Clinical trial NCT02795429
Conditions: Advanced Hepatocellular Carcinoma
Keywords: Phase Ib/II INC280 PDR001 capmatinib spartalizumab checkpoint inhibitor PD-1 Liver cancer
Sponsor: Novartis Pharmaceuticals
Start date: 2016-06-15; Completion date: 2021-06-24
Enrollment: 89 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study of capmatinib (INC280) and spartalizumab (PDR001) was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of spartalizumab administered intravenously (i.v.) as a single agent or in combination with capmatinib administered orally in adult patients with advanced hepatocellular carcinoma (HCC).

Detailed description:
This was a Phase Ib/II, open label, multicenter study starting with a Phase Ib dose escalation part followed by a randomized Phase II part in patients with advanced hepatocellular carcinoma. Capmatinib was administered orally twice daily (BID) and spartalizumab was administered i.v. every 3 weeks (Q3W) until the occurrence of unacceptable toxicity, progressive disease as per irRC and/or treatment was discontinued at the discretion of the Investigator or the participant. A complete cycle of treatment was defined as 21 days.

During the Phase Ib dose escalation part of the study, participants were treated with capmatinib in combination with a fixed dose of spartalizumab until the maximum tolerated dose (MTD) was reached or the recommended phase 2 dose (RP2D) was established. The capmatinib dose was increased and the spartalizumab dose remained constant.

Once the MTD and/or RP2D were declared for capmatinib in combination with spartalizumab, additional participants were enrolled in the Phase II part in order to assess the anti-tumor activity of capmatinib in combination with spartalizumab and spartalizumab single agent. Participants were randomly assigned, in a 1:1 ratio, to treatment with either capmatinib in combination with spartalizumab or spartalizumab single agent.

Arms: arm 1: Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib arm 2: Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib arm 3: Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib arm 4: Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II arm 5: Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
Interventions: intervention 1: Spartalizumab intervention 2: Capmatinib
Intervention descriptions: intervention 1: Spartalizumab administered via intravenous (i.v.) infusion once every 3 weeks (Q3W) intervention 2: Capmatinib administered orally as a tablet on a continuous twice daily (BID) dosing schedule

Protocol documents:
Prot_000.pdf: 
Clinical Development
INC280, PDR001
Oncology Clinical Trial Protocol CINC280X2108 / NCT02795429
A phase Ib/II, open-label, multi-center study of INC280 in 
combination with PDR001 or PDR001 single agent in 
advanced hepatocellular carcinoma 
Document type
Amended Protocol Version
EUDRACT number
2015-005417-76
Version number
v05 (Clean)
Development phase
Ib/II
Document status
Final
Release date
20-Feb-2020
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 17-Nov-2014


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of Appendices...............................................................................................................8
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Amendment 5 (14-Feb-2020)............................................................................................13
Amendment 4 (14-Sep-2018)............................................................................................15
Amendment 3 (27-Mar-2018) ...........................................................................................17
Amendment 2 (07-Nov-2017)...........................................................................................19
Amendment 1 (27-Jun-2016) ............................................................................................24
Protocol Summary:............................................................................................................27
1
Background........................................................................................................................30
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............30
1.2
Introduction to investigational treatments .............................................................30
1.2.1
Overview of INC280.............................................................................30
1.2.2
Overview of PD-1 and PDR001............................................................34
1.2.3
Overview of INC280 and PDR001 .......................................................36
2
Rationale............................................................................................................................36
2.1
Study rationale and purpose...................................................................................36
2.2
Rationale for the study design ...............................................................................37
2.3
Rationale for dose and regimen selection..............................................................39
3
Objectives and endpoints...................................................................................................40
4
Study design ......................................................................................................................42
4.1
Description of the study design .............................................................................42
4.2
Timing of interim analyses and design adaptations...............................................43
4.3
Definition of end of the study................................................................................44
4.4
Early study termination..........................................................................................44
5
Population..........................................................................................................................44
5.1
Patient population..................................................................................................44
5.2
Inclusion criteria ....................................................................................................45
5.3
Exclusion criteria...................................................................................................46
6
Treatment...........................................................................................................................49
6.1
Study treatment......................................................................................................49
6.1.1
Dosing regimen.....................................................................................49


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6.1.2
Ancillary treatments..............................................................................50
6.1.3
Treatment duration................................................................................51
6.2
Dose escalation guidelines.....................................................................................51
6.2.1
Starting dose rationale...........................................................................51
6.2.2
Provisional dose levels..........................................................................52
6.2.3
Guidelines for dose escalation and determination of MTD/RP2D .......52
6.2.4
Definitions of dose limiting toxicities (DLTs)......................................54
6.3
Dose modifications................................................................................................56
6.3.1
Dose modifications and dose delay for INC280 ...................................56
6.3.2
Dose modifications and dose delay for PDR001 ..................................56
6.3.3
Follow-up for toxicities related to PDR001..........................................57
6.4
Anticipated risks and safety concerns of the study drug .......................................68
6.4.1
PDR001.................................................................................................68
6.4.2
INC280..................................................................................................68
6.4.3
INC280 combined with PDR001 ..........................................................68
6.5
Concomitant medications ......................................................................................68
6.5.1
Permitted concomitant therapy .............................................................68
6.5.2
Permitted concomitant therapy requiring caution and/or action...........69
6.5.3
Prohibited concomitant therapy ............................................................70
6.6
Patient numbering, treatment assignment or randomization .................................71
6.6.1
Patient numbering .................................................................................71
6.6.2
Treatment assignment or randomization...............................................71
6.7
Study drug preparation and dispensation...............................................................72
6.7.1
Study drug packaging and labeling.......................................................72
6.7.2
Drug supply and storage........................................................................72
6.7.3
Study drug compliance and accountability ...........................................72
6.7.4
Disposal and destruction .......................................................................73
7
Visit schedule and assessments .........................................................................................73
7.1
Study flow and visit schedule................................................................................73
7.1.1
Screening...............................................................................................78
7.1.2
Treatment period...................................................................................78
7.1.3
Discontinuation of Study Treatment .....................................................79
7.1.4
Withdrawal of Consent .........................................................................80
7.1.5
Follow-up period...................................................................................81
7.1.6
Lost to follow-up...................................................................................82
7.2
Assessment types...................................................................................................82


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7.2.1
Efficacy assessments.............................................................................82
7.2.2
Safety and tolerability assessments.......................................................84
7.2.3
Pharmacokinetics 
 assessments............................88
7.2.4
Biomarkers............................................................................................92
8
Safety monitoring and reporting........................................................................................95
8.1
Adverse events.......................................................................................................95
8.1.1
Definitions and reporting ......................................................................95
8.1.2
Laboratory test abnormalities................................................................97
8.2
Serious adverse events...........................................................................................97
8.2.1
Definitions.............................................................................................97
8.2.2
Reporting...............................................................................................98
8.3
Pregnancies............................................................................................................99
8.4
Warnings and precautions......................................................................................99
8.5
Data Monitoring Committee................................................................................100
8.6
Steering Committee .............................................................................................100
9
Data collection and management.....................................................................................100
9.1
Data confidentiality .............................................................................................100
9.2
Site monitoring ....................................................................................................101
9.3
Data collection.....................................................................................................101
9.4
Database management and quality control..........................................................102
10 Statistical methods and data analysis ..............................................................................102
10.1
Analysis sets ........................................................................................................103
10.1.1
Full Analysis Set .................................................................................103
10.1.2
Safety Set ............................................................................................103
10.1.3
Per-Protocol Set ..................................................................................103
10.1.4
Dose-determining analysis set (DDS).................................................104
10.1.5
Pharmacokinetic analysis set...............................................................104
10.2
Patient demographics/other baseline characteristics ...........................................104
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................105
10.3.1
Study treatment ...................................................................................105
10.3.2
Concomitant therapies.........................................................................105
10.3.3
Compliance .........................................................................................105
10.4
Primary objective.................................................................................................105
10.4.1
Variable...............................................................................................105
10.4.2
Statistical hypothesis, model, and method of analysis........................106
10.4.3
Handling of missing values/censoring/discontinuations.....................108


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10.4.4
Supportive analyses.............................................................................108
10.5
Secondary objectives ...........................................................................................108
10.5.1
Key secondary objective(s).................................................................108
10.5.2
Other secondary efficacy objectives ...................................................109
10.5.3
Safety objectives .................................................................................109
10.5.4
Pharmacokinetics ................................................................................111
112
112
112
10.7
Interim analysis....................................................................................................113
10.8
Sample size calculation........................................................................................113
11 Ethical considerations and administrative procedures ....................................................114
11.1
Regulatory and ethical compliance......................................................................114
11.2
Responsibilities of the Investigator and IRB/IEC/REB.......................................114
11.3
Informed consent procedures...............................................................................115
11.4
Discontinuation of the study................................................................................115
11.5
Publication of study protocol and results.............................................................115
11.6
Study documentation, record keeping and retention of documents.....................116
11.7
Confidentiality of study documents and patient records .....................................117
11.8
Audits and inspections.........................................................................................117
11.9
Financial disclosures............................................................................................117
12 Protocol adherence ..........................................................................................................117
12.1
Amendments to the protocol................................................................................117
13 References (available upon request)................................................................................118
14 Appendices ......................................................................................................................123
14.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF,
TTP, Progression-Free Survival and Overall Survival (based on RECIST 1.1) .123
14.1.1
Introduction.........................................................................................124
14.1.2
Efficacy assessments...........................................................................124
14.1.3
Efficacy definitions .............................................................................133
14.1.4
Data handling and programming rules................................................142
14.1.5
References (available upon request) ...................................................145
14.2
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using 
one-dimensional measurements (simulating RECIST 1.1) .................................146
14.2.1
Introduction.........................................................................................146
14.2.2
New lesions and non-target lesions.....................................................146
14.2.3
Follow-up evaluation of target and non-target lesions........................146


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14.2.4
Definitions of response categories and evaluation of overall lesion 
response...............................................................................................147
14.2.5
References (available upon request) ...................................................148
14.3
Appendix 3: Statistical details of Bayesian regression models, priors, design 
operating characteristics and hypothetical dose escalation scenarios..................149
14.3.1
Bayesian logistic regression model specification for dose escalation 149
14.3.2
Bayesian logistical model for the primary analysis of ORR...............160
14.4
Appendix 4: Recommended management algorithms for suspected toxicities...162
14.4.1
References (available upon request) ...................................................168
14.5
Appendix 5: Prohibited concomitant medication for patients in INC280 + 
PDR001 combination arm ...................................................................................169
14.6
Appendix 6: Concomitant medication to be used with caution for patients in 
the INC280 + PDR001 combination arm ............................................................170
14.7
Appendix 7: Child-Pugh classification of severity of liver disease.....................172
14.7.1
References (available upon request) ...................................................172


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List of figures
Figure 4-1
Study Design .........................................................................................43
Figure 4-2
Study Flow ............................................................................................43
Figure 14-1
Probabilities of under dosing, target toxicity and excessive toxicity 
of the INC280 dose level (mg, BID) in combination with PDR001 
300mg q3w..........................................................................................155
List of tables
Table 3-1
Objectives and related endpoints ..........................................................40
Table 6-1
Starting dose and treatment schedule....................................................49
Table 6-2
Provisional dose levels (Phase Ib part – INC280 in combination 
with PDR001)........................................................................................52
Table 6-3
Criteria for defining dose limiting toxicities (DLTs) (INC280 
combined with PDR001).......................................................................55
Table 6-4
Follow-up evaluations for selected toxicities related to PDR001.........58
Table 6-5
Dose reduction and interruption criteria ...............................................59
Table 6-6
Follow-up hepatic toxicities..................................................................66
Table 7-1
Visit evaluation schedule ......................................................................74
Table 7-2
Disease assessment plan........................................................................82
Table 7-3
ECOG performance status.....................................................................84
Table 7-4
Local/Central clinical laboratory parameters collection plan ...............85
Table 7-5
12 lead ECG collection plan .................................................................88
Table 7-6
Schedule of blood collection (plasma) for INC280 (BID) PK for 
patients participating in phase Ib...........................................................89
Table 7-7
Schedule of blood collection (plasma) for INC280 (BID) PK for 
patients participating in phase II ...........................................................89
Table 7-8
Schedule of blood collection (serum) for PDR001 PK
 for 
patients participating in phase Ib...........................................................90
Table 7-9
Schedule of blood collection for PDR001 PK 
 (serum) for 
patients participating in phase II ...........................................................91
Table 7-10
Biomarker sample collection plan (tumor/blood samples) ...................92
Table 10-1
Noncompartmental pharmacokinetic parameters................................111
Table 10-2
Operating characteristics for ORRPDR001+INC280 vs. ORRPDR001
comparison..........................................................................................114
Table 14-1
Response criteria for target lesions .....................................................129
Table 14-2
Response criteria for non-target lesions..............................................131
Table 14-3
Overall lesion response at each assessment ........................................132


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Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................139
Table 14-5
Options for event dates used in PFS, TTP, duration of response........140
Table 14-6
Overall response at each assessment...................................................147
Table 14-7
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent INC280 model parameters.........151
Table 14-8
Historical dose-DLT data from INC280 single agent clinical 
studies..................................................................................................151
Table 14-9
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent PDR001 model parameters........152
Table 14-10
Historical dose-DLT data from PDR001 single agent clinical 
studies..................................................................................................153
Table 14-11
Prior distribution for the model parameters ........................................154
Table 14-12
Summary of prior distribution of DLT rates.......................................154
Table 14-13
Specification of the maximum prior effective sample size under 
infinite historical information and the between-study standard 
deviation given the level of between-study heterogeneity..................156
Table 14-14
Hypothetical dose escalation scenarios...............................................156
Table 14-15
True underlying probabilities of DLT for different scenarios ............158
Table 14-16
Simulation results................................................................................159
Table 14-17
Drugs prohibited while on study.........................................................169
Table 14-18
Drugs with a known risk of torsades de pointes .................................170
Table 14-19
Drugs to be used with caution while on study ....................................170
Table 14-20
Child-Pugh score calculation ..............................................................172
Table 14-21
Child-Pugh score interpretation ..........................................................172
List of Appendices
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, TTP, Progression-
Free Survival and Overall Survival (based on RECIST version 1.1)
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using one-dimensional 
measurements (simulating RECIST version 1.1)
Appendix 3: Statistical details of Bayesian regression models, priors, design operating 
characteristics and hypothetical dose escalation scenarios
Appendix 4: Recommended management algorithms for suspected toxicities
Appendix 5: Prohibited concomitant medication for patients in INC280 + PDR001 
combination arm
Appendix 6: Concomitant medication to be used with caution for patients in the INC280 + 
PDR001 combination arm
Appendix 7: Child-Pugh classification of severity of liver disease


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List of abbreviations
AASLD
American Association for the Study of Liver Diseases 
ADL
Activities of Daily Life
AE
Adverse Event
AFP
Alpha Fetoprotein
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
APASL
Asia Pacific Association for the Study of Liver
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
BCLC 
Barcelona Clinic Liver Cancer 
BID
Twice Daily 
BLRM
Bayesian logistic regression model
BOR
Best Overall Response
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CMO&PS
Chief Medical Office & Patient Safety
CNS
Central Nervous System
COPD
Chronic Obstructive Pulmonary Disease
eCRF
Electronic Case Report/Record Form
CRP
c-Reactive protein
CRO
Contract Research Organization
CRS
Cytokine Release Syndrome
CSF
Colony Stimulating Growth Factor
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
CV
Coefficient of Variation
DAR 
Dose Administration Record
DBP
Diastolic Blood Pressure
DC
Dendritic Cells
DDI
Drug-Drug Interaction 
DDS
Dose Determining Analysis Set
DILI
Drug-induced Liver Injury
DLT
Dose Limiting Toxicity
DOR
Duration of Overall Response
ECG
Electrocardiogram
EOT
End of Treatment
EWOC
Escalation with Overdose Control
FAS
Full Analysis Set
FDG-PET
Fluorodeoxyglucose Positron Emission Tomography
FISH
Fluorescence In Situ Hybridization
FMI
Final market image


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γ-IFN
Gamma-interferon
GCN
Gene copy number
GGT
Gamma-glutamyl transferase
GI
Gastrointestinal
HBsAg
Surface Antigen to Hepatitis B
HBcAg
Core Antigen to Hepatitis B
HBV
Hepatitis B Virus
HCC
Hepatocellular carcinoma
hCG
Human chorionic gonadotropin
HCV
Hepatitis C Virus
HGF
Hepatocyte Growth Factor
HIV
Human Immunodeficiency Virus
HLA
Human Leucocyte Antigen
HR
Hazard Ratio
HNSCC
Head and Neck Squamous Cell Carcinoma
HNSTD
Highest Non-Severely Toxic Dose
IB
Investigator’s Brochure
IC
Inhibitory Concentration
ICF 
Informed Consent Form
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IL
Interleukin
ILD
Interstitial Lung Disease
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
irAE(s)
Immune-related Adverse Event(s)
irRC
Immune-related Response Criteria
IUD
Intrauterine Device
IUS
Intrauterine System
i.v.
Intravenous(ly)
LFT
Liver Function Test
LLOQ
Lower Limit Of Quantification
LMWH
Low Molecular Weight Heparin
mAb(s)
monoclonal Antibody(ies)
MAP
Meta-Analytic-Predictive 
MF
Market Form
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NIRT 
Novartis Interactive Response Technology
NKT Cells
Natural Killer T Cells 
NSCLC
Non-Small Cell Lung Carcinoma
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PBMC
Peripheral Blood Mononuclear Cell


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PD
Pharmacodynamics
PD-1
Programmed Death-1
PD-L1/2
Programmed Death-Ligand 1/2
PFS
Progression Free Survival
PK
Pharmacokinetics
p.o.
Per os
PPI
Proton-pump inhibitor
PT
Prothrombin Time
PPS
Per Protocol Set
cPR
Confirmed Partial Response
Q3W
Every 3 weeks
RAP
Report and Analysis Plan
RBC
Red blood cells
RCC
Renal Cell Cancer
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic Acid
RP2D
Recommended phase 2 dose
RR
Response Rate
SAE(s)
Serious Adverse Event(s)
SBP
Systolic Blood Pressure 
SD
Stable Disease
SEC
Study Evaluation Completion
SHARP
SJS
Sorafenib HCC Assessment Randomized Protocol
Stevens-Johnson Syndrome
SUSAR
TEN
Suspected Unexpected Serious Adverse Reaction
Toxic Epidermal Necrolysis 
TIL(s)
Tumor Infiltrating Lymphocyte(s)
TdP
Torsades de Pointes
TKI
Tyrosine Kinase Inhibitor
Treg
Regulatory T Cell
TTP 
Time To Progression
TTR
Time To Response
ULN
Upper limit of normal
UNK
Unknown
WBC
WOC
White blood cells
Withdrawal of study consent


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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.: q21 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)
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
Subject/Patient Number 
(Patient No.)
A unique identifying number assigned to each subject/patient 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.
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
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 a patient permanently discontinues taking study treatment 
for any reason
Supportive treatment
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium.
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 5 (14-Feb-2020)
Amendment rationale
The primary purpose of this amendment is to incorporate dose modification and management 
guidelines for myocarditis, as well as the option for patients to be transferred to another study 
or an alternative treatment option to continue study treatment at the time of end of this study. 
After a recent occurrence of a case of myocarditis, the dose modification guidelines for 
protocols using INC280 in combination with PDR001 were updated to mandate permanent 
discontinuation of study treatment in case of myocarditis grade ≥2 or other cardiac event grade 
≥3. In addition, recommended clinical management guidelines in case of such an event have 
been provided.
This protocol amendment revises the definition of end of study to include the option for patients 
still on study treatment and who, in the opinion of the investigator, are still deriving clinical 
benefit at the time of end of study, to transfer to another study or to an alternative treatment 
option to continue providing study treatment to these patients.
Furthermore, the withdrawal of consent language was revised to differentiate sample use after 
a patient withdraws consent based on the different regulations/laws around the world.
Study status
This study started enrollment on 15-Jun-2016. As of 06-Feb-2020, a total of 27 patients have
been treated with INC280 in combination with PDR001 in the dose escalation part of the study.
In the Phase II part of the study, 32 patients have been treated with INC280 in combination with 
PDR001 and 30 patients with PDR001 single agent. Enrollment was closed on 27-Aug-2019.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Glossary of terms: Addition of personal data and update of withdrawal of study consent 
definition.  

