients will be regularly monitored to assess the safety and 
early anti-tumor activity of treatment. For purpose of scheduling and evaluations, a treatment 
cycle will consist of 28 days.
Patients who meet the following criteria should continue treatment in additional cycles:

Patients who do not have a PD per iRECIST (Appendix 3) or Cheson et al 2014 (DLBCL),
(and/or progressive disease per PCWG3 guidance (Appendix 5) for mCRPC).
Patients who meet the following criteria might continue treatment in additional cycles:

Patients with confirmed PD per iRECIST (Appendix 3) or Cheson et al 2014 (DLBCL),
(and/or progressive disease per PCWG3 guidance (Appendix 5) for mCRPC), if the 
Investigator considers it to be in the patient’s best interest to remain on the study, and after 
documented discussion with the Novartis medical monitor.
Patients who meet the following criteria will NOT continue treatment in additional cycles:

Patients who experience unacceptable toxicity.

Rapid disease progression or threat to vital organs or critical anatomical sites [e.g., CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression] 
requiring urgent alternative medical intervention; significant, unacceptable or irreversible 
toxicities related to study treatment.

Patients with confirmed PD per iRECIST (Appendix 3) or Cheson et al 2014 (DLBCL),
(and/or progressive disease per PCWG3 guidance (Appendix 5) for mCRPC) unless they 
meet the criteria above for continuation of treatment. These patients will then enter the 
Safety follow-up period.

Patients with an unconfirmed PD per iRECIST who show signs of clinical deterioration or 
toxicity. These patients will enter the Safety follow-up period, and will continue to be 
followed-up until confirmed irPD or initiation of a new treatment.
Clinical experience indicates that objective responses to immunotherapy follows delayed 
kinetics of weeks or months, and can be preceded by initial apparent radiological progression 
or appearance of new lesions or some enlarging lesions while other target lesions are regressing 
(“mixed response”) (Wolchok et al 2009). It is therefore reasonable to allow for these 
possibilities and continue to treat the patient until progression is confirmed and found to be 
advancing at the next imaging assessment as per iRECIST. An outline of the iRECIST is 
provided in Appendix 3.
These considerations should be balanced by clinical judgment as to whether the patient is 
clinically deteriorating and unlikely to receive any benefit from continued treatment.
Such deterioration will be assessed to have occurred after a clinical event that, in the 
Investigator’s opinion, is attributable to disease progression, is unlikely to reverse with 
continued study treatment and therefore indicates that the patient is not benefiting from study 
treatment and cannot be managed by the addition of supportive care.


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During the treatment period, the patient is obliged to follow the investigators instructions with 
regards to contraception, concomitant medications and dosing regimen. There is no fixed 
duration; patients may continue treatment with the study drug until the development of an 
unacceptable toxicity that precludes any further treatment, disease progression, and /or 
treatment is discontinued at the discretion of the Investigator or by patient refusal. For details 
of assessments during the treatment period, refer to Table 7-1, Table 7-2 and Table 7-3.
7.1.3
Discontinuation of study treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a
patient decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the patient’s chart and on the appropriate CRF pages.
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits,
or become lost to follow-up for any other reason.
The investigator may discontinue study treatment for a given patient if, he/she believes that
continuation would be detrimental to the patient’s well-being.
Study treatment may be discontinued under the following circumstances:

Adverse events

Lost to follow-up

Progressive disease as per confirmed iRECIST or Cheson et al (2014) (not as per RECIST 
v1.1); and/or as per PCWG3 guidance (Appendix 5) for mCRPC
Patients may alternatively be re-treated following progression during dosing pauses 
Patients who progress on treatment should be discontinued unless they have a subsequent 
response in the absence of further treatment

Physician’s decision

Study terminated by Novartis

Patient/guardian decision

Protocol deviation

Technical problems

Use of prohibited treatment. Refer to Appendix 1.

Any other protocol deviation that results in a significant risk to the patient’s safety

Dose interruptions longer than specified in Section 6.3.1.
Patients must be discontinued if any of the following occur:

Death

Pregnancy
Patients who discontinue study/investigational treatment should undergo an end of study
treatment visit and then be discontinued from the study treatment (please refer to Table 7-1, 
Table 7-2 and Table 7-3 for list of assessments to be performed). An End of Treatment Phase 
Disposition eCRF should be completed, giving the reason for stopping the study treatment. 
End of treatment/Premature withdrawal visit is not considered as the end of the study.


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The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment except for the Japanese run-in safety group.
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be 
performed every 8 weeks until documented disease progression, death, lost to follow-up, or 
withdrawal of consent.
Patients who transfer into another study or an alternative treatment option to continue provision 
of study treatment, will perform the end of treatment procedures (refer to Section 4.3). 
7.1.4
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time.
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore, and

Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, email, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All effort should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.
7.1.5
Follow up for safety evaluations
All patients receiving PDR001 must have safety evaluations for 150 days after the last dose of 
PDR001 or 30 days after the last dose of NIR178, whichever occurs later. The follow-up 
evaluations can be done either by telephone call or visit for the 30-, 90-, and 150-day safety 
follow-up visits.


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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. Adverse events 
should be captured on the appropriate eCRF for 150 days after the last dose of medication. 
If resolution of an adverse event continues past this timeframe, the investigator will still be 
responsible to undertake appropriate actions, but that information will not be entered into the 
clinical database. After initiation of a new post-treatment antineoplastic therapy, only AEs and 
SAEs suspected to be related to study treatment will be recorded in the Adverse Event CRF.
Data collected should be added to the Adverse Events CRF, the antineoplastic therapies since 
discontinuation of study treatment CRF, and the Concomitant Medications CRF. For female 
patients of child bearing potential, pregnancy tests will be performed as outlined in 
Section 7.2.2.5.7.
7.1.5.1
Follow- up period
For patients who transfer to another clinical study or an alternative treatment option to continue 
provision of study treatment, as described above in the end of study (Section 4.3), the follow-
up for safety, disease progression and survival will not be performed.
7.1.6
Follow-up for disease progression
Patients who discontinue study treatment for any reason other than death, disease progression 
per confirmed iRECIST (Appendix 3) or Cheson et al (2014) for DLBCL and/or progressive 
disease per PCWG3 guidance (Appendix 5) for mCRPC while on treatment, clinical 
deterioration or clinical progression, lost to follow-up, consent withdrawal or study termination, 
also should return for tumor evaluation assessments every 8 weeks (+/- 7 days) during the first 
40 weeks, and every 12 weeks (+/- 7 days) thereafter until disease progression, death, loss to 
follow-up or withdrawal of consent, whichever occurs first. Any newly started antineoplastic 
therapies during the follow-up period must be recorded on the Antineoplastic therapy since 
discontinuation eCRF. Once patient starts on new antineoplastic therapy post discontinuation 
of study treatment, patient does not need to be followed for disease progression.
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone to determine if the patient had disease 
progression. Once the Follow up for Disease progression period ended, the End of Post 
treatment Phase disposition eCRF should be completed.
Antineoplastic therapies or tumor directed surgical procedures initiated during the disease 
progression follow-up period must be recorded on the Antineoplastic therapies since 
discontinuation of study drug eCRF.
7.1.7
Follow-up for survival
Upon completion of the 150-day safety follow-up or disease progression follow-up, all patients 
(except for those in Japanese safety run in) will be followed for survival via a phone call, email 
or letter, every 12 weeks until any of the following (whichever occurs first): death, withdrawal 
of consent, loss to follow-up or at least 24 months from the first dose of study treatment.
Antineoplastic therapies or tumor directed surgical procedures initiated during the survival 


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follow-up period must be recorded on the Antineoplastic therapies since discontinuation of 
study drug eCRF.
7.1.8
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition CRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be determined locally according to three sets of criteria:

RECIST v1.1 (Appendix 2)

iRECIST (Appendix 3)

Cheson et al (2014) criteria for lymphoma

PCWG3 guidance (Appendix 5) for mCRPC
The local investigator’s assessment will be used for the analysis of response according to 
RECIST v1.1 or Cheson et al (2014) criteria. For treatment decision making around study 
discontinuation due to progressive disease, iRECIST (for solid tumors) or confirmed 
progressive disease as per Cheson et al (2014) (for lymphoma) will be followed. For mCRPC, 
efficacy will be evaluated using RECIST 1.1, iRECIST and PCWG3 guidance (Appendix 5).
In addition, imaging data will be centrally collected and checked for quality by an imaging 
Contract Research Organization (CRO) designated by Novartis. The site manual provided by 
the designated imaging CRO will provide further details regarding image collection. During the 
course of the study, Novartis may decide to have a central review of the radiological 
assessments performed.
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1).
Any imaging assessments already completed during the routine work-up of the patient within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after 
randomization cannot be considered baseline images. The following assessments are required 
at screening/baseline:

Chest, abdomen and pelvis CT or MRI

Brain CT or MRI, if clinically indicated

Whole body bone scan, if clinically indicated

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


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
Color photography for any skin lesions present

CT or MRI of other metastatic sites (e.g., neck), if clinically indicated
If a patient is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the 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.
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can be 
determined from the photograph.
At screening, lymphoma patients will undergo Fluorodeoxyglucose positron emission 
tomography (FDG-PET)CT scan and bone marrow biopsy if they have known bone marrow 
involvement. For patients with FDG avid tumors, all subsequent disease assessments will be 
performed with FDG-PET CT, using the 5-point scale (Cheson et al 2014). The avidity of up to 
six representative target lesions must be documented and the rest as non-target lesions. 
For patients with non-avid or variably FDG-avid tumors, CT scan with i.v. contrast of 
chest/abdomen/pelvis/additional known lesions will be performed. If at screening, a patient has 
a medical contraindication to CT i.v. contrast or develops a contraindication during the trial, the 
following radiologic assessments will be performed: a non-contrast chest CT and a contrast 
abdomen/pelvis Magnetic Resonance Imaging (MRI).
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
Imaging assessments as described in Table 7-4 should be performed at the time points specified 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing (see Table 7-1, Table 7-2 and Table 7-3). Imaging assessments for response 
evaluation will be performed every 8 weeks (+/- 7 days) during the first 40 weeks, and every 
12 weeks (+/- 7 days) thereafter until disease progression, death, lost to follow-up or withdrawal 
of consent or patient starts new antineoplastic therapy post discontinuation of study treatment. 


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Imaging assessments should be scheduled using the randomization 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.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment.
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 2).
If a patient has a PR or CR, the result will be confirmed by a new assessment after at least 4 
weeks.
If a solid tumor patient has progressive disease, as per iRECIST, the result will be confirmed 
after at least 4 weeks.
Similarly, if a lymphoma patient has progressive disease, the result will be confirmed after at 
least 4 weeks per Cheson et al (2014) criteria.
For mCRPC, efficacy will be evaluated using RECIST 1.1, iRECIST and PCWG3 guidance 
(Appendix 5).
If possible, a single radiologist should perform all tumor response evaluations for an individual 
patient.
Any lesion that has been previously treated with radiotherapy should be considered as a non-
target lesion. However, if a lesion previously treated with radiotherapy has clearly progressed 
since the radiotherapy, it can be considered as a target lesion.
All study imaging (including any off-schedule imaging studies) should be submitted to the 
designated imaging CRO for quality control and central review.
For patients who discontinue treatment for reasons other than documented disease progression, 
death, lost to follow-up, or withdrawal of consent or patient starts new antineoplastic therapy 
post discontinuation of study treatment, tumor assessments must continue to be performed every 
8 weeks until documented disease progression, death, lost to follow-up, or withdrawal of 
consent.


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Table 7-4
Imaging/Disease Assessment Collection Plan
Procedure
Screening/Baseline
During Treatment/Follow-up
Chest, abdomen and pelvis CT or 
MRI(with intravenous contrast 
enhancement)
Mandated
Mandated, every 8 weeks during 
the first 40 weeks, and every 12 
weeks (+/- 7 days) thereafter
Brain CT or MRI
If clinically indicated
If lesions were documented at 
baseline, follow same schedule 
as CT/MRI of chest, abdomen, 
and pelvis
Whole body bone scan
Mandatory for patients with mCRPC.
If clinically indicated for all other 
indications
For patients with mCRPC: 
Mandated, every 8 weeks (+/- 7 
days) for the first 40 weeks, and 
every 12 weeks (+/- 7 days) 
thereafter until disease 
progression, study treatment 
discontinuation**, or start of new 
antineoplastic therapy.
If clinically indicated for all other 
indications
Bone marrow biopsy or aspirate 
(for lymphoma patients)*
Mandatory at screening
To confirm complete responses 
(CR), in patients with bone 
marrow involvement prior to 
study treatment
FDG-PET/CT
For lymphoma patients with known 
bone marrow involvement and/or 
FDG-avid tumors
All subsequent disease 
assessments; every 8 weeks 
during the first 40 weeks, and 
every 12 weeks (+/- 7 days) 
thereafter for patients with FDG-
avid tumors
Localized bone CT, MRI or x-ray
(e.g. neck, bone, prostate or 
prostate bed)
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
Color photography (with 
scale/ruler)
For any skin lesions present
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
*- Documentation of status of bone marrow involvement by lymphoma based on prior bone marrow biopsy or 
aspirate findings is required at screening for all patients. If no such documentation is available then a bone 
marrow biopsy or aspirate should be performed at screening.
** Perform scan at EOT if a scan was not conducted within the 30 days prior to EOT.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, body weight, 
performance status, hematology, chemistry, coagulation, thyroid function, pregnancy, ECG, as 
well as collecting of the adverse events at every visit. For details on AE collection and reporting, 
refer to Section 8.


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During the COVID-19 pandemic that limits or prevents on-site study visits, regular phone or 
virtual calls will occur (every 4 weeks or more frequently if needed) for safety monitoring and 
discussion of the patient’s health status until the patient can again visit the site.
7.2.2.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed as indicated in Table 7-1, 
Table 7-2 and Table 7-3.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF.
For Japan only: oxygen saturation (SpO2) will be measured by pulse oximetry for Japanese 
patients every time physical examination is performed as indicated in Table 7-1. The results of 
SpO2 will be recorded only in the source documentation.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) must be performed before infusion 
and as indicated in Table 7-1, Table 7-2 and Table 7-3 as per institutional standards. Vital signs 
should be assessed in the same position through the study. These assessments will be mandatory 
while patients are receiving study medications.
More frequent examinations may be performed at the discretion of the Investigator if medically 
indicated, and will be recorded as unscheduled assessment.
7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-1, Table 7-2 and Table 7-3.
7.2.2.4
Performance status
ECOG Performance status scale will be used as described in the Table 7-5 and should be 
assessed as indicated in Table 7-1, Table 7-2 and Table 7-3.


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Table 7-5
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all 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
Note: Grade 5 (death) was removed from this table. This information will be collected on a separate eCRF.
7.2.2.5
Laboratory evaluations
Sites will use their local laboratories for the analysis of all safety lab samples collected at the 
time points indicated in Table 7-1, Table 7-2, Table 7-3 and Table 7-6. More frequent 
assessments may be performed if clinically indicated, or at the investigator’s discretion and 
these should be recorded on the Unscheduled Visit eCRFs.
Screening examinations performed ≤72 hours prior to day 1 cycle 1, do not need to be repeated 
prior to dosing for Cycle 1, Day 1.
Abnormal laboratory values that are clinically significant (e.g., require an interruption or delay 
of study treatment, lead to clinical symptoms, or require therapeutic intervention) must be 
documented in the Adverse Event eCRF.
Novartis will be provided with a copy of the site’s local laboratory certification and tabulation 
of the normal ranges for each parameter required at study start and should be kept up to date on 
an ongoing basis. In addition, if at any time a patient has laboratory parameters obtained from 
a different outside laboratory, Novartis must be provided with a copy of the certification and a 
tabulation of the normal ranges for that laboratory.


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Table 7-6
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hemoglobin, Platelets, Red blood cells, White blood cells, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Total 
Bilirubin, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Amylase, Lipase, Glucose (non-fasting)
Urinalysis
Microscopic Panel (Red Blood Cells, White Blood Cells, Bacteria, Epithelial cells)
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, pH, Protein, Specific Gravity)
Coagulation
Prothrombin time (PT), International normalized ratio [INR]), Partial thromboplastin time 
(PTT) or Activated partial thromboplastin time (aPTT)
Thyroid
T3 [free], T4 [free], TSH
Virology panel
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR (baseline), HIV
Pregnancy Test
If the patient is a woman of child-bearing potential,a serum pregnancy test should be 
performed at screening, monthly during the study, and at the end of treatment. A serum 
or urine pregnancy test should be performed monthly during the safety follow-up period.
7.2.2.5.1 Hematology
Hematology tests are to be performed as outlined in Table 7-6 by the local laboratory according 
to the visit schedule outlined in Table 7-1, Table 7-2, and Table 7-3.
7.2.2.5.2 Clinical chemistry
Clinical chemistry tests are to be performed as outlined in Table 7-6 by the local laboratory 
according to the visit schedule outlined in Table 7-1, Table 7-2, and Table 7-3. It should be 
noted in the patient’s eCRF if the patient was fasting at the time of blood sampling.
7.2.2.5.3 Coagulation
Coagulation will be measured/calculated at screening. The schedule is outlined in Table 7-1, 
Table 7-2, Table 7-3 and Table 7-6.
7.2.2.5.4 Thyroid function
A full panel for thyroid function is required at screening (TSH, T3 [free] and T4 [free]). At other 
visits, only TSH is required unless the results are abnormal or it is increasing to an extent 
deemed clinically significant. Testing is to be performed as outlined in Table 7-6 by the local 
laboratory according to the visit schedule outlined in Table 7-1, Table 7-2, and Table 7-3.
7.2.2.5.5 Virology panel
Virology panel outlined in Table 7-6 will be performed as per the assessment schedule in 
Table 7-1, Table 7-2 and Table 7-3.


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7.2.2.5.6 Serology panel
Serology testing may be done on remnant serum samples if a patient experiences an adverse 
event. The testing will be conducted by a central lab.
7.2.2.5.7 Pregnancy and assessments of fertility
A serum pregnancy test must be performed at screening, every month during the study and at 
the end of treatment visit. If the screening pregnancy test is performed within 72 hours of cycle 
1 day 1, pregnancy test does not have to be repeated.
Every month during the safety follow-up period and at the end of the safety follow-up period, 
a serum or urine pregnancy test must be performed. If the patient is not coming to the clinic 
during the safety follow-up, it can be performed at home or at a local doctor’s office, and the 
results will be communicated to the site staff. These follow-up pregnancy tests will be recorded 
only in the source documentation, not in the CRF.
A pregnancy test is only needed if the patient is a woman of child-bearing potential.
During the COVID-19 pandemic, if the patient cannot visit the site to have serum pregnancy 
tests done, locally available urine pregnancy test kits may be used. Relevant patients can 
perform the urine pregnancy test at home and report the result to the site. It is important that 
patients are instructed to perform the urine pregnancy test first and only if the test result is 
negative proceed with the administration of the study treatment. A communication process 
should be established with the patient so that the Site is informed of the pregnancy test results.
7.2.2.5.8 Urinalysis
Dipstick measurements for specific gravity, pH, protein, glucose and blood will be performed 
as outlined in Table 7-6 and as indicated in Table 7-1, Table 7-2 and Table 7-3. Any significant 
findings on dipstick will be followed up with a microscopic evaluation where Microscopic 
Panel (Red Blood Cells, White Blood Cells, Bacteria, and Epithelial cells will also be measured).
 
 
7.2.2.6
[For Japan only] Radiological examinations
7.2.2.6.1 Chest X-ray
A 2-view chest X-ray will be performed as outlined in Table 7-1, Table 7-2 and Table 7-3.
7.2.2.7
Cardiac assessments
7.2.2.7.1 Electrocardiogram (ECG)
All ECG evaluations will be independently reviewed at central labs. Instructions for the 
collection and transmission of ECGs to the central ECG laboratory will be provided in the ECG 
Manual. A standard 12-lead ECG will be performed as per the assessment schedule in 
t the same time point 


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should be taken after the ECGs are completed. The ECGs must be performed in triplicate, at 
least 1-2 minutes apart, as shown in the tables below.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present at screening should be reported on the Medical 
History CRF page. Clinically significant findings must be discussed with Novartis prior to 
enrolling the patient in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded on the Adverse Events CRF page.
Table 7-7
Central ECG collection plan
Cycle
Day
Time
ECG Type
Screening
-21 to -1 days
Anytime during the screening period
12 Lead, triplicate
1
1
Pre-dose (baseline ECG)
2-hr post-NIR178 dose, ± 15 min
12 Lead, triplicate
1
7 (only 
required for 
Part 2 NIR178 
Schedule 3)
Pre-dose
30 min, 1-hr, 2-hr, 3-hr, 4-hr post-NIR178 dose, 
± 15 min
12 Lead, triplicate
1
14 (only 
required for 
Part 2, 
NIR178 
Schedule 2)
Pre-dose
30 min, 1-hr, 2-hr, 3-hr, 4-hr post-NIR178 dose, 
± 15 min
12 Lead, triplicate
1
28 (only 
required for 
Part 1 and 
Part 2 NIR178 
Schedule 1)
Pre-dose
2-hr post-NIR178 dose, ± 15 min
12 Lead, triplicate
2 to 6 
1
Pre-dose
12 Lead, triplicate
EOT
1
Any time
12 Lead, triplicate
Unscheduled 
N/A
Any time
12 Lead, triplicate 
7.2.3
Pharmacokinetics and immunogenicity assessments
Serial blood samples will be collected at specified time points as outlined in in Table 7-8, 
Table 7-9, Table 7-10 and Table 7-11 to measure NIR178 and its metabolite, NJI765,  PDR001 
and anti-drug antibodies (ADAs). Blood samples should be collected from the arm 
oppositefrom the study drug infusion, or from another site. Complete instructions for sample 
processing, handling and shipment will be provided in the [CNIR178X2201 Laboratory 
Manual].
PK and anti-drug antibody samples will also be collected at the End of Treatment Visit and in 
the event of a clinically significant AE (such as infusion reaction/anaphylaxis) or if anti-drug 
antibody is suspected, at which time those samples could be used to measure any relevant 
biomarkers, to understand the infusion reaction/adverse event better.
The exact date and clock times of study drug administration and blood sample collection will 
be recorded on the appropriate electronic care report form (eCRF). Any sampling issues should 
be noted on the eCRF and on appropriate source documentation. If vomiting occurs within 4 


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hours following NIR178 oral administration on dosing days with a pre- and post-dose PK blood 
collection, the clock time of vomiting should be recorded in the Dose Administration Record 
(DAR) PK eCRF page. For PDR001, in case the administration is stopped or temporarily paused 
during infusion, these events should be captured in the appropriate DAR PK eCRF page.
Residual PK and ADA serum or plasma samples used for PK and/or ADA analysis may also be 
used for exploratory PK and/or PD analyses.
During the COVID-19 pandemic that limits or prevents on-site study visits, or if visits by site 
staff to a patient’s home are not feasible the collection of samples may be modified by Novartis 
and will be communicated to the Investigator.
Table 7-8
Pharmacokinetic blood collection log for PDR001 and ADA (all study 
parts and schedules, including Japanese safety run-in and Part 3)
Cycle
Study day
Scheduled time point (Sampling window)
Analytes
1 (Cycle 2 for 
Japanese 
safety run-in 
patients) e
1
Pre-dose b (0 h)
PDR001 and ADA a
1 (Cycle 2 for 
Japanese 
safety run-in 
patients) e
1
1 h (± 5 min) post end of C1D1 infusion dose c
PDR001
1 (Cycle 2 for 
Japanese 
safety run-in 
patients) e
8
168 h (± 8 hr) post dose
PDR001
1 (Cycle 2 for 
Japanese 
safety run-in 
patients) e
15
336 h (± 8 hr) post dose
PDR001
1 (Cycle 2 for 
Japanese 
safety run-in 
patients) e
22
504 h (± 8 hr) post dose
PDR001
2
1
Pre-dose b of cycle 2 (0 h)
PDR001 and ADA a
3
1
Pre-dose b of cycle 3 (0 hr)
PDR001 and ADA a
3
1
1 hr (± 5 min) post end of C3D1 infusion dose c
PDR001
3
15
336 hr (± 8 hr) post dose
PDR001
4
1
Pre-dose b of cycle 4 (0 h)
PDR001 and ADA a
5
1
Pre-dose b of cycle 5 (0 h)
PDR001 and ADA a
6
1
Pre-dose b of cycle 6 (0 h)
PDR001 and ADA a
EOT d
Anytime
PDR001 and ADA a
Unscheduled
Anytime
PDR001 and ADA a


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Cycle
Study day
Scheduled time point (Sampling window)
Analytes
Blood samples are to be collected from the arm opposite from infusion site, or alternatively, infusion site will 
need to be flushed with 10 mL of saline.
a Immunogenicity (IG) (Anti-Drug [PDR001] Antibody): blood samples to be collected for anti-drug antibody 
together with PK samples
b Pre-dose blood samples should be collected prior to start of infusion of any treatment
c PDR001 sampling time is relative to the end of PDR001 infusion
d A PK sample collection will occur at cycle 6 or EOT, whichever occurs first
Note: For Japanese safety run-in, PDR001 samples collection will begin from cycle 2 onwards.
e As of protocol amendment 6, patients enrolled in the Japanese safety run-in part will receive NIR178 in 
combination with PDR001 starting at Cycle 1 and PDR001/ADA PK sample collections will begin at Cycle 1
Table 7-9
Pharmacokinetic blood collection log for NIR178: Part 1, Part 2, Part 3 
(NIR178 Schedule 1), and Japanese safety run-in
Cycle
Day
Scheduled Time Point (h)
Analyte b
1
1
Pre-dose (0 h)
NIR178 and NJI765
1
1
15 min post-dose (± 5 min)
NIR178 and NJI765
1
1
30 min post-dose (± 5 min)
NIR178 and NJI765
1
1
1 h post-dose (± 5 min)
NIR178 and NJI765
1
1
1.5 h post-dose (± 5 min)
NIR178 and NJI765
1
1
2 h post dose (± 10 min)
NIR178 and NJI765
1
1
3 h post-dose (± 10 min)
NIR178 and NJI765
1
1
4 h post-dose (± 30 min)
NIR178 and NJI765
1
1
8 h post-dose (± 30 min)
NIR178 and NJI765
1
2
Pre-dose (0hr/12 hrs post day 1 evening dose)
NIR178 and NJI765
1
8
Pre-dose (0 h)
NIR178 and NJI765
1
15
Pre-dose (0 h)
NIR178 and NJI765
1
28
Pre-dose (0 h)
NIR178 and NJI765
1
28
15 min post-dose (± 5 min)
NIR178 and NJI765
1
28
30 min post-dose (± 5 min)
NIR178 and NJI765
1
28
1 h post-dose (± 5 min)
NIR178 and NJI765
1
28
1.5 h post-dose (± 5 min)
NIR178 and NJI765
1
28
2 h post dose (± 10 min)
NIR178 and NJI765
1
28
3 h post-dose (± 10 min)
NIR178 and NJI765
1
28
4 h post-dose (± 30 min)
NIR178 and NJI765
1
28
8 h post-dose (± 30 min)
NIR178 and NJI765
2
1
Pre-dose (0hr/12 hrs post day 28 evening dose)
NIR178 and NJI765
3
1
Pre-dose
NIR178 and NJI765
4
1
Pre-dose
NIR178 and NJI765
5
1
Pre-dose
NIR178 and NJI765
6
1
Pre-dose
NIR178 and NJI765
EOT a
Anytime
NIR178 and NJI765
Unscheduled
Anytime
NIR178 and NJI765
a a PK sample collection will occur at cycle 6 or EOT, whichever occurs first
b Same blood samples collected to assess PK of NIR178 will be used to measure its metabolite NJI765 as both 
analytes are assayed simultaneously by the analytical laboratory. 


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Table 7-10
Pharmacokinetic blood collection log for NIR178 Part 2 (NIR178 
Schedule 2)
Cycle
Day
Scheduled Time Point (h)
Analyte b
1
1
Pre-dose (0 h)
NIR178 and NJI765
1
1
15 min post-dose (± 5 min)
NIR178 and NJI765
1
1
30 min post-dose (± 5 min)
NIR178 and NJI765
1
1
1 h post-dose (± 5 min)
NIR178 and NJI765
1
1
1.5 h post-dose (± 5 min)
NIR178 and NJI765
1
1
2 h post dose (± 10 min)
NIR178 and NJI765
1
1
3 h post-dose (± 10 min)
NIR178 and NJI765
1
1
4 h post-dose (± 30 min)
NIR178 and NJI765
1
1
8 h post-dose (± 30 min)
NIR178 and NJI765
1
2
Pre-dose (0hr/ 12 hrs post day 1 evening dose)
NIR178 and NJI765
1
14
Pre-dose (0 h)
NIR178 and NJI765
1
14
15 min post-dose (± 5 min)
NIR178 and NJI765
1
14
30 min post-dose (± 5 min)
NIR178 and NJI765
1
14
1 h post-dose (± 5 min)
NIR178 and NJI765
1
14
1.5 h post-dose (± 5 min)
NIR178 and NJI765
1
14
2 h post dose (± 10 min)
NIR178 and NJI765
1
14
3 h post-dose (± 10 min)
NIR178 and NJI765
1
14
4 h post-dose (± 30 min)
NIR178 and NJI765
1
14
8 h post-dose (± 30 min)
NIR178 and NJI765
1
15
12 hrs post day 14 evening dose
NIR178 and NJI765
EOT a
Anytime
NIR178 and NJI765
Unscheduled
Anytime
NIR178 and NJI765
a a PK sample collection will occur at cycle 6 or EOT, whichever occurs first
b Same blood samples collected to assess PK of NIR178 will be used to measure its metabolite NJI765 as both 
analytes are assayed simultaneously by the analytical laboratory.


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Table 7-11
Pharmacokinetic blood collection log for NIR178 Part 2 (NIR178 
Schedule 3)
Cycle
Day
Scheduled Time Point (h)
Analyte b
1
1
Pre-dose (0 h)
NIR178 and NJI765
1
1
15 min post-dose (± 5 min)
NIR178 and NJI765
1
1
30 min post-dose (± 5 min)
NIR178 and NJI765
1
1
1 h post-dose (± 5 min)
NIR178 and NJI765
1
1
1.5 h post-dose (± 5 min)
NIR178 and NJI765
1
1
2 h post dose (± 10 min)
NIR178 and NJI765
1
1
3 h post-dose (± 10 min)
NIR178 and NJI765
1
1
4 h post-dose (± 30 min)
NIR178 and NJI765
1
1
8 h post-dose (± 30 min)
NIR178 and NJI765
1
2
Pre-dose (0hr/12 hrs post day 1evening dose)
NIR178 and NJI765
1
7
Pre-dose (0 h)
NIR178 and NJI765
1
7
15 min post-dose (± 5 min)
NIR178 and NJI765
1
7
30 min post-dose (± 5 min)
NIR178 and NJI765
1
7
1 h post-dose (± 5 min)
NIR178 and NJI765
1
7
1.5 h post-dose (± 5 min)
NIR178 and NJI765
1
7
2 h post dose (± 10 min)
NIR178 and NJI765
1
7
3 h post-dose (± 10 min)
NIR178 and NJI765
1
7
4 h post-dose (± 30 min)
NIR178 and NJI765
1
7
8 h post-dose (± 30 min)
NIR178 and NJI765
1
8
12 hrs post day 7 evening dose
NIR178 and NJI765
EOT a
Anytime
NIR178 and NJI765
Unscheduled
Anytime
NIR178 and NJI765
a a PK sample collection will occur at cycle 6 or EOT, whichever occurs first
b Same blood samples collected to assess PK of NIR178 will be used to measure its metabolite NJI765 as both 
analytes are assayed simultaneously by the analytical laboratory.
7.2.3.1
Analytical methods
Concentrations of NIR178 and NJI765 will be determined from incurred plasma samples using 
a validated LC/MS-MS assay with a lower limit of quantification (LLOQ) of 1.00 ng/mL or 
lower for both analytes. The quantification of these two analytes for PK characterization will 
occur simultaneously at a Novartis’ designated analytical laboratory and hence does not require 
collection of a separate blood sample series for each.
Concentrations of PDR001 will be determined from serum using a validated LC/MS-MS assay.
Anti-PDR001 antibodies will be determined from serum using validated homogenous ELISA.