Section 4.3, Definition of end of study has been revised including the option for patients to 
continue study treatment within another study or to an alternative treatment option.

Table 6-5, Dose reduction and interruption criteria: Updated to reflect the permanent 
discontinuation of study treatment in case of myocarditis grade ≥2 or other cardiac event 
grade ≥3, and inclusion of recommended clinical management guidelines.

Table 7-1, Visit schedule and assessments: It has been clarified that concomitant medication 
only has to be collected until the 30-day safety follow-up or the start of new antineoplastic 
therapy.

Section 7.1.3, Discontinuation of study treatment: Addition of language to specify that 
patients who transfer to another study or an alternative treatment option to continue 
provision of study treatment will complete end of treatment procedures.


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
Section 7.1.4, Withdrawal of consent: This section has been updated to match the latest 
protocol template language. 

Section 7.1.5, Follow-up period: Addition of language to specify that patients who transfer 
to another clinical study or an alternative treatment option to continue provision of study 
treatment will not complete the safety, disease progression, and survival follow-up.

Section 8.3, Pregnancies: Based on the revised pregnancy guidance, the follow-up duration 
for a newborn has been changed from 3 months to 12 months. 
Additional clarifications were made for consistency reasons and to correct minor editing 
changes from previous version.
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. In addition, if 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 amended protocol.


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Amendment 4 (14-Sep-2018)
Amendment rationale
The primary purpose of this amendment is to incorporate health authority-requested language 
requiring study treatment discontinuation in the event of Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN). 
After the recent occurrence of a case of Stevens-Johnson syndrome in a study with PDR001 in 
combination with another investigational agent, the dose modification guidelines for protocols 
using PDR001 were updated to mandate permanent discontinuation of study treatment for 
patients who experience SJS or Lyell syndrome/toxic epidermal necrolysis (TEN). This change 
has already been implemented as part of an urgent safety measure released on 15-Jun-2018. 
This protocol amendment is now formalizing these changes in the dose modification section 
and corresponding table describing the criteria for dose reduction/interruption and re-initiation 
of treatment for adverse drug reactions (Table 6-5, Dose reduction and interruption criteria). 
In addition, based on a health authority request, patients with indolent malignancies that have 
never required therapy will no longer be considered eligible for this study. Exclusion criterion 
#23 ‘Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred within 2 
years prior to study treatment; completely resected basal cell and squamous cell skin cancers; 
any malignancy considered to be indolent and that has never required therapy; and completely 
resected carcinoma in situ of any type’ has been updated accordingly. 
Study status
This study started enrollment on 15-Jun-2016. As of 10-Sep-2018, a total of 27 patients had 
been treated with INC280 in combination with PDR001 in the dose escalation part of the study, 
and in the Phase II part of the study 8 patients with INC280 in combination with PDR001 and 
8 patients with PDR001 single agent.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 5.3, Exclusion criterion #23: Removal of ‘Any malignancy considered to be 
indolent and that has never required therapy’. 

Table 6-5, Dose reduction and interruption criteria: Updated to reflect the permanent 
discontinuation of study treatment in case of SJS or TEN, as per the USM letter of 15-Jun-
2018.   
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes in this amendment identified above as being related to the USM have already been 
implemented by a USM letter issued on 15-Jun-2018. These changes are required for patient 


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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 change described in this amended protocol requires 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 3 (27-Mar-2018)
Amendment rationale
The main purpose of this amendment is to update the exclusion criteria, the list of prohibited 
medications, the list of medications to be used with caution and the criteria for dose 
modifications based on the latest INC280 clinical data as per INC280 Investigator‘s Brochure 
edition 8 with primary focus on pneumonitis/ILD events that have been reported with INC280.
Pneumonitis and ILD have been reported from both INC280 single agent and combination 
studies with the EGFR TKIs, including events with fatal outcome. Dose modification guidelines 
for INC280 have been implemented in this protocol amendment for patients with pulmonary 
symptoms indicative of ILD/pneumonitis.
Additional PK analysis has been performed to evaluate the effect of food and concomitant 
medications on INC280 exposures. There data are summarized in Section 1.2.1, entitled 
Overview of INC280. Based on the food effect evaluations, INC280 may be taken with or 
without food in this study. In addition, based on preliminary analysis from the DDI studies, in 
which strong CYP3A4 inhibitors did not significantly impact INC280 exposure and INC280 
was evaluated only as a moderate CYP1A2 inhibitor. CYP3A4 inhibitors and CYP1A2 
substrates with NTI have been removed from prohibited concomitant therapy and added to 
permitted concomitant medications to be used with caution. Furthermore, the protocol includes 
some updates on other prohibited concomitant medications and the permitted concomitant 
medications to be used with caution based on preliminary DDI study results.
Monoclonal antibodies are not genotoxic due to their high molecular weight, and are not 
expected to interact with DNA. In addition, they have a low distribution to the semen, a 
relatively small volume of semen delivered to the partner, and very low absorption. Fetal harm 
from semen delivery is therefore biologically implausible and the amount of monoclonal 
antibodies able to gain access to the partner’s systemic circulation via trans-epidermal transfer 
would be expected to be extremely low. Therefore, the use of condom for male study 
participants receiving PDR001 is no longer required.
Additional clarifications were made for consistency reasons and to correct minor editing 
changes from previous version.
Study status
This study started enrollment on 15-Jun-2016. As of 27-Mar-2018, a total of 27 patients had 
been treated with INC280 in combination with PDR001 in the dose escalation part of 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 underlined for insertions.

Protocol summary has been updated according to the changes made in main text of the 
protocol.

Section 1.2.1.2, INC280 clinical experience has been updated to match the current 
INC280 Investigator’s Brochure.


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
Section 1.2.3.1, Non-clinical and clinical experience with the combination of INC280 and 
PDR001 was updated to reflect the current status of this study.  

Section 5.3, Exclusion criteria:

Exclusion criterion #1 has been updated to be in line with inclusion criterion #9. 

Exclusion criterion #6 has been added to exclude patients with presence or history of 
interstitial lung disease or interstitial pneumonitis.

Exclusion criterion #18 has been updated to allow strong CYP3A4 inhibitors and 
CYP1A2 substrates with narrow therapeutic index.

Exclusion criterion #26 has been updated to no longer mandate use of condoms 
during intercourse during PDR001 treatment and after the last dose of PDR001. 

Section 6.1.1, Dosing regimen: It has been specified that INC280 can be administered 
with or without food.

Table 6-5, Dose reduction and interruption criteria: Recommended dose modifications for 
ILD like events/pneumonitis have been added.

Section 6.3.3.2, Follow-up on potential drug-induced liver injury (DILI) cases: It has been 
specified that potential drug-induced liver injury has to be reported as SAE.

Section 6.5.2, Permitted concomitant therapy requiring caution and/or action has been 
updated to be in line with Appendix 6. 

Section 6.5.3, Prohibited concomitant therapy has been updated to be in line with 
Appendix 5 and corticosteroid wording has been re-formatted for better readability.

Section 7.1.5, Follow-up period: Timepoints for disease progression follow-up have been 
updated to be consistent with Table 7-1.

Table 14-17, Drugs prohibited while on study: Strong and moderate CYP3A4 inhibitors as 
well as substrates of CYP1A2 with narrow therapeutic index have been removed.

Table 14-18, Drugs with a known risk of torsades de pointes has been updated with 
categories removed and drugs sorted alphabetically. 

Table 14-19, Drugs to be used with caution while on study has been updated to include 
strong CYP3A inhibitors and CYP1A2 substrates with NTI. H2 receptor antagonists, PPI
and antacids have also been added and the list of P-gp and BCRP substrates has been 
updated and sorted alphabetically. Moderate CYP3A4 inducers, sensitive substrates of 
CYP3A4, CYP2C8, CYP2C9 and CYP2C19, and substrates of OATP have been removed.
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. In addition, if 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 amended protocol.


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Amendment 2 (07-Nov-2017)
Amendment rationale
The main purpose for this amendment is threefold. The first is to reduce the focus on the cMET 
high population; the second is to expand the eligible clinical population to include patients with 
Hepatitis C virus (HCV), and patients with mild ascites; and the third to introduce additional 
biomarker collections based on emerging pharmacodynamic data.
The prospective patient stratification by cMET status in the Phase II will be removed, based on 
new pre-clinical data. Recent preclinical studies show that inhibition of MET by 
pharmacological or genetic means can enhance T cell mediated anti-tumor immunity in a 
variety of treatment regimens and mouse models (Glodde et al 2017). Consistent with these 
reports, internal data from Novartis in two syngeneic mouse models demonstrate that the 
combination treatment of PDR001 with INC280 led to increased T cell infiltration and an 
improved anti-tumor immune response with a higher cure rate than single agent PDR001. 
Importantly, neither of the cell models are sensitive to single-agent INC280 in vitro and neither 
have high cMET expression, suggesting the added benefit of INC280 to PDR001 is not 
dependent on autonomous cMET signals and further supporting the clinical evaluation of the 
combination in a molecular unselected patient population.
Based on these observations, with this amendment, patients will no longer be prospectively 
stratified by cMET status and will be enrolled without molecular pre-selection. Testing for 
cMET will be done retrospectively. The primary objective of this study has been updated to “to 
compare the efficacy of INC280 in combination with PDR001 vs. PDR001 single agent” in all 
patients, and not by c-MET molecular status. The secondary objectives that were specific to 
each molecular population have also been adjusted or removed. 
The patient population in this study will be expanded to include patients with detectable HCV. 
This is based on the emerging data showing that patients with HCV associated HCC can derive 
benefit from checkpoint inhibitors without apparent addition of treatment related risks. Patients 
with HCV were enrolled and treated on study [CINC280X2201], and no additional toxicities 
were observed in this population.  In addition, patients with clinically insignificant ascites will 
be permitted on this study. This change is in line with other clinical studies in HCC, and 
recognizes that imaging performed with the intent of tumor evaluation can detect ascites, which 
may not be otherwise clinically significant. 
 
This is based on current 
data that indicate that response to drugs targeting checkpoint inhibitors may depend on the 
mutation burden of the tumor (Rizvi et al 2015). 
 
 
Another sample from 
these patients will be collected at the end of the trial (EOT) if the reason for discontinuation is 
progression of disease. Furthermore, an optional tumor sample is requested at progression of 
disease only for patients who had a response as per investigator assessment. 
 
 
 


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In addition, clinical assessments of Child Pugh status will be introduced every 3 cycles in order 
to better assess the underlying disease/prognosis throughout the study.
To reduce patient burden, serology tests (Anti-DNA antibodies (Abs), Anti-nuclear abs, Anti-
phospholipid abs, Anti-mitochondrial abs, c-Reactive protein (CRP), Rheumatoid factor (RF)) 
are no longer mandated.    
Also based on results from a recent clinical study, [CINC280A2103], a drug-drug interaction 
(DDI) study with Midazolam (a CYP3A4 substrate), the restriction on co-administration with 
CYP3A4/5 substrates with narrow therapeutic indexes will be removed.  
Additional clarifications were made for consistency reasons. 
Study status
The CINC280X2108 study started enrollment on 15-Jun-2016. As of 18-Oct-2017, a total of 21
patients had been treated with INC280 in combination with PDR001 in the dose escalation part 
of 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 underlined for insertions.

Protocol summary has been updated according to the changed made in main text of the 
protocol.

Section 2.2, Rationale for study design, phase II: 

Removal of stratification by cMET status.    

Table 3-1, Objectives and related endpoints: 

Update of primary and secondary objectives to match the new study design. 
 
 
 
 

Figure 4-2, Study flow: Removal of pre-screening.

Section 5.2, Inclusion criteria: 


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
Inclusion criterion #3 has been updated with the addition of Asian Pacific Association 
for the Study of the Liver (APASL) as well as allowing patients with controlled 
ascites.

Inclusion criterion #5 mandating documented evidence of cMET status for Phase II 
has been removed.   

Inclusion criterion #13 excluding HCV has been removed.

Section 5.3, Exclusion criteria:

Exclusion criterion #2: Updated with only live vaccines to be prohibited. 

Exclusion criterion #17 has been updated excluding strong inducers or inhibitors of 
CYP3A4/5 and allowing CYP3A substrates with narrow therapeutic index.

Exclusion criterion #20: Thresholds for PT and INR have been corrected. 

Table 6-1, Starting dose and treatment schedule and section 6.7.1, Study drug packaging 
and labeling: ‘Lyophilisate in vial’ has been replaced by ‘powder for solution for 
infusion’. 

Section 6.1, Study treatment, PDR001 and section 6.3.1, Dose modification and dose 
delay for PDR001: Instructions for PDR001 dose delay have been updated.    

Section 6.3.1, Dose modifications and dose delay for INC280 has been added.

Section 6.4, Anticipated risks and safety concerns of the study drug (PDR001 and 
INC280) has been updated according to the latest protocol template. 

Table 6-5, Dose reduction and interruption criteria: Addition of criteria in case of 
peripheral edema.  

Section 6.5.1, Permitted concomitant therapy: The timeframe for recording concomitant 
medication has been specified.  

Section 6.5.3, Prohibited concomitant therapy: For the use of immunosuppressive drugs, 
the exception of prophylaxis against imaging contrast dye allergy has been added, 
corticosteroid treatment has been further specified, use of vaccines and drugs with a 
known risk of causing TdP have been clarified.

Section 6.6.1, Patient numbering:  Pre-screening has been deleted. 

Section 6.6.2, Randomization Phase II part:  NIRT registration process has been clarified.

Section 7.1.1, Molecular pre-screening has been deleted.  

Section 7.1.5, Follow-up period: 

Clarification regarding safety follow-up visit has been added. 

Time window of +/-7 days for survival follow-up contact has been specified.

Time point to switch frequency of response evaluation has been updated for 
practicality reasons.

Section 7.1, Study flow and visit schedule:

Removal of molecular screening.   

Follow-up period: Addition of time window +/-7 days for survival follow-up contact.   

Time point to switch frequency of response evaluation has been updated for 
practicality reasons.


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
Addition of Child Pugh status.

Time point for Alpha Fetoprotein has been moved from pre-screening to screening.
 
 

Removal of serology exam. 

Table 7-2, Disease assessment plan: 

Time point to switch frequency of response evaluation to every three cycles has been 
updated for practicality reasons.  

It has been clarified that screening brain MRI is only mandated in case of suspected 
brain metastases. 

Section 7.2.2, Safety and tolerability assessments: Child Pugh status has been added. 

Table 7-4, Local/Central clinical laboratory parameters clinical collection plan: Removal 
of serology exam in serum.  

Table 7-9, Schedule of blood collection for PDR001 PK and IG (serum) for patients 
participating in phase II: The time window for 1h post dose time point has been extended 
to 15 minutes, due to practicality reasons. 

Table 7-10, Biomarker sample collection plan: 

Addition of time point for optional biopsy at progression of disease for patients who 
had a response. 
 

Section 7.2.4.1.2, Pharmacodynamic assessments in tumor samples: Addition of tumor 
biopsy at progression; removal of Nanostring.  
 

Section 8.1, Adverse Events, definitions and reporting: Section regarding molecular ICF 
has been deleted and wording has been added to specify AE collection after initiation of 
new antineoplastic treatment.

Section 8.2, Serious Adverse Events, reporting: Section regarding molecular ICF has been 
deleted and wording has been added to specify AE collection after initiation of new 
antineoplastic treatment. 

Section 10, Statistical methods and analysis: 

Update of study arms to reflect the change in study design.

Section 10.4, Primary objective Phase II part: Modification of primary objectives to reflect 
the change in study design.

Section 10.4.2.2, Phase II part: Patient classification in cMET high/low group has been 
removed. 


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
Sections 10.5.2.2, Association of cMET status with PDR001 single agent anti-tumor effect 
and 10.5.2.3, Comparison of efficacy of INC280+PDR001 vs. INC280 single agent in 
cMET high patients, have been removed. 

Section 10.4.3.1, Analysis set and grouping for the analyses: Observation period has been 
re-defined. 
  
 
 
  

Section 10.8, Sample size calculation, Phase II part, has been updated to reflect the change 
in study design. 

Section 11.5, Publication of study protocol and results has been updated to match the most 
recent protocol template. 

Appendix 3, Statistical considerations has been updated to reflect the change in study 
design. 

Appendix 5, Prohibited concomitant medication: Appendix has been replaced by the 
current updated version.  

Appendix 6, Concomitant medication to be used with caution: Appendix has been 
replaced by the current updated version.  
Other minor/editing changes in the protocol text were made for clarification.
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. In addition, if 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 amended protocol.


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Amendment 1 (27-Jun-2016)
Amendment rationale
Based on Health Authority requests, the following changes have been implemented in this 
protocol: 

Patients who refused sorafenib treatment have been excluded from the patient population 
to be enrolled in this study. To be eligible, patients must have received prior systemic 
sorafenib treatment for HCC with documented progression during or after discontinuation 
of sorafenib treatment, or are intolerant to sorafenib (that led to sorafenib discontinuation).

A mandatory HIV test has been introduced at screening. Considering the limited clinical 
experience with PD-1 inhibitors in HIV positive patients, to reduce the potential risk of 
virus reactivation, HIV testing has been mandated and HIV positive patients will be 
excluded from the study.

Thrombocytopenia CTCAE grade 3 with clinically significant bleeding has been listed as 
DLT, as well as nausea/vomiting grade 4 (regardless of anti-emetic treatment) and 
diarrhea grade 4 (regardless of anti-diarrheal treatment). 

Enrollment of patients potentially eligible for any loco regional liver treatment (e.g. 
hepatic resection, hepatic arterial embolization, radiofrequency ablation) is not allowed. 

History of organ transplant has been added as an additional exclusion criterion. Limited 
data are reported for the efficacy and toxicity, such as organ rejection, of immune 
checkpoints including PD-1 inhibitors in patients with organ transplant, 
therefore considering the risk, patients with a history of organ transplant will be excluded 
from the study.
The following further changes have been implemented in this protocol: 
Corticosteroids and immunosuppressive therapy are widely used agents in the treatment of 
numerous autoimmune and inflammatory diseases and they may interfere with the therapeutic 
efficacy of the immune checkpoints including PDR001, therefore an exclusion criteria about 
their systemic use has been included.
With the available PK data obtained from the single agent first-in-human study 
[CPDR001X2101], an exploratory population PK (PopPK) analysis showed that the T1/2 of 
PDR001 in man is 20 [17, 23] days (mean [90% CI]). Using five times the upper limit of the 
half-life of 23 days and an added safety margin, the protocol is amended to increase the duration 
of contraception and safety follow-up periods post PDR001 treatment from 90 days to 150 days. 
These changes are related to an Urgent Safety Measure communicated on 08-June-2016 to all 
investigators. 
Section 1.2.1.3, Clinical pharmacology has been updated to add a rationale why the concomitant 
use of acid reducing agents, including PPI, gastric acid modulators and H2 receptor antagonists, 
is unlikely to have impact on the efficacy of INC280.


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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Protocol summary: Secondary objectives have been updated to be aligned with Table 3-1. 

Section 1.2.1.3: A paragraph summarizing the results of PPI study has been added. 

Section 2.1, Section 2.2 and Section 5.2, Inclusion criterion #7: Patients who refused 
sorafenib treatment have been excluded from the patient population.

Section 4.1, Study flow, Section 5.3, Inclusion criteria 25 and 26, Section 6.3.2, Follow-up 
toxicities related to PDR001, Section 7.1, Study flow and visit schedule, Section 7.1.6, 
Follow-up period, Section 8.1.1, Definitions and Reporting, Section 8.2.2, Reporting, and 

Section 10.5.3, Safety objectives: Safety follow-up period for PDR001 has been extended 
to 150 days. 

Figure 4-2 has been updated: Pre-screening and 30 days/150 days safety follow-up added.  

Section 5.2: Inclusion criterion #3: It has been specified that diagnosis can either be done 
histologically or cytologically, or for subjects with cirrhosis clinical diagnosis of HCC 
according to the American Association for the Study of Liver Diseases (AASLD) criteria.

Section 5.3, Exclusion criterion #4 has been added.  

Section 5.3, Exclusion criterion #9 has been added to specify corticosteroids use. 

Section 5.3, Exclusion criterion #10 has been added: Interferon use within 2 weeks of the 
first dose of study treatment.

Section 5.3, Exclusion criterion #13 has been amended with mandatory HIV testing at 
screening.  

Section 5.3, Exclusion criterion # 14 has been added to exclude patients with a history of 
organ transplant.

Section 5.3, Exclusion criteria #25 and #26: Contraception period for PDR001 has been 
extended to 150 days.  

Table 6-3: Thrombocytopenia CTCAE grade 3 with clinically significant bleeding has 
been added to the DLT table.

Table 6-3: Nausea/Vomiting CTCAE grade 4 and diarrhea grade 4 have been added to the 
DLT table.

Section 7.1, Study flow and visit schedule: It has been specified, that the time window for 
tumor biopsies in the Phase Ib may be longer than 21 days.

Table 7-1 and Table 7-4: HIV testing has been added.

 

Table 7-1 and section 7.2.2.5.7: Alpha Fetoprotein (AFP) has been added to have 
consistency between section 10.6.2 and Table 7-1 (for phase II only). 

Table 7-2: To be consistent with section 7.2.1, Screening assessments, it has been 
specified that brain CT/MRI at baseline should only be done in case of known brain 
metastases or symptoms.

Table 7-4: It has been specified that cytokines and serology will be assessed centrally.


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
Section 7.2.2.5.9, Pregnancy assessments: Additional time points for urine pregnancy test 
have been added.

Section 10.1.4: Minimum exposure criterion has been updated.

Appendix 7: Child-Pugh classification has been added.
Other minor/editing changes in the protocol text were made for clarification.
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. In addition, if 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 amended protocol.


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Protocol Summary: 
Protocol number
CINC280X2108
Title
A phase Ib/II, open-label, multi-center study of INC280 in combination with PDR001 
or PDR001 single agent in advanced hepatocellular carcinoma 
Brief title
Phase Ib/II study of INC280 + PDR001 or PDR001 single agent in advanced HCC
Sponsor and 
Clinical Phase
Novartis Phase Ib/II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study of INC280 and PDR001 is to characterize the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of 
PDR001 administered i.v. as a single agent or in combination with INC280 
administered orally in adult patients with advanced hepatocellular carcinoma (HCC).
Primary 
Objective(s) 
Phase Ib: To characterize the safety and tolerability of INC280 in combination with 
PDR001 and to identify the Maximum Tolerated Dose (MTD)/Recommended Phase 
2 Dose (RP2D).
Phase II: To compare the efficacy of INC280 in combination with PDR001 vs. 
PDR001 single agent. 
Secondary 
Objectives

To characterize the safety and tolerability of INC280 combined with PDR001 
and PDR001 single agent in the phase II part

To further characterize the efficacy of INC280 in combination with PDR001 and 
PDR001 single agent 

To characterize the pharmacokinetic profile of INC280 combined with PDR001 
and PDR001 single agent

To assess the pharmacodynamic effect of INC280 in combination with PDR001 
and PDR001 single agent in tumor biopsy 
Study Design
This is a phase Ib/II, open-label, multi-center study which consists of a phase Ib dose 
escalation part of INC280 in combination with PDR001 in advanced HCC. Once the 
Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of INC280 
in combination with PDR001 is achieved, a phase II part in patients with advanced 
HCC with INC280 in combination with PDR001 and PDR001 single agent will 
commence. 
INC280 will be administered orally BID on a continuous schedule, and PDR001 will 
be administered i.v. every three weeks until a patient experiences unacceptable 
toxicity, progressive disease (PD) as per irRC and/or treatment is discontinued at the 
discretion of the Investigator or the patient. Patients should not discontinue treatment 
based on progressive disease per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 unless clinical deterioration or increase in tumor markers is observed.
Population
This study will be conducted in adult patients with advanced HCC. 
Inclusion criteria 
(selected)
1.
Histologically or cytologically documented locally advanced recurrent or 
metastatic HCC or for subjects with cirrhosis clinical diagnosis of HCC according 
to the American Association for the Study of Liver Diseases (AASLD) (2011)
and Asian Pacific Association for the Study of the Liver (APASL) (2010) criteria. 
Current cirrhotic status of Child Pugh Class A (5-6 points), with no 
encephalopathy and/or clinically significant ascites (defined as requiring diuretic 
or paracentesis treatment). Child Pugh status must be calculated based on 
clinical and laboratory results during the screening period.
2.
Baseline tumor tissue (newly obtained) must be available at screening.  Patient 
must have a site of disease amenable to biopsy, and be a candidate for tumor 
biopsy according to the treating institution’s guidelines and requirements for 
such procedure. 
3.
Patients must be willing to undergo a new tumor biopsy during the study (6-9 
weeks after start of study treatment, if medically feasible).  For patients in the 
phase II part of the study, exceptions may be granted after documented 


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discussion with Novartis. After a sufficient number of paired biopsies are 
collected, the decision may be taken to stop collecting the biopsies.    
4.
Patients must have received prior systemic sorafenib treatment for HCC with 
documented progression during or after discontinuation of sorafenib treatment
(for France only: patients must have received at least 8 weeks of prior sorafenib 
treatment), or are intolerant to sorafenib (defined as documented Grade 3 or 4 
adverse events that led to sorafenib discontinuation).
5.
Patients must be tested during screening for Hepatitis-B-Virus surface antigen 
(HbsAg) status. Patients are included in the study if they have adequately 
controlled hepatitis B, defined by: 

receiving a nucleoside analog anti-viral drug for 3 or more months, and

serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level of less 
than 100 IU/ml via polymerase chain reaction quantification assays prior to 
enrollment.
Exclusion criteria 
(selected)
1.
Patient has received the following therapies prior to the first dose of study 
treatment:

Previous systemic anti-cancer therapy (including therapeutic cancer 
vaccines and immunotherapeutics) other than sorafenib (sorafenib must be 
completed within > 2 weeks prior to the first dose of study treatment) or 
INC280.

Previous locoregional therapy (e.g. hepatic arterial embolization, radio-
frequency ablation, radiation therapy) if:

administered after sorafenib treatment with the exception of 
palliative radiotherapy to a limited field, such as for the treatment 
of bone pain. Loco regional therapy for the focally painful liver 
tumor mass will be discussed on a case by case with Novartis.

completed within 4 weeks prior to the dosing and, if present any 
related acute toxicity grade > 1.
2.
Use of any live vaccines within 4 weeks of initiation of study treatment.
3.
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).
4.
Participation in an interventional, investigational study within 2 weeks of the first 
dose of study treatment, unless agreed otherwise with Novartis.
5.
Presence or history of interstitial lung disease or interstitial pneumonitis, 
including clinically significant radiation pneumonitis (i.e., affecting activities of 
daily living or requiring therapeutic intervention).
6.
Presence of CTCAE grade ≥1 toxicity (except alopecia, peripheral neuropathy 
and ototoxicity, which are excluded if CTCAE grade ≥ 3) due to prior cancer 
therapy, unless agreed otherwise with Novartis.
7.
Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, 
M-CSF) ≤ 2 weeks prior start or study drug. An erythroid stimulating agent is 
allowed as long as it was initiated at least 2 weeks prior to the first dose of study 
treatment and the patient is on a stable dose.
8.
History of severe hypersensitivity reactions to other monoclonal antibodies 
(mAbs).
9.
Positive human immunodeficiency virus (HIV) test at screening or known history 
of testing positive for HIV or known acquired immunodeficiency syndrome.
10. Clinically significant pleural effusion that either required pleurocentesis or is 
associated with shortness of breath.
11. Patients receiving treatment with medications that are strong inducers of 
CYP3A4 and that cannot be discontinued at least 1 week prior to the start of 
treatment with INC280 and for the duration of the study.


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12. Unable to stop herbal/food supplements or treatments which are considered to 
be capable of significantly causing either PK or PD herb/food-drug interactions.
13. Active autoimmune disease or a documented history of autoimmune disease, 
including ulcerative colitis and Crohn’s disease or any condition that requires 
systemic steroids or any immunosuppressive therapy, except vitiligo or resolved 
asthma/atopy that is treated with broncho-dilators (e.g., albuterol). 
14. Clinically significant, uncontrolled heart diseases:

Unstable angina within 6 months prior to screening

Myocardial infarction within 6 months prior to screening

History of documented congestive heart failure (New York Heart 
Association functional classification III-IV)

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 
160 mm Hg and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or 
without antihypertensive medication. Initiation or adjustment of 
antihypertensive medication(s) is allowed prior to screening

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

QTcF ≥ 450 ms (male patients), ≥ 460 ms (female patients) on the 
screening ECG (as mean of triplicate ECG)
Investigational and 
reference therapy
INC280 and PDR001
Efficacy 
assessments
Tumor assessment per RECIST v1.1 and per irRC.
Safety assessments
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events 
(SAEs), including changes in laboratory values, vital signs and Electrocardiograms 
(ECGs).
Other assessments

Serum PK parameters

Pharmacodynamic assessment on pre- and post-treatment newly obtained 
tumor samples 
Data analysis
The study data will be analyzed and reported based on all patients’ data of the phase 
Ib and phase II parts up to the time when all patients have completed at least nine 
cycles of treatment or discontinued the study. 
Key words
Phase Ib/II, INC280, PDR001, checkpoint inhibitor, PD-1.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Hepatocellular carcinoma (HCC) is the fifth most common form of cancer worldwide and the 
third most common cause of cancer-related deaths. HCC often occurs in the background of a 
cirrhotic liver. Most cases of HCC (approximately 80%) are associated with chronic hepatitis
B virus (HBV) or hepatitis C virus (HCV) infections (Raza and Sood 2014, El-Serag 2011).
Other common etiologies include alcohol consumption, nonalcoholic steatohepatitis, exposure 
to 
carcinogens, 
and 
the 
genetic 
metabolic 
diseases 
such 
as 
hemochromatosis 
(El-Serag et al 2004, Donato et al 2002, Adams et al 2005, Turner et al 2002). Obesity has also 
been identified as an independent risk factor for developing HCC (Park et al 2010).
Approximately 80% of HCC patients present with advanced or unresectable disease 
(Ferlay et al 2010). Conventional chemotherapy has been proven to be ineffective for HCC 
(Llovet 2003, Yeo et al 2005). The Sorafenib HCC Assessment Randomized Protocol (SHARP) 
trial demonstrated that sorafenib, a multitarget tyrosine kinase inhibitor (TKI), was able to 
increase survival in patients with advanced HCC (stage C of the Barcelona Clinic Liver Cancer 
(BCLC) classification). Overall survival (OS) of 10.7 months was observed in the sorafenib 
arm vs 7.9 months in the placebo arm (Hazard Ratio (HR) = 0.69). The median time to 
radiologic progression was 5.5 months in the sorafenib group and 2.8 months in the placebo 
group (p<0.001) (Llovet et al 2008a). Improvement in OS for patients randomized to sorafenib 
in another phase III sorafenib study in the Asia-Pacific region was consistent with the SHARP 
trial (Cheng et al 2009). Sorafenib was approved as a standard first line systemic therapy for 
non-selected HCC patients with advanced disease. Although extended by sorafenib, time to 
progression (TTP) and overall survival (OS) remain limited as a result of de novo or acquired 
resistance (Bergers and Hanahan 2008, Paez-Ribes et al 2009).
Several compounds failed in the first or second line HCC setting (e.g. sunitinib, sorafenib in 
combination with erlotinib, and brivanib) and there is no approved standard of care for second-
line treatment (Cheng et al 2011, Llovet et al 2012, Zhu et al 2012).
The management of HCC remains challenging as there is no therapeutic option available for 
patients with advanced HCC whose disease progressed while on or after treatment with 
sorafenib or who are intolerant to sorafenib treatment.
1.2
Introduction to investigational treatments 
1.2.1
Overview of INC280
The 
chemical 
name 
for 
INC280 
is 
2-fluoro-N-methyl-4-(7-(quinolin-6-ylmethyl) 
imidazo[1,2b][1,2,4]triazin-2-yl)benzamide dihydrochloride. INC280 is a small ATP 
competitive, reversible inhibitor of the cMET receptor tyrosine kinase.
INC280 dihydrochloride monohydrate is a slightly hygroscopic light yellow powder. The 
solubility of INC280 dihydrochloride at 25°C is approximately 3.47 mg/mL in water; 0.08 
mg/mL in pH 6.8 and 0.72 mg/mL in pH 3.0 buffer.


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Please refer to the [INC280 Investigator’s Brochure] for more detailed information.
1.2.1.1
INC280 Non-clinical experience 
1.2.1.1.1 In vitro and in vivo pharmacology
INC280 possesses potent inhibitory activity against the cMET kinase in vitro [inhibitory
concentration (IC)50 = 0.13 ± 0.05 nM], and is highly specific for cMET with > 10,000-fold 
selectivity over several other human kinases tested. Potent activity of blocking cMET 
activation has been observed in cell-based biochemical and functional assays that measure 
cMET-mediated signal transduction, as well as cMET-dependent cell proliferation, survival, 
and migration.
In cMET–dependent mouse tumor models (including lung cancer models), INC280 exhibits 
dose-dependent antitumor activity and causes tumor regression at well tolerated doses that 
exceeded IC90 coverage (Liu et al 2011). Importantly, plasma levels of INC280 correlate 
with both the dose administered and the extent of tumor growth inhibition in vivo.
In cMET/HGF-driven mouse xenograft tumor models, oral dosing of INC280 demonstrated
significant in vivo activity in blocking both cMET phosphorylation and tumor growth. 
Activation of cMET in such responsive models is either due to strong cMET overexpression 
(mostly as a consequence of gene amplification, e.g. in gastric or hepatocellular carcinoma) or
hepatocyte growth factor (HGF) secretion resulting in an autocrine loop (e.g. in glioblastoma).
Collectively, the data suggest that INC280 possesses potent in vitro and in vivo biological and 
pharmacologic activities, and further support its clinical development as a potentially effective 
oral treatment for human cancers with cMET dysregulation.
1.2.1.1.2 Non clinical drug metabolism and pharmacokinetics summary
INC280 was absorbed rapidly in rats, dogs and monkeys. The absolute oral bioavailability 
following a single low dose was low in dogs (28%), and moderate to complete in rats and 
monkeys (> 66%). 
INC280 plasma protein binding was moderate to high across species, and was 96% in humans 
with no concentration dependency. After oral dose of [14C]INC280 in male pigmented and
albino rats, INC280 and/or its metabolites were widely and rapidly distributed to all tissues. 
Melanin containing structures appeared to show specific uptake and prolonged retention of drug 
related material. INC280 can penetrate across the blood-brain barrier.
Metabolism is the predominant mechanism of elimination of INC280 in rats and monkeys 
after oral administration. 
After single oral administration of [14C]INC280 to rats and monkeys, the major portion of 
administered radioactivity was recovered in feces and only a minor fraction in urine. Direct 
renal excretion of INC280 was negligible and direct biliary excretion/intestinal secretion 
contributed only to a minor extent to the overall elimination of INC280.