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).


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Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 150 days following the last dose of PDR001 or 30 days after the last 
dose NIR178, whichever occurs later. After initiation of new post-treatment antineoplastic 
therapy, only AEs suspected to be related to study treatment will be collected in the Adverse 
Event CRF. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-5)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
and which seriousness criteria have been met
7. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.


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Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST 1.1 or iRECIST criteria for solid tumors or as per 
Cheson et al (2014) guidelines for hematological malignancies), should not be reported as a 
serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. 
Whenever possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should 
be followed until they have returned to normal or an adequate explanation of the abnormality 
is found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization,


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
Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 150 days after the last dose of PDR001, 
or 30 days after the last dose of NIR178, whichever occurs later, must be reported to Novartis 
within 24 hours of learning of its occurrence. If a patient starts a post-treatment antineoplastic 
therapy, then only SAEs suspected to be related to study treatment will be reported.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the 150 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis.
Detailed instructions regarding the SAE submission process and requirements for signatures are 
to be found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology Chief 
Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 


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the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries.
8.3
Emergency unblinding of treatment assignment
Not applicable.
8.4
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis 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 study treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study and the newborn will be followed up to 12 months after delivery date. 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
mother.
8.5
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.6
Data Monitoring Committee
An independent data monitoring committee will not be formed for this exploratory phase II
study. Individual patient data will be reviewed on an ongoing basis and aggregate safety data 
and the primary endpoint will be monitored on ongoing basis by the study team across the 
duration of the trial. The data review and analysis will be based on the available investigator 
reported data in the clinical database (see Section 10.7) at the respective time.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. 
If the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form 
(a signed copy is given to the patient).


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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
PK 
 (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by a Novartis designated 
laboratory, contracted central laboratories, or local laboratories. ECG data collected during the 
study will be reviewed and processed centrally by a specialist CRO. During the course of the 
study, Novartis may decide to have a central review of the radiological assessments performed. 
In such case, the investigator’s staff will be instructed on how to send data from these 
radiological assessments to a Contract Research Organization (CRO) for central review when 
needed. Designated investigational site staff will enter the information required by the protocol 
into the appropriate eCRF and/or designated laboratory requisition forms. Field monitors will 
review the eCRFs and laboratory paper requisition forms for accuracy and completeness and 
instruct site personnel to make any required corrections or additions. One copy of the requisition 
form will be forwarded to each analytical laboratory with the respective sample(s) by the field 
monitor or by the designated investigational site staff; and one copy will be retained at the 
investigational site.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).


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Randomization codes and data about all study treatments dispensed to the patient and all IRT 
assigned dosage changes will be tracked using an Interactive Response Technology. The system 
will be supplied by a vendor(s), who will also manage the database. The data will be sent 
electronically to Novartis personnel (or designated CRO).
For EDC studies, after database lock, the investigator will receive copies of the patient data for 
archiving at the investigational site.
10
Statistical methods and data analysis
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized using 
descriptive statistics (continuous data) and/or contingency table (categorical data) for 
demographic and baseline characteristics, efficacy measurements, safety measurements and all 
relevant PK and PD measurements. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented.
The study data will be analyzed and reported based on all patients’ data up to the time when all 
patients have potentially completed at least six cycles of treatment or discontinued the study. 
Any additional data for patients continuing to receive study treatment past the data cutoff date 
for the primary Clinical Study Report, as allowed by the protocol, will be reported at completion 
of the study as defined in Section 4.3.
The following rules will be followed for reporting results unless stated otherwise:

Part 1: All summaries, listings and figures will be presented by tumor type.

Part 2: All summaries, listings and figures will be presented by treatment groups.

Part 3: All summaries, listings and figures will be presented by tumor type and treatment 
group.
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings.
The data from patients in Japanese safety run-in part will be reported in the CSR separately 
from the Phase II part of the data regardless of whether Japanese patients will participate the 
Phase II part of the study.
10.1
Analysis sets
10.1.1
Full Analysis Set
For Part 1, Part 3 and Japanese safety run-in part of the study, the Full Analysis Set (FAS) 
comprises all patients who received at least one full or partial dose of assigned combination of 
study drugs. Patients will be analyzed according to the planned treatment.


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For Part 2 of the study: the Full Analysis Set (FAS) comprises all patients to whom study 
treatment has been assigned by randomization. According to the intent to treat principle,
patients will be analyzed according to the treatment they have been assigned to during the 
randomization procedure.
The FAS will be used for all listings of raw data. Unless otherwise specified, the FAS will be 
the default analysis set used for all analyses.
10.1.2
Safety set
The Safety Set includes all patients from the FAS who have received at least one dose of 
NIR178 or PDR001. Patients will be classified according to treatment received, where treatment 
received is defined as:
1. The treatment assigned if it was received at least once, or
2. The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.
The safety set will be used for the safety summary of the study.
10.1.3
Pharmacokinetic analysis set
The Pharmacokinetic analysis set (PAS) includes all patients who provide an evaluable PK 
profile. A profile is considered evaluable if all of the following conditions are satisfied:

Subject receives one of the planned treatments

Subject provides at least one PK parameter

Subject did not vomit within 4 hours after the dosing of NIR178
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by tumor type for the FAS.
Relevant medical histories and current medical at baseline will be summarized by system organ 
class and preferred term, by tumor type.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The Safety set will be used for the analyses below.
The duration of exposure in months for NIR178 and PDR001 as well as the dose intensity 
(computed as the ratio of actual cumulative dose received and actual duration of exposure) and 
the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) 
will be summarized by means of descriptive statistics using the safety set.
The duration of exposure will also be presented for the study treatment.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed.


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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
10.4
Primary objective
There are three parts to the study. The primary objective for Part 1 is to evaluate the efficacy of 
NIR178 in combination to PDR001 in patients with selected advanced solid tumors and DLBCL.
The primary objective for Part 2 is to assess several continuous and intermittent dosing schedule 
of NIR178 in combination with PDR001 in NSCLC.
The primary objective for Part 3 is to further evaluate the efficacy of intermittent or continuous 
dosing schedules (if selected) of NIR178 in combination with PDR001 in one or two selected
tumor types based on the emerging data from part 1 and part 2.
10.4.1
Variable
The variable used to evaluate the primary objective is overall response rate (ORR), defined as 
the proportion of patients with best overall response (BOR) of complete response (CR) or partial 
response (PR), as per local review and according to RECIST v1.1 (Refer to Appendix 2 for 
solid tumors and Cheson et al (2014) for DLBCL).
10.4.2
Statistical hypothesis, model, and method of analysis
Part 1:
This part will contain thirteen groups: DLBCL at NIR178 160 mg BID, pancreatic cancer at 
NIR178 160 mg BID, HNSCC IO naive at NIR178 160 mg BID, urothelial cancer at NIR178 
160 mg BID, RCC IO naive at NIR178 160 mg BID, TNBC at NIR178 160 mg BID, melanoma 
IO pretreated NIR178 160 mg BID, HNSCC IO pretreated NIR178 160 mg BID, MSS CRC 
RAS wildtype NIR178 160 mg BID, MSS CRC RAS mutant NIR178 160 mg BID, RCC IO 
pretreated at NIR178 240 mg BID, RCC IO naive at NIR178 240 mg BID, and mCPRC at 
NIR178 240 mg BID. All doses are given in combination with PDR001 400 mg Q4W.
An adaptive Bayesian design (Neuenschwander et al 2016) will be used to assess activity of 
treatment in terms of overall response rate (ORR) within tumor type and across each tumor 
types.
The efficacy data from the Non-HNSCC patients, MSS CRC patients with unknown RAS 
status and IO naive melanoma patients will not be included in the statistical model. The 
design of the trial adapts to the data that are accumulated in the trial in such a way as to 
accommodate three possibilities:

Scenario A: ORR is similar across tumor types

Scenario B: ORR is similar for some tumor types and different in others

Scenario C: The various tumor types have distinct ORR


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The pre-specified analysis is adaptive in the sense that when response is similar across tumor 
types (Scenario A), then it borrows from across the various tumor types. In case some of the 
tumor types have similar ORR (Scenario B), the model provide more precise estimate of ORR 
rates for those tumor types with similar response rates by allowing borrowing only across these 
tumor types. In the other possibility (the various tumor types have distinct anti-tumor activity 
(Scenario C)); the design allows little/no borrowing across tumor types. In this case the trial 
will be similar to traditional stratified analysis.
A hierarchical model (HM) will be used to analyze the binary data to facilitate the borrowing 
as specified above. Response rates (πj) will be inferred for tumor group j (= 1,…,13). For each 
tumor type j, the number of responders follows a binomial distribution;
rj ~ Bin (nj, πj)
We further let the parameters θj = log (πj / (1 − πj)) (logistic transformation) be either 
exchangeable with some of the tumor types, or non-exchangeable with any of them. Based on 
the number of strata in this trial, we allow for two exchangeability distributions, which, for 
example, accounts for the case where some tumor type show no efficacy and some are 
promising. Thus, for each tumor type j, three possibilities arise, with respective probabilities pj
= ( pj1, pj2, pj3 ), as follows:
1. With probability pj1 (probability group j belongs to exchangeability set 1) the parameter θj 
follows a normal distribution with exchangeability parameters µ1 and τ1:
θj ~ N(µ1,τ12)
2. With probability pj2 (probability group j belongs to exchangeability set 2) θj follows a 
normal distribution with exchangeability parameters µ1 <µ2 and τ2:
θj ~ N(µ2,τ22)
3. With remaining probability pj3 = 1−pj1−pj2 (probability group j is not exchangeable with 
any other group), θj follows a weakly-informative prior distribution
θj ~ N(mw,vw)
For the detailed specifications of mw, vw, the a-priori weights pj (j=1,…,J), and the prior 
distributions for µ1, τ1, µ2, and τ2, see (Appendix 4). At any given time of the trial, including at 
the end, posterior probabilities of the various parameters will be estimated using Markov chain 
Monte Carlo methods.
The results at the final analysis within a tumor type will be regarded to be positive if both of the 
following conditions are met:
a. posterior mean ≥“clinically meaningful activity” threshold (column for C2 in 
Table 10-1) (i.e. posterior mean ORR >= C2)
b. Posterior probability of “not being clinically meaningful” (column for C1 in 
Table 10-1) is less than 10% (i.e., prob(ORR <= C1|data) < 10%)


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Table 10-1
Type of tumors of interest with definition of being clinically 
meaningful
Disease Code
Tumor type
Not Clinically 
meaningful (C1)
Clinically meaningful 
(C2)
T1
DLBCLa
<= 10%
>= 20%
T2
Pancreaticb
<= 8%
>= 16%
T3
HNSCC naivec
<= 13%
>= 23%
T4
Urotheliald
<= 15%
>= 27%
T5
RCC naive at 160 mg
<= 25%
>= 37%
T6
TNBCg
<= 5%
>= 13%
T7
Melanoma pretreatedh
<= 10%
>= 25%
T8
HNSCC pretreated
<= 5%
>= 13%
T9
MSS CRC – RAS wildtypef
<= 5%
>= 13%
T10
MSS CRC – RAS mutantf
<= 5%
>= 13%
T11
RCC pretreated at 240 mg
<= 10%
>= 20%
T12
RCC naive at 240 mg
<= 25%
>= 37%
T13
mCRPC at 240 mg
<= 10%
>= 35%
Interim analysis will be done when at least 10 patients in any indication have at least one post-baseline 
assessment (except for MSS-CRC and RCC naive at 240 mg patients i.e. T9, T10and T12, no interim analysis 
will be done).
Extend recruitment of up to 30 patients in each tumor type according to IA outcome [P(clinically meaningful) > 
20%].
a. Ansell et al (2009) b. Kunk et al (2016) c. Fuereder (2016) d. Rosenberg et al (2016).
e. Motzer et al (2015) f. Le et al (2015) g. Goodman (2015) h. Hodi et al (2016). i. Bendell et al (2019)
Part 2:
Different schedules of NIR178 in combination with PDR001 in NSCLC will be evaluated by 
using the efficacy, safety and tolerability data. For details of safety analysis, please refer to 
Section 10.5.2.
Primary endpoint for efficacy analysis is ORR. The analysis is described as follows:
Overall response rate (ORR) will be provided for each schedule along with corresponding 90% 
confidence interval (CI). The prior distribution of ORR will be a minimally informative 
unimodal beta distribution with parameter a = 1/3 and b = 1 (note: this assumes a priori response 
rate of 25%). Posterior summaries for ORR (including 90% credible intervals and probability 
of ORR to fall in the activity interval defined below) will be provided.
[0, 20%): No improvement of ORR
[20%, 33%): Limited improvement of ORR
[33%, 100%]: Clinically meaningful improvement of ORR
The difference between the ORR in different schedules will be summarized.


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For Part 2 of the study, the probability that one schedule is greater than another schedule given 
the data will be provided, i.e.
i.
Posterior probability that ORR for schedule 1 is greater than schedule 2
ii.
Posterior probability that ORR for schedule 2 is greater than schedule 3.
iii.
Posterior probability that ORR for schedule 1 is greater than schedule 3.
In addition, posterior probability that ORR for one schedule is greater than the other two 
schedules will also be provided.
The posterior mean of the differences of ORR between the schedules and the corresponding 
90% credible intervals will also be provided.
Part 3:
As of protocol amendment 6, Part 3 will explore the safety, efficacy and pharmacokinetics of 
the FCT formulation of NIR178 continuous dosing in combination with PDR001. TNBC is one 
of the selected tumor groups in Part 3. However, the TNBC patients in Part 3 will be analyzed 
by treatment group, separately from Part 1 TNBC patients since the inclusion/exclusion criteria 
are different and the patients in Part 3 will receive FCT formulation. ORR data will be analyzed 
similarly as done for Part 1. The efficacy intervals for the TNBC group will be the same as 
reported in Table 10-1 for the TNBC group. A second tumor group may be considered for Part 
3 after completion of Part 1.   
ORR will be provided for TNBC in Part 3 along with corresponding 90% confidence interval 
(CI). The prior distribution of ORR will be a minimally informative unimodal beta distribution 
with parameter a = 0.176 and b = 1 (note: this assumes a priori response rate of 15%). Posterior 
summaries for ORR (including 90% credible intervals and probability of ORR to fall in the 
activity interval defined below) will be provided.
[0, 5%): No improvement of ORR
[5%, 13%): Limited improvement of ORR
[13%, 100%]: Clinically meaningful improvement of ORR
10.4.3
Handling of missing values/censoring/ discontinuations
At final analysis, confirmed partial or complete responses reported prior to any additional 
anticancer therapy will be considered as responses in the calculation of ORR irrespective of the 
number of missed assessments before response.
At interim analyses, patients are considered to be evaluable if they are ongoing with study 
treatment and have at least one post-baseline response assessment, or who have discontinued 
study treatment. This total will be used for percentage calculation of ORR. For the purpose of 
the IA, if a patient is still on study and the last available efficacy assessment is a PR/CR which 
is yet to be confirmed by a subsequent scan, then this patient will be considered as a responder.
For solid tumor, patients with a best overall response of ‘Unknown’ or ‘Not Assessed’ per 
RECIST v1.1 will be considered as non-responders and will be included in the denominator in 
estimating the ORR. For lymphoma, patients with unknown or missing response or who are 


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treated in the study but provide no information on response at the end of treatment will be 
treated as non-responders and will be included in the denominator when calculating ORR.
 
10.5
Secondary objectives
10.5.1
Efficacy objectives
The secondary objective is to assess the efficacy of NIR178 in combination of PDR001 with 
respect to ORR (using iRECIST), disease control rate (DCR), duration of response (DOR), 
progression free survival (PFS) and overall survival (OS) by RECIST v1.1 and iRECIST (for 
solid tumors), also as per PCWG3 guidance (Appendix 5) for mCRPC, and Cheson et al (2014)
(for DLBCL).
ORR: Overall response rate (ORR) as per iRECIST will be provided for each tumor type along 
with corresponding 90% confidence interval (CI).
DCR: DCR will be summarized by tumor type with accompanying 95% confidence intervals.
DOR, PFS and OS: DOR, PFS and OS will be presented descriptively using Kaplan-Meier 
plots by tumor types and treatment groups. In addition, the median DOR and corresponding 90% 
confidence interval will be presented. PFS and OS distributions will be summarized by tumor 
type presenting the median PFS and OS time with accompanying 90% confidence intervals 
along with Kaplan-Meier estimates for PFS and OS at 4, 6, 9, 12, 18 and 24 months. More 
details will be provided in the SAP.
For mCRPC patients, PSA at each time-point will be listed and change from baseline in PSA
may be plotted and summarized if there are sufficient patients. More details will be provided in 
the SAP.  
All efficacy data from the patients from Japanese safety run-in part will be listed separately. 
These patients will not be summarized with the other patients.
All efficacy data from the non-HNSCC patients and IO naive melanoma patients will be listed 
separately and will not be summarized with the other patients. All efficacy data from patients 
with unknown RAS status will be summarized as a separate group with all other patients if there 
are enough patients. Otherwise the efficacy data will be listed.


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10.5.2
Safety objectives
10.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group and tumor types.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study treatment
2. On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study treatment
3. Post-treatment period: starting at day 31 after last dose of study treatment.
Safety summaries will primarily be based on all data from the on-treatment period.
Following last administration of study treatment, adverse events (including serious adverse 
events), and new antineoplastic therapies are collected for a period of 150 days. Following start 
of new antineoplastic therapy only treatment related adverse events will be collected. Select 
summaries of related adverse events will be produced for the combined on-treatment and post-
treatment periods (see Section 10.5.2.2).
10.5.2.2 Adverse events (AEs)
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. Additional select summaries will be 
produced using all related AEs that started or worsened during the combined on-treatment and 
post-treatment periods.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by tumor type and treatment group.
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
All safety data from the patients from Japanese safety run-in part will be summarized separately. 
More details will be provided in the SAP.
10.5.2.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per CTCAE version 4.03.
The calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.


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For laboratory tests where grades are not defined by CTCAE 4.03, 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 4.03 
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE 4.03:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE 4.03 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE 4.03:

Shift tables using the low/normal/high/ (low and high)

Classification to compare baseline to the worst on-treatment value.
10.5.2.4 Other safety data
ECG

Shift table baseline to worst on-treatment result for overall assessments

Listing of ECG evaluations for all patients with at least one abnormality
Vital signs
Definitions of notably abnormal results will be specified in the SAP.

Shift table baseline to worst on-treatment result
10.5.2.5 Supportive analyses for secondary objectives
Any supportive analyses that are considered appropriate for secondary variables will be 
described in the SAP prior to database lock (DBL).
10.5.2.6 Tolerability
Tolerability of study drug treatment will be assessed by summarizing the number of treatment 
dose interruptions and dose reductions. Reasons for dose interruption and dose reductions will 
be listed by patient and summarized.
 
10.5.3.1 Outline of the data analysis
As a project standard, the data collected from tumor samples in the clinical database will be 
analyzed by a Novartis designated laboratory and Novartis Oncology study team.


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If the number of samples is inadequate to perform a rigorous data analysis, then only the 
available data will be listed. Additional analyses that may be performed after the completion of 
the end-of-study clinical study report will be documented in separate reports. Any additional 
data analysis will be described in an addendum of the RAP or in a stand-alone analysis plan 
document, as appropriate.
10.5.3.2 Data handling principles
All measurements below their respective Lower Limit of Quantification (LLOQ) or missing 
data will be labeled as such in the concentration data listings. Measurements below the LLOQ 
will be treated as zero in summary statistics. Change from baseline analyses will only be 
performed on patients with measurable samples and pre- and post-treatment time points.
10.5.3.3 Data analysis principles
10.5.3.3.1
Analysis sets
Patients with measureable tumor samples will be identified in the summaries and relevant 
proportion will be calculated against this number of patients.
 
10.5.3.3.3
Advanced analysis methods
Any methods that may be used will be described in the SAP.
10.5.4
Pharmacokinetics
All patients who have evaluable PK data will be included in the PK data analysis. PK parameters 
will be determined using non-compartmental method(s) for NIR178 and its metabolite and 
PDR001. PK parameters such as those listed in Table 10-2 will be estimated and reported, when 
applicable.


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Table 10-2
Noncompartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x 
volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-
1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration after 
single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic concentration-
time curve (time). Use qualifier for other half-lives
CL/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with z) (volume)
10.5.4.1 Data handling principles
Only PK blood samples with the date and time and for which the last prior dose dates and times 
are adequately recorded will be included in the PK analyses. Missing concentration values will 
be reported as is in data listings. Concentration values below Lower limit of quantitation 
(LLOQ) will be handled as zero in summary statistics, and reported as is in data listings. 
Any missing pharmacokinetic parameter data will not be imputed.
10.5.4.1.1
Basic tables, figures and listings
Descriptive statistics (mean, standard deviation, CV% or median (range)) will be presented for 
all parameters by analyte, tumor types and treatment groups and study cycle/day. When a 
geometric mean is presented, it will be stated as such. Zero concentrations will not be included 
in the geometric mean calculation. Since Tmax is generally evaluated by a nonparametric 
method, median values and ranges will be presented for this parameter. For NJI765, CL/F, Vz/F 
and elimination half-life will not be reported.
PK data for Japanese safety run-in part will be reported separately.
10.5.5
Resource utilization
Not applicable.


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10.5.6
Patient-reported outcomes
Not applicable.
10.7
Interim analysis
Part 1:
Patients will be continuously accrued and the data will be analyzed using a Bayesian 
hierarchical model mentioned in Section 10.4.2. Interim analysis for a tumor type will be 
performed when at least 10 patients which have been enrolled for that tumor type at the same 
dose level have at least one post-baseline disease assessment, except for MSS-CRC RAS 
wildtype, MSS-CRC RAS mutant and RCC IO naive at 240 mg patients, in which no interim 
analysis will be done. The futility analysis will not be binding. At each of these analyses, the 
current (posterior) probability that the response rate for each of the tumor types is greater than 
“clinically meaningful threshold (column for C2 in Table 10-1)” will be determined.
These probabilities will be used to adapt the design. All available data for evaluable patients 
(defined in Section 10.4.3) will be used for analysis at each interim analysis. However, a 
decision will be made for all tumor types with minimum of 10 patients (who have at least one 
post-baseline assessment). For a specific tumor type, a decision will be made based on the 
calculated probability as given below:
1. Accrual to a tumor type (with minimum sample size requirement described above) will 
cease for futility if it is very unlikely (posterior probability <20%) that the response rate 
for the tumor type is “clinically meaningful” (≥C2 threshold in Table 10-1)
2. Otherwise, recruitment will continue until the next IA is performed or a maximum of 30 
patients in that tumor type has been enrolled.
For the purpose of the IA, if a patient is still on study and the last available efficacy assessment 
is a PR/CR which is yet to be confirmed by a subsequent scan, then this patient will be 
considered as a responder.


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The results at the final analysis within a tumor type will be regarded as positive if the posterior 
mean ORR is greater than the threshold for clinically relevant activity and the posterior 
probability of not being clinically meaningful is low (less than 10%).
Depending on enrollment, there may be multiple interim analyses.
Japanese safety run-in part
No formal interim analyses are planned. However, the dose-escalation design for safety run-in 
part foresees that decisions based on the current data are taken before the end of the planned 
safety run-in part. Details of this procedure and the process for communication with 
Investigators are provided in Section 4.1.4.
10.8
Sample size calculation
Part 1:
The design of this part is adaptive in nature; hence, the final sample size is not fixed. 
A minimum of 10 evaluable patients and a maximum of 30 treated patients in each tumor type 
T1 through T13 will receive treatment. Thus, the total sample size across all tumor types will 
be between 130 and 310.
Patients will be continuously accrued, and, the accumulated data will be analyzed at interim as 
described in Section 10.7. Based upon the results of any of these analyses, enrollment into one 
or more tumor types may be terminated.
The operating characteristics for this Bayesian Design are evaluated using simulation. 
Simulation-based probability estimates (relative frequencies) of futility at interim and positive 
results at final analysis for each tumor type in four scenarios (see Table 14-12) are provided in 
Appendix 4. The number of simulations generated for each scenario is 1000. For additional 
details, please see Appendix 4. Presented below is a summary of the operating characteristics
based on eight tumor types included in the initial protocol design prior to interim analysis:
Table 14-13 (Scenario 1) presents the operating characteristics of the design when the true 
underlying ORR of none the eight tumor types is clinically meaningful (in other words, null 
case for all tumor types). The false positive rate (for final analysis) for each of the tumor types 
are appropriately controlled, ranging between 2.6% and 6.8%. Similarly, the chances of 
stopping for futility at IA are high, ranging from 45.8% to 69.7%.
Table 14-14 presents the operating characteristics for two scenarios (2a and 2b):

Scenario 2a presents the operating characteristics when the true underlying ORR of all the 
eight tumor types is clinically meaningful (in other words, alternative case for all tumor 
types). The probability of positive conclusion (for final analysis) for each of the tumor 
types are appropriately high, ranging between 78.2% and 90.7%. Similarly, the chances of 
stopping for futility at IA are low, ranging between 3% and 11.9%.

Scenario 2b, in contrast to Scenario 2a, presents the case where, out of all eight tumor 
types there is one single tumor type (T4-Bladder) which does not have clinically 
meaningful ORR while all other seven tumor types have clinically meaningful ORR. 
However, the model adapts appropriately and the false positive rate (1.1%) for T4 is 


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effectively controlled. For the rest seven tumor types which have clinically meaningful 
ORR (same as Scenario 2a), the probability of positive conclusion has slightly changed 
(vs Scenario 2a) but remained acceptably high (ranging between 79.6% and 88.7%).
Table 14-15 (Scenario 3) presents the operating characteristics when four tumor types have 
clinically meaningful ORR while the other four do not have clinically meaningful ORR. In this 
scenario as well, the false positive rates for the inactive tumor types are properly controlled 
(4.9% - 6.9%) while the probability of positive conclusion for the active tumor types are high
(78.2% - 86.6%).
Similar operating characteristics are expected based on the thirteen tumor groups.
Part 2:
At least 20 patients will be enrolled in each of the dosing schedules. Table 10-3 shows the 
posterior mean and corresponding 90% credible interval for N = 20 (since it is planned to have 
approximately 20 patients in each schedule) for various observed ORR using a minimally 
informative unimodal beta prior distribution with parameters a = 1/3 and b = 1 (note: this 
assumes a priori response rate of 25%). This is same for all dosing schedules.
Table 10-3
Posterior summaries for given number of responses (ORR)
Observed 
ORR 
(N, %)
Posterior mean 
(90% credible 
interval)
Probability of no 
improvement
[0% - 20%)
Probability of 
limited 
improvement
[20% - 33%)
Probability of clinically 
meaningful 
improvement
[33%-100%]
0 (0%)
0.016 (0.00,0.070)
0.999
0.001
0.000
3 (15%)
0.156 (0.051, 0.299)
0.744
0.228
0.028
4 (20%)
0.203 (0.081, 0.356)
0.534
0.385
0.080
5 (25%)
0.250 (0.115, 0.414)
0.316
0.498
0.185
10 (50%)
0.484 (0.311, 0.657)
0.002
0.070
0.928
15 (75%)
0.718 (0.548, 0.863)
0
0
1
20 (100%)
0.954 (0.866,0.997)
0
0
1
From Table 10-3, with a sample size of 20 patients, if the observed ORR is 25%, the probability 
of true ORR to be at least 33% is 18.5%. If the observed ORR is 50%, the probability of true 
ORR to be at least 33% is 92.8%. Also, with a sample size of 20, if the observed ORR is 15%, 
the probability of true ORR to be less than 20% is 74.4%.
Table 10-4 shows the posterior probability that ORR for schedule 1 (S1) is greater than ORR 
for schedule 2 (S2) for various observed ORR using a minimally informative unimodal beta 
prior distribution with parameters a = 1/3 and b = 1. Similar approach can be used to compare 
schedule 2 to schedule 3 and schedule 1 to schedule 3.


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Table 10-4
Posterior probability that schedule 1 (S1) has higher ORR than 
schedule 2 (S2)
Observed ORR 
in S1 (N, %)
Observed ORR in 
S2 (N, %)
Posterior mean of the 
difference (90% credible 
intervals)
Probability that ORR in S1 is 
greater than ORR in S2 given 
data
3 (15%)
0 (0%)
0.141 (0.027, 0.287)
0.981
4 (20%)
3 (15%)
0.046 (-0.142, 0.236)
0.660
5 (25%)
4 (20%)
0.047 (-0.160, 0.254)
0.646
5 (25%)
5 (25%)
0.000 (-0.213, 0.212)
0.499
10 (50%)
5 (25%)
0.234 (-0.001, 0.459)
0.949
10 (50%)
8 (40%)
0.095 (-0.152, 0.336)
0.740
15 (75%)
10 (50%)
0.235 (-0.003, 0.463)
0.948
15 (75%)
12 (60%)
0.140 (-0.094, 0.371)
0.839
20 (100%)
15 (75%)
0.235 (0.071, 0.414)
0.990
From Table 10-4, with a sample size of 20 patients in each schedule, the posterior probability 
that ORR in S1 is greater than ORR in S2 is 50% if the difference between observed ORR in 
the two schedules is 0% respectively. However, if the difference between observed ORR in S1 
and S2 is 5% respectively, the posterior probability that ORR in S1 is greater than ORR in S2 
is approximately 65.0%. If the difference between observed ORR in S1 and S2 is 25% 
respectively, the posterior probability that ORR in S1 is greater than ORR in S2 is 
approximately 95.0%.
Table 10-5
Posterior probability that schedule 1 (S1) has higher ORR than both 
schedule 2 (S2) and schedule 3 (S3)
Observed ORR 
in S1 (N, %)
Observed ORR in 
S2 (N, %)
Observed ORR in S3 (N, %)
Probability that ORR in S1 is 
greater than ORR in S2 and S3 
given data
3 (15%)
0 (0%)
0 (0%)
0.963
4 (20%)
3 (15%)
3 (15%)
0.509
5 (25%)
4 (20%)
3 (15%)
0.568
5 (25%)
5 (25%)
5 (25%)
0.335
10 (50%)
5 (25%)
5 (25%)
0.911
10 (50%)
8 (40%)
5 (25%)
0.719
15 (75%)
10 (50%)
10 (50%)
0.906
15 (75%)
12 (60%)
10 (50%)
0.814
20 (100%)
15 (75%)
12 (60%)
0.990
From Table 10-5, with a sample size of 20 patients in each schedule, the posterior probability 
that ORR in S1 is greater than ORR in both S2 and S3 is 33.5% if the difference between 
observed ORR in the three schedules is 0% respectively. However, if the observed ORR in S1, 
S2 and S3 are 10%, 8% and 5% respectively, the posterior probability that ORR in S1 is greater 
than ORR in both S2 and S3 is 71.9%.