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1.2.1.1.3 Safety pharmacology and toxicology
A series of preclinical safety studies were completed to support human clinical trials with 
INC280, including safety pharmacology studies, genetic toxicology studies, general 
toxicology studies in rat and Cynomolgus monkey (up to 13 weeks in duration), and
embryofetal developmental studies in rats and rabbits. Additionally, photosensitization 
potential was also assessed.
Safety pharmacology studies indicate that INC280 had no significant effects on central nervous
system (CNS) and respiratory functions in rats, and no effects on cardiovascular function in 
monkeys. 
Repeat-dose toxicity studies in rats and monkeys revealed the main target organs of toxicity: 
kidneys (monkeys only, crystalline-like material surrounded by multinucleated giant cells 
within the renal interstitium and/or tubular lumen), pancreas (both species, pancreatic acinar 
cell vacuolation and/or apoptosis, and elevations of amylase or lipase), CNS/brain (rats only, 
tremors and/or convulsions, white matter vacuolation in thalamus/caudate/putamen region), 
and the liver (both species, increase of serum enzymes).
In vitro and in vivo genetic toxicology studies indicate that INC280 did not induce mutations 
or cause chromosome aberrations.
Embryo-fetal studies in rats and rabbits indicate that INC280 is teratogenic to both species, 
thus INC280 should be considered potentially teratogenic to humans.
Additionally, INC280 has shown photosensitization potential in in vitro and in vivo assays.
1.2.1.2
INC280 clinical experience
1.2.1.2.1 Clinical safety and tolerability
As of the cut-off date of 28-Sep-2017, a total of 1109 cancer patients and 158 non-cancer 
subjects have received INC280.
A total of 622 patients with solid tumors have been treated with INC280 as a single agent, and 
487 patients have been treated with INC280 in combination therapies. Twenty one clinical 
studies are currently ongoing with INC280. A total of 19 patients have experienced 25 DLTs: 
6 patients in single agent studies and 13 in combination studies. 
Overall, the majority of the reported adverse events (AEs) have been of mild or moderate
severity. The most frequent AEs suspected to be related to INC280 of any grade reported in the 
largest single agent trial [CINC280A2201] (220 patients) were peripheral edema (77 patients, 
[35.0%]), nausea (69 patients, [31.4%]), vomiting (40 patients, [18.2%]), increased blood 
creatinine (39 patients, [17.7%]), and fatigue (34 patients, [15.5%]), the majority Grade 1/2. 
The most frequently occurring Grade 3/4 AEs suspected to be related to INC280 as a single 
agent included peripheral edema and increased lipase (each in 9 patients, [4.1%]), fatigue (8 
patients, [3.6%]), increased alanine aminotransferase (7 patients, [3.2%]), increased aspartate 
aminotransferase, hypophosphataemia, nausea  and vomiting (each in 3 patients, [1.4%]).
Caution is recommended when INC280 is administered in combination with other anticancer 
drugs with known risk of hepatotoxicity. One case of abnormal liver function test meeting Hy’s 
Law criteria for hepatotoxicity (PHHO2015CN003025,) has been reported for a patient enrolled 
in the NSCLC combination study with gefitinib [CINC280X2202]. The event was suspected to 


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be related to the combination of INC280 plus gefitinib. The patient permanently discontinued 
both study drugs. Liver function tests improved after treatment discontinuation. Hepatotoxicity 
could not be attributed solely to either drug alone or to the combination.
As of the IB cut-off of 28-Sep-2017, pneumonitis and ILD have been reported from both 
INC280 single agent and combination studies with the EGFR TKIs, including events with fatal 
outcome. Investigators are advised to carefully monitor patients for signs and symptoms of 
pneumonitis and implement dose modification and follow up evaluations described in the 
protocol in all INC280 studies, both single agent and in combination studies.
The maximum tolerated dose (MTD) for INC280 capsules or tablets as single agent was not 
reached. The recommended phase II dose (RP2D) for INC280 as a single agent has been 
determined to be 600 mg BID in capsule formulation and 400 mg BID in tablet formulation. 
In this study, INC280 tablets will be used.
1.2.1.2.2 Clinical pharmacology
As of 28-Sep-2017, INC280 (capsule and tablet) single agent steady state pharmacokinetic (PK) 
data are available from five single agent and four combination studies. INC280 was rapidly 
absorbed after oral administration in humans. The median time to reach the maximum drug 
concentration (Tmax) ranged from 1 to 2 hours for tablets and 1 to 4 hours for capsules. The 
elimination half-life (T1/2) estimated from [CINC280X1101] ranged from 3.5 to 6.3 hours 
across the cohorts. Accumulation of INC280 exposure following repeated administration of 400 
mg BID tablets is low, with geometric mean accumulation ratio of 1.4-fold in the single agent 
[CINC280A2201] study. Steady state INC280 exposure is expected to be reached by the third 
day of consecutive BID dosing. The mean plasma exposures (Cmax and AUC) for INC280 
generally increased with dose up to 600 mg QD and 600 mg BID administration with capsule 
formulation. The mean plasma exposure increase is roughly dose proportional for INC280 tablet 
from 200 to 400 mg BID.
A relative bioavailability study, [CINC280X2103], was conducted to compare the INC280 MF 
(market form) tablet formulation to INC280 capsule formulation. The outcome of this study 
showed that tablets provided higher systemic exposures (Cmax and AUC) and lower inter-
subject variability in healthy subjects. In the study [CINC280X2102], the INC280 MF tablet at 
400 mg BID (N=8) provided comparable mean AUC0-12h,ss (1.05-fold) and slightly higher 
Cmax,ss (1.44-fold) compared with the INC280 capsule at 600 mg BID (RP2D, N=45) in the 
limited subjects tested. Based on the tablet PK and safety data from these studies, the dosage of 
INC280 at 400 mg BID in tablet form has been declared as the RP2D for the single agent studies.
INC280 displayed pH-dependent solubility in vitro. Daily treatment with 20 mg rabeprazole (a 
long proton pump inhibitor) for 4 days resulted in a modest reduction in the extent of INC280 
absorption with a 25.2% decrease in AUCinf and a 37.5% decrease in Cmax
([CINC280A2101]). Compared to fasting conditions, a low fat meal increased AUCinf and 
Cmax by 1.20- and 1.11-fold, respectively; and a high fat meal increased AUCinf and Cmax by 
1.46- and 1.15-fold, respectively ([CINC280X2107]). Preliminary pharmacokinetics data from 
the ongoing study [CINC280A2108] in which INC280 tablet was administered with food in 
cancer patients, showed no positive food effect of high fat meal on INC280 exposure. While 
the data on the concurrent use of PPI and food have to be considered preliminary as they have 


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been generated in a small cohort of patients of the study [CINC280A2108], the decrease in 
exposure imposes caution on the use of PPI when INC280 is taken with no regards of food.
Several studies were conducted to assess the DDI between INC280 and concomitant 
medications. As a potential perpetrator, [CINC280A2103] showed that multiple doses of 
INC280 tablets at 400 mg BID did not lead to clinically significant increase of CYP3A4 
substrate (midazolam) exposure. However, AUC of CYP1A2 substrate (caffeine) was increased 
by 135%. Therefore, INC280 is not a CYP3A4 inhibitor, but a moderate CYP1A2 inhibitor. In 
addition in study [CINC280A2105], multiple doses of INC280 tablets at 400 mg BID led to a 
74% increase in digoxin (P-gp substrate) Cmax and a 47% increase in AUC, and a 204% and
108% increase in rosuvastatin (BCRP substrate) Cmax and AUC, respectively. Therefore, 
INC280 is an inhibitor of P-gp as well as BCRP transporters, with clinically relevant DDI 
potential.
As a potential causative agent, in study [CINC280A2102], when co-administered with 
itraconazole, INC280 AUC increased by approximately 40% while there was no change in 
Cmax. When co-administered with rifampicin, INC280 AUC and Cmax decreased by 
approximately 66% and 56%, respectively.
INC280 does not show a risk of QT prolongation. Preliminary analysis on 110 patients in study 
[CINC280A2201] showed that no patients had new post-baseline QTcF values greater than 500 
ms. Based on the PK/QT analysis, the estimated mean ΔQTcF (upper one-sided 95% CI) at 
mean steady state INC280 concentration 2 hours post-dose (4584 ng/mL) was 0.11 ms (1.85 
ms) at the recommended phase 2 dose of 400 mg BID with tablets. The upper one-sided 95% 
CIs for the estimated mean ΔQTcF at clinically relevant INC280 concentrations are below the 
regulatory threshold of 10 ms.
An exploratory population PK (PopPK) analysis indicated that the INC280 exposure in HCC 
patients in those studies was similar to those in non-HCC-patients.
For more information, please refer to the most updated version of the [INC280 Investigator’s 
Brochure].
1.2.2
Overview of PD-1 and PDR001
PD-1 is a critical checkpoint receptor that is expressed by effector T cells upon activation 
(Okazaki et al 2013). It is also expressed by B cells, natural killer T (NKT) cells, CD4+ 
regulatory T (Tregs) cells, and some dendritic cells (DC) subsets upon activation 
(Francisco et al 2010). Its ligands, Programmed Death-Ligand 1 (PD-L1) and Programmed 
Death-Ligand 2 (PD-L2) are expressed by dendritic cells, macrophages and monocytes, and can 
be induced on virus-infected cells and many types of tumors (Keir 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 effector T cells.
The PD-1/PD-L1 axis is exploited by many tumor types to avoid detection by the adaptive 
immune system (Murphy 2011). Blockade of the PD-1 pathway has been shown to lead to 
increased numbers of effector T cells through induction or expansion and improved cytolytic 
activity towards tumors. Additionally, PD-1 blockade is associated with accumulation of 
effector T cells and a reduced number of Tregs at the tumor site (Wang et al 2009, 
Mangsbo et al 2010, Mkrtichyan et al 2011, Rosenblatt et al 2011). 


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Both preclinical and clinical studies have demonstrated that anti-PD-1 blockade restores activity 
of “exhausted” effector T cells and results in robust anti-tumor response. Clinical data with 
other anti-PD-1 antibodies have demonstrated that PD-1 checkpoint inhibition results in 
clinically relevant anti-tumor activity in a variety of solid tumors, including melanoma, non-
small cell lung carcinoma (NSCLC), renal cell cancer (RCC) and head and neck squamous cell 
cancer (HNSCC) (Topalian et al 2012, Hamid et al 2013, Topalian et al 2014, 
Lyford-Pike et al 2013).
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody (stabilized 
hinge, S228P) which blocks the binding of PD-L1 and PD-L2 to PD-1. PDR001 is cynomolgus 
monkey cross-reactive and shows functional activity in vitro and in vivo.
1.2.2.1
PDR001 Non-clinical experience
PDR001 binds specifically and with high affinity to human PD-1 and shown to enhance the 
interleukin-2 production in ex vivo lymphocyte stimulation assays. Repeat administration of 
PDR001 to monkeys was well tolerated at all doses tested in the GLP toxicology study. No test 
article-related in-life, mortality, organ weight changes, or macroscopic findings were noted. 
There were no PDR001-related effects seen in any of the safety pharmacology endpoints 
assessed (cardiovascular, neurobehavioral, and respiratory). Macrophage infiltrates into the 
splenic white pulp were observed in animals given 100 mg/kg/week and mononuclear cell 
infiltrates, often associated with fibrosis, around the injection site blood vessel (saphenous vein) 
in a few animals given 25 mg/kg/week. These PDR001-related microscopic changes were 
fully reversible after an eight week recovery. Additionally, mostly low grade mononuclear 
infiltrates in the vascular and perivascular space in several tissues of main and recovery treated 
animals and in recovery controls but with a slightly higher incidence in treated animals. No 
evidence of parenchymal damage was associated with the vascular/perivascular changes in any 
of the organs examined and the changes were not associated with any frank tissue injury. 
The Highest Non-Severely Toxic Dose (HNSTD) dose in this study was 100 mg/kg. PDR001 
has a favorable safety profile in monkeys that supported a projected human starting dose of 1 
mg/kg in the first in human study [CPDR001X2101].  
1.2.2.2
PDR001 Clinical experience
PDR001 is currently being tested in a multi-center, open-label study starting with a phase I dose 
escalation part followed by a phase II part. The [CPDR001X2101] study started enrollment on 
27 April 2015 and is ongoing. As of 17 December 2015, a total of 58 patients had been treated 
in the study at the dose levels of 1, 3 and 10 mg/kg Q2W and 3 and 5 mg/kg Q4W. No patient 
experienced a DLT and the toxicity profile appears to be similar to that of marketed inhibitors 
of PD-1. The PK data obtained from the dose escalation, and modeling of the exposure data, 
support the use of flat dosing for PDR001 of 400 mg given every 4 weeks. The expected 
PDR001 Ctrough concentrations are in line with observed steady state mean Ctrough 
concentrations for pembrolizumab, which is approved with substantial efficacy in several 
cancer types. The data also support the use of 300 mg Q3W as an alternative dose regimen if it 
is more convenient for scheduling purposes, for example in combination treatment regimens.
It is also within the objective of the phase II part of the [CPDR001X2101] study to assess 
PDR001 anti-tumor activity in various advanced solid tumors including the “benchmark 


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diseases” such as NSCLC and melanoma, where response rates to nivolumab and 
pembrolizumab are known.
For further details, please refer to the [PDR001 Investigator’s Brochure].
1.2.3
Overview of INC280 and PDR001
1.2.3.1
Non-clinical and clinical experience with the combination of INC280 
and PDR001
As of 27-Mar-2018, a total of 27 patients had been treated with INC280 in combination with 
PDR001 in the dose escalation part of the study, at dose levels of 200 mg INC280 BID, 300 mg 
INC280 BID, and 400mg INC280 BID, all in combination with 300 mg PDR001 Q3W. 
2
Rationale
2.1
Study rationale and purpose
HCC is associated with high mortality and morbidity due to the limited efficacy of the current 
available treatment in this population. For patients who were treated with sorafenib and 
discontinued treatment due to disease progression or intolerability, there is no standard 
approved therapy as outlined in Section 1. 
cMET overexpression has been associated with increased vascular invasion, resistance to 
chemo- and radiotherapy, and poor clinical outcome in HCC (Boix et al 1994, Suzuki et al 1994, 
Ueki et al 1997, Tavian et al 2000, Kaposi-Novak et al 2006, Liu et al 2008). Tissue localization 
studies of HGF and cMET protein support the existence of both autocrine and paracrine 
mechanisms of action of HGF in HCC (Ljubimova et al 1997, Luo et al 1999). Targeting the 
disease through a different class of drugs might be beneficial to these patients with no standard 
of care available.
INC280 has shown anti-tumor activity in several pre-clinical models of HCC that are driven 
either by cMET gene amplification or by HGF stimulation. Autocrine or paracrine activation of 
cMET by HGF was found to drive growth and migration of HCC cell lines in vitro
(Xie et al 2001). Paracrine stimulation of cancer cells by HGF originating from non-cancerous 
liver tissue that could promote growth and metastasis was reported (Wu et al 2006). Preclinical 
studies performed at Novartis have shown that HGF overexpression is found in almost all liver 
tissue samples adjacent to HCC tumors and that cMET is expressed by the majority of HCC 
tumors. Functional studies showed that knockdown of cMET by adenovirus-delivered siRNA 
inhibited growth of HCC lines with particularly high cMET expression in vitro and in vivo
(Zhang et al 2005), underlining the potential of activated cMET to drive liver carcinogenesis.
The recently reported positive results (TTP and OS advantage: HR=0.43, p=0.03; HR=0.38, 
p=0.01 respectively) of tivantinib (cMET inhibitor) in the treatment of HCC provide a strong 
rationale for the evaluation of cMET targeted agents in HCC (Santoro et al 2012).
Low expression of programmed cell death 1 ligand 1 (PD-L1) in combination with high human 
leucocyte antigen (HLA) class 1 expression was found to be prognostic for improved outcomes 


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in HCC patients (Umemoto et al 2014), suggesting that novel therapies targeting the PD-L1/PD-
1 pathway may thus show therapeutic benefit in HCC.
Recently, a phase I/II study in advanced HCC (El-Khoueiry et al 2015) showed that Nivolumab 
monotherapy has a manageable safety profile, including in patients with HBV and HCV 
infections. Durable responses were observed across all dose levels and etiologic cohorts. 7 out 
of 8 tumor responses occurred within three months of starting study treatment and 6 out of 8 
patients had ongoing responses after several months of study treatment. The 12-month overall 
survival rate was 62%.
In conclusion, the purpose of this phase Ib/II study is to determine in the phase Ib part the 
MTD/RP2D for the combination treatment of INC280 plus PDR001 and to further assess in the 
phase II part the safety and clinical activity of both INC280 in combination with PDR001, and 
single agent PDR001 in patients with advanced HCC with cMET dysregulation, who 
experienced progression during or after discontinuation of sorafenib treatment, or intolerance 
to sorafenib treatment.
2.2
Rationale for the study design
This is an open-label, multicenter, randomized and controlled phase Ib/II study of INC280 in 
combination with PDR001 or PDR001 single agent in patients with advanced HCC, who 
experienced progression during or after discontinuation of sorafenib treatment, or intolerance 
to sorafenib treatment.
Phase Ib part
The phase Ib part of the study is a dose escalation of INC280 in combination with PDR001. 
Cohorts of patients will receive escalating doses of INC280 combined with a fixed dose of 
PDR001 until MTD/RP2D is reached. The MTD/RP2D will be determined from the collective 
experience in the clinic considering the safety data, pharmacokinetic data, pharmacodynamic 
data and any early anti-tumor activity observed along with the statistical inference from the 
Bayesian logistic regression model (BLRM).
This open-label dose escalation study design using a BLRM is a well-established method to 
estimate the MTD/RP2D in cancer patients. The adaptive BLRM will be guided by the 
Escalation with Overdose Control (EWOC) principle to control the risk of DLT in future 
patients on study. The use of Bayesian response adaptive models for small datasets has been
accepted by European Medicines Agency (Guideline on clinical trials in small populations, 13-
Feb-2007) 
and 
endorsed 
by 
numerous 
publications 
(Zacks
et 
al
1998, 
Neuenschwander et al 2010, Neuenschwander et al 2014), and its development and appropriate 
use is one aspect of the FDA’s Critical Path Initiative.
Phase II part
A randomized controlled design for the phase II part is appropriate to assess clinical activity of 
INC280 in combination with PDR001 versus PDR001 single agent. This design is stratified by 
region (Asian vs. non-Asian).


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The phase II part of the study will begin after the MTD/RP2D is determined. Patients will be 
randomized 1:1 to treatment INC280+PR001 or PDR001 single agent with the stratification 
factor of region (Asian vs. non-Asian). The cMET status will be assessed retrospectively, after 
randomization.  
2.2.1.1
Rationale for including cMET high patients
High cMET expression is defined as either IHC 3+ in at least 50% of tumor cells, or IHC 2+ 
in at least 50% of tumor cells and at the same time a gene copy number ( GCN) of at least 5
(which is considered as evidence for cMET gene amplification (Schildhaus et al 2012).
As of 28-Oct-2015, 28 HCC patients have been treated in the phase II part of study 
[CINC280X2201] of INC280 single agent in first line HCC. Among the eight cMET high 
patients,  three out of the eight HCC patients treated with INC280 capsules at the dose level of 
600 mg BID (RP2D with INC280 capsules) achieved a confirmed partial response (cPR), lasting 
for 5 (discontinuation due to patient’s decision), 7.5+ (ongoing) and 5+ (ongoing) months 
respectively.
The preliminary efficacy data clearly suggest that patients with cMET high HCC may obtain 
therapeutic benefit from treatment with single agent INC280, including long lasting responses.
In addition to the well-documented role of cMET in cancer cell autonomous survival and growth, 
evidence is emerging to suggest that cMET activation could also have a profound effect on 
tumor immune-tolerance, at least partially through the direct induction of negative co-
stimulatory molecule PD-L1 in the cancer cell. Balan and colleagues have demonstrated that 
cMET is co-expressed with PD-L1 in renal cell carcinoma and elucidated that PD-L1 expression 
is a direct consequence of the transcriptional regulation downstream of cMET (Balan et al 2015).
Beyond oncogenic genetic aberrations of the cMET pathway in cancer cells, the canonical 
autocrine/paracrine effects of HGF, which could be produced either by HCC or liver stroma 
cells, also play an important role in the regulation of the inflammatory process. HGF alters the 
antigen-presenting function and differentiation of DCs and macrophage and subsequently may 
negatively impact T cells and thus INC280 might restore immune cell functions by 
preventing/reducing the HGF signaling (Molnarfi et al 2015).
Blockade of the PD-1 pathway has demonstrated preliminary clinical efficacy with durable 
responses in second line HCC (El-Khoueiry et al 2015), leading to a phase III study of 
nivolumab
against 
sorafenib 
in 
1st
Line 
HCC
(https://clinicaltrials.gov/ct2/show/NCT02576509).
In conclusion, in cMET high HCC patients, PDR001 single agent should provide a clinical
benefit similar to Nivolumab; while the combination of PDR001 + INC280 should provide 
additional clinical benefit mediated by:

INC280 which inhibits any suppressive effects of HGF on cells of the immune system 
such as dendritic cells and potentially a cMET pathway inhibition in cancer cells.

PDR001 which blocks the PD-1 pathway triggering a better immune response that might 
result in durable anti-tumor responses.


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2.2.1.2
Rationale for including cMET low patients
As of 28-Oct-2015, 20 patients with cMET low (IHC 2+/GCN <5 or IHC 1+/any FISH) were 
treated with INC280 600 mg BID (capsules). No response was reported and the stable disease 
(SD) rate at 9 weeks was 25% (5/20 patients).
Although in cMET low HCC the direct impact of the cMET pathway in cancer cell is less clear
(see Section 2.2.1.1), HGF produced by HCC and liver stroma cells might alter the antigen-
presenting function and differentiation of dendritic cells and macrophage and subsequently may 
negatively impact the T cells and thus might reduce the capacity of the immune system to react 
against cancer cells (Molnarfi et al 2015). 
In cMET low HCC patients, PDR001 single agent should provide a clinical benefit similar to 
Nivolumab (El-Khoueiry et al 2015). The combination of INC280 + PDR001 should provide a 
sustained clinical benefit mediated by:

INC280 which inhibits any suppressive effects of HGF on cells of the immune system 
such as dendritic cells and potentially a cMET pathway inhibition in cancer cells 
(cMET/HGF dependency less clear)

PDR001 which blocks the PD-1 pathway triggering a better immune response resulting in
anti-tumor activity.
2.3
Rationale for dose and regimen selection
This is the first study evaluating the combination of INC280 and PDR001. In order to 
understand the safety, tolerability and PK of the combination, starting doses for the combination 
of INC280 and PDR001 are planned as 200 mg BID and 300 mg Q3W, respectively. The 
PDR001 dose will remain constant during the phase Ib and phase II part.
To date, PDR001 has been tested up to 10mg/kg every 2 weeks which was not considered an 
MTD dose. RP2D from the ongoing [CPDR001X2101] study is 300 mg given every 3 weeks. 
The PDR001 exposure at this dose regimen is expected within the range of those observed in 
the CPDR001X2101 study with no DLTs. In addition, the expected PDR001 Ctrough 
concentrations are in line with observed mean steady state Ctrough concentrations for 
Pembrolizumab. In accordance with clinical experience of nivolumab and pembrolizumab 
(Topalian et al 2012, Topalian et al 2014, Hamid and Carvajal 2013, Robert et al 2014), PDR001 
is expected to demonstrate antitumor activity at 300 mg dosed every 3 weeks.
INC280 tablet 400 mg BID is the RP2D selected in phase I and phase II single agent studies 
(including in the first line HCC patients), as well as in combination with gefitinib. For the dose 
escalation phase of this study, the starting dose of INC280 will be 200 mg BID, which is two 
dose levels below the RP2D of 400 mg BID. Strong pharmacokinetic drug-drug interaction is 
not expected between INC280 and PDR001. However as INC280 metabolism is moderately 
mediated by CYP3A4/5 and PDR001 treatment might have impact on metabolizing enzymes 
through cytokine regulation, INC280 exposure will be monitored in the dose escalation phase 
to assess drug-drug interaction (DDI).


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.3
Phase Ib part: 
To characterize the safety and 
tolerability of INC280 in combination 
with PDR001 and identify the MTD 
and/or RP2D
Phase II part: 
-
To compare the efficacy of INC280 
in combination with PDR001 vs. 
PDR001 single agent
Phase Ib part:
Safety: Incidence and severity of AEs 
and SAEs, including changes in 
laboratory values, vital signs and 
ECGs. Incidence of DLT during the first 
2 cycles of treatment.
Tolerability: Dose interruptions, 
reductions, and dose intensity
Phase II part:
Overall response rate (ORR) per 
Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1)
Secondary
Refer to Section 10.4
Phase Ib/II part: To further characterize 
the efficacy of INC280 in combination 
with PDR001 and PDR001 single agent 
Best overall response (BOR), duration 
of overall response (DOR), time to 
response (TTR), progression-free 
survival (PFS), time to progression 
(TTP), overall survival (OS), and for 
phase Ib: Overall response rate (ORR)
Phase II part: To characterize the 
safety and tolerability of INC280 in 
combination with PDR001 and PDR001 
single agent
Safety: Incidence and severity of 
adverse events (AEs) and serious 
adverse events, including changes in 
laboratory parameters, vital signs and 
electrocardiograms (ECGs)   
Tolerability: Dose interruptions, 
reductions and dose intensity


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Objective
Endpoint
Analysis
Phase Ib/II parts: To characterize the 
pharmacokinetic profile of INC280 in 
combination with PDR001 and PDR001 
single agent    
Plasma/serum PK parameters (e.g., 
AUC, Cmax, Tmax) 
Plasma/serum concentration vs. time 
profiles
Phase Ib/II parts: 
To assess the pharmacodynamic effect 
of INC280 in combination with PDR001 
and PDR001 single agent in tumor 
biopsy 
TIL characterization & CD8 and PD-L1 
protein expression 


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4
Study design
4.1
Description of the study design
This is a phase Ib/II, open label, multicenter study starting with a phase Ib dose escalation part 
followed by a randomized phase II part. INC280 will be administered orally twice daily and 
PDR001 will be administered i.v. every three weeks until a patient experiences unacceptable 
toxicity, progressive disease as per irRC and/or treatment is discontinued at the discretion of 
the investigator or the patient. Patients should not discontinue treatment based on progressive 
disease per RECIST unless clinical deterioration or increase in tumor markers is observed. The 
study design is summarized in Figure 4-1.
Phase Ib dose escalation part
During the phase Ib part of the study, cohorts of patients will be treated with INC280 in 
combination with a fixed dose of PDR001 until the MTD is reached or RP2D is established. 
The INC280 dose will be increased and the PDR001 dose will remain constant. The dose 
escalation will be guided by a BLRM following the EWOC principle. A minimum of 12 patients 
are required during dose escalation to determine the MTD of INC280 in combination with 
PDR001. If a recommended phase II dose is identified without determination of the MTD, fewer 
than 12 patients may be required (for further details see Section 6.2.3).
Phase II part
Once the MTD and/or RP2D have been declared for INC280 in combination with PDR001, 
additional patients will be enrolled in the phase II part in order to assess the anti-tumor activity 
of INC280 in combination with PDR001 and PDR001 single agent. 
In total, approximately 60 patients will be enrolled. Patients will be randomly assigned, in a 1:1 
ratio, to treatment with either INC280 in combination with PDR001 or PDR001 single agent. 
Considering that the treatment guidance for HCC (specifically the locoregional treatments such 
as percutaneous hepatic arterial embolization, radiofrequency ablation, and percutaneous 
interventional therapy) are different in various parts of the world reflected in the difference in 
OS and TTP results observed in the SHARP study and the Asia-Pacific sorafenib studies 
(Llovet et al 2008b, Cheng et al 2009, Lencioni et al 2012, Johnson et al 2013), the 
randomization for treatment assignment in this study will be stratified by geographical region 
(Asian vs. non-Asian).
Analysis for cMET status will be performed after randomization.


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Figure 4-1
Study Design
A complete cycle of treatment is defined as 21 days of twice daily treatment with INC280 and 
the DLT period in the phase Ib part as 2 cycles.
This study will use a Novartis Interactive Response Technology (NIRT) system for 
randomization and management of INC280 and PDR001 study drug (see Section 6.6.2). 
Study flow
The study is comprised of 3 periods: Screening, Treatment, Follow-up period (150-day Safety 
for PDR001 and 30-day for INC280 (in case PDR001 has been discontinued > 120 days before), 
Disease Progression and Survival. Patients will undergo safety and efficacy assessments during 
screening and periodically during treatment and follow-up as outlined in Table 7-1.
Figure 4-2
Study Flow
4.2
Timing of interim analyses and design adaptations
No formal interim analyses are planned. However, in the phase I part, the dose-escalation design 
foresees that decisions based on the current data are taken before the end of the study (see 
Section 10.6). 


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4.3
Definition of end of the study
The end of the study will be when:

A minimum of 80% of patients have died, have been lost to follow-up, or have been 
followed for a minimum of 18 months after the first dose of study treatment, and all 
patients have completed treatment and the safety follow-up period
or

the study is terminated early
or

another clinical study becomes available that can continue to provide study treatment 
in this patient population, all patients ongoing  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).
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative treatment option to patients who, in the opinion of the 
investigator, are still deriving clinical benefit.
The disease and survival follow-up evaluations might not be completed in case Novartis decides 
to stop enrollment prematurely. In such cases, end of study will be upon the Study Evaluation 
Completion (SEC) or the last patient treated, including the completion of the safety follow-up 
period.
See Section 10 Statistical Methods and Data Analysis 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. Should this be necessary, 
the patient should be seen as soon as possible for End of Treatment (EOT) visit and the 
assessments for EOT should be performed as described in Section 7.1.3 and Section 7.1.4 for a 
discontinued or withdrawn patient. 
The Investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The Investigator 
will be responsible for informing Institutional Review Boards (IRBs) and/or independent ethics 
committees (IECs) of the early termination of the trial.
5
Population
5.1
Patient population
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies.


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The Investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any procedures that are not considered 
standard of care. [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. Age ≥ 18 years. 
3. Histologically or cytologically documented locally advanced recurrent or metastatic HCC
or for patients with cirrhosis clinical diagnosis of HCC according to the 
American Association for the Study of Liver Diseases (AASLD) and Asian Pacific 
Association for the Study of the Liver (APASL) criteria. Current cirrhotic status of Child 
Pugh Class A (5-6 points), with no encephalopathy and/or clinically significant ascites
(defined as requiring the use of diuretics or paracentesis treatment).  Child Pugh status 
(see Appendix 7) must be calculated based on clinical and laboratory results during the 
screening period.
4. Baseline tumor tissue (newly obtained) must be available at screening.  Patient must have 
a site of disease amenable to biopsy, and be a candidate for tumor biopsy according to the 
treating institution’s guidelines and requirements for such procedure. 
5. Patients must be willing to undergo a new tumor biopsy during the study (6 to 9 weeks 
after start of study treatment, if medically feasible).  For patients in the phase II part of the 
study, exceptions may be granted after documented discussion with Novartis. After a 
sufficient number of paired biopsies are collected, the decision may be taken to stop 
collecting the biopsies.    
6. Patients must have received prior systemic sorafenib treatment for HCC with documented 
progression during or after discontinuation of sorafenib treatment (for France only: 
patients must have received at least 8 weeks of prior sorafenib treatment), or are intolerant
to sorafenib (defined as documented Grade 3 or 4 adverse events that led to sorafenib 
discontinuation).
7. ECOG Performance Status ≤ 1.
8. Willing and able to swallow and retain oral medication.
9. The last dose of sorafenib must have been given ≥ 2 weeks prior to mandatory tumor 
biopsy at baseline.
10. At least 1 measurable lesion as per RECIST v1.1 present at screening (progressing or new 
since last anti-tumor therapy). Lesions previously treated with local therapy, such as 
radiation therapy, hepatic arterial embolization, radiofrequency ablation, and percutaneous 
interventional therapy should not be selected unless progression is noted at baseline, in 
which case, these lesions would be considered as non-target lesions.   
11. Patients must be tested during screening for Hepatitis-B-Virus surface antigen (HbsAg) 
status. Patients are included in the study if they have adequately controlled hepatitis B, 
defined by: 

receiving a nucleoside analog anti-viral drug for 3 or more months, and


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
serum hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level of less than 100 
IU/ml via polymerase chain reaction quantification assays prior to enrollment.
12. Willing and able to comply with scheduled visits, treatment plan and laboratory tests.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Patient has received the following therapies prior to the first dose of study treatment:

Previous systemic anti-cancer therapy (including therapeutic cancer vaccines and 
immunotherapeutics) other than sorafenib (sorafenib must be completed within > 2
weeks prior to the first dose of study treatment) or INC280. 

Previous locoregional therapy (e.g. hepatic arterial embolization, radio-frequency 
ablation, radiation therapy) if:

administered after sorafenib treatment with the exception of palliative 
radiotherapy to a limited field, such as for the treatment of bone pain. Loco 
regional therapy for the focally painful liver tumor mass will be discussed on a 
case by case with Novartis.

completed within 4 weeks prior to the dosing and, if present any related acute 
toxicity grade > 1.
2. Use of any live vaccines within 4 weeks of initiation of study treatment.
3. 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).
4. Patients potentially candidate for any loco regional treatment (e.g. hepatic resection, 
hepatic arterial embolization).
5. Participation in an interventional, investigational study within 2 weeks of the first dose of 
study treatment, unless agreed otherwise with Novartis.
6. Presence or history of interstitial lung disease or interstitial pneumonitis, including 
clinically significant radiation pneumonitis (i.e., affecting activities of daily living or 
requiring therapeutic intervention).
7. Presence of CTCAE grade ≥ 1 toxicity (except alopecia, peripheral neuropathy and 
ototoxicity, which are excluded if CTCAE grade ≥ 3) due to prior cancer therapy, unless 
documented agreement with Novartis.
8. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) 
≤ 2 weeks prior start or study drug. An erythroid stimulating agent is allowed as long as it 
was initiated at least 2 weeks prior to the first dose of study treatment and the patient is on 
a stable dose.
9. Presence of symptomatic central nervous system (CNS) metastases, or CNS metastases 
that require local CNS-directed therapy (such as radiotherapy or surgery), or 
corticosteroids within 2 weeks of the first dose of study treatment.
10. Systemic chronic steroid therapy or any immunosuppressive therapy (≥ 10mg/day 
prednisone or equivalent).  Topical, inhaled, nasal and ophthalmic steroids are allowed.
11. Interferon use within 2 weeks of the first dose of study treatment.


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12. History of severe hypersensitivity reactions to other mAbs.
13. History of HCC tumor rupture.
14. Positive human immunodeficiency (HIV) testing at screening or known history of testing 
positive for HIV or known acquired immunodeficiency syndrome.
15. History of organ transplant. 
16. Clinically significant pleural effusion that either required pleurocentesis or is associated 
with shortness of breath.
17. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures.
18. Patients receiving treatment with medications that are strong inducers of CYP3A4 and that 
cannot be discontinued at least 1 week prior to the start of treatment with INC280 and for 
the duration of the study. Refer to Appendix 5. 
19. Unable to stop herbal/food supplements or treatments which are considered to be capable 
of significantly causing either PK or PD herb/food-drug interactions. From a PK point of 
view, refer to Appendix 5. From a PD point of view, this definition includes any health 
authority approved herbal medication for HCC.
20. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of INC280 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
or malabsorption syndrome).
21. Patient having out of range laboratory values defined as:

Total bilirubin > 2 mg/dL, except for patients with Gilbert’s syndrome who are 
excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN

Alanine aminotransferase (ALT) > 5 x ULN

Aspartate aminotransferase (AST) > 5 x ULN

Coagulation: Prothrombin Time (PT) > 4 seconds more than the ULN or International 
Normalized Ratio (INR) > 1.7

Absolute neutrophil count (ANC) < 1.5 x 109/L

Platelet count < 75 x 109/L

Hemoglobin < 9 g/dL

Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 45 
mL/min

Asymptomatic serum amylase grade > 2 (1.5-2.0 x ULN). Patients with grade 1 or 
grade 2 serum amylase at the beginning of the study must be confirmed to have no 
signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-
amylase, abnormal imaging findings of pancreas, etc.)

Serum lipase > ULN

Potassium, Magnesium, Phosphorus, total Calcium (corrected for serum albumin) 
outside of normal limits (patients may be enrolled if  corrected to within normal limits 
with supplements during screening)
22. Active autoimmune disease or a documented history of autoimmune disease, including 
ulcerative colitis and Crohn’s disease or any condition that requires systemic steroids or 


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any immunosuppressive therapy, except vitiligo or resolved asthma/atopy that is treated 
with broncho-dilators (e.g., albuterol). 
23. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers; and completely resected carcinoma in situ of any type.
24. Clinically significant, uncontrolled heart diseases.

Unstable angina within 6 months prior to screening

Myocardial infarction within 6 months prior to screening

History of documented congestive heart failure (New York Heart Association 
functional classification III-IV)

Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 160 mm Hg 
and/or Diastolic Blood Pressure (DBP) ≥ 100 mm Hg, with or without 
antihypertensive medication. Initiation or adjustment of antihypertensive 
medication(s) is allowed prior to screening

Ventricular arrhythmias

Supraventricular and nodal arrhythmias not controlled with medication

Other cardiac arrhythmia not controlled with medication

QTcF ≥ 450 ms (male patients), ≥ 460 ms (female patients) on the screening ECG (as 
mean of triplicate ECG)
25. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive hCG laboratory 
test. 
26. 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 and 7 days after the last dose 
of INC280 (in case PDR001 was discontinued > 150 days before). Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient.

Use of oral, injected or implanted hormonal methods of contraception or placement if 
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. 