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Part 3:
If initiated, 20 patients will be enrolled in each of the one or two tumor groups (max two) 
selected based on emerging data from Part 1 and Part 2. For the one or two tumor groups 
selected in Part 3, appropriate intervals will be defined and specified before any reporting 
activity in the statistical analysis plan. Novartis may decide to not open Part 3 for enrollment 
based on emerging data from Part 1 and Part 2.
As of protocol amendment 6, 20-30 patients will enroll in TNBC tumor group using NIR178 
continuous dosing schedule in combination with PDR001. A second tumor group may be 
considered for Part 3 after completion of Part 1, see Section 4.1.3.
A sample size of 10 patients treated at 160 mg BID FCT NIR178 in combination with PDR001
in TNBC tumor group in Part 3 provides a high probability, 77%, of observing 0 or 1 adverse 
event when the true incidence rate is 9%. (Table 10-6).
Table 10-6
Probability of detecting adverse events with specified incidence rate
based on N=10 patients 
Number of adverse 
events
AE incidence rate
0.05
0.09
0.12
0.15
0 or 1
0.91
0.77
0.66
0.54
2 or 3
0.09
0.22
0.32
0.41
>3
0.00
0.01
0.02
0.05
Regarding the efficacy of part 3, Table 10-7 shows the posterior mean and corresponding 95% 
credible interval for N=20 for various observed ORR rates using a minimally informative 
unimodal beta prior distribution with parameters a=0.176 and b=1 for TNBC patients (Note: 
this assumes a priori response rate of 15%). From Table 10-7, with a sample size of 20 patients, 
if the observed ORR rate is 15%, the probability of true ORR rate for TNBC patients to be at 
least 13% is 54.8%
Table 10-7
Posterior mean and 95% credible intervals for given ORR rates
ORR
(N, %)
Posterior mean 
(95% credible 
interval)
Probability of no 
improvement
[0% - 5%]
Probability of 
limited 
improvement
(5%-13%)
Probability of clinically 
meaningful 
improvement
[13%-100%]
0(0%)
0.008 (0.00,0.066)
0.958
0.038
0.004
2 (10%)
0.103 (0.015, 0.259)
0.220
0.495
0.285
3 (15%)
0.150 (0.036, 0.326)
0.060
0.392
0.548
4 (20%)
0.197 (0.062, 0.386)
0.012
0.217
0.771
5 (25%)
0.244 (0.091, 0.443)
0.002
0.092
0.906
10 (50%)
0.481 (0.277, 0.688)
0.000
0.000
1.000


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Japanese safety run-in part
The period for evaluating DLTs will be cycle 1 (i.e. the first 28 days of treatment with single 
agent NIR178 or in combination with PDR001). The safety run-in will evaluate three NIR178 
dose levels sequentially. Each dose level may consist of 3 to 6 newly enrolled patients who have 
tumor histologies specified in Section 5, and meet all other inclusion/exclusion criteria. The 
dose escalation is detailed in Section 4.1.4.
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.


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Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
During the COVID-19 pandemic that may challenge the ability to obtain a standard written 
informed consent due to limits that prevent an on-site visit, the Investigator may conduct the 
informed consent discussion remotely (e.g. telephone, videoconference). 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.).
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov before study start. In 
addition, results of interventional clinical trials in adult patients are posted
on
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 
of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to novartis.com.


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11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.


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


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14
Appendices
14.1
Appendix 1: Concomitant medications
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or NIR178 and/or PDR001.
The following lists are not comprehensive and are only meant to be used as a guide. The lists 
are based on the Oncology Clinical Pharmacology guidance, Drug-Drug Interaction and Co-
Medication Considerations (v07, release date: 2018), which was compiled from the Indiana 
University 
School 
of 
Medicine’s 
P450 
Drug 
Interaction 
Table 
(/medicine.iupui.edu/clinpharm/ddis/main-table/) and supplemented with the FDA Draft 
Guidance for Industry, Drug Interaction Studies – Study Design, Data Analysis, and 
Implications 
for 
Dosing 
and 
Labeling 
(October 
2017) 
(/fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.
pdf), and the University of Washington’s Drug Interaction Database (druginteractioninfo.org/). 
For current lists of medications that may cause QT prolongation, refer to the CredibleMeds®
website (crediblemeds.org/). Please contact the Novartis medical monitor with any questions.


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Table 14-1
List of prohibited medications
Category
Drug Names
Strong inhibitors of CYP1A2
Ciprofloxacin (also known risk of TdP/QT prolongation), clinafloxacin, 
enoxacin, fluvoxamine, rofecoxib, Zafirlukast, Angelicae dahuricae radix 
extract (Angelica dahurica)
Moderate inducers of CYP1A2
montelukast, phenytoin, cigarette smoking, rifampin, eriflunomide, 
ritonavir, Cannabis sativa smoking
Substrates of CYP1A2 with narrow 
therapeutic index
theophylline, tizanidine (also sensitive substrate)
Sensitive substrates of CYP1A2
alosetron, duloxetine, melatonin, pirfenidone, ramelteon, selegiline, 
tacrine, tasimelteon, tizanidine
Drugs with known TdP risk/QT 
prolongation
Aclarubicin (not on US mkt), amiodarone, anagrelide, arsenic trioxide, 
astemizole (off US mkt), azithromycin, bepridil (off US mkt), chloroquine, 
chlorpromazine, cilostazol, cisapride (off US mkt), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not on 
US mkt), donepezil, dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, fluconazole, gatifloxacin (off mkt in North 
America), grepafloxacin (off market worldwide), halofantrine, 
haloperidol, ibogaine (not on US mkt), ibutilide, levofloxacin, ,
levomepromazine (methotrimeprazine [not on US mkt]), levomethadyl 
(off mkt worldwide), levosulpiride (not on US mkt), mesoridazine (off mkt 
worldwide), methadone, moxifloxacin, ondansetron, oxaliplatin, 
papaverine HCl, pentamidine, pimozide, probucol (off mkt worldwide), 
procainamide (oral off US mkt), propofol, quinidine, roxithromycin (not 
on US mkt), sevoflurane, sotalol, sparfloxacin (off US mkt), sulpiride (not 
on US mkt), sultopride (not on US mkt), terfenadine (off US mkt),
terlipressin (not on US mkt), terodiline (not on US mkt), thioridazine, 
vandetanib
Table 14-2
List of medications to be used with caution
Category
Drug Names
Moderate inhibitors of CYP1A2
3,4-methylene-dioxymethamphetamine (MDMA), idrocilamide, 
methoxsalen (8-methoxypsoralen), mexiletine, oral contraceptives, 
phenylpropanolamine, pipemidic acid, propafenone, propranolol, 
troleandomycin, vemurafenib, genistein
Weak inhibitors of CYP1A2
Acyclovir,allopurinol, antofloxacin, artemisinin, caffeine (and caffeine 
containing products (also sensitive substrate of CYP1A2), cimetidinem 
curcuminm daidzein, deferasirox, disulfiram, echinacea (Echinacea 
purpurea), famotidine, grapefruit juice, grepafloxacin, hormone 
replacement therapy, interferon alpha, interferon beta, norfloxacin, 
pefloxacin, peginterferon alpha-2a, simeprevir, sirukumab, terbinafine, 
thiabendazole, ticlopidine, verapamil, viloxazine, zileuton Seijo-bofu-to, 
genistein
Substrates of BCRP
Atorvastatin, daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, mitoxantrone, paritaprevir, pitavastatin, 
rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, sofosbuvir, 
sulfasalazine, tenofovir, topotecan, venetoclax


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14.2
Appendix 2: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free and Overall Survival 
(based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Document type:
TA Specific Guideline
Document status:
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
List of Contributors
Authors (Version 3.1):
 
Authors (Version 3):
 
 
Authors (Version 2):
 
Authors (Version 1):


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


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14.2.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.2.2 and the definition of best response in 
Section 14.2.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.2.18 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.2.28 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.
14.2.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
14.2.3
Definitions
14.2.4
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.2.26.
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.


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
Cystic lesions:

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques.
14.2.5
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 14.2.26.
14.2.6
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to 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 anti-tumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.


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


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
Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.2.7
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.2.4.

Nodal target: See Section 14.2.4.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.


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14.2.8
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated 
(at baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-3) and non-target lesions (Table 14-4) identified at baseline. 
These evaluations are then used to calculate the overall lesion response considering both the 
target and non-target lesions together (Table 14-5) as well as the presence or absence of new 
lesions.
14.2.9
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.
14.2.10
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.
14.2.11
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement. This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.


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However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
14.2.12
Determination of target lesion response
Table 14-3
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to 
< 10 mm.1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded 
at or after baseline. In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.2
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have 
not been assessed or have been assessed using a different method than 
baseline.3
1 SOD for CR may not be zero when nodal lesions are part of target lesions
2 Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all 
nodal lesions are <10 mm in size. In this case, the target lesion response is CR
3 Methodology change See Section 14.2.6.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following three 
possibilities:

The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 14-3 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.


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


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14.2.13
Determination of non-target lesion response
Table 14-4
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a 
non-target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have 
not been assessed or have been assessed using a different method than 
baseline.
1 Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of 
the treating physician does prevail and the progression status should be confirmed later on by the review panel 
(or study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of treatment. treatment A modest 
“increase” in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the 
basis of change in non-target disease in the face of CR, PR or SD of target disease is 
therefore expected to be rare. In order for a PD to be assigned on the basis of non-target 
lesions, the increase in the extent of the disease must be substantial even in cases where 
there is no measurable disease at baseline. If there is unequivocal progression of non-
target lesion(s), then at least one of the non-target lesions must be assigned a status of 
“Worsened”. Where possible, similar rules to those described in Section 14.2.12 for 
assigning PD following a CR for the non-target lesion response in the presence of non-
target lesions nodal lesions should be applied.


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14.2.14
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF.

If a new lesion is equivocal, for example because of its small size, continued treatment 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the date 
of the first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where 
the particular baseline scan is not available for some reason, then this should be 
considered as a PD. The one exception to this is when there are no baseline scans at 
all available for a patient in which case the response should be UNK, as for any of 
this patient's assessment (see Section 14.2.15).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.2.6.
14.2.15
Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in
Table 14-5.
Table 14-5
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 14.2.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).


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If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall response must be ‘unknown’ unless progression was seen. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.2.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.2.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.2.17
Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer treatment 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 treatment 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.


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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)
Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.


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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.
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).


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14.2.18
Time to event variables
14.2.19
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.2.20
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
14.2.21
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.
14.2.22
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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14.2.23
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.
14.2.24
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 14.2.23. It is recommended that an 
analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.2.25
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.
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 14.2.26).
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 treatment is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.2.26
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 measurable 
disease is derived slightly differently according to Table 14-6.


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Table 14-6
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.2.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
14.2.27
Sensitivity analysis
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 SAP 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 14.2.25, 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 14-7
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 SAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP 
and 
duration of 
response)
1. =Definitions can be found in Section 14.2.25.
2. =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.2.25.
3. =The rare exception to this is if the patient dies no later than the time of the second scheduled assessment 
as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 


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of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-7 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or SAP documentation.
14.2.28
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.2.29
Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
SAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the SAP 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 SAP 
documentation before database lock).
14.2.30
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 14 days of the last 
study treatment.


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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

Death

Progressive disease

Study terminated by Novartis

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)
14.2.31
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

New therapy for study indication

Progressive disease

Study terminated by Novartis
14.2.32
Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, data 
review reports will be available to identify assessments for which the investigators’ or central 


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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 
SAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.2.33
Programming rules
The following should be used for programming of efficacy results:
14.2.34
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.2.35
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.2.25). If all measurement dates have no 
day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.2.36
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.
14.2.37
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)’.


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14.2.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.2.39
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-7)

Death due to reason other than underlying cancer

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.2.25. 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.


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14.2.40
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 E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47.
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18.
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.


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14.3
Appendix 3: iRECIST Guidelines for response in trials testing 
immunotherapeutics
14.3.1
Introduction
This appendix outlines the definitions and rules for response assessment in cancer 
immunotherapy trials (iRECIST) following the guideline developed by the RECIST working 
group using modified RECIST 1.1 (Seymour 2017, EORTC website).
Immunotherapeutics may result in infiltration of immune cells leading to transient increase in 
the 
size 
of 
malignant 
lesions, 
or 
undetectable 
lesions 
becoming 
detectable
(‘pseudoprogression’). The iRECIST criteria are identical to RECIST 1.1 in many respects but 
have been adapted to account for instances where an increase in tumor burden, or the appearance 
of new lesions, does not reflect true tumor progression.
14.3.1.1 Terminology
All responses defined using iRECIST criteria are designated with the prefix ‘i’ in order to 
differentiate them from responses assigned using RECIST 1.1. Additionally, an overall 
response of progression may be unconfirmed (iUPD) or subsequently confirmed (iCPD). New 
lesions are evaluated and subcategorized into those that qualify as target lesions (New Lesion 
Target; NLT), while all others are referred to as non-target (New Lesion Non-Target; NLNT).
14.3.1.2 iRECIST
RECIST 1.1 (Appendix 14.2) should be followed to define whether tumor lesions, including 
lymph nodes, are measurable or non-measurable; for the management of bone lesions, cystic 
lesions and lesions with prior local treatment (such as radiation); for the handling of lesions that 
become too small to measure, split or coalesce; and for recommendations regarding the method 
of measurement.
The principles used to determine objective tumor response are largely unchanged from RECIST 
1.1, while a major change of iRECIST is the concept of ‘resetting the bar’ if RECIST 1.1 
progression is followed at the next assessment by tumor shrinkage.


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14.3.2
iRECIST response assessment
14.3.2.1 Confirming progression
iRECIST defines iUPD (i.e. unconfirmed progression) based on RECIST 1.1 principles. 
However, unlike RECIST 1.1, iRECIST requires the confirmation of progression (iCPD). 
Confirmatory scans should be performed at least 4 weeks, but no longer than 8 weeks after 
iUPD.
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is 
evident by one or more of the following:

Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, non-target disease or new lesions

Progression in target disease worsens with an increase of at least 5 mm in the absolute 
value of the sum

Continued unequivocal progression in non-target disease with an increase in tumor 
burden

Increase in size of previously identified new lesion (s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions.

RECIST 1.1 criteria are met in lesion types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new 
lesions.
14.3.2.2 Assessments following unconfirmed progression (iUPD)
If iUPD is not confirmed at the next assessment, but instead tumor shrinkage (compared to 
baseline) occurs then an overall response of iCR, iPR or iSD may be assigned as appropriate. 
Note that new lesions do not need to resolve for iSD or iPR to follow iUPD, provided an increase 
in size or number of new lesions does not lead to iCPD.
Following iCR, iPR, or iSD the bar is reset so that iUPD must occur again (compared to nadir 
values) and then be confirmed (by further growth) at the next assessment for iCPD (confirmed 
progression) to be assigned.
If there is no change in tumor size/extent from iUPD, then the response assessment would again 
be iUPD.
As can be seen in Table 14-8, the prior documentation of iUPD does not preclude assigning 
iCR, iPR, or iSD in subsequent assessments providing that iCPD is not documented at the next 
assessment after iUPD. This approach allows atypical responses, such as delayed responses that 
occur after pseudoprogression, to be identified, further understood and better characterized.


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14.3.2.3 New lesions
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria, and 
recorded as New Lesions-Target (NLT) or New Lesion-Non-Target (NLNT) to allow clear 
differentiation from baseline target and non-target lesions. A maximum of 5 NLT may be 
recorded, no more than 2 per organ, at least 10 mm in long axis (or 15 mm in short axis for 
nodal lesions).
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, 
the measurements of NLTs should not be included in the sum of measures (SOM) of original 
target lesions identified at baseline. These measurements will be collected on a separate case 
report form (CRF).
14.3.2.4 Confirming response
As for RECIST 1.1, responses (iCR or iPR) should also be confirmed under iRECIST by a 
repeat assessment not less than 4 weeks after the criteria for response are first met. Should an 
unconfirmed response be followed by an assessment of iUPD, then the response will remain as 
unconfirmed, and any subsequent return to response will again require confirmation. For 
example, a patient is assessed as iPR, and is subsequently assessed as iUPD then iPR again. 
This would not be considered as confirmed iPR unless the second occurrence of iPR is 
confirmed (e.g., sequence of assessments: iPR-iUPD-iPR-iPR; date of confirmed PR would be 
the date of the third of these assessments).


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14.3.2.5 Examples of iResponse assignation
Table 14-8
Time Point (TP) iResponse
Target 
Lesions*
Non-Target
Lesions*
New 
Lesions*
Time Point Response
No 
prior 
iUPD*
Prior iUPD**; ***
iCR
iCR
No
iCR
iCR
iCR
Non-iCR/ Non-
iPD
No
iPR
iPR
iPR
Non-iCR/ Non-
iUPD
No
iPR
iPR
iSD
Non-iCR/ Non-
iUPD
No
iSD
iSD
iUPD with 
no change 
OR 
decrease 
from last 
TP
iUPD with no 
change OR 
decrease from 
last TP
Yes
NA
NLs confirms iCPD if NLs were previously 
identified and increase in size (≥5mm in SOM for 
NLT or any increase for NLNT) or number. If no 
change in NLs (size or number) from last TP, 
remains iUPD.
iSD, iPR, 
iCR
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based on 
further increase in size of NT disease (need not 
meet RECIST 1.1 criteria for unequivocal PD)
iUPD
Non-iCR/Non-
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based on 
further increase in SOM of at least 5mm
iUPD
iUPD
No
iUPD
Remains iUPD unless iCPD confirmed based on 
further increase in:

Previously identified T lesion iUPD SOM 
≥5mm and/or

NT lesion iUPD (prior assessment – need 
not be unequivocal progression)
iUPD
iUPD
Yes
iUPD
Remains iUPD unless iCPD confirmed based on 
further increase in:

Previously identified T lesions iUPD ≥5mm 
and/or

Previously identified NT lesion iUPD (need 
not be unequivocal) and/or

Size or number of new lesions previously 
identified
Non-
iUPD/PD
Non-iUPD/PD
Yes
iUPD
Remains iUPD unless iCPD confirmed based on

Increase in size or number of new lesions 
previously identified
* Using RECIST 1.1 principles. If no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for CR, 
PR and SD would be the same.
** in any lesion category.
*** identified in the assessment immediately prior to this assessment.
14.3.3
References (available upon request)
Seymour L, Bogaerts J, Perrone A (2017) iRECIST: guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet Oncol; 18:e143-e152.


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14.4
Appendix 4: Details of statistical methodology
This section provides the details of model stated in Section 10.4.2 for Part 1 of the study. Prior 
specifications of model parameters are provided in details. Data analysis and decision making 
in real trial are illustrated using some hypothetical data scenarios. Further operating 
characteristics by simulation are provided in Section 10.8 as part of sample size justification.
Section 14.4.1 to Section 14.4.3 are part of the original protocol with 8 tumor groups. 
Section 14.4.4 has been added to consider new groups (MSS CRC RAS wildtype, MSS CRC
RAS mutant and HNSCC pretreated). Moreover, Section 14.4.5 has been added at the time of
the amendment 5 when two more tumor groups have been included in the study (i.e. RCC IO 
pretreated at 240mg and mCRPC at 240mg). Prior specification of model parameters in 
Section 14.4.1 is applicable to Section 14.4.4. – Section 14.4.5.
14.4.1
Prior specification of model parameters
Bayesian model requires prior specification of parameters. The detailed prior specification of 
µ1, µ2, 1, 2, mw, vw, and pj (j= 1,2,..,8) are described in this section.
14.4.1.1 Prior specification of exchangeability distribution (µ1, µ2, 1 and 2)
Prior for 1 and 2 are assumed to be half-normal distribution with scale 0.25, implying a prior 
95% intervals for 1 and 2 as (0.008, 0.560), which allows for small to substantial between 
strata heterogeneity (see Spiegelhalter et al 2004).
µ1 and µ2 are given normal prior distributions. For first exchangeability distribution µ1, the 
mean of the prior distribution (mµ1) is set to logit(0.15) (or mµ1 = log(3/17)) which corresponds 
to no treatment effect. For second exchangeability distribution µ2, the prior mean (mµ2) was set 
to logit(0.6) (or mµ2 = log(3/2)). This corresponds to a substantial treatment effect. The variance 
parameter (Vµ1 and Vµ2) are derived using the following formula from law of total variance
Vµi = V(θ) - E( ) and V(θ)=1/π + 1/(1- π); π= 0.15, 0.60 and i=1,2
This yields Vµ1 = 7.781 (≈2.7892) and Vµ2 = 4.104 (≈2.0262). This allows a considerable
uncertainty on prior belief of θ.
14.4.1.2 Prior specification for stratified or “non-exchangeability” distributions
(mw and vw)
The strata-specific normal priors for the stratified or “non-exchangeable” case are defined by 
mw and vw were. The prior median for the response probability was set as 10% (no treatment 
effect) i.e., mw = logit(0.1) (or mw = log(1/9)) and the corresponding variance (vw) is set to 9 
(=32) to allow large variability in prior.


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14.4.1.3 Specification of mixture weights (pj)
Finally, for each stratum j, the prior mixture weights pj were chosen as
pj = (0.25, 0.25, 0.50), j=1,…,8.
This means that each stratum has 25% prior probability to belong to the first exchangeability 
distribution (µ1 and 1), 25% probability to belong to the second exchangeability distribution 
(µ2 and 2), and 50% probability to be stratified or non-exchangeable with some (or all) of the 
other strata.
The prior distributions are summarized in Table 14-9, which also shows the prior medians and 
95% credible intervals for the overall response rate (ORR) πj.
Table 14-9
Specifications for model parameters, and prior median (95 percent
credible intervals) for ORR
Parameter
Prior distribution
µ1
N(-1.735, 2.7892)
µ2
N(0.405, 2.0262)
1
Half Normal(scale = 0.25)
2
Half Normal(scale = 0.25)
mj, vj
N(-2.197, 32)
pj = (pj1, pj2, pj3), j = 1,…,8
(0.25, 0.25, 0.5)
14.4.2
Hypothetic scenario testing
It is important to know that the design should make reasonable decisions at interim and final 
analysis based on the observed responses in each tumor type. This section shows on-study 
decisions made under the model. The hypothetical data scenarios for interim and final analysis 
can be found in Table 14-10 and Table 14-11 respectively. For each scenario, the posterior 
probability of being “clinically meaningful” and “not clinically meaningful” (Table 10-1) are 
calculated by tumor type and displayed in the tables.
Table 14-10 shows 9 different scenarios for interim analyses. The scenarios show one or more 
tumor types having 10 patients. It is to be noted that the decision to stop or continue enrollment 
of patients in that tumor type is made only if the number of patients in that tumor type is at least 
10. Otherwise, no decision is made. As stated in Section 10.7 at interim, a tumor type is stopped 
if the probability of being “clinically meaningful” is less than 20%. 
At interim, if tumor type with at least 10 patients does not show any activity (scenarios 1, 2 and 
3) the decision based on model are reasonable. The posterior probabilities of “clinically 
meaningful” are less than 20% for all tumor types in all scenarios for scenario 3 (Column 6 of 
Table 14-11) and hence further enrollment is stopped in all the tumor types. Similarly for 
scenarios 4, 5 and 6 where all tumor types show some clinically meaningful activity the 
proposed decision rule suggests to “continue” for the tumor types which had enrolled 10 patients 
(posterior probability of “clinically meaningful” > 20%). The proposed design also shows 
reasonable decision for mixed scenarios (7, 8 and 9). For example, under scenario 9, data for 
tumor types T2, T3, T5 and T8 show no clinically activity but the rest shows some activity. 
Based on the calculated probability of being clinically meaningful, the design allows correctly 


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stopping (probability < 0.20) for T2, T3, T5 and T8 at the interim while continues for the other 
tumor types.
Table 14-10
Hypothetical data scenarios and decision at interim
Scenario
Tumor
Code
Tumor Type
No of responder/
No of patients
Observed 
ORR
Posterior 
probability 
of clinically 
meaningful
Decision
1
T1
DLBCL
1/10
10%
0.1680
Stop
T2
Pancreatic
0/6
0%
0.1232
-
T3
H&N
2/7
28.57%
0.4122
-
T4
Bladder
1/8
12.5%
0.0837
-
T5
RCC
2/9
22.22%
0.0688
-
T6
Colon (MSS)
1/9
11.11%
0.4495
-
T7
TNBC
0/7
0%
0.1642
-
T8
Melanoma
1/6
16.67%
0.0253
-
2
T1
DLBCL
1/10
10%
0.1385
Stop
T2
Pancreatic
0/9
16%
0.0632
-
T3
H&N
1/7
14.29%
0.1578
-
T4
Bladder
0/8
0%
0.0108
-
T5
RCC
2/10
20%
0.0482
Stop
T6
Colon (MSS)
1/8
12.5%
0.4350
-
T7
TNBC
0/7
0%
0.1432
-
T8
Melanoma
2/10
20%
0.0198
Stop
3
T1
DLBCL
1/10
10%
0.1450
Stop
T2
Pancreatic
0/10
0%
0.0390
Stop
T3
H&N
0/10
0%
0.0098
Stop
T4
Bladder
1/10
10%
0.0565
Stop
T5
RCC
2/10
20%
0.0625
Stop
T6
Colon (MSS)
0/10
0%
0.0688
Stop
T7
TNBC
0/10
0%
0.0802
Stop
T8
Melanoma
3/10
30%
0.1035
Stop
4
T1
DLBCL
3/8
37.5%
0.8792
-
T2
Pancreatic
4/9
44.4%
0.9775
-
T3
H&N
3/7
42.9%
0.8348
-
T4
Bladder
3/10
30.0%
0.5805
Continue
T5
RCC
2/9
22.2%
0.1362
-
T6
Colon (MSS)
1/7
14.3%
0.7045
-
T7
TNBC
1/8
12.5%
0.6548
-
T8
Melanoma
2/8
25.0%
0.0855
-


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Scenario
Tumor
Code
Tumor Type
No of responder/
No of patients
Observed 
ORR
Posterior 
probability 
of clinically 
meaningful
Decision
5
T1
DLBCL
3/8
37.5%
0.9085
-
T2
Pancreatic
4/10
40.0%
0.9785
Continue
T3
H&N
3/7
42.9%
0.8890
-
T4
Bladder
3/8
37.5%
0.7600
-
T5
RCC
2/9
22.2%
0.2098
-
T6
Colon (MSS)
1/7
14.3%
0.6998
-
T7
TNBC
2/10
20.0%
0.8430
Continue
T8
Melanoma
5/10
50.0%
0.4378
Continue
6
T1
DLBCL
2/10
20.0%
0.5922
Continue
T2
Pancreatic
2/10
20.0%
0.7355
Continue
T3
H&N
2/10
20.0%
0.4658
Continue
T4
Bladder
3/10
30.0%
0.5048
Continue
T5
RCC
4/10
40.0%
0.3535
Continue
T6
Colon (MSS)
2/10
20.0%
0.8215
Continue
T7
TNBC
1/10
10.0%
0.5608
Continue
T8
Melanoma
5/10
50.0%
0.3932
Continue
7
T1
DLBCL
2/8
25.0%
0.5460
-
T2
Pancreatic
0/6
0.0%
0.1698
-
T3
H&N
2/10
20.0%
0.3380
Continue
T4
Bladder
2/9
22.2%
0.2545
-
T5
RCC
1/7
14.3%
0.0435
-
T6
Colon (MSS)
1/9
11.1%
0.5522
-
T7
TNBC
1/7
14.3%
0.6260
-
T8
Melanoma
3/9
33.3%
0.1172
-
8
T1
DLBCL
2/8
25.0%
0.6012
-
T2
Pancreatic
0/6
0.0%
0.1495
-
T3
H&N
1/10
10.0%
0.1713
Stop
T4
Bladder
2/9
22.2%
0.3180
-
T5
RCC
2/7
28.6%
0.2095
-
T6
Colon (MSS)
0/10
0.0%
0.1095
Stop
T7
TNBC
1/7
14.3%
0.5918
-
T8
Melanoma
5/10
50.0%
0.4365
Continue
9
T1
DLBCL
2/10
20.0%
0.5138
Continue
T2
Pancreatic
0/10
0.0%
0.0870
Stop
T3
H&N
0/10
0.0%
0.0260
Stop
T4
Bladder
3/10
30.0%
0.4185
Continue
T5
RCC
2/10
20.0%
0.0503
Stop
T6
Colon (MSS)
2/10
20.0%
0.7872
Continue
T7
TNBC
2/10
20.0%
0.7900
Continue
T8
Melanoma
3/10
30.0%
0.0762
Stop


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Similar to interim, Table 14-11 shows 6 different hypothetical scenarios for final analyses in 
order to illustrate final decision making process in the proposed design. As stated in 
Section 10.4.2 at final a Proof of Concept (PoC) about treatment with NIR178 in combination 
with PDR001 will be declared for a tumor type if both of the following conditions are met:
a. posterior mean ORR (Column 5) ≥ “Clinically meaningful” threshold (C2) (Column 6)
b. Posterior probability of “not being clinically meaningful” (Column 7) is less than 10%
If no tumor type shows any significant activity (scenario 1 and 2) at final analysis, the decision 
using the model are reasonable (declared fail to support PoC for all tumor types that made to 
the final analysis). The posterior probabilities of “not clinically meaningful” are greater than 
10% for all tumor types in scenario 2 (Column 7 of Table 14-11). Similarly for scenario 4 where 
all tumor types show clinically meaningful activity the proposed decision rule (to be declared 
success) leads to PoC for all tumor types (posterior probability of “not clinically meaningful” 
< 10% and posterior means of ORR are more than “clinically meaningful” threshold (Column 
6 of Table 14-11)). The proposed design also shows reasonable decision for mixed scenarios (5 
and 6). For example, under scenario 6, data for tumor types T2, T3, T6 and T8 show no clinically 
activity but the rest of the tumor types show activity. Based on the posterior probability of being 
not clinically meaningful and posterior mean of ORR, the design correctly declared failure for 
T2, T3, T6 and T8 while success for the other tumor types.
Table 14-11
Hypothetical data scenarios and decision at final
Scenario
Tumor
Code
Tumor Type
No of 
responder/
No of patients
Posterior 
mean 
ORR
Clinically 
meaningful 
threshold 
(C2)
Posterior 
probability 
of not 
clinically 
meaningful
Decision
1
T1
DLBCL
3/30
0.0950
0.20
0.6142
Fail
T2
Pancreatic
0/10
0.0448
0.16
0.8222
-
T3
H&N
0/10
0.0441
0.23
0.9388
-
T4
Bladder
2/30
0.0735
0.27
0.9435
Fail
T5
RCC
2/10
0.1643
0.37
0.8080
-
T6
Colon (MSS)
1/30
0.0495
0.13
0.5840
Fail
T7
TNBC
1/30
0.0494
0.13
0.5795
Fail
T8
Melanoma
3/10
0.2508
0.43
0.6715
-
2
T1
DLBCL
4/30
0.1373
0.20
0.2915
Fail
T2
Pancreatic
2/30
0.0850
0.16
0.5240
Fail
T3
H&N
3/30
0.1104
0.23
0.6875
Fail
T4
Bladder
4/30
0.1367
0.27
0.6242
Fail
T5
RCC
7/30
0.2117
0.37
0.7290
Fail
T6
Colon (MSS)
1/30
0.0551
0.13
0.5310
Fail
T7
TNBC
1/30
0.0559
0.13
0.5168
Fail
T8
Melanoma
9/30
0.2656
0.43
0.6820
Fail


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Scenario
Tumor
Code
Tumor Type
No of 
responder/
No of patients
Posterior 
mean 
ORR
Clinically 
meaningful 
threshold 
(C2)
Posterior 
probability 
of not 
clinically 
meaningful
Decision
3
T1
DLBCL
7/30
0.2259
0.20
0.0140
Success
T2
Pancreatic
0/10
0.0520
0.16
0.7535
-
T3
H&N
0/10
0.0509
0.23
0.8668
-
T4
Bladder
10/30
0.2968
0.27
0.0135
Success
T5
RCC
2/10
0.2045
0.37
0.7200
-
T6
Colon (MSS)
4/30
0.1557
0.13
0.0282
Success
T7
TNBC
4/30
0.1558
0.13
0.0228
Success
T8
Melanoma
3/10
0.2561
0.43
0.7068
-
4
T1
DLBCL
7/30
0.2351
0.20
0.0107
Success
T2
Pancreatic
5/30
0.1886
0.16
0.0290
Success
T3
H&N
7/30
0.2355
0.23
0.0427
Success
T4
Bladder
9/30
0.2890
0.27
0.0220
Success
T5
RCC
13/30
0.3967
0.37
0.0485
Success
T6
Colon (MSS)
4/30
0.1634
0.13
0.0208
Success
T7
TNBC
4/30
0.1644
0.13
0.0242
Success
T8
Melanoma
15/30
0.4610
0.43
0.0345
Success
5
T1
DLBCL
7/30
0.2146
0.20
0.0190
Success
T2
Pancreatic
0/10
0.0538
0.16
0.7375
-
T3
H&N
0/10
0.0529
0.23
0.8625
-
T4
Bladder
6/30
0.1931
0.27
0.2585
Fail
T5
RCC
2/10
0.1855
0.37
0.8055
-
T6
Colon (MSS)
4/30
0.1482
0.13
0.0268
Success
T7
TNBC
2/30
0.0916
0.13
0.2552
Fail
T8
Melanoma
3/10
0.2430
0.43
0.7560
-
6
T1
DLBCL
7/30
0.2424
0.20
0.0160
Success
T2
Pancreatic
2/30
0.0835
0.16
0.5407
Fail
T3
H&N
3/30
0.1139
0.23
0.6625
Fail
T4
Bladder
9/30
0.2918
0.27
0.0230
Success
T5
RCC
13/30
0.3901
0.37
0.0365
Success
T6
Colon (MSS)
1/30
0.0525
0.13
0.5695
Fail
T7
TNBC
4/30
0.1457
0.13
0.0298
Success
T8
Melanoma
9/30
0.2893
0.43
0.5660
Fail


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14.4.3
Operating characteristics
14.4.3.1 Scenarios
In order to demonstrate the operating characteristics of the design, four scenarios have been 
considered. The scenarios have been presented in Table 14-12.
1. Scenario 1 presents the case where the true underlying ORR of none the eight tumor types 
is clinically meaningful (in other words, null case for all tumor types).
2. Scenario 2a presents the case where the true underlying ORR of all the eight tumor types 
is clinically meaningful (in other words, alterative case for all tumor types).
3. Scenario 2b presents the case where only one single tumor type (T4-bladder) does not 
have clinically meaningful ORR but all other seven tumor types have clinically 
meaningful ORR (same as Scenario 2a).
4. Scenario 3 presents the case where four tumor types have clinically meaningful ORR 
while the other four do not have clinically meaningful ORR.
Table 14-12
True underlying ORR (percent) in the four scenarios
Disease 
Code
Tumor Type
True ORR (%)
Sce 1
(All tumor 
types 
inactive)
Sce 2a
(All tumor 
types 
active)
Sce 2b
(One single tumor type 
inactive, other seven 
active)
Sce 3
(Four tumor types 
active, four other 
inactive)
T1
DLBCL
10.0
30.0
30.0
10.0
T2
Pancreatic
8.0
25.0
25.0
25.0
T3
H&N
13.0
35.0
35.0
13.0
T4
Bladder
15.0
35.0
10.0
15.0
T5
RCC
25.0
50.0
50.0
50.0
T6
Colon (MSS)
5.0
20.0
20.0
5.0
T7
TNBC
5.0
20.0
20.0
20.0
T8
Melanoma
30.0
58.0
58.0
58.0
Clinically significant responses are shown in bold font.
14.4.3.2 Simulation details
In all four scenarios (Table 14-12), it is assumed that an average accrual rate per tumor type is 
2 patients per group every month on average. The number of simulations generated for each 
scenario is 1000.
14.4.3.2.1
Metrics to assess operating characteristics
In a given tumor type, the type I error (false positive rate) of the adaptive design can be viewed 
as the probability estimate of a positive conclusion at final analysis in Scenario 1 
(Table 14-13). The power of the adaptive design is defined as the probability estimate of 
positive conclusion at final analysis in Scenario 2a (Table 14-14).