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In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy), 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. 
27. Sexually active males must use a condom during intercourse while taking INC280 and for 
7 days after the last dose of INC280 and should not father a child in this period. A condom 
is required to be used also by vasectomized men in order to prevent delivery of the drug 
via seminal fluid.
6
Treatment
6.1
Study treatment
For this study, the investigational drugs are INC280 and PDR001. The study treatment is 
defined as INC280 in combination with PDR001 or PDR001 single agent.
All dosages prescribed and dispensed to patients and all dose changes during the study must be 
recorded on the Dosage Administration Record (DAR) eCRF page.
6.1.1
Dosing regimen
Table 6-1
Starting dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Starting dose
Frequency and/or 
Regimen
INC280
FMI tablets for oral use
200mg 
Twice daily (BID) on a 
continuous schedule
PDR001
Powder for solution for i.v. 
infusion
300mg
Every 3 weeks (Q3W)
INC280
INC280 tablet will be administered orally on a continuous twice daily (BID) dosing schedule, 
on a flat scale of mg/day and not individually adjusted by weight or body surface area. The 
Investigator must instruct the patient to take the study drug exactly as prescribed.

Except on days of PK sampling, patients should take INC280 tablets twice daily (BID) at 
approximately the same time each day starting at Cycle 1 Day 1.

Each dose of INC280 is to be taken with a glass of water (at least 8 ounces  –
approximately 250 mL) and consumed over as short a time as possible (i.e., not slower 
than 1 tablet every 2 minutes).

Patients should be instructed to swallow the tablets whole and not to chew them.

INC280 may be administered with or without food. The morning and the evening doses 
should be taken 12 (± 4) hours apart, although 12-hour interval is highly recommended. If 


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a dose is not taken within 4 hours of the planned dosing time, the missed dose should not 
be replaced.

On days when PK blood samples are to be collected, patients will be instructed to
hold their dose until arrival at the study center. INC280 will be administered at the site in
the morning. The exact time of drug administration should be recorded in the appropriate
eCRF. The PK blood draws will be supervised by a member of the research team. If a
patient vomits within 4 hours of INC280 dosing, the time of vomiting should be recorded 
on the eCRF.

Patients should be instructed not to make up for missed doses or partial doses (i.e.,
when the entire dose is not taken as instructed). A missed or partial dose will be
defined as a case when the full dose is not taken within 4 hours of the scheduled twice
daily dosing. If that occurs, then the dose (or part remaining dose) should not be taken and
dosing should restart with the next scheduled dose. If vomiting occurs, no attempt should
be made to replace the vomited dose before the next scheduled dose.

During the whole duration of treatment with INC280, the patient is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective 
clothing, avoid sunbathing or using a solarium).

All dosages prescribed and dispensed to the patient and all dose changes during the study 
must be recorded on the DAR eCRF page.
PDR001
PDR001 will be administered via i.v. infusion over 30 minutes (up to 2 hours, if clinically 
indicated) once every 3 weeks. PDR001 may be delayed due to toxicities. The PDR001 dosing 
may resume once the adverse event has resolved to grade 1 or baseline, and the start of the cycle 
will be shifted accordingly. 
Sequence of INC280 and PDR001 treatment
INC280 will be administered prior to PDR001 along with its pre-medication (if pre-medication 
is necessary). The sequence will allow consistent time of daily dosing for INC280. A minimum 
of 1 hour must pass from the time of INC280 (morning dose) administration to the 
administration of PDR001.
6.1.2
Ancillary treatments
Patients should not receive pre-medication to prevent infusion reaction before the first infusion 
of PDR001, in order to determine if pre-medication is necessary. If a patient experiences an 
infusion reaction, he/she may receive pre-medication on subsequent dosing days. The pre-
medication should be chosen per institutional standard of care, at the discretion of the treating 
physician.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a patient experiences a Grade 3 anaphylactic/anaphylactoid 
reaction, the patient will discontinue study treatment. The patient may resume study treatment 
following documented discussion with Novartis.


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Patients should be treated in a facility equipped for cardiopulmonary resuscitation. Appropriate 
resuscitation equipment should be available at the bedside and a physician readily available.
Guidelines on management of PDR001 infusion reactions are provided in Section 6.3.2, 
Table 6-4 and Appendix 4.
The CTCAE category of “Infusion related reaction” should be used to describe PDR001 
infusion reactions, unless the Investigator considers another category, such as “Allergic 
reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation.
6.1.3
Treatment duration
All patients will begin treatment on Cycle 1 Day 1. Patients may be discontinued from treatment 
with the study drug due to: 

unacceptable toxicities

confirmed disease progression per irRC 

at the discretion of the Investigator (e.g. clinical deterioration) 

patient’s decision. 
Note: Patients will not be withdrawn from the study due to progressive disease per RECIST 
v1.1. Please refer to Section 7.1.3 and Section 7.1.4 for further details.
6.2
Dose escalation guidelines
6.2.1
Starting dose rationale 
This is the first study evaluating the combination of INC280 and PDR001. In order to 
understand the safety, tolerability and PK of the combination, starting doses for the combination 
of INC280 and PDR001 are planned as 200 mg BID and 300 mg Q3W, respectively. The 
PDR001 dose will remain constant during the phase Ib and phase II part.
To date, PDR001 has been tested up to 10mg/kg every 2 weeks which was not considered an 
MTD dose. RP2D from the ongoing [CPDR001X2101] study is 300 mg (3.75mg/kg) given 
every 3 weeks. The PDR001 exposure at this dose regimen is expected within the range of those 
observed in the [CPDR001X2101] study with no DLTs. It is expected to achieve mean steady 
state Ctrough concentrations that are >70-fold higher than the in vitro/ex vivo potency EC50 for 
PDR001 (assessed as 0.42 µg/mL). In addition, the expected PDR001 Ctrough concentrations 
are in line with observed mean steady state Ctrough concentrations for Pembrolizumab. In 
accordance with clinical experience of nivolumab and pembrolizumab (Topalian et al 2012, 
Topalian et al 2014, Hamid and Carvajal 2013, Robert et al 2014), PDR001 is expected to 
demonstrate antitumor activity at 300 mg dosed every 3 weeks.
INC280 tablet 400 mg BID is the RP2D selected in phase I and phase II single agent studies 
(including in the first line HCC patients), as well as in combination with gefitinib. For the dose 
escalation phase of this study, the starting dose of INC280 will be 200 mg BID, which is two 
dose levels below the RP2D of 400 mg BID. Strong pharmacokinetic drug-drug interaction is 
not expected between INC280 and PDR001. However as INC280 metabolism is moderately 
mediated by CYP3A4/5 and PDR001 treatment might have impact on metabolizing enzymes 


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through cytokine regulation, INC280 exposure will be monitored in the dose escalation phase 
to assess DDI.
6.2.2
Provisional dose levels
Table 6-2 describes the starting dose for the phase Ib part and the dose levels that may be 
evaluated during this trial. PDR001 dose will be a fixed dose and only INC280 will be escalated.
Table 6-2
Provisional dose levels (Phase Ib part – INC280 in combination with 
PDR001)
Dose level
INC280 Proposed dose
PDR001 Proposed dose *
-1**
100 mg
300 mg
1 (starting dose)
200 mg
300 mg
2***
400 mg
300 mg
*PDR001 will be given at a stable dose (no escalation).
**Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study.
***An intermediate dose of INC280 may be explored if needed.
6.2.3
Guidelines for dose escalation and determination of MTD/RP2D
MTD definition
The MTD is defined as the highest combination drug doses expected to cause DLT in less than 
33% of the treated patients in the first two cycles of treatment. AEs and laboratory abnormalities 
considered to be DLTs are defined in Table 6-3.
The applied adaptive Bayesian methodology provides an estimate of the combinations of
INC280 and PDR001 not exceeding the MTD. Typically the MTD is a tested combination with 
maximum probability of targeted toxicity (DLT rate between 16% and <33%). The use of the 
EWOC principle, i.e., a dose may only be used for newly enrolled patients if the risk of 
excessive toxicity (DLT rate between 33% and 100%) at the dose is less than 25%, limits the 
risk that a potential next dose will exceed the MTD (Appendix 3).
Dose cohort modification
For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
patients who will be treated at the specified dose level. The first cohort will be treated with the 
starting dose of INC280 200 mg BID (p.o.) combined with PDR001 300 mg q3w (i.v.).
Patients must complete a minimum of 2 cycles of treatment with the minimum safety evaluation 
and drug exposure or have had a DLT within the first two cycles of treatment to be considered 
evaluable for dose escalation decisions (Section 10.1.4). Dose escalation decisions will occur 
when the cohort of patients has met these criteria. If only 2 patients in a cohort are evaluable 
and neither patient has experienced a treatment-related toxicity CTCAE grade > 1, dose 
escalation decisions may be considered.
Dose escalation decisions will be made by Investigators and Novartis study personnel. 
Decisions will be based on a synthesis of all relevant data available from all dose levels 


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evaluated in the ongoing study including safety information, DLTs, all CTCAE grade ≥ 2 
toxicity data during cycles 1 and 2, and available PK, and available PD data from evaluable 
patients. The recommended dose for the next cohort of patients will be guided by the BLRM 
with EWOC principle. 
Bayesian logistic regression model of DLT rate
The adaptive Bayesian methodology provides an estimate of DLT rate for all dose levels of 
INC280 combined with PDR001 that do not exceed the MTD and incorporates all DLT 
information from all dose levels for this estimation. In general, the next dose will have the 
highest chance that the DLT rate will fall in the target interval [16-33%) and will always satisfy 
the EWOC principle. In all cases, the dose for the next cohort will not exceed a 100% increase 
of INC280 from the previous dose. Smaller increases in dose may be recommended by the 
Investigators and Novartis upon consideration of all of the available clinical data. Any dose 
escalation decisions made by Investigators and Novartis personnel will not exceed the dose 
level recommended by the BLRM using the EWOC principle. If needed to better define the 
dose-toxicity relationship additional patients may be enrolled to the current dose level, to a 
preceding dose level, or to an intermediate dose level before proceeding with further dose 
escalation.
If two patients in a previously untested dose level experience a DLT, enrollment to that cohort
will stop, the BLRM will be updated and the next cohort will be opened at the next lower dose
level or an intermediate dose level that satisfies the EWOC principle. However, if two patients 
in a new cohort at a previously tested dose level experience a DLT (e.g., a total of eight patients 
are treated on this dose level with two DLTs observed), further enrollment to that cohort will 
stop, the BLRM will be updated with this new information and re-evaluation of the available 
safety and PK data will occur. By incorporating information gained at the preceding dose 
cohorts, additional patients may be enrolled into the current dose cohort only if the combination 
still meets the EWOC principle and as agreed by Investigators and Novartis personnel. 
Alternatively, if recruitment to the same cohort may not resume, a new cohort of patients may 
be recruited to a lower dose level as agreed by Investigators and Novartis personnel and if the 
BLRM predicts that the risk for this lower dose level to exceed the MTD remains below 25% 
(EWOC). Re-escalation may then occur if data in subsequent cohorts supports this (EWOC 
principle is satisfied) and Investigators and Novartis personnel agree.
Dose escalation will continue until identification of the MTD or a suitable lower dose for the
phase II part.
The MTD is identified when the following 3 conditions are met:
a. at least 6 patients have been treated at this dose
b. this dose satisfies one of the following conditions: 

the posterior probability of targeted toxicity at this dose exceeds 50%  and is the 
highest among potential doses, or

minimum of 12 patients have already been treated on the trial to identify the MTD. 
Recommendation of RP2D may be made with fewer patients, prior to identification of 
MTD, or


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
significant activity is seen early in the phase Ib part, in which case a  recommended 
dose for expansion may be identified and the phase II groups may be initiated without 
determination of the MTD.
c. it is the maximum dose recommended for patients, either per the model or by review of all 
clinical data by Novartis and Investigators in a dose-escalation teleconference see 
Section 6.2.3.1.
Multiple dose levels may be evaluated in simultaneous cohorts, as long as none exceeds the 
maximum dose permitted by the BLRM, and a maximum of 6 patients are treated at a dose level 
greater than the highest dose previously shown to be safe.
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first two cycles of treatment, 
then the BLRM will be updated with this new information before any additional patients are 
enrolled at that higher dose level. Patients ongoing will continue treatment at their assigned 
dose levels.
6.2.3.1
Implementation of Dose Escalation Decisions
To implement dose escalation decisions, the available toxicity information (including AEs and 
laboratory abnormalities that are not DLTs), the recommendations from the BLRM, and the 
available PK and PD information will all be evaluated by the Investigators and Novartis study 
personnel (including the study physician and statistician) during a dose decision meeting by 
teleconference. Drug administration at the next higher dose level may not proceed until the 
Investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level.
6.2.3.2
Intra-Patient dose escalation
Intra-patient dose escalation is not permitted at any time within the first 2 cycles of treatment. 
After cycle 2 has been completed, individual patients may be considered for treatment at a dose 
of INC280 higher than the dose to which they were initially assigned. In order for a patient to 
be treated at a higher dose of INC280, he or she must have tolerated the lower dose for at least 
2 cycles of therapy (i.e. he or she must not have experienced any INC280-related toxicity 
CTCAE grade ≥ 2 at the lower dose originally assigned). Moreover, the new, higher dose with 
which the patient is to be treated must be a dose that has completed evaluation and has not 
exceeded the MTD/RP2D. Consultation and agreement with Novartis must occur prior to any 
intra-patient dose escalation occurring. These changes must be recorded on the DAR eCRF 
page. Data from the first two cycles of treatment at the new dose level will not be formally 
included in the statistical model describing the relationship between dose and occurrence of 
DLT. However, these data will be incorporated into the clinical assessment of safety within a 
dose escalation teleconference.
6.2.4
Definitions of dose limiting toxicities (DLTs)
A DLT is defined as an AE or abnormal laboratory value of CTCAE grade ≥ 3 (assessed as 
unrelated to disease, disease progression, inter-current illness, or concomitant medications) that 
occurs within the first two cycles of treatment with INC280 in combination with PDR001 during 
the dose escalation part of the study, with the exceptions described in Table 6-3.


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National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) 
version 4.03 will be used for all grading. For the purpose of dose-escalation decisions, DLTs 
will be considered and included in the BLRM.
The Investigator must notify Novartis immediately of any unexpected CTCAE grade ≥ 3 AEs 
or laboratory abnormalities. Prior to enrolling patients into a higher dose level, CTCAE grade 
≥ 2 AEs will be reviewed for all patients at the current dose level.
Table 6-3
Criteria for defining dose limiting toxicities (DLTs) (INC280 combined 
with PDR001)
DLTs include any AE of CTCAE grade 3 or higher occurring in cycle 1 and/or 2, during the dose 
escalation part of the study, for which relationship to study treatment cannot be ruled out, with the 
following exceptions:
Hematology
Neutropenia CTCAE grade 3 (for > 7 consecutive days) and CTCAE grade 4
Thrombocytopenia CTCAE grade 3 with clinically significant bleeding
Thrombocytopenia CTCAE grade 3 (for > 7 consecutive days) 
Thrombocytopenia CTCAE grade 4
Anemia CTCAE grade 4
Lymphopenia CTCAE grade 4
Hepatic
For patients with normal bilirubin baseline: Isolated* total bilirubin CTCAE 
grade 2 for > 7 consecutive days is a DLT, except for patients with Gilbert’s 
syndrome, for whom isolated total bilirubin is a DLT if CTCAE grade 3 for > 7 
days.
For patients with baseline bilirubin out of normal range: blood bilirubin 
increased to > 1.5 times above baseline
For patients with normal baseline AST and ALT and bilirubin value: 
AST or ALT > 5.0 x ULN combined with total bilirubin > 2.0 x ULN without 
evidence of cholestasis*** 
OR
For patients with abnormal baseline AST or ALT or bilirubin value: 
[AST or ALT > 3 x baseline AND > 5.0 x ULN] OR [AST or ALT > 8.0 x ULN], 
whichever is lower, combined** with [total bilirubin > 2 x baseline] without 
evidence of cholestasis
Cardiac
Grade ≥ 3 or cardiac event that is symptomatic or requires medical intervention
Clinical signs of cardiac disease, such as unstable angina or myocardial 
infarction, or Grade ≥ 3 Troponin
QTc interval prolonged Grade ≥ 3 (QTcF ≥ 501 ms) on at least two separate 
ECGs for > 7 consecutive days 
Gastrointestinal
Nausea and vomiting:

Recurrence of CTCAE grade 2 (despite standard anti-emetics) 

CTCAE grade ≥ 3 despite standard anti-emetics

CTCAE grade 4
Diarrhea:

Recurrence of CTCAE grade 2 (despite anti-diarrheal treatment)

CTCAE grade ≥ 3 despite maximal anti-diarrheal treatment

CTCAE grade 4
Hypertension
CTCAE grade 3 hypertension if it persists > 7 days despite treatment 
Grade 4 hypertension
Pneumonitis
CTCAE grade 2 pneumonitis if it persists > 7 days despite treatment with 
corticosteroids. 


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DLTs include any AE of CTCAE grade 3 or higher occurring in cycle 1 and/or 2, during the dose 
escalation part of the study, for which relationship to study treatment cannot be ruled out, with the 
following exceptions:
CTCAE Grade 3-4 pneumonitis of any duration.
Infection
CTCAE grade 3 infection or fever in the absence of neutropenia if they 
persist > 5 days. 
CTCAE Grade 4 infection of any duration is a DLT.
Electrolytes
CTCAE grade 3 electrolyte abnormalities if they persist > 7 days despite 
treatment or are clinically significant. Grade 4 electrolyte abnormality of any 
duration is a DLT.
Pancreas
Asymptomatic CTCAE grade ≥ 3 serum amylase or lipase (> 2.0 × ULN) 
occurring for > 7 consecutive days is a DLT
Symptomatic serum amylase or lipase elevation, medical intervention required
is a DLT
Fatigue/Asthenia
Fatigue/Asthenia CTCAE grade ≥ 3 and lasting > 7 consecutive days is a DLT
Immune-related toxicities
CTCAE grade 3 immune related toxicities if they persist > 7 days despite 
treatment with corticosteroids 
Immune related toxicities CTCAE grade 4 of any duration are DLTs.
Other AEs
Other clinically significant toxicities, including  a single event or multiple 
occurrences of the same event that lead to a dosing delay of > 7 days in cycles 
1 and 2, may be considered to be DLTs by the Investigators and Novartis, even 
if not CTCAE grade 3 or higher.
*“Isolated total bilirubin” increase defined as:  total bilirubin increase without ALT or AST increase; “isolated 
AST or ALT” increase defined as: AST or ALT increase without total bilirubin increase
**“Combined” defined as:  total bilirubin increase to the defined threshold concurrently with ALT/AST increase 
to the defined threshold
***“Cholestasis” defined as: ALP elevation [>2xULN and R value < 2] in patients without bone metastasis, or 
elevation of ALP liver fraction 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)
6.3
Dose modifications
6.3.1
Dose modifications and dose delay for INC280
Dose reductions and modifications for INC280 are described in Table 6-5.
Patients who missed more than 28 consecutive days of INC280 dosing should be discontinued 
from the study treatment and enter the Safety Follow-up period. In exceptional situations, if the 
patient is clearly benefiting from the study treatment (i.e. stable disease, partial response, 
complete response), and in the opinion of the Investigator no safety concerns are present, after 
documented discussion with Novartis, the patient may remain on study treatment.
Patients who discontinue treatment due to INC280 related toxicities may continue treatment 
with PDR001 single agent after documented discussion with Novartis.
6.3.2
Dose modifications and dose delay for PDR001
There will be no dose modifications allowed for PDR001.