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14.4.3.2.2
Results
Table 14-13 (Scenario 1) presents the operating characteristics of the design when the true 
underlying ORR of none the eight tumor types is clinically meaningful (in other words, null 
case for all tumor types). The false positive rate (for final analysis) for each of the tumor types 
are appropriately controlled, ranging between 2.6% and 6.8%. Similarly, the chances of 
stopping for futility at IA are high, ranging from 45.8% to 69.7%.
Table 14-13
Simulation results for Scenario 1 (NIR178 and PDR001 combination 
inactive for all tumor types)
Disease 
code
Tumor type
True ORR (%)
Probability of stopping at 
IA for futility (%)
Probability for positive 
conclusion in final 
analysis (%)
T1
DLBCL
10.0
64.3
4.2
T2
Pancreatic
8.0
45.8
6.8
T3
H&N
13.0
61.9
5.1
T4
Bladder
15.0
65.7
2.6
T5
RCC
25.0
69.7
4.1
T6
Colon (MSS)
5.0
59.8
5.8
T7
TNBC
5.0
59.8
5.8
T8
Melanoma
30.0
65.0
3.8
Table 14-14 presents the operating characteristics for two scenarios (2a and 2b):

Scenario 2a presents the operating characteristics when the true underlying ORR of all the 
eight tumor types is clinically meaningful (in other words, alternative case for all tumor 
types). The probability of positive conclusion (for final analysis) for each of the tumor 
types are appropriately high, ranging between 78.2% and 90.7%. Similarly, the chances of 
stopping for futility at IA are low, ranging between 3% and 11.9%.

Scenario 2b, in contrast to Scenario 2a, presents the case where, out of all eight tumor 
types there is one single tumor type (T4-Bladder) which does not have clinically 
meaningful ORR while all other seven tumor types have clinically meaningful ORR. 
However, the model adapts appropriately and the false positive rate (1.1%) for T4 is 
effectively controlled. For the rest seven tumor types which have clinically meaningful
ORR (same as Scenario 2a), the probability of positive conclusion has slightly changed 
(vs Scenario 2a) but remained acceptably high (ranging between 79.6% and 88.7%).


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Table 14-14
Simulation results for Scenario 2a (all tumor types active) and 
Scenario 2b (one single tumor type [T4-Bladder] inactive, all other 
active)
Disease 
code
Tumor type
True ORR (%)
Probability of stopping at 
IA for futility (%)
Probability for positive 
conclusion in final 
analysis (%)
2a
2b
2a
2b
2a
2b
T1
DLBCL
30.0
30.0
3.0
4.0
90.7
88.7
T2
Pancreatic
25.0
25.0
6.6
6.6
86.7
86.2
T3
H&N
35.0
35.0
4.5
6.7
90.5
87.6
T4
Bladder
35.0
10.0
9.7
72.8
78.2
1.1
T5
RCC
50.0
50.0
6.9
8.6
82.5
80.5
T6
Colon (MSS)
20.0
20.0
11.9
11.9
79.5
79.6
T7
TNBC
20.0
20.0
11.9
11.9
79.5
79.6
T8
Melanoma
58.0
58.0
7.6
8.4
83.9
84.1
Tumor type which has different ORR between the two scenarios has been shaded.
Clinically significant responses are shown in bold font.
Table 14-15 (Scenario 3) presents the operating characteristics when four tumor types have 
clinically meaningful ORR while the other four do not have clinically meaningful ORR. In this 
mixed scenario as well, the false positive rates for the inactive tumor types are appropriately 
controlled (4.9% - 6.9%) while the probability of positive conclusion for the active tumor types 
are high (78.2% - 86.6%).
Table 14-15
Simulation results for scenario 3 (four tumor types active while other 
four inactive)
Disease code
Tumor type
True ORR (%)
Probability of 
stopping at IA for 
futility (%)
Probability for 
positive conclusion 
in final analysis (%)
T1
DLBCL
10.0
48.9
5.9
T2
Pancreatic
25.0
6.8
84.3
T3
H&N
13.0
58.2
5.7
T4
Bladder
15.0
55.8
4.9
T5
RCC
50.0
10.6
82.2
T6
Colon (MSS)
5.0
59.8
6.9
T7
TNBC
20.0
11.9
78.2
T8
Melanoma
58.0
8.4
86.6
The tumor types which are assumed to be clinically meaningful are shown in bold fonts.


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14.4.4
Hypothetical scenario testing after addition of new groups
This section was added after the inclusion of MSS CRC RAS mutant, MSS CRC RAS wildtype
and HNSCC pretreated groups. For the updated version with 13 tumor groups, please see 
Section 14.4.5.
This section shows on-study decisions made under the model after the new groups are added. 
The hypothetical data scenarios for interim and final analysis can be found in Table 14-16 and 
Table 14-17 respectively. For each scenario, the posterior probability of being “clinically 
meaningful” and “not clinically meaningful” (T1-T10 in Table 10-1) are calculated by group 
and displayed in the tables.
Table 14-16 shows 6 different scenarios for interim analyses. The scenarios show one or more 
groups having 10 or more patients. It is to be noted that the decision to stop or continue 
enrollment of patients in that group is made only if the number of patients in that group is at 
least 10. Otherwise, no decision is made. As stated in Section 10.7 at interim, a group is stopped 
if the probability of being “clinically meaningful” is less than 20%. 
Scenario 1 and 2 shows two possible scenarios with the current data. There are 17 MSS CRC 
patients with 1 responder. The data for mutation status of CRC patients are not available but 
will be collected retrospectively after implementation of this protocol amendment. Hence, two 
different scenarios are considered. In scenario 1, we considered 2 out of the 17 patients are RAS 
mutant patients and 15 out of 17 patients have RAS status unknown. Hence the patients with 
unknown RAS status are not included in the model. One of the two RAS mutant patients is a 
responder. In scenario 2, we considered 2 out of 17 patients are RAS mutant patients and 7 out 
of 17 patients are RAS wildtype patients. The other 8 patients have RAS status unknown. One 
of the two RAS mutant patients is a responder. We will have 20 additional patients in the MSS 
CRC RAS wildtype and mutant group after expansion.
Based on the interim analysis done, the decision was made to expand to 30 patients in TNBC 
(T6). Decision was also made to enroll 20 additional patients to CRC RAS-wildtype (T9) and 
CRC RAS-mutant (T10) groups. Also, it was decided to stop further enrollment in Pancreatic 
(T2) group. Hence no decision will be made in the subsequent interim analyses for these groups, 
although the data will be included in the statistical model. Hence Scenario 3-6 does not show 
any decisions for T2, T6, T9 and T10. Further decisions to stop enrollment or to expand will be 
made for groups DLBCL (T1), HNSCC naive (T3), Urothelial (T4), RCC (T5), Melanoma pre 
(T7) and HNSCC pre (T8). 
At interim, if a group with at least 10 patients does not show any activity (scenarios 3 and 4) 
the decision based on model are reasonable. The posterior probabilities of “clinically 
meaningful” are less than 20% for all groups that are ongoing and have not expanded for 
scenario 3 (Column 6 of Table 14-16) and hence further enrollment is stopped in all these groups. 
Similarly for scenario 6 where all groups show some clinically meaningful activity the proposed 
decision rule suggests to “continue” for the groups which had enrolled 10 patients (posterior 
probability of “clinically meaningful” > 20%). The proposed design also shows reasonable 
decision for mixed scenario 5. For example, under scenario 5, data for groups T4 and T5 show 
no clinically activity but T1, T3, T7 and T8 shows some activity. Based on the calculated 
probability of being clinically meaningful, the design allows correctly stopping (probability < 
0.20) for T4 and T5 at the interim while continues for the other groups.


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Table 14-16
Hypothetical data scenarios and decision at interim
Scenario
Tumor
Code
Tumor Type
No of responder/
No of patients
Observed 
ORR
Posterior 
probability of 
clinically 
meaningful
response
Decision
1
T1
DLBCL
1/6
16.7%
0.3340
-
T2
Pancreatic
0/14
0%
0.0295
Stopped
T3
HNSCC naive
1/7
14.3%
0.2175
-
T4
Urothelial
1/8
12.5%
0.1090
-
T5
RCC
1/5
20.0%
0.1038
-
T6
TNBC
2/13
15.4%
0.5748
Expanded
T7
Melanoma pre
0/0
-
0.3312
-
T8
HNSCC pre
0/0
-
0.5425
-
T9
CRC-RAS wt
0/0
-
0.5328
Expanded
T10
CRC-RAS mu
½
50%
0.8062
Expanded
2
T1
DLBCL
1/6
16.7%
0.3027
-
T2
Pancreatic
0/14
0%
0.0282
Stopped
T3
HNSCC naive
1/7
14.3%
0.1910
-
T4
Urothelial
1/8
12.5%
0.0942
-
T5
RCC
1/5
20.0%
0.0810
-
T6
TNBC
2/13
15.4%
0.5618
Expanded
T7
Melanoma pre
0/0
-
0.3080
-
T8
HNSCC pre
0/0
-
0.5208
-
T9
CRC-RAS wt
0/7
0%
0.1538
Expanded
T10
CRC-RAS mu
½
50%
0.7810
Expanded
3
T1
DLBCL
1/10
10.0%
0.1108
Stop
T2
Pancreatic
0/14
0%
0.0212
-
T3
HNSCC naive
1/11
9.1%
0.0558
Stop
T4
Urothelial
1/10
10.0%
0.0365
Stop
T5
RCC
1/10
10.0%
0.0082
Stop
T6
TNBC
4/18
22.2%
0.7395
-
T7
Melanoma pre
0/10
0%
0.0060
Stop
T8
HNSCC pre
1/5
20%
0.5190
-
T9
CRC-RAS wt
0/12
0%
0.0660
-
T10
CRC-RAS mu
1/8
12.5%
0.3938
-
4
T1
DLBCL
1/10
10.0%
0.0832
Stop
T2
Pancreatic
0/14
0%
0.0102
-
T3
HNSCC naive
1/11
9.1%
0.0405
Stop
T4
Urothelial
1/10
10.0%
0.0275
Stop
T5
RCC
1/10
10.0%
0.0050
Stop
T6
TNBC
2/13
15.4%
0.3912
-
T7
Melanoma pre
0/10
0%
0.0032
Stop
T8
HNSCC pre
0/10
0%
0.0565
Stop
T9
CRC-RAS wt
0/17
0%
0.0207
-
T10
CRC-RAS mu
1/12
8.3%
0.2023
-


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Scenario
Tumor
Code
Tumor Type
No of responder/
No of patients
Observed 
ORR
Posterior 
probability of 
clinically 
meaningful
response
Decision
5
T1
DLBCL
2/10
20.0%
0.4670
Continue
T2
Pancreatic
0/14
0%
0.0557
-
T3
HNSCC naive
2/11
18.2%
0.2932
Continue
T4
Urothelial
2/10
20.0%
0.1758
Stop
T5
RCC
2/10
20.0%
0.0328
Stop
T6
TNBC
5/18
27.8%
0.9512
-
T7
Melanoma pre
2/10
20.0%
0.2368
Continue
T8
HNSCC pre
2/10
20.0%
0.8128
Continue
T9
CRC-RAS wt
3/17
17.6%
0.8065
-
T10
CRC-RAS mu
2/12
16.6%
0.7695
-
6
T1
DLBCL
2/10
20.0%
0.5578
Continue
T2
Pancreatic
0/14
0%
0.0520
-
T3
HNSCC naive
2/11
18.2%
0.3780
Continue
T4
Urothelial
3/10
30.0%
0.4025
Continue
T5
RCC
4/10
40.0%
0.2522
Continue
T6
TNBC
5/18
27.8%
0.9658
-
T7
Melanoma pre
2/10
20.0%
0.3332
Continue
T8
HNSCC pre
2/10
20.0%
0.8385
Continue
T9
CRC-RAS wt
3/17
17.6%
0.8405
-
T10
CRC-RAS mu
2/12
16.6%
0.8042
-
Similar to interim, Table 14-17 shows 6 different hypothetical scenarios for final analyses in 
order to illustrate final decision making process in the proposed design. As stated in 
Section 10.4.2 at final a Proof of Concept (PoC) about treatment with NIR178 in combination 
with PDR001 will be declared for a tumor type if both of the following conditions are met:
posterior mean ORR (Column 5) ≥ “Clinically meaningful” threshold (C2) (Column 6)
Posterior probability of “not being clinically meaningful” (Column 7) is less than 10%
If no group shows any significant activity (scenario 1 and 2) at final analysis, the decision using 
the model are reasonable (declared fail to support PoC for all groups that made to the final 
analysis). The posterior probabilities of “not clinically meaningful” are greater than 10% for all 
groups in scenario 2 (Column 7 of Table 14-17). Similarly for scenario 4 where all groups show 
clinically meaningful activity the proposed decision rule (to be declared success) leads to PoC 
for all groups (posterior probability of “not clinically meaningful” < 10% and posterior means 
of ORR are more than “clinically meaningful” threshold (Column 6 of Table 14-17). 
The proposed design also shows reasonable decision for mixed scenarios (5 and 6). For example, 
under scenario 6, data for groups T3, T4, T7 and T10 show no clinically activity but the rest of 
the groups show activity. Based on the posterior probability of being not clinically meaningful 
and posterior mean of ORR, the design correctly declared failure for T3, T4, T7 and T10 while 
success for the other groups.


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Table 14-17
Hypothetical data scenarios and decision at final
Scenario
Tumor
Code
Tumor Type
No of 
responder/
No of patients
Posterior 
mean 
ORR
Clinically 
meaningful 
threshold 
(C2)
Posterior 
probability of 
not clinically 
meaningful
response
Decision
1
T1
DLBCL
3/30
0.0990
0.20
0.5685
Fail
T2
Pancreatic
0/14
0.0416
0.16
0.8178
-
T3
HNSCC 
naive
1/11
0.0949
0.23
0.7960
-
T4
Urothelial
2/30
0.0807
0.27
0.9500
Fail
T5
RCC
2/10
0.1467
0.37
0.8742
-
T6
TNBC
2/30
0.0806
0.13
0.2170
Fail
T7
Melanoma 
pre
1/30
0.0589
0.25
0.4300
Fail
T8
HNSCC pre
1/10
0.0999
0.13
0.5952
-
T9
CRC-RAS wt
3/27
0.1026
0.13
0.0825
Fail
T10
CRC-RAS 
mu
3/22
0.1155
0.13
0.0545
Fail
2
T1
DLBCL
4/30
0.1251
0.20
0.3125
Fail
T2
Pancreatic
0/14
0.0444
0.16
0.7632
-
T3
HNSCC 
naive
3/30
0.1097
0.23
0.7212
Fail
T4
Urothelial
4/30
0.1240
0.27
0.7640
Fail
T5
RCC
6/30
0.1618
0.37
0.9085
Fail
T6
TNBC
3/30
0.1088
0.13
0.0620
Fail
T7
Melanoma 
pre
2/30
0.0911
0.25
0.1720
Fail
T8
HNSCC pre
2/30
0.0902
0.13
0.6188
Fail
T9
CRC-RAS wt
3/27
0.1149
0.13
0.0482
Fail
T10
CRC-RAS 
mu
3/22
0.1246
0.13
0.0350
Fail
3
T1
DLBCL
7/30
0.2234
0.20
0.0098
Success
T2
Pancreatic
0/14
0.0381
0.16
0.8302
-
T3
HNSCC 
naive
1/11
0.1428
0.23
0.4568
-
T4
Urothelial
10/30
0.2852
0.27
0.0142
Success
T5
RCC
2/10
0.2019
0.37
0.7358
-
T6
TNBC
4/30
0.1585
0.13
0.0202
Success
T7
Melanoma 
pre
9/30
0.2643
0.25
0.0000
Success
T8
HNSCC pre
1/10
0.1482
0.13
0.3095
-
T9
CRC-RAS wt
4/27
0.1708
0.13
0.0125
Success
T10
CRC-RAS 
mu
4/22
0.1933
0.13
0.0048
Success


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Scenario
Tumor
Code
Tumor Type
No of 
responder/
No of patients
Posterior 
mean 
ORR
Clinically 
meaningful 
threshold 
(C2)
Posterior 
probability of 
not clinically 
meaningful
response
Decision
4
T1
DLBCL
7/30
0.2377
0.20
0.0068
Success
T2
Pancreatic
0/14
0.0364
0.16
0.8452
-
T3
HNSCC 
naive
9/30
0.2781
0.23
0.0052
Success
T4
Urothelial
9/30
0.2760
0.27
0.0165
Success
T5
RCC
13/30
0.3761
0.37
0.0628
Success
T6
TNBC
4/30
0.1699
0.13
0.0155
Success
T7
Melanoma 
pre
9/30
0.2776
0.25
0.0000
Success
T8
HNSCC pre
5/30
0.1946
0.13
0.0598
Success
T9
CRC-RAS wt
4/27
0.1822
0.13
0.0115
Success
T10
CRC-RAS 
mu
4/22
0.2086
0.13
0.0045
Success
5
T1
DLBCL
7/30
0.2082
0.20
0.0162
Success
T2
Pancreatic
0/14
0.0420
0.16
0.7930
-
T3
HNSCC 
naive
1/11
0.1331
0.23
0.5055
-
T4
Urothelial
10/30
0.2854
0.27
0.0247
Success
T5
RCC
2/10
0.1826
0.37
0.8240
-
T6
TNBC
4/30
0.1481
0.13
0.0145
Success
T7
Melanoma 
pre
4/30
0.1478
0.25
0.0190
Fail
T8
HNSCC pre
1/10
0.1337
0.13
0.3400
-
T9
CRC-RAS wt
4/27
0.1581
0.13
0.0132
Success
T10
CRC-RAS 
mu
3/22
0.1511
0.13
0.0230
Success
6
T1
DLBCL
7/30
0.2121
0.20
0.0160
Success
T2
Pancreatic
0/14
0.0390
0.16
0.8170
-
T3
HNSCC 
naive
3/30
0.1300
0.23
0.5157
Fail
T4
Urothelial
9/30
0.2616
0.27
0.0470
Fail
T5
RCC
13/30
0.3956
0.37
0.0620
Success
T6
TNBC
5/30
0.1733
0.13
0.0048
Success
T7
Melanoma 
pre
5/30
0.1733
0.25
0.0030
Fail
T8
HNSCC pre
5/30
0.1740
0.13
0.0800
Success
T9
CRC-RAS wt
4/27
0.1632
0.13
0.0130
Success
T10
CRC-RAS 
mu
2/22
0.1267
0.13
0.1100
Fail


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Protocol No. CNIR178X2201
14.4.5
Addition of RCC naive, RCC pretreated group and mCRPC group at 
NIR178 240 mg BID
This section shows on-study decisions made under the statistical model with the three additional 
tumor groups included in the protocol amendment 5 (i.e RCC IO naive, RCC IO pretreated 
patients and mCRPC all treated at 240 mg BID dose of NIR178 in combination with PDR001.
The hypothetical data scenarios for interim and final analysis can be found in Table 14-18 and 
Table 14-19 respectively. 
Table 14-18 shows 4 different scenarios for the interim analyses, where one or more groups 
having 10 or more patients treated. It has to be noted that the decision to stop or continue 
enrollment of patients in that group is made only if the number of patients in a group is at least 
10. As stated in Section 10.7 a group is stopped at interim if the probability of being “clinically 
meaningful” is less than 20%. 
Scenario 1 considers the current available data, which is subject to change. 
Based on the last interim analysis done, the decision was made to enroll 20 more patients to 
CRC RAS-wildtype (T9) at 160 mg NIR178 and CRC RAS-mutant (T10) at 160 mg NIR178. 
Decision was also made to stop enrolling RCC naive patients at 160 mg BID NIR178 (T5) and 
expand RCC naive patients at 240 mg BID NIR178 (T12) as a separate group. Final decision 
has also been made for TNBC (T6) group. Also, it was decided to stop further enrollment in 
Pancreatic (T2) and Urothelial (T4) groups. Hence, no further decisions will be made in the 
subsequent interim analyses for these groups, although the data will be included in the statistical 
model. Further decisions to stop enrollment or to expand will be made for groups DLBCL (T1), 
HNSCC naive (T3), Melanoma pre (T7), HNSCC pre (T8), RCC IO pretreated (T11), and 
mCRPC (T13). 
For Scenario 2, none of the groups with at least 10 patients shows any activity (at interim, the 
relative posterior possibilities of “clinically meaningful” are less than 20%). In Scenario 3, for 
all groups that show some clinically meaningful activity with at least 10 patients treated, the 
proposed decision rule suggests to “continue” (posterior probability of “clinically meaningful” > 
20%). The proposed statistical model shows reasonable decisions also under mixed scenarios 3 
and 4.
Table 14-18
Hypothetical data scenarios and decision at interim
Scen
ario
Tum
or
Cod
e
Tumor Type
No of 
responder/
No of 
patients
Observed 
ORR
Posterior 
probability of 
clinically 
meaningful 
response
Decision
1
T1
DLBCL
1/10
10%
0.1060
Stop
T2
Pancreatic
0/14
0%
0.0175
Decided to stop
T3
HNSCC naive
2/9
22.2%
0.2788
-
T4
Urothelial
1/14
7.1%
0.0135
Decided to stop
T5
RCC naive at 160
mg
4/11
36.4%
0.3167
Decided to expand*
T6
TNBC
3/30
10%
0.2468
Final
T7
Melanoma pre
0/2
0%
0.0850
-
T8
HNSCC pre
0/3
0%
0.1970
-


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Amended Protocol Version v06 (Clean)
Protocol No. CNIR178X2201
Scen
ario
Tum
or
Cod
e
Tumor Type
No of 
responder/
No of 
patients
Observed 
ORR
Posterior 
probability of 
clinically 
meaningful 
response
Decision
T9
CRC-RAS wt
0/11
0%
0.0578
Decided to expand
T10
CRC-RAS mu
1/19
5.3%
0.1148
Decided to expand
T11
T12
T13
RCC pre at 240 mg
RCC naive at 240
mg
mCRPC
0/0
0/0
0/0
0%
0%
0%
0.3002
0.1805
0.1952
-
-**
-
2
T1
DLBCL
1/10
10%
  0.0782
Stop
T2
Pancreatic
0/14
0%
  0.0173
Decided to stop
T3
HNSCC naive
2/11
18.2%
  0.1427
Stop
T4
Urothelial
1/14
7.1%
  0.0082
Decided to stop
T5
RCC naive at 160 
mg
4/11
36.4%
  0.2888
Decided to expand*
T6
TNBC
3/30
10%
  0.219
Final
T7
Melanoma pre
0/10
0%
  0.004
Stop
T8
HNSCC pre
1/14
7.1%
  0.176
Stop
T9
CRC-RAS wt
0/11
0%
  0.0538
Decided to expand
T10
T11
T12
T13
CRC-RAS mu
RCC pre at 240 mg
RCC naive at 240 
mg
mCRPC
1/19
1/10  
0/0
1/10
5.3%
8.3%
0%
10%
0.1158
0.0795
0.161
0.0102
Decided to expand
Stop
-**
Stop
3
T1
DLBCL
3/10
30%
  0.7235
Continue
T2
Pancreatic
0/14
0%
  0.0475
Decided to stop
T3
HNSCC naive
3/11
27.3%
  0.546
Continue
T4
Urothelial
1/14
7.1%
  0.051
Decided to stop
T5
RCC naive at 160 
mg
4/11
36.4%
  0.2023
Decided to expand*
T6
TNBC
3/30
10%
  0.5088
Final
T7
Melanoma pre
2/10
20%
  0.324
Continue
T8
HNSCC pre
2/10
20%
  0.8358
Continue
T9
CRC-RAS wt
3/14
0%
  0.8815
Decided to expand
T10
T11
T12
T13
CRC-RAS mu
RCC pre at 240 mg
RCC naive at 240 
mg
mCRPC
5/21
2/10
0/0
4/10
5.3%
16.7%
0%
40%
0.946
0.5588
0.1905
0.3058
Decided to expand
Continue
-**
Continue
4
T1
DLBCL
3/10
30%
  0.6038
Continue
T2
Pancreatic
0/14
0%
  0.025
Decided to stop
T3
HNSCC naive
2/11
18.2%
  0.2312
Continue
T4
Urothelial
1/14
7.1%
  0.0205
Decided to stop
T5
RCC naive at 160 
mg
4/11
36.4%
  0.259
Decided to expand*
T6
TNBC
3/30
10%
  0.319
Final
T7
Melanoma pre
0/10
0%
  0.0118
Stop
T8
HNSCC pre
1/10
10%
  0.3852
Continue


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Protocol No. CNIR178X2201
Scen
ario
Tum
or
Cod
e
Tumor Type
No of 
responder/
No of 
patients
Observed 
ORR
Posterior 
probability of 
clinically 
meaningful 
response
Decision
T9
CRC-RAS wt
0/11
0%
  0.0905
Decided to expand
T10
T11
T12
T13
CRC-RAS mu
RCC pre at 240 mg
RCC naive at 240 
mg
mCRPC
1/19
2/10
3/8
1/10
5.3%
16.7%
37.5%
10%
0.1737
0.3645
0.2725
0.0168
Decided to expand
Continue
-**
Stop
* Stopped enrolling RCC naive patients at 160 mg BID NIR178, decided to expand RCC naive patients at 240 mg 
BID NIR178 as a separate group.
** Enroll 20 more RCC naive patients at 240 mg BID NIR178 and no decision will be made at interim. 
Similar to interim, Table 14-19 shows 4 different hypothetical scenarios for final analyses in 
order to illustrate final decision making process in the proposed design. For scenario 1, the 
posterior probabilities of “not clinically meaningful” are greater than 10% for all groups and 
hence none of the groups leads to success at final analysis. In scenario 2, for all groups that 
show clinically meaningful activity, the proposed decision rule leads to PoC for all groups 
(posterior probability of “not clinically meaningful” < 10% and posterior means of ORR are 
more than “clinically meaningful” threshold). The proposed statistical model shows reasonable 
decisions also under mixed scenarios 3 and 4.
Table 14-19
Hypothetical data scenarios and decision at final
Sce
nari
o
Tum
or
Code
Tumor Type
No of 
respon
der/
No of 
patient
s
Posterio
r mean 
ORR
Clinically 
meaningf
ul 
threshold 
(C2)
Posterior 
probabilit
y of not 
clinically 
meaningf
ul
response
Decision
1
T1
DLBCL
1/10
  0.0949
0.20
  0.648
-
T2
Pancreatic
0/14
  0.0416
0.16
  0.842
-
T3
HNSCC naive
2/30
  0.075
0.23
  0.9288
Fail
T4
Urothelial
1/14
  0.0803
0.27
  0.9155
-
T5
RCC naive at 160 mg
4/11
  0.304
0.37
  0.399
-
T6
TNBC
3/30
  0.0913
0.13
  0.1315
Final Decision 
made
T7
Melanoma pre
1/14
  0.0807
0.25
  0.7338
-
T8
HNSCC pre
1/10
  0.0933
0.13
  0.2332
-
T9
CRC-RAS wt
0/11
  0.0449
0.13
  0.6142
-
T10
T11
T12
T13
CRC-RAS mu
RCC pre at 240 mg
RCC naive at 240 mg
mCRPC
1/19
1/30
3/20
2/30
0.07
0.0547
0.1181
0.0742
0.13
0.20
0.37
0.35
0.3392
0.9
0.9512
0.7915
-
Fail
Fail
Fail


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Protocol No. CNIR178X2201
Sce
nari
o
Tum
or
Code
Tumor Type
No of 
respon
der/
No of 
patient
s
Posterio
r mean 
ORR
Clinically 
meaningf
ul 
threshold 
(C2)
Posterior 
probabilit
y of not 
clinically 
meaningf
ul
response
Decision
2
T1
DLBCL
1/10
  0.1276
0.20
  0.456
-
T2
Pancreatic
0/14
  0.0377
0.16
  0.8325
-
T3
HNSCC naive
8/30
  0.2598
0.23
  0.0357
Success
T4
Urothelial
1/14
  0.103
0.27
  0.788
-
T5
RCC naive at 160 mg
4/11
0.3183
0.37
  0.3182
-
T6
TNBC
3/30
0.1153
0.13
  0.0798
Final Decision 
made
T7
Melanoma pre
3/24
0.1349
0.25
  0.3325
-
T8
HNSCC pre
3/27
0.1245
0.13
  0.0712
-
T9
CRC-RAS wt
0/11
0.0474
0.13
  0.6492
-
T10
T11
T12
T13
CRC-RAS mu
RCC pre at 240 mg
RCC naive at 240 mg
mCRPC
1/19
7/30
11/20
12/30
0.0819
0.2281
0.5005
0.3699
0.13
0.20
0.37
0.35
0.3342
0.0265
0.0065
0
-
Success
Success
Success
3
T1
DLBCL
1/10
0.1225
0.20
  0.4362
-
T2
Pancreatic
0/14
  0.041
0.16
  0.8125
-
T3
HNSCC naive
8/30
  0.236
0.23
  0.0588
Success
T4
Urothelial
1/14
0.1033
0.27
  0.793
-
T5
RCC naive at 160 mg
4/11
0.2906
0.37
  0.4525
-
T6
TNBC
3/30
0.1134
0.13
  0.0802
Final Decision 
made
T7
Melanoma pre
4/30
0.1352
0.25
  0.2795
Fail
T8
HNSCC pre
1/10
0.1222
0.13
  0.156
-
T9
CRC-RAS wt
0/11
0.0489
0.13
  0.6278
-
T10
T11
T12
T13
CRC-RAS mu
RCC pre at 240 mg
RCC naive at 240 mg
mCRPC
1/19
3/30
11/20
6/30
0.0845
0.1133
0.5154
0.1847
0.13
0.20
0.37
0.35
0.3042
0.4302
0.0098
0.0662
-
Fail
Success
Fail
4
T1
DLBCL
7/30
0.2111
0.20
  0.0105
Success
T2
Pancreatic
0/14
0.0397
0.16
  0.8128
-
T3
HNSCC naive
8/30
0.2328
0.23
  0.031
Success
T4
Urothelial
1/14
0.1217
0.27
  0.6445
-
T5
RCC naive at 160 mg
4/11
0.2771
0.37
  0.503
-
T6
TNBC
3/30
0.1342
0.13
  0.058
Final Decision 
made
T7
Melanoma pre
4/30
0.1572
0.25
  0.1458
Fail
T8
HNSCC pre
6/30
0.1944
0.13
  0
Success
T9
CRC-RAS wt
4/27
0.1653
0.13
  0.0118
Success
T10
T11
T12
T13
CRC-RAS mu
RCC pre at 240 mg
RCC naive at 240 mg
mCRPC
6/28
3/30
11/20
6/30
0.2022
0.1334
0.5112
0.1936
0.13
0.20
0.37
0.35
0.0008
0.2798
0.0168
0.0245
Fail
Fail
Success
Fail


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Amended Protocol Version v06 (Clean)
Protocol No. CNIR178X2201
14.5
Appendix 5: Efficacy guideline for prostate cancer (based on 
PCWG3)
The predominant manifestations of progression of prostate cancers are rising prostate-specific 
antigen (PSA) values, new lesions on bone scan, new symptoms of disease, and an increase in 
a measurable tumor mass. Biochemical failure as represented by rising PSA is generally the 
first indication of recurring disease. Moreover, the prostate Cancer Clinical Trials Working 
Group emphasizes the importance of keeping patients on trial until radiographic or symptomatic 
progression, which better reflects a change in clinical status, is documented and that an effort 
is made not to discontinue therapy solely on the basis of a rise in PSA in the absence of other 
indicators of disease progression. This is particularly relevant for patients with low PSA values 
at entry and those with a slow rate of rise in PSA at progression (Scher et al 2016). Please refer 
to Table 14-19 for assessments and progression criteria on the basis of changes in PSA, bone 
metastases, and measurable disease (Scher et al 2016).
Table 14-20
PCWG3 criteria of progression by disease manifestation
Assessment
Evaluation Criteria for disease progression
PSA
Obtain sequence of rising values at a minimum of 1-week intervals
1 ng/mL minimum starting value if confirmed rise is only indication of progression 
unless pure small-cell carcinoma
Estimate pre-therapy PSA-DT if 3 or more values available 4 or more weeks apart
Target lesions
Nodal or visceral progression sufficient for trial entry independent of PSA
Measurable lesions not required for entry
Use RECIST (v1.1) to record soft-tissue (nodal and visceral) lesions as target or 
non-target
Previously normal (< 1.0-cm) lymph nodes must have grown by ≥ 5 mm in the 
short axis from baseline or nadir and be ≥ 1.0 cm in the short axis to be 
considered to have progressed. If the node progresses to ≥ 1.5 cm in the short 
axis, it is measurable; nodes that have progressed to 1.0 to less than 1.5 cm are 
pathologic, subject to clinical discretion, and nonmeasurable. For existing 
pathologic adenopathy, progression is defined per RECIST 1.1 
Record presence of nodal and/or visceral disease separately
Prostate
Record prior treatment of primary tumor
Perform directed pelvic imaging (CT, MRI, PET/CT, endorectal MRI, transrectal 
ultrasound) to document presence or absence of disease
Bone
Progression = appearance of 2 or more new lesions
Confirm ambiguous results by other imaging modalities (eg, CT or MRI), but only 
positivity on the bone scan defines metastatic disease to bone 
Abbreviations: PCWG3, Prostate Cancer Clinical Trials Working Group 3; PSA, prostate-specific antigen; PSA-
DT, PSA doubling time; RECIST, Response Evaluation Criteria in Solid Tumors; CT, computed tomography; 
MRI, magnetic resonance imaging; PET, positron emission tomography.
Outcomes based on measurable disease and bone lesions
For the purposes of this study, patients should be reevaluated for response every 8 weeks using 
the RECIST Guideline v1.1 for radiological assessments and bone scans (if necessary).


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Amended Protocol Version v06 (Clean)
Protocol No. CNIR178X2201
Outcomes based on post-therapy PSA changes:

PSA Response (PR): Decrease in PSA value by >50% from baseline, confirmed by two 
successive evaluations at least three weeks apart.

Secondary PSA Response: At least 30% decrease in PSA at ≥ 12 weeks from baseline 
which is confirmed at least 4 weeks later.

Stabilization (SD): Patients who do not meet the criteria for PR or POD will be 
considered stable

Progression (POD): A 25% or greater increase and an absolute increase of 2ng/mL or 
more from baseline (or after 12 weeks: ≥ 25% increase from nadir level) is documented, 
which is confirmed by a second value obtained 3 or more weeks later.

Time to PSA Progression: The date that a 25% or greater increase and an absolute 
increase of 2ng/mL or more from baseline (or after 12 weeks: ≥ 25% increase from nadir) 
is documented, which is confirmed by a second value obtained 3 or more weeks later.
Progressive disease
Progressive disease will be based on POD and skeletal progression in addition to RECIST 1.1 
(Appendix 1) and iRECIST (Appendix 2).  
Reference section
Scher HI, Morris MJ, Stadler WM, et al (20016) Trial Design and Objectives for Castration-
Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials 
Working Group 3. J Clin Oncol; 34:1402-18.


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Protocol No. CNIR178X2201
14.6
Appendix 6: Calculation - Cockcroft-Gault formula for GFR 
estimate 
Creatinine clearance will be calculated using the following formulas:

Male GFR = (140 - age) x (weight) / (sCr x 72)

Female GFR = (140 - age) x (weight) x 0.85 / (sCr x 72)
GFR is Glomerular Filtration Rate in ml/min; Age is in years; Weight is Lean Body Mass in 
kilograms; sCr is Serum Creatinine in mg/dl
The formulas above should be altered in the following cases: 
1. Overweight (GFR >25 kg/m2)
a.
Calculate based on adjusted body weight
b. Adjusted body weight = wtKgIdeal + 0.4 * (wtKgActual - wtKgIdeal)
2. Underweight
a.
Use actual weight
b. Do not round up to Serum Creatinine (significantly underestimates GFR)
3. Elderly
a.
Do not round up to Serum Creatinine (significantly underestimates GFR)
4. Amputation
a.
Measure 24 hour Creatinine Clearance
Wallach, J.  Interpretation of Diagnostic Tests.  Ed. 8 (2007) Lippincott Williams and Wilkins.

SAP_001.pdf: 
Clinical Development 
NIR178, PDR001 
CNIR178X2201 / NCT03207867
A Phase II, multi-center, open label study of NIR178 in combination 
with PDR001 in patients with selected advanced solid tumors and non-
Hodgkin lymphoma 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: Final Amendment 2 (v2) 
Release date: 
12-Apr-2023
Number of pages: 
64 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 of 64 
SAP Final Amendment 2 
 
Study No. CNIR178X2201 
 
 
 
Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title impacted 
(Current) 
12-Jan-
2023 
Prior to 
DB lock 
Creation of final 
version per Protocol 
Amendment 6  
The new TCO SAP template v4.0 is being 
used. Update per Protocol Amendment 6. 
 
NA 
 
 
 
 
 
 
 
 
 
 
12-Apr-
2023 
Prior to 
final DB 
Lock 
Major/Minor 
changes 
Final Amendment 2 (v2) 
Major changes 
- Updated list of abbreviations 
- Tightened the study design with regards to 
Protocol Amendments, introduced 
terminology for treatment indications, 
clarified contradictory statements 
andremoved duplicacy of information. 
- Distinguished efficacy and safety treatment 
groups for reporting on Part 1. Treatment 
indication precisely defined.  
- Precisely defined date of first/last 
administration of a study drug and study 
treatment 
- Corrected formula for Study day 
- Introduced different types of follow-ups as 
part of post-treatment period 
- Revised definition of  Full analysis  set 
- Revised definitions of  IG analysis sets 
- Corrected the duration of exposure for Part 
2 intermittant dosing 
- Aligned the organization of treatment 
indications with those mentioned Section 
1.1.1 and Table 2-4 
- Added a sentence to allow  addition of any  
new  qualifying treatment indication to 
inform the model. 
- Clarified that Secondary efficacy endpoints 
are to be evaluated inall Treatment groups 
contributing toprimary efficacy objective. 
- Time to event endpoints to be estimated 
for trt groups >= 10 patients 
- Added precise definition of “sufficient” 
number of patients for change from 
baseline PSA analysis. 
- Clarified the criteria for summarizing 
efficacy endpoints for unknown RAS 
status. 
-  Moved the paragraph on Safety summary 
from Section 2.1.1.5 to the right section 
under Section 2.6.2 
- Tightened the reporting of AEs, SAEs, 
Deaths in line with the protocol with 
listings required on Screen failure 
patients. 
- Clarified that AESIs associated with 
combination trt  will be reported using 
PDR001-specific  eCRS . 
 
 
• List of abbreviations  
• Section 1.1 and sub-
sections. 
 
 
• Section 2.1 
 
• Section 2.1.1.2 
 
• Section 2.1.1.3 
• Section 2.1.1.5 
 
• Section 2.2.1 
• Section 2.2.4 
• Section 2.4.1.1 
 
• Section 2.5.2 
• Table 2-4 
 
• Section 2.5.2 
 
• Section 2.6.1 
 
• Section 2.6.1 
 
• Section 2.6.1 
 
 
• Section 2.6.1 
 
• Section 2.6.2 
 
• Section 2.6.2.1 
 
 
• Section 2.6.2.2 
 
 


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Date 
Time 
point 
Reason for update 
Outcome for update 
Section and title impacted 
(Current) 
- Corrected deliverables for EudraCT 
- Corrected the IG analysis to be in line with 
the latest IG protocol. 
- Corrected that changes in tumor immune 
infiltrate will be assessed by “change from 
baseline” and not “percentage” change. 
- Added a short description and reference to 
sample size estimation for addition of 
groups to Part 1after the first IA during the 
course of Phase II study. 
 
Minor changes 
- other minor editorial changes include 
grammatical corrections, sentence 
conciseness, replacement of “tumor 
types”  redefined by “treatment 
indications” for preciseness where 
applicable. 
• Section 2.6.2.4 
• Section 2.6.5 
• Section 2.6.7 
 
• Section 3.1 
 
 
 
 
 
• Throughout the document 
 
 
  
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 7 
1 
Introduction ......................................................................................................................... 9 
1.1 
Study design............................................................................................................. 9 
1.1.1 
Part 1: Bayesian adaptive signal finding in solid tumors and DLBCL . 12 
1.1.2 
Part 2: NIR178+PDR001 schedule optimization .................................. 13 
1.1.3 
Part 3: NIR178+PDR001 additional exploration in selected treatment 
indications ............................................................................................. 14 
1.1.4 
Japanese safety run-in study .................................................................. 14 
1.2 
Study objectives, endpoints and estimands ........................................................... 16 
2 
Statistical Methods ............................................................................................................ 18 
2.1 
Data analysis general information ......................................................................... 18 
2.1.1 
General definitions ................................................................................ 20 
2.2 
Analysis sets .......................................................................................................... 22 
2.2.1 
Full analysis set ..................................................................................... 22 
2.2.2 
Safety set ............................................................................................... 23 
2.2.3 
Pharmacokinetic analysis set ................................................................. 23 
2.2.4 
Immunogenicity analysis set ................................................................. 23 
2.2.5 
PK/ECG Analysis Set ........................................................................... 23 
2.2.6 
Patient Classification ............................................................................. 23 
2.2.7 
Withdrawal of Informed Consent .......................................................... 24 
2.2.8 
Subgroup of interest .............................................................................. 24 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 24 
2.3.1 
Patient disposition ................................................................................. 25 
2.3.2 
Demographics and other baseline characteristics ................................. 25 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 26 
2.4.1 
Study treatment / compliance ................................................................ 26 
2.4.2 
Prior, concomitant and post therapies ................................................... 30 
2.5 
Analysis supporting primary objective(s) .............................................................. 32 
2.5.1 
Primary endpoint(s) ............................................................................... 32 


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2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 32 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 36 
2.5.4 
Sensitivity analyses ............................................................................... 37 
 
 37 
2.6 
Analysis supporting secondary objectives ............................................................. 37 
2.6.1 
Efficacy objectives ................................................................................ 37 
2.6.2 
Safety objectives ................................................................................... 38 
2.6.3 
Pharmacokinetic endpoints ................................................................... 45 
2.6.4 
PD and PK/PD analyses ........................................................................ 46 
2.6.5 
Immunogenicity .................................................................................... 47 
2.6.6 
Patient-reported outcomes ..................................................................... 49 
 
 49 
 
 50 
2.8 
Interim analysis ...................................................................................................... 50 
3 
Sample size calculation ..................................................................................................... 51 
3.1 
Part 1 ...................................................................................................................... 51 
3.2 
Part 2 ...................................................................................................................... 52 
3.3 
Part 3 ...................................................................................................................... 54 
4 
Change to protocol specified analyses .............................................................................. 55 
5 
Appendix ........................................................................................................................... 55 
5.1 
Imputation rules ..................................................................................................... 55 
5.1.1 
Study drug ............................................................................................. 55 
5.1.2 
AE date imputation ............................................................................... 56 
5.1.3 
Concomitant medication date imputation ............................................. 57 
5.1.4 
Other imputations .................................................................................. 58 
5.2 
AEs coding/grading ............................................................................................... 58 
5.3 
Laboratory parameters derivations ........................................................................ 59 
5.4 
Definition and derivation rules for iRECIST......................................................... 60 
5.4.1 
Total measurable disease burden .......................................................... 60 
5.4.2 
Assessment of disease progression ....................................................... 60 
5.4.3 
Best overall response ............................................................................. 62 
5.4.4 
Time-to-event analyses ......................................................................... 62 
5.5 
PK/ECG dataset preparation .................................................................................. 63 


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5.5.1 
ECG data ............................................................................................... 63 
5.5.2 
PK concentration data ........................................................................... 64 
5.5.3 
Algorithm to match PK and ECG data .................................................. 64 
6 
Reference ........................................................................................................................... 64 
 


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List of abbreviations 
ADA 
AE 
AESI 
AUC 
BID 
CRF 
CSR 
CRO 
CTC 
CTCAE 
DCR 
DI 
DLBCL 
DLT 
DMS 
DoR 
ECG 
Anti-Drug Antibody 
Adverse Event 
Adverse Event of Special Interest 
Area Under the Curve 
Bis In Die 
Case Report Form 
Clinical Study Report 
Clinical Research Organization 
Common Toxicity Criteria 
Common Terminology Criteria for Adverse Events 
Disease Control Rate 
Dose Intensity 
Diffuse Large B Cell Lymphoma 
Dose Limiting Toxicity 
Document Management System 
Duration of Response 
Electrocardiogram  
FAS 
FCT 
HGC 
HNSCC 
IA 
IB 
IC 
IHC 
ITT 
IV 
mCRPC 
Full Analysis Set 
Film Coated Tablet 
Hard Gelatin Capsule 
Head and Neck Cancer 
Interim Analyses 
Investigator’s Brochure 
Non-tumor immune cell staining score 
Immunohistochemistry 
Intent to Treat 
Intra-Venious 
metastatic castration resistant prostate cancer 
MedDRA 
MSS CRC 
MTD 
NSCLC 
ORR 
OS 
PCWG3 
PD 
PDS 
PFS 
Medical Dictionary for Drug Regulatory Affairs 
Microsatellite Stable Colorectal Cancer 
Maximum Tolerated Dose 
Non-Small Cell Lung Cancer 
Overall Response Rate 
Overall Survival 
Prostate Cancer Working Group 3 
Phar 
Programming Datasets Specifications 
Progression Free Survival 
PK 
PD 
Pharmacokinetics 
Pharmacodynamic 


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PPS 
Per-Protocol Set 
PRO 
PSA 
Patient-reported Outcomes 
Prostate-specific antigen 
PT 
QD 
Preferred Term 
Once Daily 
RAP 
RCC 
RD 
RDI 
RECIST 
RR 
Reporting & Analysis Process 
Renal Cell Carcinoma 
Recommended Dose 
Relative Dose Intensity 
Response Evaluation Criteria in Solid Tumours 
RR interval (the distance between 2 consecutive R peaks) 
SAP 
SAS 
SAE 
SD 
Statistical Analysis Plan 
Statistical Analysis System 
Serious Adverse Events 
Standard Deviation 
SOC 
System Organ Class 
TFLs 
TNBC 
Tables, Figures, Listings 
Triple-negative breast cancer  
WHO 
World Health Organization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1 
Introduction 
This Statistical Analysis Plan (SAP) describes all planned analyses for the Clinical Study Report(s) 
(CSR) of study NIR178X2201, a phase II, multi-center, open label study of NIR178 in combination 
with PDR001 in patients with select advanced solid tumors and non-Hodgkin lymphoma (NHL). 
The content of this SAP is based on NIR178X2201- Protocol Amendment 6. All decisions 
regarding interim analysis, as defined in the SAP document, have been made prior to database lock 
of the study data. 
The output shells accompanying this document can be found in the Tables, Figures and Listings 
(TFL) shells document. The specifications for derived variable and datasets can be found in the 
Programming Datasets Specifications (PDS) document.  
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious corrections 
will be made at the time of analysis to address minor formatting or spelling mistakes present in the 
TFL shells document without the need to amend. 
The SAP, TFL shells, and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., MTD/RD declaration, Investigator’s Brochure (IB) 
updates, abstracts, posters, presentations, manuscripts, and management updates. Data used for 
these analyses will have a status aligned to the database lock guidance. 
  
1.1 
Study design 
This is an open-label multi-part, phase II study evaluating the combination of NIR178 and PDR001 
in patients with advanced solid tumors and diffuse large B cell lymphoma (DLBCL). Patients will 
receive combination treatment, NIR178 + fixed PDR001 400 mg Q4W, until disease progression 
(assessed by investigator as per iRECIST (Appendix 3) for solid tumors, Cheson et al (2014) for 
DLBCL or PCWG3 guidelines for mCRPC), unacceptable toxicity, start of a new anti-neoplastic 
therapy, or discontinuation at investigator’s or patient’s discretion, lost to follow-up, death or study 
termination by the sponsor. All patients who discontinue from study treatment due to disease 
progression must have their progression clearly documented. All disease assessments will be 
performed locally by the investigator. 
 
 
 
Note: For the rest of the document, PDR001 400 mg Q4W  will be referred to as ‘PDR001’;  
patients receiving single agent (SA) NIR178 as ‘SA patients’ and those receiving combination 
treatment as ‘combination patients’. 
This phase II study has 3 parts (Figure 1-1). Parts 1 and 2 will enroll patients in parallel, and 
consequent to results from the two parts, Part 3 will open in not more than two select study 


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indications once recommended dose and dosing schedule is determined. The study parts have the 
following objectives:   
• Part 1: Multi-arm Bayesian adaptive signal finding design in groups of 13 treatment 
indications - 9 tumor types  including DLBCL, with categories based on mutation status or 
prior IO treatment, and assigned continuous dosing of NIR178 (160 mg BID or following 
Protocol Amendment 5, 240 mg BID) in combination with PDR001.  
Protocol Amendment 5 mandated administration of  NIR178 240 mg BID + PDR001in all 
newly enrolled patients having any of the Part 1 indications or 2 newly added  indications, 
mCRPC and RCC IO-pretreated, leading to 13 groups (see Section 2.5.2). 
• Part 2: Exploration of continuous and intermittent schedules of NIR178 160 mg BID in 
combination patients with advanced non-small cell lung cancer (NSCLC).  
By the time  Protocol Amendment 6 was formalized , this part was closed to enrollment and 
‘continuous’ schedule was inferred as ‘optimal’. 
• Part 3: Further evaluation of ‘optimal’ NIR178 schedule (consequent to Part 2 results) in 
combination patients with selected Part 1 treatment indication.  
Protocol Amendment 6 opened enrollment to Part 3 for exploring the safety and 
pharmacokinetics of the new FCT formulation of NIR178 160 mg BID at ‘continuous’ 
schedule in combination TNBC patients with PD-L1 SP-142 IC score of 0 (<1%). Provision 
to add another Part 1 treatment indication to Part 3, contingent on Part 1 analysis,  was 
introduced as well.  
 
In addition to the Phase II study, a safety run-in study will be conducted in Japanese patients with 
treatment indications specified in the Phase II study parts to evaluate the safety and 
pharmacokinetic profiles of NIR178 as a single-agent or in combination with PDR001 (Figure1-2).  
As of Protocol Amendment 6, total 6 patients were treated - 3 with  SA NIR178 80mg and 3 with 
SA NIR178 160mg, during Cycle 1 and with PDR001 initiated at the beginning of Cycle 2 . This 
amendment required administration of NIR178 240 mg BID in combination with PDR001among 
all newly enrolled Japanese patients. The dose escalation algorithm is detailed in Section 1.1.4. 
 
 
 
 
 
 
 
 
 


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Figure 1-11 
Study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1-22 
Study design- Japanese run-in part (NIR178 Single Agent and NIR178 
+PDR001)  
 
 
Advanced 
NSCLC, 
IO naive 


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1.1.1 
Part 1: Bayesian adaptive signal finding in solid tumors and DLBCL 
Part 1 of the study will enroll patients in the combination arm with the following treatment 
indications and NIR178 BID doses (160 mg at the study beginning and 240 mg consequent to 
Protocol Amendment 5): renal cell carcinoma (RCC) - IO naive (160 mg, 240 mg) and IO pretreated 
(240 mg), pancreatic cancer (160 mg), urothelial cancer (160 mg), squamous cell carcinoma of 
head and neck cancer (HNSCC) - IO naïve (160 mg) and IO pretreated (160 mg, 240 mg), 
microsatellite stable colorectal cancer (MSS CRC) - RAS wildtype (160 mg) and  RAS mutant (160 
mg), triple negative breast cancer (TNBC) (160 mg), cutaneous melanoma (BRAF V600E) (160 
mg), diffuse large B-cell lymphoma (DLBCL) (160 mg, 240 mg), and metastatic castration resistant 
prostate cancer (mCRPC) (240 mg). Each indication will initially enroll at least 10 patients (with 
minimum requirements described in Protocol Section 4.2). Depending on whether or not pre-
specified criteria for futility are met, each indication group may enroll up to a maximum of 30 
patients with the exception of the MSS CRC RAS mutant and RAS wildtype groups, wherein 20 
additional patients will be enrolled per group.  
Accrual to each indication group in Part 1 will be based on futility assessment of observed ORR 
via non-binding interim analysis (IA) (explained below). The hierarchical model (see Section 2.5) 
is implemented to assess clinical significance of observed ORR, allowing dynamic borrowing of 
information between indications such that more borrowing occurs across those that have similar 
ORR and less borrowing occurs between those that differ. In this way, the model is a compromise 
between the two alternate extremes of either a completely pooled analysis or a separate analysis in 
each indication.  
Note: For analysis, each of the indications - HNSCC IO pretreated & DLBCL, that has both 160 
and 240 mg dose groups, was pooled into a single indication group due to limited observed 
responses, thus, maintaining the number of treatment indications contributing to the model to 13 
that the study (Protocol Amendment 6) was designed for.   
1.1.1.1 
Timing of interim analyses and design adaptations 
Given the adaptive enrollment model and signal finding nature of Part 1, multiple interim analyses 
(IAs) will be performed to either stop early for futility or enroll patients until the next IA is 
performed or indication-specific maximum enrollment is reached.  
The first IA will occur when at least one indication group has accrued 10 patients who have at least 
one post-baseline disease assessment.  Futility assessment at the first IA and subsequent IAs  will 
inform a “go/no-go" decision for continuing enrollment in each indication group based on dynamic 
borrowing of ORR data across groups (See Protocol Section 10). Note: As of Protocol Amendment 
6, the groups, RCC IO naïve (NIR178 240 mg BID) and MSS-CRC, were extension of the earlier 
cohorts - the former had new patients enrolled at 240 mg as a result of Protocol Amendment 5; and, 
the latter was split in two groups, RAS wild type and RAS mutant, with 20 patients each upon 
decision to expand enrollment at their respective IA. 


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Subsequent IAs will occur when one or more additional indication groups accrue 10 patients at the 
same dose level (with minimum requirements described before). While all available data will be 
used from all indications, the decision to stop early at the IA will be made only for indications with 
the minimum sample size requirement described above.  
Non-binding: Novartis will have the flexibility to choose IA time points if it appears that multiple 
indications may qualify for IA requirements within a reasonable time between them. The futility 
assessment for an indication will not be binding even when the ORR-based early stopping criteria 
is met at respective IA. Novartis along with investigators may decide to continue enrolling patients 
to that indication group if comprehensive review of all available data suggests that the patients are 
receiving clinical benefit (Refer to Section 2.8). 
For an IA, if a patient is still on study and the last available efficacy assessment is a PR/CR which 
is yet to be confirmed by a subsequent scan, then this patient is considered a responder. 
1.1.2 
Part 2: NIR178+PDR001 schedule optimization 
Part 2 of the study will enroll only patients with advanced/metastatic NSCLC who are naïve to 
prior immunotherapy. Each treatment group characterized by a different dosing schedule of 
NIR178 160 mg BID will enroll 20 patients. Eligible patients will be randomized in a 1:1:1 fashion 
to one of the 3 dosing schedules of NIR178 160mg BID (listed below) in combination with PDR001 
within a 28-day cycle (Figure 1-3): 
• NIR178 S1: BID continuous 
• NIR178 S2: BID 14 days on/14 days off 
• NIR178 S3: BID 7 days on/7 days off 
Figure 1-33 
Alternate NIR178 dosing schedules within one cycle 
 
The safety, tumor response rates, and tumor immune modulation of the intermittent NIR178 
schedules (NIR178 S2 and S3) will be clinically assessed in comparison  to that in the continuous 
schedule (NIR178 S1). Based on cumulative data (including safety, tolerability, 
 PK, 
) across the three schedules, a dosing schedule may be selected by 
Novartis for further evaluation in Part 3 after documented discussion with study investigators. 


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Additionally, correlation between PD-L1 expression and response to PD-1 inhibitors in NSCLC 
will be further explored in a supportive analysis. 
 