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If a patient experiences an AE meeting the criteria for DLT as outlined in Section 6.2.4
(including events occurring after cycle 2), treatment should be withheld. The same applies for 
any grade 3 immune related AE (irAE) that would require the use of systemic steroids. Patients 
can only resume treatment if they are on a prednisone dose of ≤10 mg/day (or equivalent dose 
if another steroid is used). Following resolution of the toxicity to grade 1 or to the patient’s 
baseline value, the patient may resume study treatment, if there is no evidence of disease 
progression as per irRC. A decision to resume treatment with PDR001 following the occurrence 
of a DLT or any grade 3 irAE is at the discretion of the Investigator. If the Investigator considers 
it to be in the patient’s best interest to resume therapy before the toxicity has resolved to grade 
1, this may be permitted on a case by case basis, following discussion with Novartis. In case 
the infusion cannot be administered at the scheduled visit, it has to be administered as soon as 
possible, and the start of the cycle will be shifted accordingly. 
Patients who missed 2 infusions should be discontinued from the study treatment and enter the 
Safety Follow-up period. In exceptional situations, if the patient is clearly benefiting from the 
study treatment (i.e. stable disease, partial response, complete response), and in the opinion of 
the Investigator no safety concerns are present, after discussion with Novartis, the patient may 
remain on the study treatment
Patients who discontinue the study for an AE or clinically significant abnormal laboratory value 
must be followed as described in Section 6.3.2. Patients who discontinue treatment due to 
PDR001 related toxicities may continue treatment with INC280 single agent after documented 
discussion with Novartis.
All changes in study drug administration must be recorded on the DAR eCRF page.
6.3.3
Follow-up for toxicities related to PDR001
The emergence of irAE may be anticipated based on general experience in clinical studies with 
similar class of compounds that block the negative immune regulators.
An irAE is a clinically important AE of unknown etiology associated with the study drug 
exposure. irAEs are typically low grade and self-limited, often occurring after multiple doses, 
and most frequently involving the GI tract (diarrhea/colitis), skin (rashes), liver (hepatitis), and 
endocrine systems (a variety of endocrinopathies). Serologic, histologic (tumor sample) and 
immunological assessments should be performed as deemed appropriate by the Investigator, to 
verify the immune related nature of the AE, and exclude the neoplastic, infectious or metabolic 
origin of the AE. Management Algorithms (Appendix 4) have been developed to assist 
Investigators in assessing and managing the following groups of AEs: Gastrointestinal; Renal; 
Pulmonary; Endocrinopathy; and Skin.
For all the patients whose treatment is interrupted or permanently discontinued due to an irAE, 
AE or clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 30 days, and 
subsequently at approximately 30-day intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
In case of a suspected irAE, the relevant immunological assessments (e.g. rheumatoid factor, 
anti-DNA Ab, etc.) should be performed. In case of a toxicity suspected to be a cytokine release 
syndrome, the assessments outlined in Section 7.2.2.5.6 must be performed. All patients must 


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be followed-up for irAEs, AEs and SAEs for 150 days following the last dose of PDR001 and 
30 days following the last dose of INC280 (in case PDR001 was discontinued >120 days before). 
Table 6-4 and Appendix 4 outline the follow-up evaluations recommended for selected 
toxicities.
Table 6-4
Follow-up evaluations for selected toxicities related to PDR001
TOXICITY
FOLLOW-UP EVALUATION
Infusion Reaction
Grade 1
Infusion interruption not indicated;
intervention not indicated.
Grade 2
Stop infusion immediately, and keep line open. Provide supplemental oxygen 
and fluids, as needed.
Monitor vital signs (e.g., blood pressure, pulse, respiration, and temperature) 
every 15 ± 5 minutes until resolution.
Administer medications for symptomatic relief as needed:
-
Urticaria: Diphenhydramine (25 to 100 mg i.v.) as needed every 4 to 6 
hours, or alternative as appropriate.
-
Fever: Acetaminophen/paracetamol (650-1000 mg by mouth) as needed 
every 4 to 6 hours, or alternative as appropriate.
-
Rigors: Meperidine 25 mg i.v. as needed every 6 hours or alternative as 
appropriate.
Corticosteroids may be administered, as needed.
Resume infusion once infusion reaction resolves (within 8 hours of initial 
start of infusion):
Maintain dose level. Administer oral pre-medication (e.g.1000 mg of 
acetaminophen/paracetamol, 50-100 mg diphenhydramine hydrochloride or 
alternative antihistamine), within 60 minutes of restarting the infusion.
Restart infusion at 50% of previous rate under continuous observation. 
Ensure that there is a minimum observation period of 1 hour prior to restarting 
the infusion.
If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-
medication, then discontinue patient from PDR001.
Grades 3 and 4
Discontinue infusion immediately, and discontinue patient from study.
Provide supplemental oxygen, fluids, and other resuscitative measures as 
needed. Monitor vital signs (e.g., blood pressure, pulse, respiration, and 
temperature) every 15 ± 5 minutes until resolution.
Pneumonitis
Management Algorithms (Appendix 4)
Renal AE-
Creatinine increase
Management Algorithms (Appendix 4)
Skin AE- Rash
Management Algorithms (Appendix 4)
Endocrinopathy-
TSH
Management Algorithms (Appendix 4)
GI AE
Diarrhea/Colitis
Management Algorithms (Appendix 4)


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TOXICITY
FOLLOW-UP EVALUATION
Other immune 
related toxicities 
Grade 1
Monitor closely until resolution and treat symptoms as appropriate.
Grade 2
Hold study drug and treat with corticosteroids (up to 10 mg prednisone or 
equivalent per day) and other supportive care as clinically indicated until 
resolution to grade 1.
Grades 3 and 4
Permanently discontinue study drug. Treat with high dose corticosteroids (≥ 
40 mg prednisone or equivalent per day) and other supportive care as 
clinically indicated.
Cytokine Release 
Syndrome (CRS)
Grades 2, 3 and 4
If CRS is suspected (very high fever and precipitous drops in blood pressure) 
treat with corticosteroids. 
Take blood for cytokine measurements immediately after the occurrence of 
the AE and during treatment. If very high levels of IL-6 can be confirmed, a
more specific treatment may be used.
6.3.3.1
Dose modifications and dose delay for INC280 and PDR001
Table 6-5
Dose reduction and interruption criteria 
Worst toxicity
CTCAE Gradea (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing
HEMATOLOGIC
Neutrophil count decreased (ANC) Neutropenia
Grade 1 and 2 (< LLN - 1000/mm3, < 
LLN – 1.0 x 109/L)
Maintain dose level of INC280 and continue PDR001 dosing.
Grade 3 (< 1000 - 500/mm3; < 1.0 –
0.5 x 109/L)
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 2, 
then:
If resolved ≤ 7 days, resume INC280 treatment at same dose level and 
resume PDR001 dosing.
If resolved > 7 days, resume INC280 treatment at ↓1 dose level and 
resume PDR001 dosing*.
Grade 4 (< 500/mm3; < 0.5 x 109/L)
Omit INC280 dose/delay PDR001 dosing until resolved to ≤ grade 2, 
then resume INC280 treatment ↓1 dose level and resume PDR001 
dosing*.
Febrile neutropenia (ANC 1000/mm3
(< 1.0 x 109/L), fever > 38.3°C (101 °F)
Omit dose/delay PDR001 dosing, then: 
If resolved in ≤ 7 days, resume INC280 treatment at ↓1 dose level and 
resume PDR001 dosing*.
If resolved in > 7 days, discontinue INC280 treatment and consider 
resuming PDR001 dosing alone*.
Platelet count decreased (Thrombocytopenia)
Grade 1 or 2 (< LLN – 50 x 109/L)
Maintain dose level of INC280 and continue PDR001 dosing.
Grade 3 (< 50 – 25 x 109/L) without 
clinically significant bleeding
Maintain dose level of INC280 and continue PDR001 dosing.
If resolved ≤ 7 days, continue INC280 treatment at same dose level and 
continue PDR001 dosing*.
If resolved > 7 days, continue INC280 treatment at ↓1 dose level and 
continue PDR001 dosing.


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Worst toxicity
CTCAE Gradea (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing
Grade 3 (< 50 – 25 x 109/L) with 
clinically significant bleeding
Omit dose until resolved to grade ≤ 2, then:
If resolved ≤ 7 days, resume INC280 treatment at same dose level and 
resume PDR001 dosing*.
If resolved > 7 days, resume INC280 treatment at ↓1 dose level and 
resume PDR001 dosing.
Grade 4 (< 25 x 109/L)
Omit dose until resolved to grade ≤ 2, then resume INC280 treatment at
↓1 dose level and resume PDR001 dosing***.
If toxicity recurs, discontinue patient from INC280 treatment and 
consider resuming PDR001 dosing alone*.
RENAL
Serum creatinine
Grade 1 (> ULN - 1.5 x ULN)
Maintain dose level of INC280 and PDR001
Grade 2 (> 1.5 - 3.0 x ULN)
Grade 3 (> 3.0 – 6.0 x ULN)
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1 or 
baseline, then:
If resolved in ≤ 7 days: Resume INC280 treatment at ↓1 dose level 
and resume PDR001 dosing.
If resolved in > 7 days, permanently discontinue patient from INC280 
and PDR001 treatment.
Grade 4 (> 6.0 x ULN)
Permanently discontinue patient from INC280 and PDR001 treatment. 
HEPATIC
Isolated total bilirubin elevation - For patient’s whose baseline total bilirubin is ≤ULN
>ULN – 2.0 x ULN 
Maintain dose level of INC280 and continue PDR001 dosing with liver 
function tests (LFTs) monitored.
>2.0 – 3.0 x ULN
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1, 
then
If resolved in ≤ 7 days, resume treatment at the same dose level and 
resume PDR001 dosing.
If resolved in > 7 days, resume INC280 treatment at ↓1 dose level and 
resume PDR001 dosing.
Grade 3 (> 3.0 - 10.0 x ULN) d
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1, 
then
If resolved in ≤ 7 days, resume treatment at ↓ 1 dose level and resume 
PDR001 dosing*.
If resolved in > 7 days, discontinue patient from INC280 treatment and 
consider resuming PDR001 dosing alone*.
Grade 4 (> 10.0 x ULN) c
Permanently discontinue patient from INC280 treatment and delay 
PDR001 dosing until resolved to grade ≤ 1, then consider resuming 
PDR001 dosing alone*.
Isolated total bilirubin elevation - For patient’s whose baseline total bilirubin is > ULNc
>ULN – 2.0 times above baseline
Maintain dose level of INC280 and continue PDR001 dosing with LFTs 
monitored.
>2.0 – 3.0 times above baseline
Omit INC280 dose/delay PDR001 dosing until resolved to baseline, 
then
If ≤ 7 days, resume treatment at the same dose level and resume 
PDR001 dosing.
If > 7 days, resume INC280 treatment at ↓1 dose level and resume 
PDR001 dosing.


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Worst toxicity
CTCAE Gradea (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing
>3.0 times above baseline
Omit INC280 dose/delay PDR001 dosing until resolved to baseline, 
then
If ≤ 7 days, resume treatment at ↓ 1 dose level and resume PDR001 
dosing*.
If > 7 days, discontinue patient from INC280 treatment and consider 
resuming PDR001 dosing alone*.
Grade 4 (> 10.0 x ULN) c
Permanently discontinue patient from INC280 treatment and delay 
PDR001 dosing until resolved to grade ≤ 1, and consider resuming 
PDR001dosing alone*.
Isolated AST or ALT elevation for patient’s baseline AST/ALT are ≤ULN
Grade 1 and 2 (> ULN - 5.0 x ULN)
Maintain dose level of INC280 and continue PDR001 dosing.
Grade 3 (> 5.0 – 20.0 x ULN)
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1, 
then
If resolved in ≤ 7 days, resume INC280 treatment at ↓ 1 dose level and 
resume PDR001 dosing.
If resolved in > 7 days, discontinue INC280 permanently and continue 
with PDR001 alone.
Grade 4 (>20.0 x ULN)
Discontinue INC280 permanently. Once resolved to grade ≤ 1, consider 
resuming PDR001 dosing alone*.
Isolated AST or ALT elevation for patient’s baseline AST/ALT are > ULN
> ULN - 3.0 times above baseline
Maintain dose level of INC280 and continue PDR001 dosing.
> 3.0 – 5.0 times above baseline but 
<5.0 x ULN
Maintain dose level of INC280 and continue PDR001 dosing.
> 3.0 – 5.0 times above baseline 
but >5.0 x ULN
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 
1/back to baseline, then
If resolved in ≤ 7 days, resume INC280 treatment at ↓ 1 dose level and 
resume PDR001 dosing.
If resolved in > 7 days, discontinue INC280 permanently and continue 
with PDR001 dosing alone.
5.0 times above baseline
Discontinue INC280 permanently. Once resolved to grade ≤ 1 or 
baseline, consider resuming PDR001 dosing alone*.
Combined b e elevations of AST or 
ALT and total bilirubin
For patients with normal baseline ALT 
or AST or total bilirubin value:
AST or ALT >3.0 x ULN combined  
with total bilirubin >2.0 x ULN without 
evidence of cholestasis d
OR  
For patients with elevated baseline 
AST or ALT or  total bilirubin value  
[AST or ALT>2 x baseline AND > 3.0 x 
ULN] OR [AST or ALT > 8.0 x ULN], 
combined with [total bilirubin >2x 
baseline] AND >2.0 x ULN without 
evidence of cholestasis d
Discontinue INC280 permanently in the absence of signs of cholestasis, 
hemolysis, and alternative causes of the liver injury have been excluded 
(e.g., concomitant use of hepatotoxic drug(s), alcoholic hepatitis, etc.). 
Once resolved to grade ≤ 1 or baseline, consider resuming PDR001 
dosing alone*.


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Worst toxicity
CTCAE Gradea (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing
METABOLIC
Asymptomatic amylase and/or lipase elevation (If symptomatic elevations of any grade, discontinue 
INC280 permanently)
Grade 1 and 2 (> ULN - 2.0 x ULN)
Maintain dose level of INC280 and continue PDR001 dosing.
Grade 3 (> 2.0 - 5.0 x ULN)
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 2, 
then
If resolved in ≤ 14 days, resume treatment at same dose level and 
resume PDR001 dosing.
If resolved in > 14 days, resume treatment at ↓ 1 dose level and resume 
PDR001 dosing.
Grade 4 (> 5.0 x ULN)
Permanently discontinue patient from INC280 treatment. Once resolved 
to grade ≤ 1 or baseline, consider resuming PDR001 dosing alone*.
CARDIAC
Myocarditis or other cardiac event
Recommended clinical management of myocarditis grade ≥2 or other cardiac event grade ≥3: Initiate systemic 
corticosteroids (prednisone or equivalent) at a dose of 1-2 mg/kg QD and consult with a cardiologist (hospitalization 
as indicated)
Grade 1
Maintain dose level of INC280 and continue PDR001 dosing
Myocarditis grade ≥2 
Permanently discontinue IN280 and PDR001
Other cardiac event grade ≥3
Permanently discontinue IN280 and PDR001
Electrocardiogram QT corrected (QTc) interval prolonged
Grade 1 and 2 (QTcF 450-500 ms)  
Maintain dose level of INC280 and continue PDR001 dosing
Grade 3 (QTcF ≥ 501 ms on at least 
two separate ECGs)  
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 2, 
then:
If resolved ≤ 7 days, resume treatment at the same dose level and 
resume PDR001 dosing.
If resolved > 7 days, resume treatment at ↓1 dose level and resume 
PDR001 dosing.
Grade 4 (QTcF ≥ 501 ms or > 60 ms 
change from baseline and Torsades de 
pointes or polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia)
Permanently discontinue patient from INC280 treatment. Once resolved 
to grade ≤ 1 or baseline, consider resuming PDR001 dosing alone*.
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS
ILD like events/Pneumonitis
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. In addition, withhold INC280 for acute 
onset of new or progressive unexplained pulmonary symptoms, such as dyspnea, cough and fever and during 
diagnostic workup for ILD/pneumonitis to exclude alternative causes such as, but not limited to infections, 
lymphangitic carcinomatosis, cardiogenic edema, or pulmonary hemorrhage. 
For the follow-up and management of ILD like events/pneumonitis, also refer to Appendix 4, Pulmonary Adverse 
Event Management Algorithm. 
Grade 1
Interrupt INC280 during diagnostic workup for ILD/Pneumonitis; 
consider delay of PDR001 dosing. Exclude infections and other 
etiologies.
In presence of diagnosis of ILD/Pneumonitis after diagnostic workup, it 
is mandatory to permanently discontinue INC280.
Only in the absence of a diagnosis of ILD/Pneumonitis, INC280 may be 
restarted at the same dose. 


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Worst toxicity
CTCAE Gradea (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing
If it recurs after resumption of study drug permanently discontinue 
INC280.
Grade 2
Mandatory: Interrupt INC280 and delay PDR001 dose during diagnostic 
workup for ILD until improvement to ≤ Grade 1. Exclude infections and 
other etiologies.
In presence of diagnosis of ILD/Pneumonitis after diagnostic workup, it 
is mandatory to permanently discontinue INC280. 
Only in the absence of a diagnosis of ILD/Pneumonitis, study drug may 
be restarted following these guidelines: 

If resolves to ≤ Grade 1 in ≤ 7 days reduce INC280 by 1 dose level. 