1.1.3 
Part 3: NIR178+PDR001 additional exploration in selected treatment 
indications 
Part 3 of the study will be an expansion of the optimal NIR178 dosing schedule (if selected) with 
the objective of further evaluating safety, efficacy, and immune modulation of  the combination 
treatment with NIR178 dosing at “optimal”schedule in one or two select indication groups (from 
Part 1) of 20-30 patients. A maximum of 50 patients will be enrolled to this part, if initiated. 
The selected indications in Part 3 will be based on emerging data from Part 1 and Part 2. If one of 
the treatment indications selected for Part 3 is NSCLC, this group will enroll patients previously 
exposed to immunotherapy.   
As of Protocol Amendment 6, the one selected indication group, TNBC, will have enrollment of 
patients with a known PD-L1 SP142 status of IC=0 (<1%) using a new FCT formulation of NIR178 
at continuous dosing schedule in combination with PDR001. An additional indication group of 20 
patients may be considered consequent to Part 1 analysis.  
This part will initiate as PK/safety run-in of NIR178 160mg BID in combination with PDR001. 
After the first 10 patients complete at least 1 cycle of the study treatment, a safety analysis will be 
conducted to decide whether to escalate the NIR178 dose level to 240mg BID in newly enrolled 
patients or to complete Part 3 at NIR178 160mg BID. The dose escalation criteria is as follows: 
• If < 2 of the 10 evaluable patients have Grade 3/4 AEs suspected to be related to study drug in 
cycle 1, escalate dose to 240 mg BID in 20 additional newly enrolled patients.  
• If 2 or 3 of the 10 evaluable patients have Grade 3/4 AEs suspected to be related to study drug 
in cycle 1, 10 additional patients will be enrolled at the same dose level of 160 mg BID. 
• If > 3 of the 10 evaluable patients have Grade 3/4 AEs suspected to be related to study drug in 
cycle 1, no additional patients will be enrolled and development of the FCT formulation will 
be reassessed.  
Cumulative data (including safety, tolerability, 
 PK, 
) will 
be reviewed on an ongoing basis by Novartis and study investigators via teleconferences. 
1.1.4 
Japanese safety run-in study 
A separate safety run-in study will be conducted in Japan in order to adequately characterize the 
safety and pharmacokinetic profiles of NIR178 as a single-agent or in combination with 
PDR001(Figure 1-2). Patients enrolled in this part will be excluded from the primary analysis for 
efficacy and will also be exempt from the mandatory paired biopsy requirement. 
Based on the findings of CPDR001X1101 study, wherein no significant differences in the safety 
and PK of single agent PDR001 were found between Japanese and non-Japanese patients and the 


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recommended dose determined for PDR001 in non-Japanese patients was found to be acceptable 
for Japanese patients, the dose for PDR001 in the safety run-in of this sub-study will be 400 mg IV 
Q4 weeks. 
Patients enrolled in the safety run-in part must be hospitalized for safety monitoring during the 
DLT evaluation period, which is the first cycle of therapy. Patients must complete a minimum of 
80% of planned therapy during cycle 1 with the minimum required safety evaluation and drug 
exposure or have had a DLT within the first cycle of treatment to be considered evaluable for dose 
escalation decisions. Dose escalation decisions will occur when the cohort of patients has met these 
criteria.  
The safety run-in will initiate with evaluating two SA NIR178 dose levels sequentially: 
1. NIR178 80mg BID continuous (1st dose level) 
2. NIR178 160mg BID continuous 
Following Protocol Amendment 6, the dose level: NIR178 240 mg BID continuous will be initiated 
in combination with PDR001 with 3 newly enrolled patients. 
Each dose level may consist of 3 to 6 newly enrolled patients who have tumor histologies (see 
Protocol Section 5), and meet all other inclusion/exclusion criteria. 
The first three patients enrolled to receive SA NIR178 80mg dose level will be observed for a full 
cycle of treatment with NIR178 before additional patients are enrolled. All patients will have 
enrollment staggered by at least 24 hours. 
• If 1/3 SA patient at 80 mg experiences a DLT at the 80mg dose level, the safety run-in part will 
be terminated and Japanese patients will not join the phase II study. 
• If 0/3 SA patients at 80 mg  experience a DLT in cycle 1, evaluation of the 80 mg dose level 
will be complete and the next dose levelof SA, NIR178 160mg BID, will be initiated with 3 
new patients unless Protocol Amendment 6 has been executed.  
• If 0/3 SA patients at 160 mg experience a DLT in cycle 1, NIR178 160mg dose in combination 
with PDR001 may be declared safe in Japanese patients upon review of all available safety, PK, 
and PD data, and Japanese patients may join the phase II part of the study. This is based on the 
findings from other studies wherein no obvious ethnic differences in safety and PK of single 
agent PDR001 were observed between Japanese versus non-Japanese patients and no DDI 
between NIR178 and PDR001 was observed. 
• If 1/3 SA patients at 160 mg experience a DLT in cycle 1, 3 additional patients will be enrolled 
to this dose level. If ≤1/6 SA patients at 160mg experience DLT during cycle 1, NIR178 in 
combination with PDR001 may be declared safe upon comprehensive review of the all 
available safety, PK, and PD data, and new Japanese patients may directly join the phase II part 
of the study. 
• If >1/3 SA patients at 160 mg experience a DLT in cycle 1, the safety-run-in part will be 
terminated and Japanese patients will not join the phase II part of the study. 


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Patients who do not complete at least 80% of planned therapy during cycle 1 for reasons other than 
interruption/discontinuation due to AEs (e.g. Due to disease, progression or withdrawal of consent) 
will be replaced. If the 160mg dose of NIR178 in combination with PDR001 is declared well-
tolerated (based on the observed DLTs and other available safety data), patients at the 80mg dose 
level who have completed at least 2 cycles of combination therapy with PDR001 without grade 2 
or higher treatment related toxicity, may be allowed to escalate the NIR178 dose to 160mg after 
documented discussion with Novartis. 
Based on the data from the Japanese safety run-in at the 80 mg and 160 mg NIR178 doses, no 
obvious ethnic differences on safety and pharmacokinetics were observed as compared with the 
data from non-Japanese patients who were enrolled in CNIR178X2103J and CNIR178X2201. 
Therefore, Japanese patients can join other parts of this study.  
Following Protocol Amendment 6, Japanese patients in safety run-in will receive NIR178 240mg 
BID in combination with PDR001 starting cycle 1. 
• If 0/3 combination patients at NIR178 240mg experience a DLT in cycle 1, NIR178 240mg 
BID + PDR001 may be declared safe in Japanese patients upon review of all available safety, 
PK, and PD data, and Japanese patients may join the other parts of the study. 
• If 1/3 combination patients at NIR178 240mg experience a DLT in cycle 1, 3 additional patients 
will be enrolled to this dose level. If ≤1/6 combination patients at NIR178 240mg  experience 
DLT in cycle 1, NIR178 240mg BID + PDR001 may be declared safe upon comprehensive 
review of all the available safety, PK, and PD data, and new Japanese patients may directly join 
the other parts of the study. 
• If >1/3 combination patients at NIR178 240mg experience a DLT in cycle 1, the safety-run-in 
part will be terminated and Japanese patients will not join the rest of the study. 
Note: No interim analysis is planned for this study. The decision for dose escalation and to allow 
participation in phase II study will be based on all available safety data and the recommendation of 
participating investigators in Japan (Refer to Section 2.8). 
 
1.2 
Study objectives, endpoints and estimands  
Objectives and related endpoints are described in Table 1-1 below. 
Table 1-11 
Objectives and related endpoints 
Objective 
Endpoint 
Primary 
 
Part 1:To evaluate the efficacy of 
NIR178 and PDR001 combination in 
patients with selected advanced solid 
tumors and diffuse large B cell 
lymphoma (DLBCL) 
Overall Response Rate (ORR) by RECIST v1.1 
(for solid tumors) or Cheson (for DLBCL) or 
PCWG3 criteria for mCRPC   


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Objective 
Endpoint 
Part 2: To assess the efficacy of 
continuous and several intermittent 
dosing schedules of NIR178 in 
combination with PDR001 in NSCLC 
Overall Response Rate (ORR) by RECIST v1.1 
(for solid tumors) 
Part 3: To evaluate efficacy of 
intermittent or continuous dosing 
schedule of NIR178 in one or two 
selected tumor types 
Overall Response Rate (ORR) by RECIST v1.1 
(for solid tumors) or Cheson (for DLBCL) or 
PCWG3 criteria for mCRPC  
Secondary 
 
To assess efficacy of 
NIR178+PDR001 in select advanced 
solid tumors and lymphoma 
Overall Response rate (ORR) by iRECIST and in 
addition, for mCRPC, best PSA change from 
baseline. 
To assess efficacy of 
NIR178+PDR001 in select advanced 
solid tumors and lymphoma 
Disease Control Rate (DCR), duration of response 
(DoR), Progression Free Survival (PFS), 2 year 
Overall Survival (OS) rate by RECIST v1.1 and 
iRECIST (for solid tumors), Cheson (for DLBCL), 
and PCWG3 criteria for mCRPC  
To assess the safety and tolerability of 
the NIR178 and PDR001 combination 
using NIR178 hard gelatin capsule 
and FCT formulation  
Frequency, severity and seriousness of AEs, 
laboratory abnormalities  
and other safety parameters. Dose interruptions, 
reductions and dose intensity. 
To characterize changes in the 
immune infiltrate in tumors 
Change from baseline in TILs by 
immunohistochemistry (IHC) (such as CD8) 
To characterize the pharmacokinetics 
(PK) of NIR178, its metabolite NJI765 
and PDR001 in combination using 
hard gelatin capsule and FCT 
formulation 
Plasma concentration time profiles of NIR178, 
NJI765 and PK parameters. 
Serum concentration time profiles of PDR001 and 
PK parameters 
To assess immunogenicity of PDR001 
Presence and/or concentration of anti-PDR001 
antibodies 
Japanese Safety Run-in:To assess the 
preliminary safety, and PK of single 
agent NIR178 and in combination with 
PDR001 in Japanese patients  
Frequency, severity and seriousness of DLTs, 
AEs, laboratory abnormalities and other safety 
parameters (ECG, physical exams etc). 
Plasma concentration time profiles of 
NIR178/PDR001 and PK parameters. 


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2 
Statistical Methods 
2.1 
Data analysis general information 
Study data will be analyzed by Novartis personnel and/or designated CRO(s) using the most 
updated SAS® version in the GPS environment. For the Bayesian analyses using R and/or 
WinBUGS and/or JAGS the most updated version in the MODESIM environment will be used. PK 
parameters will be calculated using non-compartmental methods available in Phoenix WinNonlin 
version 5.2 or later. 
The study data will be reported at completion of the study, as defined in Protocol Section 4.3. A 
cutoff date will be established based on last patient last visit date. Statistical analyses will be 
performed using all data collected in the database up to the data cut-off date. All data with an 
assessment date or event start date (e.g., vital sign assessment date or start date of an adverse event) 
prior to or on the cut-off date will be included in the analysis. Any data collected beyond the cut-
off date will not be included in the analysis and will not be used for any derivations.  
General analysis conventions 
Pooling of centers: Unless otherwise specified, data from all study centers will be pooled for the 
analysis, so that an adequate number of patients will be available for analysis. Due to expected 
small number of patients enrolled at centers, no center effect will be assessed.  
The data will be summarized and listed with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) 
 measurements. All tables, figures and listings 
(TFLs) will be presented by treatment groups specific to the study parts and safety/efficacy 
objective. 
A treatment group will refer to patients receiving the same treatment (same type and dosage at 
the same schedule) for the same indication (tumor types  with subgroups, based on mutation status 
or prior IO treatment), collectively termed as “treatment indication”.  Treatment will be presented 
at the most granular level determined by its type, dosage and schedule. 
Phase II study 
Note: As of Protocol Amendment 6, Part 1 constitutes patients receiving varying dose levels of 
combination treatment at the same schedule for varying indications; Part 2 constitutes patients 
receiving a single dose level of combination treatment at varying schedules for a single indication; 
and,  Part 3 constitutes patients receiving same dose level at the same schedule for a single 
indication.  
The following rules will be followed for reporting results unless stated otherwise: 
• Part 1: In general, all TFLs will be presented by treatment indications unless specified 
otherwise.  


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- 
Disposition, demographics and baseline characteristics: Treatment groups at the most 
granular levels of treatment indication will be used for reporting on disposition, analysis 
sets, demographics, disease history, prior treatment and other baseline characteristics. If in 
the given programming environment,  presentation of summaries on all the treatment groups 
is visually constraining, then these summaries may be presented separately for safety and 
efficacy using their respective consolidated treatment groupings as defined below. 
- 
Safety/PK/IG: Treatment groups at the dose level of any treatment indication consolidating 
the categories of indication (consolidated by tumor types with no sub-grouping) will be 
used for reporting on safety and related endpoints like PK/IG. 
 
  
 
• Part 2: All TFLs will be presented by the treatment dosing schedule. 
• Part 3: If done, the presentation of TFLs will be similar to Part 1; however, if the indications 
selected from Part 1 do not have categories, then  the Part 3 summaries may be consolidated 
with Part 2 for condensed CSR reporting. 
Japanese safety run-in study  
The data from this study is planned to be reported in the CSR separately from the Phase II study 
regardless of the Japanese patients’ participation in the latter. However, for the brevity of CSR 
reporting, if deemed necessary, its reporting may be consolidated with safety  reporting of Part 2. 
The efficacy data from this cohort will not be summarized but only listed. 
 
Note: In a scenario that the results from part2, part 3 or the Japanese safety run-in are presented 
consolidatively and sorting on output data is involved for better interpretation of the results (e.g., 
AE summaries), then the results will be presented by study parts (part2, part 3, Japanese safety run-
in) within the same output to have their own independent sorting. 
 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
(frequencies and percentages) by treatment group; a missing category will be included as applicable. 
Percentages will be calculated using the number of patients in the relevant population or subgroup 
as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e., n, mean, standard deviation, median, interquartile range (Q1-Q3), minimum, and 
maximum) by treatment group. 
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings. 


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2.1.1 
General definitions  
2.1.1.1 
Investigational drug and study treatment 
For this study, the investigational drugs are NIR178 and PDR001, each also referred as ‘study drug’. 
When administered solely, it will be referred as ‘single agent’.The study treatment is defined as 
NIR178 in combination with PDR001, also termed as ‘combination treatment’.  They will be 
administered in the following dose strengths and forms:  
Table 2-11 
Dose and treatment schedule  
Study 
treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or Regimen 
NIR178 
40mg, 80mg and/or 160mg 
capsules for oral use 
160mg, 
240mg* 
Part 1 
Part 2 
Part 3 
Continuous BID 
Continuous and 
intermittent BID per 
randomization 
Continuous  
or intermittent BID 
based on Part 1 
and Part 2 results 
NIR178** 
80mg, 240mg  Film-coated 
tablet for oral use 
160mg 
240mg 
Not applicable 
Not applicable 
Continuous BID  
PDR001 
100mg powder for solution 
for infusion 
400mg 
Every 4 weeks                                    
*All newly enrolled patients under Amendment 5 will receive NIR178 240mg BID 
**As of Protocol Amendment 6, patients enrolled in Part 3 will receive continuous dosing of NIR178 FCT in combination with 
PDR001  
2.1.1.2 
Date of first/last administration of a study drug and study treatment 
The date of first (last) administration of a study drug is defined as the first (last) date when a non-
zero dose of a drug is administered and recorded on the treatment page eCRF. The date of first/last 
administration of study drug will also be referred as start/end date of study drug. 
The date of first (last) administration of study treatment is derived as the first (last) date when a 
non-zero dose of either component of the treatment (NIR178 or PDR001) was administered and 
recorded on the DAR eCRF.  
2.1.1.3 
Study day 
The study day represents the number of days elapsed since the study treatment start date including 
the day of treatment. It will be calculated as: study day = study date - treatment start date + 1, where 
study date could be an event onset date, assessment date etc. The first day of study treatment is 
therefore, study day 1. Example: if start of study treatment is on 05-Jan-2014 and start date of an 
adverse event is on 09-Jan-2014 then the study day of the adverse event onset is 5.  
However, for study dates before the treatment start date, the study day is negative and derived by 
study day = study date - treatment start date. For example: if start of study treatment is on 05-Jan-
2014 and date of lab measurement is on 02-Jan-2014 then the study day of the laboratory 


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abnormality is -3. Note, the day of start of study treatment is day 1, and the day before the date of 
first study treatment is day – 1, not day 0. 
2.1.1.4 
Baseline 
Baseline is the result of an investigation describing the “true” state of the patient before start of 
study treatment administration. 
For safety evaluations, the last available assessment on or before the date of start of study treatment 
for all three parts. In case time of assessment and time of treatment start is captured (e.g. pre-dose 
ECG), the last available assessment before the treatment start date/time is used for baseline. 
For safety parameters (e.g. ECGs or vital signs), where study requires multiple replicates per time 
point, 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 values 
are from central and local laboratories, the value from central assessment should be considered as 
baseline. If multiple values are from the same laboratory (local or central) or collected for ECGs 
or vital signs, then the last value should be considered as baseline. 
If patients have no value as defined above, the baseline result will be missing. 
2.1.1.5 
On-treatment assessment/event and observation periods 
The overall observation period will be divided into three mutually exclusive segments:  
pre-treatment period: from day of patient’s first informed consent to the day before first 
administration of study treatment 
on-treatment period: from date of first administration of study treatment to 30 days after date of 
last actual administration of study treatment (including start and stop date). This period 
constitutes safety follow-up on all patients for 30 days after the last administration of study 
treatment. 
post-treatment period: starting at day 31 after the last administration of study treatment. This period 
will constitute the following follow-up periods: 
- 
extended safety follow-up period: all patients receiving PDR001 will continue to have 
safety evaluations for 150 days after the last dose of PDR001 or 30 days after the last dose 
of NIR178, whichever occurs later. 
- 
disease progression follow-up period: Patients who discontinue study treatment for any 
reason other than death, disease progression per confirmed iRECIST or per Cheson (for 
DLBCL) or per PCWG3 guidance (for mCRPC) while on treatment, clinical deterioration 
or clinical progression, lost to follow-up, consent withdrawal or study termination, will 
have tumor evaluation assessments every 8 weeks (+/- 7 days) during the first 40 weeks, 


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and every 12 weeks (+/- 7 days) thereafter until disease progression, death, loss to follow-
up or withdrawal of consent, whichever occurs first. 
- 
survival follow-up period: Upon completion of the 150-day safety follow-up or disease 
progression follow-up, all patients (except for those in Japanese safety run in) will be 
followed for survival every 12 weeks until any of the following events(whichever occurs 
first): death, withdrawal of consent, loss to follow-up or at least 24 months from the first 
dose of study treatment. 
Patients enrolled to another clinical study or alternate treatment (Protocol Section 4.3) will not have 
follow-up for safety, disease progression and survival assessments performed.  
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot be 
made, then the respective data will be assigned to the on-treatment period. 
 
2.2 
Analysis sets  
A patient is considered to be enrolled into the study if he/or she has signed informed consent. Only 
a patient who has signed informed consent will be included in the analysis data sets. 
In addition, screen failure patients are those who signed the informed consent, but never started the 
study treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings. 
2.2.1 
Full analysis set 
For the Phase II - Part 1 and Part 3 and for the Japanese safety run-in study, the Full Analysis Set 
(FAS) comprises all patients who received at least one full or partial dose of assigned combination 
of study drugs. Patients will be analyzed according to the planned, which is the assigned treatment. 
For Part 2 of the study, the FAS comprises all patients randomized to a study treatment, which in 
this case is treatment dosing schedule. According to the intent to treat (ITT) principle, patients will 
be analyzed according to the treatment they have been assigned to during the randomization 
procedure. 
Unless otherwise specified, misrandomized patients (misrandomized in the interactive response 
technology (IRT) system) will be excluded from the full analysis set. Misrandomized patients 
include patients who are screen-failures, but have been randomized by the investigator before 
eligibility was finally assessed, however have not been treated. If patients were re-screened and 
successfully randomized, they will be included in the randomized set according to the dosing 
schedule treatment assigned in the last randomization. 
The FAS will be used for all listings of raw data. Unless otherwise specified, the FAS will be the 
default analysis set used for all analyses. 


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2.2.2 
Safety set 
The Safety Set includes all patients from the FAS who have received at least one dose of NIR178 
or PDR001. Patients will be classified according to treatment received, where treatment received 
is defined as: 
1. The treatment assigned if it was received at least once, or 
2. The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
The safety set will be used for the safety summary of the study. 
2.2.3 
Pharmacokinetic analysis set 
The Pharmacokinetic analysis set (PAS) includes all patients who provide an evaluable PK profile. 
A profile is considered evaluable if all of the following conditions are satisfied: 
• Patient receives one of the planned treatments 
• Patient provides at least one PK parameter 
• Patient did not vomit within 4 hours after the dosing of NIR178 
2.2.4 
 Immunogenicity analysis set 
The immunogenicity (IG) set includes two parts: IG prevalence set and IG incidence set: 
• The IG prevalence set includes all patients in the Safety set with a non-missing baseline ADA 
sample or at least one non-missing post-baseline ADA sample. 
• The IG incidence set includes all patients in the Immunogenicity prevalence set with a non-
missing baseline ADA sample and at least one non-missing post-baseline ADA sample. 
Note that the two datasets are specific to a study drug (in this study, only PDR001) with ADA 
sample drawn to detect monoclonal antibodies specific to that drug.  
2.2.5 
PK/ECG Analysis Set 
The PK/ECG analysis set includes all patients who provide baseline ECG data and at least one 
post-dose matched PK-ECG record (as defined in Section 5.6). Any PK-ECG analyses will be 
based on the PK/ECG analysis set.  
2.2.6 
Patient Classification 
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations (PD) entered in the database and/or on specific patient classification rules defined in 
Table 2-2.  
 


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Table 2-2 
Patient classification based on PDs and non-PD criteria 
 
Analysis set 
Protocol deviations leading to 
exclusion 
Non protocol deviation leading to 
exclusion 
Full analysis set  
No written informed consent 
Mis-randomized patients as defined 
in Section 2.2.1 
Patients who did not receive at least 
one dose of NIR178 or PDR001 
Safety set 
No written inform consent 
Patient who did not receive at least 
one dose of NIR178 or PDR001 or 
did not have at least one valid post-
baseline safety assessment. 
PK Analysis Set 
See definition of PK set 
Patient who did not have at least one 
evaluable PK data for NIR178 or 
PDR001 
IG Prevalence Set 
No written informed consent 
Patient did not have a non-missing  
baseline IG sample or at least one 
non-missing  post-baseline IG sample 
IG Incidence Set 
No written informed consent 
Patient  did not have a non-missing 
baseline IG sample and at least one 
non-missing post-baseline IG sample 
PK/ECG analysis set 
See definition of PK/ECG set 
Patient who did not have at least one 
post-dose matched PK-ECG record 
2.2.7 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a patient withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF.   
Additional data for which there is a separate informed consent, e.g. PK, 
 etc., collected 
in the clinical database without having obtained that consent will not be included in the analysis. 
These data will be excluded by the presence of the appropriate protocol deviation criterion. 
2.2.8 
Subgroup of interest 
Given the known correlation between PD-L1 expression and response to PD-1 inhibitors in NSCLC, 
the dosing schedule groups will be analyzed for their post-treatment response rate based on their 
baseline PD-L1 expression (present/absent), as defined by expression levels <1% or > 1% by 
immunohistochemistry (IHC) in part 2 of this study.  
 
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The FAS will be used for all baseline and demographic summaries and listings unless otherwise 
specified. Summaries will be reported by treatment group and for all patients and listings will be 
reported by treatment group, both following the general analysis conventions defined under Section 
2.1. No inferential statistics will be provided.  


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2.3.1 
Patient disposition 
The number (%) of treated (Part 1 and Part 3) /randomized (Part 2) patients, who are still on 
treatment, who discontinued the study phases, and the reason for discontinuation will be presented. 
The screened and not-randomized/not-treated patients and the reasons for screening failure will be 
listed.  
For patient disposition the following summaries, when applicable, will be provided: 
• Number (%) of patients who were treated/randomized; 
• Number (%) of patients who were not treated / were randomized but not treated; 
• Primary reason for not being treated;  
• Number (%) of patients who are still on-treatment (based on the ‘End of Treatment Phase’ 
page not completed); 
• Number (%) of patients who discontinued the study treatment phase;  
• Primary reason for study treatment phase discontinuation; 
• Number (%) of patients who have entered the post-treatment follow-up; 
• Number (%) of patients who have discontinued from the post-treatment follow-up; 
• Reasons for discontinuation from the post-treatment follow-up; 
• Number (%) of patients who have entered the survival follow-up. 
2.3.2 
Demographics and other baseline characteristics 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g., gender, age groups: 18- < 65, ≥65 years, race, ethnicity, ECOG performance 
status, smoking history, others as applicable) will be summarized by frequency counts and 
percentages; the number and percentage of patients with missing data will be provided. Continuous 
data (e.g., age, weight, height, body surface area, body mass index) will be summarized by 
descriptive statistics (N, mean, median, Q1, Q3, standard deviation, minimum and maximum).  
BMI and BSA are calculated using the following formulas: 
• BMI [kg/m2] = weight[kg] / (height[m]**2) 
• BSA [m2] = 234.94*(height[cm]**0.422)*(weight[kg]**0.515)/10000 
 
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, time 
(in months) since initial diagnosis of primary site, time (in months) from initial diagnosis to first 
recurrence/progression, time (in months) since most recent relapse/progression,  current extent of 
disease (metastatic sites). 


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Medical history 
A listing of medical history and current medical conditions will be provided by primary system 
organ class (SOC) and preferred term (PT). Medical history and current medical conditions will be 
coded using the latest Medical Dictionary for Regulatory Activities (MedDRA) terminology 
available at the time of reporting.  
 
Protocol deviations 
The number (%) of patients with any protocol deviation will be tabulated by deviation category (as 
specified in the study Edit Check Specifications). All protocol deviations will be listed. 
 
Analysis sets 
The number (%) of patients 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 
The safety set will be used for all summaries and listings of study treatment, the reporting of which 
will be in accordance to the general analysis conventions defined under Section 2.1 for safety.  
Duration of exposure in days, actual cumulative dose, dose intensity (DI), and relative dose 
intensity (RDI) will be summarized by treatment group, separately for each component of study 
treatment (NIR178 and PDR001). Duration of exposure will be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of patients in each interval. 
The number (%) of patients who have dose reductions or interruptions, and the reasons, will be 
summarized by treatment group.  
Patient-level listings of all administered treatment doses with change reasons will be produced.   
2.4.1.1 
Duration of exposure to study treatment 
Duration of exposure (DoE) to study treatment is considered by taking into account the duration of 
exposure to the investigational or control drug and any combination partner, if applicable: 
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) – (start 
date of study treatment) + 1.  
Duration of exposure to study drug (days) = (last date of exposure to study drug) – (start date of 
study drug) + 1.  
The start/end dates of study drug and study treatment are defined in Section 2.1.1.2.  


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Part 1, Part 2 and Part 3 (if done): 
The last date of exposure to study drug (NIR178 or PDR001) is defined as the end date of  that 
drug + X, where X for a study drug with  
- cyclic administration, is (cycle length - # planned treatment days in a cycle)  
- daily administration, is zero. 
Thus (see Table 2-3 for examples),  
• For NIR178 continuous BID dosing, the last date of exposure is defined as the last date of 
administration. 
• For PDR001 Q4W dosing, the last date of exposure is defined as the last date of 
administration + 27 days. 
• For NIR178 intermittent regimens in a 28-day cycle with: 
- 
2wk-on/2wk-off BID dosing, the last date of exposure is defined as the last date of 
administration + 14 days. 
- 
1wk-on/1wk-off BID dosing (effectively 14-day sub-cycle),  the last date of exposure 
is defined as the last date of administration + 7 days.  
The last date of exposure to study treatment is defined as the latest of the last date of exposure for 
study drugs in the combination. 
Note: If the patient died or was lost to follow-up before the derived last date, the last date of 
exposure to investigational drug is the date of death or the date of last contact, respectively. If the 
derived last date of exposure goes beyond the data cutoff date, it should be truncated to the date of 
data cutoff. 
Table 2-3 
Definition of last date of exposure of study drug 
Scenario 
Definition of last date of 
exposure of study drug 
Example 
Scenario 1: Study drug 
with 
a 
cyclic 
administration   
The planned end date of the last 
cycle in which the last non-zero 
dose of the investigational drug 
was last administered. 
 
Date of last administration of study 
treatment in the last cycle + (cycle 
length - # planned treatment days 
in a cylce) 
 
Example 1: In a once a week administration the 
cycle length is 7 days. The last date of exposure is 
the date of last  administration in the last cycle + 6 
days. 
 
Example 2: In a 1 week on and 3 weeks off 
administration the cycle length is 28 days. The last 
day of exposure is the date of last administration in 
the last cycle + 21 days. 
 
Example 3: In a 2 weeks on and 2 weeks off 
administration the cycle length is 28 days. The last 
day of exposure is the date of last administration in 
the last cycle + 14 days. 
 


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Example 4: For an every 2 weeks administration 
(Q2W) the cycle length is 14 days. The last date of 
exposure is the date of last administration in the last 
cycle + 13 days.  
 
Example 5: In a 21-day cycle with one or several 
infusions in the beginning of the cycle, the last date 
of exposure is the date of last infusion in the last 
cycle + 20 days. 
Scenario 
2: 
Daily 
administration 
of 
the 
study drug, i.e. BID, QD, 
and every other day 
(This 
includes 
other 
intermittent 
treatment 
regimens 
with 
drug 
holidays 
to 
manage 
toxicities e.g., 3 weeks 
on/1 week off, 5 days 
on/2 days off) 
Date of last administration of a non -
zero dose of the study drug. 
Example 
6: 
A 
patient 
had 
a 
permanent 
discontinuation of the study drug 06Jan2021 after 
being put on a temporary interruption since 
01Jan2021. In this case the last date of exposure is 
31Dec2020.  
 
Example 7: In a 3 week on and 1 week off 
administration of a small molecule compound the 
last date of exposure is the last day of 
administration of a non-zero dose.  
 
Example 8: In a 5 days on and 2 days off 
administration of a small molecule compound the 
last date of exposure is the last day of 
administration of a non-zero dose.   
Summaries of duration of exposure of study drugs and study treatment, expressed in weeks 
(DoE(days)/7) will include categorical summaries (based on clinically meaningful time intervals) 
and continuous summaries (i.e. mean, standard deviation etc.). 
2.4.1.2 
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.  
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 study drug administration. The planned cumulative dose is 
not summarized/listed. It is used for relative dose intensity calculations.  
The actual cumulative dose refers to the total actual dose administered, over the duration for which 
the patient is on the study treatment as documented in the treatment page eCRF.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded over 
the dosing period and the planned cumulative dose is the planned starting dose summed over the 
same dosing period. 


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For intermittent dosing, the actual cumulative dose should be defined based on the days when the 
patient is assumed to have taken a non-zero dose during dosing periods. For eg., if a patient’s 
duration of exposure is 31 days with assigned dose (X mg, BID) 2wk-on/2wk-off  in 28-days dosing 
period, then the actual cumulative dose  is the total dose administered (includes zero or reduced 
doses) during the initial 14 days of cycle 1 (ceiling of 31/28 = 1 complete cycle = 2 wk of dosing) 
and initial 3 days of cycle 2 ( min(3,14) = 3). However, the planned cumulative dose is the planned 
dose for that patient (constant Y mg) cumulated over the dosing days within the duration of 
exposure. 
As the study treatment is a combination agent, there might be patients in the safety set who did not 
take one component of study treatment and the cumulative dose for that component would be zero.  
2.4.1.3 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI (mg / day) = Actual Cumulative dose (mg) / Duration of exposure to study treatment (day). 
If for example the dosing unit is mg and the unit of time is a day: 
DI (mg/day)    = Actual Cumulative dose (mg) / Duration of exposure (day) 
 
 
= 1200 (mg) / 18 (Day) = 66.7 (mg/day) 
For patients who did not take any drug the DI is by definition equal to zero.  
 
Planned dose intensity (PDI) is defined as follows: 
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (day). 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg / day)  / PDI (mg / day).   
DI and RDI will be summarized separately for each component of the study treatment by using 
their respective duration of exposure. For the purposes of reporting, DI and PDI for PDR001 will 
be expressed in the unit, mg/4week = mg/28 days; whereas, for NIR178, they will continue to be 
expressed in mg/day. Summary of RDI will include categorical summaries. The RDI categories are 
< 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. 
The duration considered for the derivation of the DI and the RDI will be derived from the 
start date of study treatment to the end of the last cycle initiated, irrespective of date of death, last 
contact date for withdraw consent and cut-off date. 
2.4.1.4 
Dose reductions, interruptions or permanent discontinuations 
The number of patients who have dose reductions, permanent discontinuations, or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components.  


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‘Dose interrupted’, and ‘Dose permanently discontinued’ fields 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 a ‘change in prescribed dose level’ or an ‘error’. For the latter, 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, these interruptions will be counted as 
separate. 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. 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. 
Dose interruption: Actual dose administered equal to zero, between the first and last non-zero 
doses, following a non-zero actual dose administered. Dose interruption is collected as such in the 
treatment page eCRF. Number of dose interruptions and corresponding reason will be summarized. 
A patient with continued interruptions and no return will be considered as a permanent 
discontinuation. 
Missing data: If dose is recorded but regimen is missing or entered as ‘none’, it is assumed that the 
investigational drug was taken as per-protocol. 
In some cases the total dose administered may not be the same as the total prescribed dose - for 
example when the dose is prescribed by BSA (mg/m2) even though the total dose administered in 
(mg). In such cases there may be variations in the administered dose due to variations in BSA.  
2.4.1.5 
Compliance 
Compliance to the study treatment will be summarized in terms of the RDI or percentage of patients 
who took a predefined percentage of the number of prescribed doses. The predefined RDI 
categories are < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and proportion 
of patients falling in each category will be presented. 
2.4.2 
Prior, concomitant and post therapies 
Summaries and listings of prior and post treatment anti-neoplastic treatments will be presented by 
treatment group and overall, using the FAS following the general analysis conventions defined 
under Section 2.1. 


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Prior anti-neoplastic therapy 
The number (%) of patients who received any prior anti-neoplastic medication will be summarized 
and listed. The summary of prior anti-neoplastic medications may include the total number of 
regimens (note: there can be more than one medication per regimen), setting at last medication, 
time (in days) from last treatment to progression, best (hematological/cytogenetic/molecular) 
response at last treatment (defined to be the best response during the last treatment regimens 
recorded), duration (in months) of last response (last response is the response at last medication) 
and reason for discontinuation at last medication. The last medication is defined based on the last 
start date of all prior regimen components. Prior anti-neoplastic medications will also be 
summarized by Anatomical Therapeutic Chemical (ATC) class and preferred term (PT). 
The summary and listing of prior anti-neoplastic surgery may include prior surgery, procedure at 
last surgery, and residual disease at last surgery.  
The summary and listing of prior anti-neoplastic radiotherapy may include the radiotherapy 
locations (including all locations recorded for each patient), setting at last radiotherapy, and 
whether last radiotherapy was 30% of bone marrow. 
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and WHO-DD 
version will be included in the footnote in the tables/listings.  
Post treatment anti-neoplastic therapy 
Anti-neoplastic therapies since discontinuation of study treatment will be listed by ATC and PT. 
Concomitant medications 
Concomitant therapy is defined as any intervention (therapeutic treatment and procedure) other 
than the study treatment administered to a patient 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 
WHO Drug Reference Listing (DRL) dictionary that  employs the WHO ATC classification system.  
All concomitant therapies and significant non-drug therapies will be summarized and listed 
using the safety set. Any concomitant therapies and significant non-drug 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.  


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2.5 
Analysis supporting primary objective(s) 
There are three parts in the study.  
The primary objective for Part 1 is to evaluate the efficacy of NIR178 in combination to PDR001 
in patients with selected advanced solid tumors and DLBCL. 
The primary objective for Part 2 is to assess the efficacy of several continuous and intermittent 
dosing schedule of NIR178 in combination with PDR001 in NSCLC. 
The primary objective for Part 3 is to further evaluate the efficacy of intermittent or continuous 
dosing schedules (if selected) of NIR178 in combination with PDR001 in one or two selected 
treatment indications based on the emerging data from part 1 and part 2. 
The reporting of efficacy analyses for respective parts will follow the general analysis conventions 
defined under Section 2.1. 
2.5.1 
Primary endpoint(s) 
The variable used to evaluate the primary objective is overall response rate (ORR), defined as the 
proportion of patients with best overall response (BOR) of complete response (CR) or partial 
response (PR), as per local review and according to RECIST v1.1 (see Protocol Appendix 2 for 
details) for solid tumors, Cheson et al (2014) for DLBCL, or PCWG3 criteria for mCRPC (see 
Protocol Appendix 5 for details). 
2.5.2 
Statistical hypothesis, model, and method of analysis  
2.5.2.1 
Part 1 
This part will contain thirteen groups: (1) RCC IO naive at NIR178 160 mg BID, (2) RCC IO naive 
at NIR178 240 mg BID, (3) RCC IO pretreated at NIR178 240 mg BID, (4) pancreatic cancer at 
NIR178 160 mg BID, (5) urothelial cancer at NIR178 160 mg BID, (6) HNSCC IO naive at NIR178 
160 mg BID, (7) HNSCC IO pretreated NIR178 160 mg BID, (8) MSS CRC RAS wildtype NIR178 
160 mg BID, (9) MSS CRC RAS mutant NIR178 160 mg BID, (10) TNBC at NIR178 160 mg BID 
(11) melanoma IO pretreated NIR178 160 mg BID, (12) DLBCL at NIR178 160 mg BID, and (13) 
and mCPRC at NIR178 240 mg BID. 
Note: The efficacy data from the Non-HNSCC patients, MSS CRC patients with unknown RAS 
status and melanoma IO naive patients will not be included in the statistical model. The efficacy 
data from any new treatment indications added to the existing 13 groups before the study closure 
(as a consequence of Protocol Amendment 5) that qualify the criteria for Part 1 may be used to 
inform the model.     
All doses are given in combination with PDR001 400 mg Q4W. An adaptive Bayesian design 
(Neuenschwander et al 2016) will be used to assess activity of treatment in terms of overall 


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response rate (ORR) within each and across treatment indications. The design of the trial adapts to 
the data that are accumulated in the trial in such a way as to accommodate three possibilities: 
• Scenario A: ORR is similar across treatment indications 
• Scenario B: ORR is similar for some treatment indications and different in others 
• Scenario C: The various treatment indications have distinct ORR 
The pre-specified analysis is adaptive in the sense that when response is similar across all treatment 
indications (Scenario A), then it borrows information from across all the various treatment 
indications. In cases when few of the treatment indications have similar ORR (Scenario B), the 
model provides more precise estimates of ORR rates for the treatment indications that have similar 
response rates by allowing to borrow information only across these treatment indications. In the 
other possibility when the various treatment indications have distinct anti-tumor activity (Scenario 
C), the design allows little/no borrowing of information across treatment indications. In this case 
the trial will be similar to traditional stratified analysis. 
A hierarchical model (HM) will be used to analyze the binary data to facilitate the borrowing as 
specified above. Response rates (πj) will be inferred for treatment indication j (= 1,…, J=13). For 
each treatment indication j, the number of responders follows a binomial distribution; 
 
rj ~ Bin (nj, πj) 
We further let the parameters θj = log (πj / (1 − πj)) (logistic transformation) be either exchangeable 
with few of the treatment indications, or non-exchangeable with any of them. Based on the number 
of strata in this trial, we allow for two exchangeability distributions, which, for example, account 
for the case where a few treatment indications show no efficacy and others are promising. Thus, 
for each treatment indication j, three possibilities arise, with respective probabilities pj = ( pj1, pj2, 
pj3 ), as follows: 
1. With probability pj1 (probability group j belongs to exchangeability set 1) θj follows a normal 
distribution with exchangeability parameters µ1 and τ1: 
 
θj ~ N(µ1,τ12) 
2. With probability pj2 (probability group j belongs to exchangeability set 2) θj follows a normal 
distribution with exchangeability parameters µ1 <µ2 and τ2: 
 
θj ~ N(µ2,τ22) 
3. With remaining probability pj3 = 1−pj1−pj2 (probability group j is not exchangeable with any 
other group), θj follows a weakly-informative prior distribution 
 
θj ~ N(mw,vw) 
For the detailed specifications of mw, vw, the a-priori weights pj, and the prior distributions for µ1, 
τ1, µ2, and τ2, see Protocol Appendix 4. At any given time of the trial, including at the end, posterior 
probabilities of the various parameters will be estimated using Markov chain Monte Carlo methods. 


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The results at the final analysis within a treatment indication will be regarded to be positive if both 
of the following conditions are met: 
a. posterior mean ≥“clinically meaningful activity” threshold (column for C2 in Table 2-4) 
(i.e. posterior mean ORR >= C2) 
b. Posterior probability of “not being clinically meaningful” (column for C1 in Table 2-4) is 
less than 10% (i.e., prob(ORR <= C1|data) < 10%) 
Table 2-4 
Type of tumors of interest with definition of being clinically meaningful 
Serial no. 
Disease Code 
Treatment indication 
Not Clinically 
meaningful (C1) 
Clinically 
meaningful (C2) 
1 
T5 
RCC naive at 160 mge 
<= 25% 
>= 37% 
2 
T12 
RCC naive at 240 mge 
<= 25% 
>= 37% 
3 
T11 
RCC pretreated at 240 mge 
<= 10% 
>= 20% 
4 
T2 
Pancreaticb 
<= 8% 
>= 16% 
5 
T4 
Urotheliald 
<= 15% 
>= 27% 
6 
T3 
HNSCC naivec 
<= 13% 
>= 23% 
7 
T8 
HNSCC pretreatedc 
<= 5% 
>= 13% 
8 
T9 
MSS CRC – RAS wildtypeh 
<= 5% 
>= 13% 
9 
T10 
MSS CRC – RAS mutanth 
<= 5% 
>= 13% 
10 
T6 
TNBCf 
<= 5% 
>= 13% 
11 
T7 
Melanoma pretreatedg 
<= 10% 
>= 25% 
12 
T1 
DLBCLa 
<= 10% 
>= 20% 
13 
T13 
mCRPC at 240 mgi 
<= 10% 
>= 35% 
Interim analysis will be done when at least 10 patients in any indication have at least one post-baseline assessment 
(except for MSS-CRC and RCC naive at 240 mg patients i.e. T9, T10 and T12, no interim analysis will be done). 
Extend recruitment of up to 30 patients in each treatment indication according to IA outcome [P(clinically meaningful) > 
20%]. 
a. Ansell et al (2009) b. Kunk et al (2016) c. Fuereder (2016) d. Rosenberg et al (2016). 
e. Motzer et al (2015) f. Goodman (2015) g. Hodi et al (2016) h. Le et al (2015) . i. Bendell et al (2019) 
 
 
Details of statistical methodology : 
This section provides the details of model for Part 1 of the study. Prior specifications of model 
parameters are provided in detail. Data analysis and decision making in real trial are illustrated 
using hypothetical data scenarios, see Protocol Appendix 4. 
Prior specification of model parameters 
Bayesian model requires prior specification of parameters. The detailed prior specification of µ1, 
µ2, 1, 2, mw, vw, and pj are described in this section. 


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Prior specification of exchangeability distribution (µ1, µ2, 1 and 2) 
Prior for 1 and 2 are assumed to be half-normal distribution with scale 0.25, implying a prior 95% 
intervals for 1 and 2 as (0.008, 0.560), which allows for small to substantial between-strata 
heterogeneity (see Spiegelhalter et al 2004). 
µ1 and µ2 are given normal prior distributions. For first exchangeability distribution µ1, the mean 
of the prior distribution (mµ1) is set to logit(0.15) (or mµ1 = log(3/17)) which corresponds to no 
treatment effect. For second exchangeability distribution µ2, the prior mean (mµ2) was set to 
logit(0.6) (or mµ2 = log(3/2)). This corresponds to a substantial treatment effect. The variance 
parameter (Vµ1 and Vµ2) are derived using the following formula from law of total variance 
 
Vµi = V(θ) - E( ) and V(θ)=1/π + 1/(1- π) ; π= 0.15, 0.60 and i=1,2 
This yields Vµ1 = 7.843 – 0.252 = 7.781 (≈ 2.7892) and Vµ2 = 4.167 – 0.252 = 4.104 (≈ 2.0262).  
This allows a considerable uncertainty on prior belief of θ. 
Prior specification for stratified or “non-exchangeability” distributions 
(mw and vw) 
The strata-specific normal priors for the stratified or “non-exchangeable” case are defined by mw 
and vw were. The prior median for the response probability was set as 10% (no treatment effect) 
i.e., mw = logit(0.1) (or mw = log(1/9)) and the corresponding variance (vw) is set to 9 (=32) to allow 
large variability in prior. 
Specification of mixture weights (pj) 
Finally, for each stratum j, the prior mixture weights pj were chosen as 
 
pj = (0.25, 0.25, 0.50), j=1,…, J. 
This means that each stratum has 25% prior probability to belong to the first exchangeability 
distribution (µ1 and 1), 25% probability to belong to the second exchangeability distribution (µ2 
and 2), and 50% probability to be stratified or non-exchangeable with some (or all) of the other 
strata. 
2.5.2.2 
Part 2 
Different schedules of NIR178 160 mg BID in combination with PDR001 in NSCLC will be 
evaluated for efficacy using ORR as the primary endpoint. The analysis is described as follows: 
Overall response rate (ORR) will be provided for each schedule along with corresponding 90% 
confidence interval (CI). The prior distribution of ORR will be a minimally informative unimodal 
beta distribution with parameter a = 1/3 and b = 1 (note: this assumes a priori response rate of 25%). 
Posterior summaries for ORR (including 90% credible intervals and probability of ORR to fall in 
the activity interval defined below) will be provided. 


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[0, 20%): No improvement of ORR 
[20%, 33%): Limited improvement of ORR 
[33%, 100%]: Clinically meaningful improvement of ORR 
The difference between the ORR in different schedules will be summarized.  
The probability that one schedule is greater than another schedule given the data will be provided:  
i. 
Posterior probability that ORR for schedule 1 is greater than schedule 2 
ii. 
Posterior probability that ORR for schedule 2 is greater than schedule 3. 
iii. 
Posterior probability that ORR for schedule 1 is greater than schedule 3. 
In addition, the posterior probability that ORR for one schedule is greater than the other two 
schedules will be provided. 
The posterior mean of the differences of ORR between the schedules and the corresponding 90% 
credible intervals will also be provided. 
2.5.2.3 
Part 3 
As of Protocol Amendment 6, TNBC is one of the selected treatment indications in Part 3. A second 
treatment indication may be considered for Part 3 after completion of Part 1. Separately from Part 
1 TNBC patients (since the inclusion/exclusion criteria are different), the patients in Part 3 who 
will receive the new FCT formulation of NIR178 160 mg continuous dosing in combination with 
PDR001 will be analyzed for efficacy by treatment group using ORR as a primary endpoint with 
efficacy intervals as reported in Table 2-4 for the TNBC group.    
ORR will be provided with corresponding 90% confidence interval (CI). The prior distribution of 
ORR will be a minimally informative unimodal beta distribution with parameter a = 0.176 and b = 
1 (note: this assumes a priori response rate of 15%). Posterior summaries for ORR (including 90% 
credible intervals and probability of ORR to fall in the activity interval defined below) will be 
provided. 
 [0, 5%): No improvement of ORR 
 [5%, 13%): Limited improvement of ORR 
[13%, 100%]: Clinically meaningful improvement of ORR  
2.5.3 
Handling of missing values/censoring/discontinuations 
At final analysis, confirmed partial or complete responses reported prior to any additional 
anticancer therapy will be considered as responses in the calculation of ORR irrespective of the 
number of missed assessments before response. 


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At interim analyses, patients are considered to be evaluable if they are ongoing with study treatment 
and have at least one post-baseline response assessment, or who have discontinued study treatment. 
This total will be used for percentage calculation of ORR. For the purpose of the IA, if a patient is 
still on study and the last available efficacy assessment is a PR/CR which is yet to be confirmed by 
a subsequent scan, then this patient will be considered as a responder. 
For solid tumor, patients with a best overall response of ‘Unknown’ or ‘Not Assessed’ per RECIST 
v1.1 will be considered as non-responders and will be included in the denominator in estimating 
the ORR. For lymphoma, patients with unknown or missing response or who are treated in the 
study but provide no information on response at the end of treatment will be treated as non-
responders and will be included in the denominator when calculating ORR. 
2.5.4 
Sensitivity analyses  
Not applicable. 
 
 
 
 
 
  
  
2.6 
Analysis supporting secondary objectives  
2.6.1 
Efficacy objectives 
The secondary objective is to assess the efficacy of NIR178 in combination of PDR001 using ORR 
per iRECIST, and other efficacy measures including disease control rate (DCR), duration of 
response (DOR), progression free survival (PFS) and 2 year overall survival (OS) by both RECIST 
v1.1 and iRECIST for solid tumors, by PCWG3 guidance (see Protocol Appendix 5) for mCRPC, 
and by Cheson et al (2014) for DLBCL.  
These efficacy endpoints will be summarized for all the treatment groups contributing to the 
analysis of primary efficacy objective (see Section 2.1 general analysis conventions). 
 
ORR:  
Overall response rate (ORR) is defined as the proportion of patients with best overall response 
(BOR) of immuno-related complete response (iCR) or immuno-related partial response (iPR), as 
per local review and according to iRECIST (see Protocol Appendix 3 for details) for solid tumors. 


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ORR as per iRECIST will be provided for each treatment indication along with corresponding 95% 
confidence interval (CI). 
DCR:  
DCR is the proportion of patients with a best overall response of CR, PR or stable disease (SD). 
DCR will be summarized by treatment indication with accompanying 95% confidence intervals. 
OS, PFS and DOR:  
OS is defined as the time from date of start of treatment to date of death due to any cause. If a 
patient is not known to have died, OS time will be censored at the date of last contact. The 2 year 
OS rate is the proportion of patients with at least 2 years of OS.  
PFS is defined as the time from start of treatment date to date of the first documented disease 
progression or date of death, whichever happens first. If a patient has not had the event at the date 
of analysis cut-off, PFS will be censored at the time of the adquate tumor assessment before the 
cut-off.   
For patients with a confirmed CR or confirmed PR, the DoR is the time from date of first 
documented response (CR or PR) to date of first documented progression or death due to 
underlying cancer, whichever happens first. If progression or death has not occurred at the date of 
analysis cut-off, then DoR will be censored at the date of last adequate tumor assessment before 
the cut-off.  
Kaplan-Meier (KM) plots and estimates for time-to-event endpoints including OS, PFS, and DOR 
will be presented for treatment groups of size ≥10 patients with estimable median. Median with 
accompanying 90% confidence intervals along with KM estimates for PFS and OS at 4, 6, 9, 12, 
18 and 24 months will be reported. 
For mCRPC patients, PSA at each time-point will be listed and change from baseline in PSA may 
be plotted and summarized if there are sufficient (≥ 10) patients.  
All efficacy data from the patients from Japanese safety run-in part will be listed separately. These 
patients will not be summarized with the other patients. 
All efficacy data from the non-HNSCC patients and melanoma IO naive patients will be listed 
separately and will not be summarized with the other patients. All efficacy data from patients with 
unknown RAS status will be summarized as a separate group with all other patients using estimable 
endpoints (enough patients for the endpoints to be estimated); otherwise, the efficacy data will be 
listed.  
2.6.2 
Safety objectives 
All safety analyses will be based on the safety set (see Section 2.2.2), which will be used for 
presenting summaries and listings by treatment groups and overall patients following the general 
analysis conventions defined under Section 2.1.  


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The assessment of safety is based on the type and frequency of AEs as well as on the number of 
laboratory values that fall outside of pre-determined ranges (CTCAE grading limits or normal 
ranges as appropriate). Other safety data include electrocardiogram and vital signs. 
All safety reporting will be based on observation periods defined in Section 2.1.1.5.  
Safety summaries (tables, figures) will primarily be based on all data from the on-treatment period 
with the exception of baseline data which will also be summarized where appropriate (e.g. change 
from baseline summaries). In addition, a separate summary for death including on treatment and 
post treatment deaths will be provided.  Following the last administration of study treatment, 
adverse events (including serious adverse events), and new antineoplastic therapies will be 
collected for a period of 150 days.  Following start of new antineoplastic therapy only treatment 
related adverse events will be collected.  Select summaries of related adverse events will be 
produced for the combined on-treatment and post-treatment periods (see Protocol Section 10.5.2.2). 
2.6.2.1 
Adverse events (AEs) 
Summary tables for adverse events (AEs) will include AEs that started or worsened during the on-
treatment period, also termed as treatment-emergent AEs.  
AEs will be summarized by number and percentage of patients having at least one AE, having at 
least one AE in each primary SOC and for each PT. AEs will be coded using the MedDRA and 
assessed according to the CTCAE version 4.03, respectively. The latest available MedDRA version 
at the time of the analyses should be used. The MedDRA and CTCAE version used should be 
specified in the footnote of relevant tables. 
A patient with multiple occurrences of an AE will be counted only once in the respective AE 
category. A patient 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 of the PTs will be based on their frequency in the most relevant group.  
Note: In AE summaries with consolidated study parts, AEs will be presented by study parts, with 
each part having its own sort order (see General analysis conventions  under Section 2.1 for detail).  
The following AE summaries will be produced:   
• Overview of adverse events (number and % of patients with any AE, any SAE, any fatal 
SAEs, any AE with dose reductions/interruptions/discontinuations, and correspondingly, 
with treatment-related AEs; also, AEs requiring additional therapy ); 
• AEs regardless of study drug relationship by SOC and/or PT, and severity; 
• AEs suspected to be study drug related by SOC and/or PT, and severity; 
• AEs leading to dose interruption/adjustment regardless of study drug relationship, by SOC 
and/or PT, and severity; 


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• AEs leading to dose interruption/adjustment suspected to be study drug related, by SOC 
and/or PT, and severity; 
• AEs leading to study drug discontinuation regardless of study drug relationship by SOC 
and/or PT, and severity; 
• AEs leading to study drug discontinuation suspected to be study drug related by SOC and/or 
PT, and severity; 
• SAEs regardless of study drug relationship by SOC and/or PT, and severity; 
• SAEs suspected to be study drug related by SOC and/or PT, and severity; 
All AEs collected on the AE eCRF page will be listed with the information collected on those AEs 
e.g. AE relationship to study drug, AE outcome, etc. AEs with start date in the post-treatment period 
will be flagged in the listings; those that start in the pre-treatment period will be identified by study 
day prefixed with a ‘-‘ (a negative sign). Additionally, listings for AEs and SAEs on screened 
patients who are not treated will be provided with information on those AEs including start-end 
dates, outcome etc.  
2.6.2.2 
Adverse events of special interest (AESI) / grouping of AEs 
An adverse event of special interest is a grouping of adverse events that are of scientific and medical 
concern specific to compounds PDR001 or NIR178. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high level 
terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) may also 
be used. A NMQ is a customized group of search terms which defines a medical concept for which 
there is no official SMQ available or the available SMQ does not completely fit the need. It may 
include a combination of single terms and/or an existing SMQ, narrow or broad. 
The reporting of AESIs will follow similar conventions as used for AEs (see General analysis 
conventions in Section 2.1). 
Given that only PDR001 specific electronic Case Retrieval Strategy (eCRS) exists, summaries of 
AESI associated with the combination (NIR178 + PDR001) will be reported using PDR001 specific 
eCRS for the combination arm by treatment groups.  For each specified AESI, number (%) of 
patients with at least one event of the AESI occurring during on-treatment period will be 
summarized together with the individual preferred terms in that grouping. In addition, number (%) 
of patients with at least one AESIs by maximum CTC grade will be summarized.   
A listing of all grouping levels down to the MedDRA preferred terms, based on the eCRS used to 
define each AESI, will be generated. 
2.6.2.3 
Deaths 
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All deaths will be listed and post-treatment deaths will be flagged. A separate listing of deaths prior 
to the treatment initiation will be provided for all screened patients. 
Note: “Study indication” as primary reason of death should be coded using MedDRA terms based 
on the diagnosis eCRF field at start of study. If not coded accordingly in the database, it still must 
be included in the summary table. Coded reasons for deaths will then be summarized by category 
‘Study indication’ and ‘Other’ (as selected by the investigator). 
The death summaries cover patients from the safety set. The count of deaths reported in safety 
analyses may differ from that  reported in the efficacy analyses. 
2.6.2.4 
EudraCT and clinicaltrials.gov requirements for AEs and Death summaries 
For the legal requirements of clinicaltrials.gov and EudraCT, two tables (listed below) must be 
produced for treatment-emergent safety events (AEs/SAEs and deaths) that occurred for 150 days 
after the last dose of PDR001 or 30 days after the last dose of NIR178, whichever occured later.   
1. Deaths and serious adverse events, by system organ class and preferred term. 
2. Non-serious AEs regardless of study drug relationship, with an incidence rate greater than 
5% by SOC and PT. 
These summaries will include any events starting or worsening in the on-treatment period. 
If for the same patient, 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. 
The presence of at least one SAE / SAE suspected to be study drug related / 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. 
At the time of xml preparation, a single file per registry (i.e., 1 file for EudraCT and 1 file for CT.gov). 
with all reporting groups in the study will need to be submitted to the CDO. 
2.6.2.5 
Laboratory data 
Grading of laboratory values will be assigned programmatically as per CTCAE version 4.03. The 
calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will 
not be used. 


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For laboratory tests where grades are not defined by CTCAE 4.03, results will be categorized as 
low/normal/high) based on laboratory normal ranges. 
The following summaries will be produced for hematology and biochemistry laboratory data (by 
laboratory parameter and treatment): 
• Worst post-baseline CTC grade (regardless of the baseline status). Each patient will be 
counted only for the worst grade observed post-baseline; 
• Shift tables using CTC grades to compare baseline to the worst on-treatment value; 
• For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value; 
The following listing(s) will be produced for the laboratory data: 
• Listing of all CTC grade 3 or 4 laboratory toxicities. 
Liver function parameters   
Liver function parameters of interest are total bilirubin (TBL), ALT, AST, and alkaline phosphatase 
(ALP). The number (%) of patients with worst post-baseline values as per Novartis Liver Toxicity 
guidelines will be summarized: 
The following summaries will be produced: 
• ALT or AST > 3xULN  
• ALT or AST > 5xULN 
• ALT or AST > 8xULN 
• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• TBL > 2xULN 
• TBL > 3xULN 
• ALT or AST > 3xULN & TBL > 2xULN 
• ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  (potential Hy’s law) 
Potential Hy’s Law events are defined as those patients with concurrent occurrence of AST or ALT > 
3xULN and TBL > 2xULN and ALP < 2xULN in the same assessment sample during the on-
treatment period. Further medical review should be conducted to assess potential confounding 
factor such as, liver metastases, liver function at baseline etc.  
For more details and adaptation of above summary, Oncology Hepatic Safety guidance should be 
referred. 


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2.6.2.6 
Other safety data 
2.6.2.6.1 ECG and cardiac imaging data 
In case the study requires ECG replicates at any assessment, the average of the ECG parameters at 
that assessment should be used in the analyses. 
12-lead ECGs including PR, QRS, QT, QTcF, QTcB, and RR intervals will be obtained 
centrally/locally for each patient during the study. ECG data will be read and interpreted 
centrally/locally.  
The following summaries will be presented: 
• 
Change from baseline for ECG parameters by timepoint  
• 
Number and percentage of patients with notable ECG values. 
o QT, QTcF, or QTcB 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from baseline of > 30 ms to ≤ 60 ms 
- 
Increase from baseline of > 60 ms 
o HR 
- 
Increase from baseline >25% and to a new HR > 100 bpm 
- 
Decrease from baseline >25% and to a new HR < 50 bpm 
o PR 
- 
Increase from baseline >25% and to a new PR > 200 ms 
- 
New PR > 200 ms 
o QRS  
- 
Increase from baseline >25% and to a new QRS > 120 ms  
- 
New QRS > 120 ms  
A listing of patients with only notable ECG values will be produced. For patients with at least one 
notable ECG parameter value, all parameters should be listed.  
PK-ECG analysis   
A linear mixed effects model will be used to analyze QTcF change from baseline versus plasma 
NIR178 concentration using the PK/ECG analysis set. The linear mixed effects model is as follows:  
∆QTcF𝑖𝑗 = (𝛽0 + 𝑏0𝑖) + 𝛽1𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒_𝑄𝑇𝑐𝐹𝑖+ 𝛽2𝑐𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛𝑖𝑗+  𝜖𝑖𝑗 
In this model, b0i is the patient's random effect. A compound symmetry covariance structure is 
assumed; other covariance structures may be explored.  


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The estimated mean QTcF change from baseline will be presented along with the two-sided 90% 
CI for different concentration thresholds (mean, Q1, median, and Q3) of Cmax for dose levels 
160mg BID and 240 mg BID, corresponding to C1D1 and/or steady state.  
o These thresholds will be determined from C1D1 and/or steady state Cmax  
o Baseline QTcF will be set to its median baseline value  
QTcF is suggested by the ICH E14 guidance (attached at the end of this document (Section 6)) and 
is more accurate than other correction methods in patients with altered heart rates. 
 
 
 
  
A check of mean concentration versus time and mean QTcF change from baseline versus time 
should be performed to rule out any delayed effect (hysteresis). 
 
 
  
 
  
2.6.2.6.2 Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The following 
parameters will be collected: weight (kg), body temperature (°C), heart rate (beats per minute), 
systolic and diastolic blood pressure (mmHg).  
The number and percentage of patients with on-treatment notable vital sign values (high/low) will 
be presented.          
A listing of patients with only notable vital sign values will be produced. For patients with at least 
one notable vital sign parameter value, all parameters should be listed.  
For analysis of vital signs, the clinically notable vital sign criteria are provided in Table 2-5 below. 
Table 2-5 
Clinically notable changes in vital signs 
Vital sign (unit) 
Clinically notable criteria 
 
above normal value 
below normal value 
Weight (kg) 
increase ≥10% from baseline 
decrease ≥10% from baseline 
Systolic blood pressure 
(mmHg) 
≥180 with increase from baseline of ≥20 
≤90 with decrease from baseline of ≥20 
Diastolic blood pressure 
(mmHg) 
≥105 with increase from baseline of ≥15 
≤50 with decrease from baseline of ≥15 
 
Pulse rate (bpm) 
≥100 with increase from baseline of >25% 
≤50 with decrease from baseline of > 25% 
 
Body temperature (°C) 
≥ 39.1  
- 


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2.6.2.6.3 Additional analyses 
Tolerability of study drug treatment will be based on the safety set and assessed by summarizing 
the number of treatment dose interruptions and dose reductions by part. Reasons for dose 
interruption and dose reductions will be listed and summarized. Cumulative dose, DI and RDI of 
each study drug will be summarized by treatment group (for reporting and definitions, see Section 
2.1 and Section 2.4.1).  
For Japanese safety run-in study, frequency, severity and seriousness of dose limiting toxicities, 
AEs, laboratory abnormalities and other safety parameters (ECG, physical exams etc) will be 
summarized separately from the Phase II study or in a consolidated setting using safety set (see 
General analysis conventions in Section 2.1). 
2.6.3 
Pharmacokinetic endpoints   
Pharmacokinetics of the study drugs will be assessed to support a secondary objective using the 
PK datasets and will be reported by treatment groups following the general analysis conventions 
used for the safety set (see Section 2.1). 
PK parameters 
PK parameters such as those listed in in Table 2-6 will be estimated and reported, when applicable. 
The PK parameters are derived based on non-compartmental methods for NIR178 and its 
metabolite NJI765 and PDR001. 
Table 2-6 
Non-compartmental PK parameters  
AUCinf 
The AUC from time zero to infinity (ng*hr*mL-1) 
AUClast 
The AUC from time zero to the last measurable plasma concentration sampling time (tlast) 
(ng*hr*mL-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-
1) 
Cmax 
The maximum (peak) observed plasma concentration following a single dose administration 
(ng/mL) 
Tmax 
The time to reach maximum (peak) plasma concentration following a single dose administration 
(hr) 
T1/2 
The elimination half-life associated with the terminal slope ( z) of a semi logarithmic 
concentration-time curve (hr). 
1CL/F 
The total apparent body clearance of drug (L*hr-1) 
1Vz/F 
The apparent volume of distribution during terminal phase (associated with z) (L) 
1 For parent drug only 
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, geometric 
mean, CV% geo-mean, minimum, and maximum) will be presented by treatment groups using the 


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PAS for all PK parameters defined in Table 2-6 except Tmax, where only n, median, minimum, 
and maximum will be presented.  
For NJI765, CL/F, Vz/F and elimination half-life will not be reported. 
PK parameters estimated for the Japanese patients in Japanese safety run-in study may be reported 
consolidatively with rest of the Phase II study patients. 
All individual PK parameters will be listed by treatment using the safety set. 
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 NIR178,NJI765, and 
PDR001 concentration will be presented at each scheduled timepoint by treatment using the PAS. 
Individual concentration-time profiles for NIR178,NJI765, and PDR001 concentrations with 
median will be displayed graphically by treatment using the safety set on the semi-log view. In 
addition, the mean (+/- SD) concentration-time profiles for NIR178,NJI765, and PDR001 by 
treatment over time will be displayed graphically using the PAS on the linear and semi-log view. 
PK plasma concentration time profiles of Japanese patients in Japanese safety run-in study will be 
reported separately from Phase II study patients. 
All individual plasma NIR178,NJI765, and PDR001 concentration data will be listed by treatment 
using the safety set.   
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. 
Missing values for any PK data will not be imputed and will be treated as missing. 
At the time of analysis, concentration data from patients may be removed from the estimation of 
certain PK parameters depending on the number of available blood samples, concomitant 
medications, vomiting, etc. Reason(s) for removing concentration data will be provided. Specific 
timepoints might be removed from the analysis set if technical issues with the sample are reported 
(e.g., sampling issues, missing information). These patients and concentration data points will be 
identified at the time of analysis. 
2.6.4 
PD and PK/PD analyses 
Not applicable. 


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2.6.5 
Immunogenicity 
Immunogenicity of PDR001 will be assessed to support a secondary objective using the IG datasets 
and will be reported by treatment groups following the general analysis conventions used for the 
safety set (see Section 2.1). 
2.6.5.1 
Sample ADA status 
Each anti-drug anti-body (ADA) sample is assessed in a three tiered anti-drug anti-body (ADA) 
testing approach. All ADA samples are analyzed in the initial screening assay (first tier). Samples 
testing negative in the screening assay are not patient to a confirmatory assay. Samples testing 
positive in the screening assay are then patiented to the confirmatory assay to demonstrate that 
ADA are specific for the therapeutic protein product (second tier). The titer of confirmatory 
positive samples will be subsequently determined in the titration assay (third tier).  
Samples identified as positive in the confirmatory assay are considered ADA positive.  
Samples can test negative in either the screening or confirmatory assay but for analysis purposes 
they are not differentiated. The following properties of each sample will be provided in the source 
data:  
• Result of assay according to pre-specified confirmatory cut point: ‘POSITIVE’, ‘NEGATIVE’, 
or ‘NOT REPORTABLE’ 
• Titer: numerical representation of the magnitude of ADA response 
• 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 ADA 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 Immunogenicity 
prevalence set specific to a study drug:  


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• 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 patients at that time 
point with a non-missing sample. 
Listings will be provided of ADA sample status specific to the PDR001 component of the study 
treatment. 
2.6.5.2 
Patients ADA status 
Any ADA sample collected after extended follow up period of 150 days of the last dose of the drug 
spartalizumab will not be used for summaries or derivations and will only be included in the listing. 
Patient ADA status is defined as follows: 
• Treatment-induced ADA-positive patient: patient with ADA-negative sample at baseline and at 
least one treatment-induced ADA-positive sample.  
• Treatment-boosted ADA-positive patient: patient with ADA-positive sample at baseline and at 
least one treatment-boosted ADA-positive sample.  
• Treatment-unaffected ADA-positive patient: patient 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 patient: patient with ADA-positive sample at baseline and at 
least one non-missing post-baseline sample, all of which are ADA-negative samples.  
• ADA-negative patient: patient with ADA-negative sample at baseline and at least one non-
missing post-baseline sample, all of which are ADA-negative samples.   
• Inconclusive patient: patient who does not qualify for any of the above definitions or a patient 
for which the baseline sample is missing. 
The following summaries of ADA patient status (n and %) will be provided using Immunogenicity 
incidence set (for % the denominator is the number of patients in the Immunogenicity incidence 
set unless otherwise specified):  
• Patients with ADA-negative sample at baseline 
• Patients with ADA-positive sample at baseline 
• ADA-negative patients: for %, the denominator is the number of patients in Immunogenicity 
incidence set. 
• Treatment-induced ADA-positive patients; for %, the denominator is the number of patients 
with ADA-negative sample at baseline.  
• Treatment-boosted ADA-positive patients; for %, the denominator is the number of patients 
with ADA-positive sample at baseline.  
• Treatment-reduced ADA-positive patients; for %, the denominator is the number of patients 
with ADA-positive sample at baseline. 


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• ADA-positive patients (i.e. ADA incidence): calculated as the number of treatment-induced,  
treatment-boosted and treatment-reduced ADA-positive patients; for %, the denominator is the 
number of patients in Immunogenicity incidence set.  
Listings will be provided of ADA patient status.  
2.6.6 
Patient-reported outcomes 
Not applicable. 


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2.8 
Interim analysis 
Part 1: 
Patients will be continuously accrued and the data will be analyzed using a Bayesian hierarchical 
model mentioned in Section 2.5.2. Interim analysis for a treatment indication will be performed 
when at least 10 enrolled patients have at least one post-baseline disease assessment. Note: As of 
Protocol Amendment 6,  the groups, RCC IO naïve (NIR178 240 mg BID) and MSS-CRC, were 
extension of the earlier cohorts - the former had new patients enrolled at 240 mg as a result of 
Protocol Amendment 5; and, the latter was split in two groups, RAS wild type and RAS mutant, 
with 20 patients each upon decision to expand enrollment at their respective IA.  
The futility analysis will not be binding. At each of these analyses, the current (posterior) 
probability that the response rate for each of the treatment indications is greater than “clinically 
meaningful threshold (column for C2 in Table 2-4)” will be determined.  
These probabilities will be used to adapt the design. All available data for evaluable patients will 
be used for analysis at each interim analysis. However, a decision will be made only for the 
qualified treatment indication (≥ 10 patients with at least one post-baseline assessment) based on 
the calculated probability as given below: 
1. Accrual to a treatment indication will cease for futility if it is very unlikely (posterior 
probability <20%) that the response rate for the treatment indication is “clinically 
meaningful” (≥C2 threshold in Table 2-4) 
2. Otherwise, recruitment will continue until the next IA is performed or a maximum of 30 
patients in that treatment indication has been enrolled. 


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For the purpose of the IA, if a patient is still on study and the last available efficacy assessment is 
a PR/CR which is yet to be confirmed by a subsequent scan, then this patient will be considered as 
a responder. 
The results at the final analysis within a treatment indication will be regarded as positive if the 
posterior mean ORR is greater than the threshold for clinically relevant activity and the posterior 
probability of not being clinically meaningful is low (less than 10%). 
Depending on enrollment, there may be multiple interim analyses. 
Japanese safety run-in study: 
No formal interim analyses are planned. However, the dose-escalation design for safety run-in part 
foresees that decisions based on the current data are taken before the end of the planned safety run-
in part. Details of this procedure and the process for communication with Investigators are provided 
in Section 1.1.4. 
  
3 
Sample size calculation 
3.1 
Part 1 
The design of this part is adaptive in nature; hence, the final sample size is not fixed. As of Protocol 
Amendment 6, a minimum of 10 and a maximum of 30 evaluable patients will have enrollment in 
13 treatment indication groups (see Section 2.5.2.1). Thus, the total sample size across all treatment 
indications will be between 130 and 310. 
Patients will be continuously accrued, and the accumulated data will be analyzed at interim as 
described in Section 2.8. Based upon the results of any of these analyses, enrollment into one or 
more treatment indications may be terminated. 
The operating characteristics for this Bayesian Design are evaluated using simulation. Simulation-
based probability estimates (relative frequencies) of futility at interim and positive results at final 
analysis for each tumor type in four scenarios (see  Protocol Table 14-12) are provided in Protocol 
Appendix 4. The number of simulations generated for each scenario is 1000. For additional details, 
please see Protocol Appendix 4. Presented below is a summary of the operating characteristics 
based on eight tumor types included in the initial protocol design prior to interim analysis: 
Protocol Table 14-13 (Scenario 1) presents the operating characteristics of the design when the true 
underlying ORR of none of the eight tumor types is clinically meaningful (in other words, null case 
for all tumor types). The false positive rate (for final analysis) for each tumor type is appropriately 
controlled, ranging between 2.6% and 6.8%. Similarly, the chances of stopping for futility at IA 
are high, ranging from 45.8% to 69.7%. 
Protocol Table 14-14 (Scenarios 2a and 2b): 


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• Scenario 2a presents the operating characteristics when the true underlying ORR of all the eight 
tumor types is clinically meaningful (in other words, alternative case for all tumor types). The 
probability of positive conclusion (at final analysis) for each  tumor type is appropriately high, 
ranging between 78.2% and 90.7%. Similarly, the chances of stopping for futility at IA is low, 
ranging between 3% and 11.9%. 
• Scenario 2b, in contrast to Scenario 2a, presents the case where, out of all eight tumor types 
there is one single tumor type (T4-Bladder) which does not have clinically meaningful ORR 
while all other seven tumor types have clinically meaningful ORR. However, the model adapts 
appropriately and the false positive rate (1.1%) for T4 is effectively controlled. For the rest 
seven tumor types which have clinically meaningful ORR (same as Scenario 2a), the probability 
of positive conclusion has slightly changed (vs Scenario 2a) but remained acceptably high 
(ranging between 79.6% and 88.7%). 
Protocol Table 14-15 (Scenario 3) presents the operating characteristics when four tumor types 
have clinically meaningful ORR while the other four do not have clinically meaningful ORR. In 
this scenario as well, the false positive rates for the inactive tumor types are properly controlled 
(4.9% - 6.9%) while the probability of positive conclusion for the active tumor types are high 
(78.2% - 86.6%). 
Note:  
Simulations were run after the inclusion of MSS CRC RAS mutant, MSS CRC RAS wildtype and 
HNSCC pretreated groups that show on-study decisions made under the model after the new groups 
are added (refer Protocol Section 14.4.4). The hypothetical data scenarios for interim and final 
analysis can be found in Protocol Table 14-16 and Protocol Table 14-17 respectively. For each 
scenario, the posterior probability of being “clinically meaningful” and “not clinically meaningful” 
(T1-T10 in Protocol Table 10-1) are calculated by group and displayed in the tables. 
Similar exercise was conducted with the three additional tumor groups included in the protocol 
amendment 5 (i.e RCC IO naive, RCC IO pretreated patients and mCRPC, all treated at 240 mg 
BID dose of NIR178 in combination with PDR001) (refer Protocol Section 14.4.5). The 
hypothetical data scenarios for interim and final analysis can be found in Protocol Table 14-18 and 
Protocol Table 14-19 respectively.  
3.2 
Part 2 
At least 20 patients will be enrolled in each of the dosing schedules.  
Table 3-1 shows the posterior mean and corresponding 90% credible interval for N = 20 (since it 
is planned to have approximately 20 patients in each schedule) for various observed ORR using a 
minimally informative unimodal beta prior distribution with parameters a = 1/3 and b = 1 (Note: 
this assumes a priori response rate of 25%). This is same for all dosing schedules. 


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Table 3-1 
Posterior summaries for given number of responses (ORR) 
Observed 
ORR (N, %) 
Posterior mean (90% 
credible interval) 
Probability of no 
improvement 
[0% - 20%) 
Probability of limited 
improvement 
[20% - 33%) 
Probability 
of 
clinically 
meaningful 
improvement 
[33%-100%] 
0 (0%) 
0.016 (0.00,0.070) 
0.999 
0.001 
0.000 
3 (15%) 
0.156 (0.051, 0.299) 
0.744 
0.228 
0.028 
4 (20%) 
0.203 (0.081, 0.356) 
0.534 
0.385 
0.080 
5 (25%) 
0.250 (0.115, 0.414) 
0.316 
0.498 
0.185 
10 (50%) 
0.484 (0.311, 0.657) 
0.002 
0.070 
0.928 
15 (75%) 
0.718 (0.548, 0.863) 
0 
0 
1 
20 (100%) 
0.954 (0.866,0.997) 
0 
0 
1 
From Table 3-1, with a sample size of 20 patients, if the observed ORR is 25%, the probability of 
true ORR to be at least 33% is 18.5%. If the observed ORR is 50%, the probability of true ORR to 
be at least 33% is 92.8%. Also, with a sample size of 20, if the observed ORR is 15%, the 
probability of true ORR to be less than 20% is 74.4%. 
Table 3-2 shows the posterior probability that ORR for schedule 1 (S1) is greater than ORR for 
schedule 2 (S2) for various observed ORR using a minimally informative unimodal beta prior 
distribution with parameters a = 1/3 and b = 1. Similar approach can be used to compare schedule 
2 to schedule 3 and schedule 1 to schedule 3. 
Table 3-2 
Posterior probability that schedule 1 (S1) has higher ORR than schedule 2 
(S2) 
Observed ORR in 
S1 (N, %) 
Observed ORR in 
S2 (N, %) 
Posterior mean of the difference 
(90% credible intervals) 
Probability that ORR in S1 is 
greater than ORR in S2 given data 
3 (15%) 
0 (0%) 
0.141 (0.027, 0.287) 
0.981 
4 (20%) 
3 (15%) 
0.046 (-0.142, 0.236) 
0.660 
5 (25%) 
4 (20%) 
0.047 (-0.160, 0.254) 
0.646 
5 (25%) 
5 (25%) 
0.000 (-0.213, 0.212) 
0.499 
10 (50%) 
5 (25%) 
0.234 (-0.001, 0.459) 
0.949 
10 (50%) 
8 (40%) 
0.095 (-0.152, 0.336) 
0.740 
15 (75%) 
10 (50%) 
0.235 (-0.003, 0.463) 
0.948 
15 (75%) 
12 (60%) 
0.140 (-0.094, 0.371) 
0.839 
20 (100%) 
15 (75%) 
0.235 (0.071, 0.414) 
0.990 
From Table 3-2, with a sample size of 20 patients in each schedule, the posterior probability that 
ORR in S1 is greater than ORR in S2 is 50% if the difference between observed ORR in the two 
schedules is 0% respectively. However, if the difference between observed ORR in S1 and S2 is 
5% respectively, the posterior probability that ORR in S1 is greater than ORR in S2 is 
approximately 65.0%. If the difference between observed ORR in S1 and S2 is 25% respectively, 
the posterior probability that ORR in S1 is greater than ORR in S2 is approximately 95.0%. 


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Table 3-3 
Posterior probability that schedule 1 (S1) has higher ORR than both 
schedule 2 (S2) and schedule 3 (S3) 
Observed ORR in 
S1 (N, %) 
Observed ORR in 
S2 (N, %) 
Observed ORR in S3 (N, %) 
Probability that ORR in S1 is 
greater than ORR in S2 and S3 
given data 
3 (15%) 
0 (0%) 
0 (0%) 
0.963 
4 (20%) 
3 (15%) 
3 (15%) 
0.509 
5 (25%) 
4 (20%) 
3 (15%) 
0.568 
5 (25%) 
5 (25%) 
5 (25%) 
0.335 
10 (50%) 
5 (25%) 
5 (25%) 
0.911 
10 (50%) 
8 (40%) 
5 (25%) 
0.719 
15 (75%) 
10 (50%) 
10 (50%) 
0.906 
15 (75%) 
12 (60%) 
10 (50%) 
0.814 
20 (100%) 
15 (75%) 
12 (60%) 
0.990 
From Table 3-3, with a sample size of 20 patients in each schedule, the posterior probability that 
ORR in S1 is greater than ORR in both S2 and S3 is 33.5% if the difference between observed 
ORR in the three schedules is 0% respectively. However, if the observed ORR in S1, S2 and S3 
are 10%, 8% and 5% respectively, the posterior probability that ORR in S1 is greater than ORR in 
both S2 and S3 is 71.9%. 
3.3 
Part 3 
If initiated, 20 patients will be enrolled in each group of treatment indication (max two) selected 
based on emerging data from Part 1 and Part 2.  For the treatment indication/s selected in Part 3, 
appropriate intervals will be defined and specified before any reporting activity in the statistical 
analysis plan. Novartis may decide to not open Part 3 for enrollment based on emerging data from 
Part 1 and Part 2.  
As of Protocol Amendment 6, 20-30 patients will enroll in TNBC indication using NIR178 160 mg 
BID continuous dosing schedule in combination with PDR001 (see Section 1.1.3). 
A sample size of 10 patients treated at FCT NIR178 160 mg BID in combination with PDR001 in 
TNBC indication in Part 3 provides a high probability, 77%, of observing 0 or 1 adverse event 
when the true incidence rate is 9% (Table 3-4). 
Table 3-4 
Probability of detecting adverse events with specified incidence rate based 
on N=10 patients  
Number of adverse events 
AE incidence rate 
 
0.05 
0.09 
0.12 
0.15 
0 or 1 
0.91 
0.77 
0.66 
0.54 
2 or 3 
0.09 
0.22 
0.32 
0.41 
>3 
0.00 
0.01 
0.02 
0.05 


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Regarding the efficacy of part 3, Table 3-5 shows the posterior mean and corresponding 95% 
credible interval for N=20 for various observed ORR rates using a minimally informative unimodal 
beta prior distribution with parameters a=0.176 and b=1 for TNBC patients (Note: this assumes a 
priori response rate of 15%). From Table 3-5, with a sample size of 20 patients, if the observed 
ORR rate is 15%, the probability of true ORR rate for TNBC patients to be at least 13% is 54.8% 
Table 3-5 
Posterior mean and 95% credible intervals for given ORR rates 
ORR (N, %) 
Posterior mean (95% 
credible interval) 
Probability of no 
improvement [0% - 
5%] 
Probability of limited 
improvement 
(5%-13%) 
Probability 
of 
clinically 
meaningful improvement 
[13%-100%] 
0(0%) 
0.008 (0.00,0.066) 
0.958 
0.038 
0.004 
2 (10%) 
0.103 (0.015, 0.259) 
0.220 
0.495 
0.285 
3 (15%) 
0.150 (0.036, 0.326) 
0.060 
0.392 
0.548 
4 (20%) 
0.197 (0.062, 0.386) 
0.012 
0.217 
0.771 
5 (25%) 
0.244 (0.091, 0.443) 
0.002 
0.092 
0.906 
10 (50%) 
0.481 (0.277, 0.688) 
0.000 
0.000 
1.000 
Japanese safety run-in part 
The period for evaluating DLTs will be cycle 1 (i.e. the first 28 days of treatment with single agent 
NIR178 or in combination with PDR001). The safety run-in will evaluate three NIR178 dose levels 
sequentially. Each dose level may consist of 3 to 6 newly enrolled patients who have tumor 
histologies specified in Protocol Section 5, and who meet all other inclusion/exclusion criteria. The 
dose escalation strategy is detailed in Section 1.1.4. 
 
4 
Change to protocol specified analyses 
The study is closed out due to lack of sufficient efficacy and there is only TNBC indication opened 
in Part 3 at a single dose level - NIR178 160 mg BID. The dose increment criteria of Part 3 
described in Section 1.1.3 will not be evaluated as no patients are enrolled at 240mg in Part 3.  
  
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The following rule applies to daily dosing and should be used for the imputation of the dose end 
date for a given study treatment component: 


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Scenario 1: If the dose end date is completely missing and there is no EOT page and no death date, 
the patient should be treated as on-going, and the cut-off date should be used as the dose end date.  
This scenario should not be applicable for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR.  
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available:  
Please note that date of assessment on EOT CRF might be very different from last date of dose.  
Case 1: The dose end date is completely missing, and the EOT completion date is complete, then 
this latter date should be used.   
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:  
            Use EOT date 
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the year of 
EOT date and mm < the month of EOT date:  
            Use last day of the Month (mm) 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
After imputation, compare the imputed date with start date of treatment, if the imputed date is < 
start date of treatment:  
Use the treatment start date 
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing, then end-date should 
not be imputed. 
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. 


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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. 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to adverse events starting before or on the cut-
off date and not having documented end 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). For concomitant medication reports with no documented end date, 
medication will be reported as ‘ongoing’ if captured as such in the eCRF, otherwise it will be 
reported missing.  
No imputation will be performed for concomitant medication end dates. 
5.1.3.1 
Prior therapies date imputation 
Start date 
The same rule which is applied to the imputation of AE/concomitant medication start date will be 
used with the exception that scenario (B) will be replaced to be ‘start date of study treatment - 1’. 
(see Section 5.1.2) 
End date 
Imputed date = min (start date of study treatment, last day of the month), if day is missing; 
Imputed date = min (start date of study treatment, 31DEC), if month and day are missing. 
If the end date is not missing and the imputed start date is after the end date, use the end date as the 
imputed start date. 
If both the start date and the end date are imputed and if the imputed start date is after the imputed 
end date, use the imputed end date as the imputation for the start date. 


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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 
5.1.4 
Other imputations 
Diagnosis and extent of cancer 
When a date is recorded as a partial date, the missing day is imputed to the 1st of the month (e.g., 
DEC2021 imputed to 01DEC2021) and if the day and month are both missing then to 1st of January 
of that year (e.g., 2021 imputed to 01JAN2021). 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. 
 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects of 
cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding to mild, 
moderate, severe, life threatening, and death. This grading system inherently places a value on the 


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importance of an event, although there is not necessarily proportionality among grades (a grade 2 
is not necessarily twice as bad as a grade 1).  
 
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be taken 
into account. The criteria to assign CTCAE grades are given in Novartis internal criteria for 
CTCAE grading of laboratory parameters. The latest available version of the document based on 
the underlying CTCAE version 4.03 at the time of analysis will be used. For laboratory tests where 
grades are not defined by CTCAE version 4.03, results will be graded by the low/normal/high (or 
other project-specific ranges, if more suitable) classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized as 
hyponatremia and hypernatremia. 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC.  
If laboratory values are provided as ‘<X’ (i.e., below limit of detection) or ‘>X’, prior to conversion 
of laboratory values to SI unit, these numeric values are set to X.   
The following rules will be applied to derive the WBC differential counts when only percentages 
are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by multiplying 
by 0.1, calcium values in mmol/L will be converted to mg/dL by dividing by 0.2495. For calculation 
of laboratory CTC grades 0 and 1, the normal range for derived corrected calcium is set to the same 
limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above. 


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5.4 
Definition and derivation rules for iRECIST 
Assessment by irRECIST 
For iRECIST the key difference from RECIST in the assessment of these endpoints is the 
recommendation that iPD be confirmed at least 4 weeks after the criteria for iPD are first met. A 
single assessment of iPD followed by a subsequent assessment of iSD or better will be considered 
as a pseudo-progression. These are not considered as progression events for the purposes of 
analysis. When iPD is confirmed by a second assessment, the date of the first of these two 
assessments is then the date of progression. For patients who have ended treatment without a valid 
confirmation assessment, for the purposes of analysis the single assessment of iPD will be treated 
as a confirmed iPD. At time of analysis there may be patients whose last adequate assessment is an 
unconfirmed iRECIST progression (iUPD) but who are continuing treatment. In these cases that 
progression will be treated as a confirmed progression for the primary analysis, and sensitivity 
analysis of time-to-event endpoints may be conducted in which the patient is censored at the time 
of last adequate assessment.  
5.4.1 
Total measurable disease burden 
In iRECIST, target and new measurable lesions are used to evaluate the total measurable tumor 
burden (TMTB). TMTB is the sum of diameters (SOD) of all target and new measurable lesions.  
Similar to RECIST v1.1, where SOD of the target lesions is used for determination of target lesion 
response, for iRECIST TMTB is used for determination of target and new measurable lesion 
response. 
5.4.1.1 
Best percentage change from baseline in TMTB 
Best percentage change from baseline in TMTB is defined as the percentage change from baseline 
to the smallest measured post-baseline TMTB occurring at or before the time of confirmed iPD. 
5.4.2 
 Assessment of disease progression 
To facilitate analysis, each assessment of progression is categorized as one of three types: pseudo-
progression, confirmed progression, and unconfirmed progression. 
5.4.2.1 
Pseudo-progression  
Patients with a single iPD, followed by an assessment of iSD or better will be considered to have a 
pseudo-progression (pPD). For the analysis purposes, pseudo-progressions are not treated as 
progression events.  
5.4.2.2 
Confirmed progression  
Confirmed progression 1 (type 1, iCPD1) is declared if a patient has 2 consecutive tumor 
assessments at least 4 weeks (28 days) apart, both showing disease progression. Assessments with 


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an iUNK response or iPD assessments <28 days after initial iPD, are discarded. The first iPD is 
flagged as iCPD1, while all subsequent iPDs are flagged as iXPD1. 
The table below shows two hypothetical data scenarios and programming instructions. 
Sequence of assessments 
Instructions 
1    iPD 
2    iUNK 
3    iPD (Assessment 1 + 30 days) 
• 
Assessment 3 is ≥28 days after Assessment 1  
• 
Assessment 3 represents confirmation of iPD at assessment 1 
• 
Assessment 1 iPD is flagged iCPD1 
• 
Assessment 3 iPD is flagged iXPD1 
1    iSD 
2    iPD 
3    iPD (Assessment 2 + 20 days)  
4    iPD (Assessment 2 + 30 days) 
• 
Assessment 3 is <28 days after Assessment 2 
• 
Assessment 4 is ≥28 days after Assessment 2  
• 
Assessment 4 represents confirmation of iPD at assessment 2 
• 
Assessment 2 iPD is flagged iCPD1 
• 
Assessment 3 and 4 iPDs are flagged iXPD1 
Confirmed progression 2 (type 2, iCPD2) is declared if a patient discontinues treatment following 
a single iPD with no subsequent assessments ≥28 days later. Assessments with an iUNK response 
or iPD assessments <4 weeks (28 days) after initial iPD, are discarded. Discontinuation of treatment 
is obtained from EOT eCRF. 
The assessment is flagged as iCPD2 and subsequent iPDs (<28 days after first iPD) are flagged as 
iXPD2.  
The table below shows two hypothetical data scenarios and programming instructions. 
 
Sequence of assessments 
Instructions 
1    iSD 
2    iPD 
-     EOT 
• 
Patient withdraws after initial progression (Assessment 2) without 
confirmation 
• 
Assessment 2 iPD is flagged as iCPD2 
1    iPD 
2    iPD (Assessment 1  + 20 days) 
-     EOT  
• 
Assessment 2 iPD is <28 days after Assessment 1, so it does not 
represent confirmation 
• 
However, patient has completed treatment  
• 
Assessment 1 iPD is flagged iCPD2 
• 
Assessment 2 iPD is flagged iXPD2 
5.4.2.3 
Unconfirmed progression  
Unconfirmed progression is applicable to patients who are continuing treatment at time of analysis 
cut-off, but whose last assessment showed iPD. For the primary analysis, these patients will be 
analyzed as though this event represents confirmed progression, however sensitivity analyses may 
be conducted in which these patients are censored at the time of last assessment. In later analyses, 
additional data will lead to iUPD events being reclassified as pPD, iCPD1, or iCPD2. 
Patients with a single iPD and no assessment of iSD or better (assessment with an iUNK response 
or iPD assessments <4 weeks after initial iPD, are discarded) continuing treatment at the time of 
the analysis will be considered as unconfirmed (iUPD). 


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5.4.3 
Best overall response 
Assessment of BOR will be based on all assessments up to and including the first assessment of 
iPD (iCPD1, iCPD2, or iUPD). Assessments made more than 150  after EOT will be excluded.   
BOR will be defined with the following hierarchy: 
iCR 
Two consecutive determinations of iCR ≥28 days (4 weeks) apart. Non-consecutive 
assessments of iCR may also result in BOR of iCR if all intervening assessments are 
iUNK. 
iPR 
Two determinations of iPR (or better) ≥28 days (4 weeks) apart. The two determinations 
of iPR (or better) may be separated by one or more assessments of iSD, but may not be 
separated by an assessment of iPD. 
iSD 
At least one iSD assessment (or better) >42 days (6 weeks) after start of 
treatment/randomization 
iPD 
Event flagged as iCPD1, iCPD2 or iUPD ≤84 days (12 weeks) after start of 
treatment/randomization 
iUNK All other cases 
5.4.4 
Time-to-event analyses 
5.4.4.1 
Progression events 
iUPD should only be used for sensitivity analyses. For the primary analysis iUPD events will be 
treated as confirmed progression. 
iPDs flagged as pPD are not included in time-to-event analyses.  
Patients are classified as follows: 
0 
No event (censored) 
1 
Confirmed iPD (iCPD1 or iCPD2) 
2 
Unconfirmed iPD (iUPD) 
For the primary analysis of time-to-event endpoints, both confirmed and unconfirmed progression 
will be included as progression events with date of progression being the date of the assessment 
flagged as iCPD1, iCPD2, or iUPD according to the algorithm defined in Section 5.5.2. 
A sensitivity analysis of time-to-event endpoints may be conducted in which patients with iUPD 
are treated as censored, with date of last adequate assessment = visit date for assessment flagged 
iUPD. 
5.4.4.2 
Definition of start and end dates for time-to-event variables 
Assessment date 
Assessment date is defined as for RECIST v1.1 (CSP Appendix 2). 
 


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Start date  
Start date is as defined for RECIST v1.1 (CSP Appendix 2). 
End dates for time-to-event variables 
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 death as recorded on death eCRF. 
• 
Date of progression is as defined in Section 5.5.2. 
• 
Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of iCR, iPR, or iSD, which was made before progression 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 start of 
treatment/randomization is used.   
Note: for sensitivity analyses of time-to-event endpoints ongoing patients with an iUPD may be 
censored at the time of last assessment.   
5.4.4.3 
Censoring reason 
Censoring reason is derived as for RECIST v1.1 (CSP Appendix 2). 
5.4.4.4 
Duration of response 
Duration of response is defined as a time interval between the first date of confirmed iCR/iPR 
and the date of progression as defined in Section 5.5.2. Intervening assessments of pPD are 
excluded from the assessment. 
 
5.5 
PK/ECG dataset preparation  
5.5.1 
ECG data 
If QTcF change from baseline for a particular record is missing, then the record will be excluded. 
In specific, two scenarios will cause this exclusion: (1) if the patient does not have valid baseline 
ECG information, then all the records for this patient will be excluded; (2) if a patient has missing 
post baseline QTcF at a certain visit/timepoint, then the record for that particular visit/timepoint 
will be excluded.  
After the aforementioned exclusions are applied, the average of replicate ECG records at each 
timepoint (scheduled or unscheduled) will be taken. Unscheduled ECG measurements taken within 
the first and last replicates at a scheduled visit (as determined by ECG date and time) will be 
included in this computation (if present).  


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The ECG date and time is the date and time associated with the average is the date and time of the 
single ECG record or the date and time of the first of any replicate ECG records.  
The ECG data after the aforementioned processing steps are considered the basis ECG data. All 
records in this data set have non-missing QTcF change from baseline (ΔQTcF) and non-missing 
ECG date and time. 
5.5.2 
PK concentration data 
The basis PK concentration data for PK-ECG matching will include all concentrations that are not 
missing and have non-missing sample date and time. 
5.5.3 
Algorithm to match PK and ECG data 
One-to-one matching using the basis ECG data and basis PK concentration data is defined as the 
PK/ECG data. Such dataset is used in the PK-QTc analysis and is established based on the 
following algorithm: 
To be considered for a match, the ECG date/time should be within 15 minutes of PK sample 
date/time, inclusive; the closest record (that is not already matched with PK) should be chosen if 
there are multiple matched ECG measurements; the ECG record after the PK sample/date time 
should be chosen if there are more than one closest match.  
 
6 
 Reference 
ICH E9(R1) Harmonized Guideline: addendum on estimands and sensitivity analysis in clinical 
trials to the guideline on statistical principles for clinical trials. Final version on 20 November 2019.  
Novartis internal criteria for Common Toxicity Criteria (CTC) grading of laboratory parameters  
 
CTC grading 
4.03.pdf
 
ICH guideline E14: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs (R3) - questions and answers 
 
ICH_E14_qtc-interva
l-prolongation.pdf