If fails to resolve to ≤ Grade 1 within 7 days or recur after 
resumption of study drug at decreased dose, permanently 
discontinue INC280.
Grade 3 and Grade 4
Mandatory: Permanently discontinue study drugs.
Treat with IV steroids as clinically indicated. Oxygen therapy as 
indicated.
GASTROINTESTINAL
Pancreatitis
Grade 2
Maintain dose level of INC280 and continue PDR001 dosing.
Grade ≥ 3
Permanently discontinue patient from INC280 treatment. Once resolved 
to grade ≤ 1 or baseline, resume PDR001 dosing alone*.
Diarrhea **
Grade 1 (despite maximal anti-
diarrheal medication)
Maintain dose level of INC280 and continue PDR001 dosing.
Grade 2 (despite maximal anti-
diarrheal medication)
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1, 
then resume INC280 treatment/PDR001 dosing at same dose level.
If diarrhea returns as grade ≥ 2, omit INC280/delay PDR001 dosing 
dose until resolved grade ≤ 1, then resume INC280 treatment↓1 dose 
level.
Continue PDR001 dosing*.
Grade 3 or 4 (despite maximal anti-
diarrheal medication)
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1, 
then resume INC280 treatment at ↓1 dose level and discontinue
PDR001 dosing*.
Vomiting
Grade 1 (despite standard anti-
emetics)
Maintain dose level of INC280 and continue PDR001 dosing.
Grade 2 (despite standard anti-
emetics)
Omit INC280 dose until resolved to grade ≤ 1, then resume treatment at 
same dose level.
If vomiting returns as grade ≥ 2, omit INC280 dose until resolved to 
grade ≤ 1, then resume INC280 treatment at ↓1 dose level and 
continue PDR001 dosing*.
Grade 3 and 4 (despite standard anti-
emetics)
Omit INC280 dose/delay PDR001 dosing until  resolved to  grade ≤ 1, 
then resume INC280 treatment at↓1 dose level and discontinue 
PDR001 dosing*.
Nausea
Grade 1 or 2 (despite standard anti-
emetics)
Maintain dose level of INC280 and continue PDR001 dosing.


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Protocol No. CINC280X2108
Worst toxicity
CTCAE Gradea (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing
Grade 3 (despite standard anti-
emetics)
Omit INC280 dose/delay PDR001 dosing until  resolved to grade ≤ 1, 
then resume INC280 treatment at↓1 dose level and consider 
resuming PDR001 dosing*.
SKIN AND SUBCUNTANEOUS TISSUE DISORDERS
Rash/photosensitivity ***
Grade 1 or 2
Maintain dose level of INC280 and continue PDR001 dosing. 
Grade 3, despite skin toxicity therapy
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1, 
then:
If resolved in ≤ 7 days, resume INC280 treatment at ↓ 1 dose level and 
resume PDR001 dosing.
If resolved in > 7 days (despite appropriate skin toxicity therapy), 
discontinue patient from INC280 treatment and consider resuming 
PDR001 dosing alone*.
Grade 4, despite skin toxicity therapy
Discontinue patient from INC280 treatment. Once resolved to grade ≤ 1 
or baseline, consider resuming PDR001 dosing alone*.
Stevens-Johnson syndrome (SJS), or 
Lyell syndrome/toxic epidermal 
necrolysis (TEN)
Permanently discontinue PDR001 and INC280 treatment. 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
Fatigue/Asthenia
Grade 1 or 2
Maintain dose level of INC280 and continue PDR001 dosing.
Grade 3
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 1, 
then:
If resolved in ≤ 7 days, resume INC280 treatment at same dose level 
and resume PDR001 dosing.
If resolved in > 7 days, resume INC280 treatment at ↓1 dose level and 
resume PDR001 dosing.
Grade 4
Discontinue patient from INC280 treatment. Once resolved to grade ≤ 1 
or baseline, consider resuming PDR001 dosing alone*.
Peripheral edema
Grade 1 or 2
Maintain dose level of INC280 and continue PDR001 dosing  
Grade 3
Omit INC280 dose until resolved to grade ≤ 1, then resume INC280 
treatment at ↓1 dose level; continue PDR001 dosing 
Grade 4
Discontinue patient from INC280 treatment and delay PDR001. Once 
resolved to grade ≤ 1 or baseline, consider resuming PDR001 dosing 
alone*.
Other adverse events
Grade 1 or 2
Maintain dose level of INC280 and continue PDR001 dosing, consider 
initiating appropriate support medication. 
For any intolerable grade 2 (e.g. limiting instrumental ADL), consider 
omitting the dose until resolved to grade ≤ 1, then ↓1 dose level.   
Grade 3
Omit INC280 dose/delay PDR001 dosing until resolved to grade ≤ 2, 
then resume INC280 treatment ↓1 dose level and resume PDR001 
dosing.
Grade 4
Discontinue patient from INC280 treatment. Once resolved to grade ≤ 1 
or baseline, consider resuming PDR001 dosing alone*.


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Worst toxicity
CTCAE Gradea (value)
Recommended dose modifications any time during a cycle of 
therapy, including intended day of dosing
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03)
b ‘Combined’ defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the 
defined threshold. 
c Note: If total bilirubin > 3.0 x ULN 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 ↓1 dose level and continue treatment at the discretion of the Investigator.   
d ‘Cholestasis’ defined as: ALP elevation (> 2 x ULN and R value (ALT/ALP in x ULN) < 2) in patients without bone 
metastases, or elevation of ALP liver fraction in patients with bone metastases   
e If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of AST/ALT, and take a conservative action based on the degree of the 
elevations (e.g., discontinue treatment at the situation when omit dose is needed for one parameter and 
discontinue treatment is required for another parameter). After all elevations resolve to the defined thresholds that 
allow treatment re-initiation, re-start treatment either at the same dose or one dose lower if meeting a criterion for 
dose reduction. 
*If the Investigator considers it to be at the patient’s best interest to resume therapy before the toxicity has 
resolved to Grade 1, this may be permitted on a case by case basis, following discussion with Novartis.  
**Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea.
***During the whole duration of treatment with INC280, the patient is recommended to use precautionary 
measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing and avoid sunbathing or using a 
solarium extensively).
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.


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Table 6-6
Follow-up hepatic toxicities
TOXICITY 
FOLLOW-UP EVALUATION
HEPATIC
Isolated total bilirubin elevation
Isolated AST/ALT elevation
Total bilirubin CTCAE Grade 1:
Monitor (liver function tests) LFTs per protocol or more frequently if clinically 
indicated
Total bilirubin CTCAE Grade 2:
Weekly monitoring of LFTs, or more frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN
Total bilirubin CTCAE Grade 3:
Weekly monitoring of LFTs, or more frequently if clinically indicated, until 
resolved to ≤ 1.5 x ULN. If resolved in > 7 days, after discontinuing the patient 
from INC280 permanently, the patient should be monitored weekly (including 
LFTs), or more frequently if clinically indicated, until total bilirubin have resolved 
to baseline or stabilization over 4 weeks
Total bilirubin CTCAE Grade 4:
After discontinuing the patient from INC280 permanently, the patient should be 
monitored weekly (including LFTs), or more frequently if clinically indicated, until 
total bilirubin have resolved to baseline or stabilization over 4 weeks
AST/ALT CTCAE Grade 2 elevation:
For patients with baseline value ≤ 3.0 x ULN: repeat LFTs as soon as possible, 
preferably within 48-72 hours from awareness of the abnormal results; if 
abnormal lab values are confirmed upon the repeat test, then monitor LFTs 
weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 x ULN
For patients with baseline value  > 3.0 - 5.0 x ULN: monitor LFTs per protocol or 
more frequently if clinically indicated
AST/ALT CTCAE Grade 3 elevation:
For AST/ALT elevation > 5.0 - 10.0 x ULN:
-
For patients with baseline value ≤ 3.0 x ULN: repeat LFTs as soon as 
possible, preferably within 48-72 hours from awareness of the abnormal 
results; monitor LFTs weekly, or more frequently if clinically indicated, until 
resolved to ≤3.0 x ULN
-
For patients with baseline value  > 3.0 - 5.0 x ULN: repeat LFTs as soon as 
possible, preferably within 48-72 hours from awareness of the abnormal 
results; if abnormal lab values are confirmed upon the repeat test, then  
monitor LFTs, weekly, or more frequently if clinically indicated, until 
resolved to ≤5.0 x ULN
For AST/ALT elevation > 10.0 - 20.0 x ULN:
-
Repeat LFTs as soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor LFTs weekly, or more 
frequently if clinically indicated, until resolved to ≤ baseline
AST/ALT CTCAE Grade 4 elevation:
Repeat LFTs as soon as possible, preferably within 48-72 hours from awareness 
of the abnormal results; monitor LFTs weekly, or more frequently if clinically 
indicated, until resolved to baseline or stabilization over 4 weeks.
Combined AST or ALT and total bilirubin 
elevation
Combined elevations of AST or ALT and total bilirubin:
After discontinuing the patient from INC280 permanently, repeat LFTs as soon 
as possible, preferably within 48 hours from awareness of the abnormal results, 
then with weekly monitoring of  LFTs, or more frequently if clinically indicated, 
until AST, ALT, or bilirubin have resolved to baseline or stabilization over 4 
weeks.
Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and 
indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.)
*Note: this table refers only to the evaluation schedule to monitor selected toxicities. Refer to Table 6-5 for dose 
modifications required for applicable toxicities


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6.3.3.2
Follow-up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
values; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R≤2), hepatocellular (R≥5), or mixed (R>2 and <5) liver injury.   
In the absence of cholestasis, these patients should be immediately discontinued from INC280
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.

Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.

A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.

Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g., biliary 
tract) may be warranted.

Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study.

Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus meeting the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented.


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6.4
Anticipated risks and safety concerns of the study drug
6.4.1
PDR001
Appropriate eligibility criteria and stopping rules are included in this protocol. Recommended 
guidelines for prophylactic or supportive treatment for expected toxicities, including 
management of study-drug induced AEs, i.e. infusion reaction, pneumonitis, are provided in 
Section 6.3.2 and Appendix 4. The risk to subjects in this trial may be minimized by compliance 
with the eligibility criteria and study procedures, as well as close clinical monitoring. 
6.4.2
INC280
Based upon the clinical experience with INC280, the overall risk-benefit assessment of INC280 
is considered favorable. Most of the AEs that have been reported, irrespective of relationship 
to study drug, have been manageable and generally mild or moderate in severity. Hepatic 
toxicity events and liver function test alterations (ALT and/or AST increase) have been 
observed in a number of patients. Appropriate eligibility criteria as well as specific dose 
modification and stopping rules and toxicity follow-up criteria have been included in this 
protocol. For more details refer to clinical toxicity data provided in the [INC280 Investigator’s 
Brochure]. The risk to subjects in this trial may be minimized by compliance with the eligibility 
criteria and study procedures, as well as close clinical monitoring.
6.4.3
INC280 combined with PDR001
This is the first time INC280 in combination with PDR001 will be tested in humans. 
PDR001 is a monoclonal antibody, and is not metabolized by cytochrome P450 (CYP450) 
enzymes, or transported by P-gylcoprotein (P-gp) or related ABC membrane transporters. The 
clinical relevance of cytokines impacting the levels of P-gp and CYP450 with administration 
of PDR001 is unknown but considered unlikely. INC280 is moderately metabolized by 
cytochrome P450 (CYP) 3A4 in vitro, with an expected contribution by aldehyde oxidase.
Pharmacokinetic drug-drug interaction (DDI) is expected to be low between INC280 and 
PDR001.
6.5
Concomitant medications
6.5.1
Permitted concomitant therapy 
In general, concomitant medications and therapies deemed necessary for the supportive care 
and safety of the patient are allowed.

Antivirus medications to manage HBV or HCV infection and/or prevent reactivation (e.g. 
tenofovir); supportive care.

Medications to prevent or treat nausea or vomiting.

Anti-diarrheal medications (e.g., loperamide) for patients who develop diarrhea.

Pain medication to allow the patient to be as comfortable as possible.

Localized radiotherapy and treatment with bisphosphonates for pre-existing, painful 
bone/liver metastases is permitted (non-target lesions).


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
Nutritional support or appetite stimulants (e.g. megestrol).

Oxygen therapy and blood products or transfusions.
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 within 21 days prior 
to the first administration of study treatment through 30 days after the last administration of 
INC280/150 days after the last administration of PDR001 must be listed on the Prior and 
Concomitant Medications or the Surgical and Medical Procedures eCRF. Prior antineoplastic 
therapies including medications, radiotherapy, and surgery are to be recorded on the separate 
Prior Antineoplastic Therapy eCRF page during screening.
6.5.2
Permitted concomitant therapy requiring caution and/or action
Treatment with hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-
CSF) may not be initiated during the study. If a patient is using erythroid stimulating agents 
(ESAs) prior to enrollment (at least 2 weeks before start of study treatment), they may continue 
at the same dose.
Anticoagulation is permitted if the patients are already at stable doses of warfarin or stable doses 
of low molecular weight heparin (LMWH) for >2 weeks at time of first dose and 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 
the institutional guidelines.
Anti-hypertensives are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with PDR001.
INC280 is a moderate CYP1A2 inhibitor. Co-administration of INC280 increased sensitive 
CYP1A2 probe substrate (caffeine) AUC by 135% (see Section 1.2.1.2). The dose of CYP1A2 
substrates with narrow therapeutic index may need to be reduced when used concurrently with 
INC280 as INC280 may increase their exposure. Consult the product information of 
concomitant drug for dose adjustment.
INC280 is a weak to moderate inhibitor of CYP2C8, CYP2C9 and CYP2C19 in vitro. 
Substrates of CYP2C8, CYP2C9 and CYP2C19 with a narrow therapeutic window should be 
administered with caution.
Co-administration of INC280 with a strong CYP3A4 inhibitor (itraconazole) increased INC280 
AUC by 40%. There is no change in INC280 Cmax. Execute caution when use strong CYP3A4 
inhibitor concurrently with INC280.
While the data on the concurrent use of PPI and food have to be considered preliminary, as they 
have been generated in a small cohort of patients of the study [CINC280A2108], the decrease 
in exposure imposes caution on the use of PPI when INC280 is taken with no regards of food.


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Short acting gastric acid modulators containing aluminum hydroxide and magnesium hydroxide, 
or calcium carbonate can be taken. However, it is recommended to take these drugs at least 3 
hours before or 3 hours after administration of INC280. 
H2 receptor antagonists should be used with caution. If patients are using H2 receptor 
antagonists during the course of this study, patients should not take INC280 within 2 hours of 
taking H2 receptor antagonists. In addition, the next scheduled dose of INC280 should be
administered at least 8 hours after taking H2 receptor antagonists.
Co-administration of INC280 increased exposure of P-gp substrate and BCRP substrate. 
Monitor patients closely for symptoms of increased exposure to P-gp or BCRP substrates. 
Consult the concomitant P-gp or BCRP substrate product information when considering dose 
adjustment.
Drugs with known risk of causing Torsades de Pointes (TdP) should be avoided. If such drugs 
cannot be avoided, patients should be more closely monitored by ECG, according to local 
practice. For identification of drugs with known risk of TdP please refer to qtdrugs.org and 
Appendix 6 for a list of drugs with known risk of TdP.
6.5.3
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. 
Additionally, no other therapeutic monoclonal antibodies and no immunosuppressive 
medication may be administered while on this study.
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed while 
patients are receiving study drugs, with the exception of:

replacement-dose steroids (defined as 10mg/day (or lower dose) of prednisone or 
equivalent dose of corticosteroids) such as in the setting of adrenal insufficiency,

prophylactic use for patients with contrast dye allergies, given as per local guidelines or 
practice,

the treatment of transient exacerbation of chronic inflammatory conditions such as COPD. 
In cases where patients are not discontinued from study drugs, steroids must be reduced to 
10mg/day (or lower dose) of prednisone or equivalent dose of corticosteroids, prior to the 
next treatment with PDR001,

the treatment of PDR-related irAEs or PDR001 infusion reaction. In cases where patients 
are not discontinued from study drugs, steroids must be reduced to no more than 
10mg/day of prednisone or equivalent dose of corticosteroids, prior to the next treatment 
with PDR001.
Topical, inhaled, nasal and ophthalmic steroids are not prohibited. 
The use of live vaccines is not allowed through the whole duration of the study.  Inactivated 
vaccines are allowed. 
Co-administration of INC280 with a strong CYP3A4 inducer (rifampicin) decreased INC280 
AUC by 66% and Cmax by 56%. Strong inducers of CYP3A4 should be discontinued 7 days 


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prior to the start of INC280 treatment and are prohibited during the course of the study as 
decreased INC280 exposure may lead to reduced efficacy. 
Therapeutics or supplements with herbal-origination for the purpose of hepatic protection or 
supportive care of liver diseases, which are particularly considered as common practices in Asia, 
are also prohibited during the study treatment.
6.6
Patient numbering, treatment assignment or randomization
6.6.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.) that is assigned when 
the patient is enrolled for screening/baseline. The Patient No. is retained as the primary 
identifier for the patient throughout his/her entire participation in the trial. The Patient No. 
consists of the Center Number (Center No.) (as assigned by NIRT to the investigative site) with 
a sequential patient number suffixed to it, so that each patient is numbered uniquely across the 
entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Patient No. available to the Investigator through the NIRT interface. Once assigned, 
the Patient No. must not be reused for any other patient and the Patient No. for that individual 
must not be changed, even if the patient is re-screened. If the patient fails to start treatment for 
any reason, the reason will be entered into the Screening Disposition eCRF page.
6.6.2
Treatment assignment or randomization
The assignment of a patient to a particular cohort during phase Ib and the assignment of a patient 
into one of the two treatment groups (INC280 in combination with PDR001 or PDR001 single 
agent) during the phase II part will be coordinated a Novartis Interactive Response Technology 
(NIRT) system. 
Randomization Phase II part 
Once the patient has signed the ICF, the Investigator or his/her delegate will log on to the NIRT 
and register the patient. Prior to dosing he/she or delegate will log on to the NIRT again (at the 
cycle 1 day 1 visit) to confirm that the patient fulfills all screening inclusion/exclusion criteria 
and that the patient can initiate study treatment. If the patient fails to start treatment for any 
reason, the reason will be entered into the Screening Disposition eCRF page. NIRT must be 
updated within 2 days if the patient will not start treatment.
Prior to dosing, all patients in the phase II part of the study, who fulfill all inclusion/exclusion 
criteria will be randomized via NIRT to one of the treatment arms (Section 4.1 and Section 6.1)
in a ratio of 1:1. Randomization will be stratified by region (Asian versus non-Asian patients). 
The NIRT system will assign a randomization number to the patient, which will be used to link 
the patient to a treatment arm and will specify a unique medication number for the first package 
of study treatment to be administered to the patient. 


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6.7
Study drug preparation and dispensation
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, all dose changes and interruptions during 
the study must be recorded on the Dosage Administration Record eCRF page.
Study treatment INC280 and PDR001, will be provided as global clinical supply and will be 
packed and labeled under the responsibility of Novartis, Drug Supply Management.
INC280
INC280 tablets (in bottles) including instructions for administration are dispensed by study 
personnel on an outpatient basis. Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least their next scheduled visit.
PDR001
PDR001 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 [INC280X2108 Pharmacy Manual].
6.7.1
Study drug packaging and labeling
PDR001 100 mg powder for solution for infusion will be supplied by Novartis to Investigators 
as open label bulk medication. 
The INC280 packaging has a 2-part label. Immediately before dispensing the package to the 
patient, site personnel will detach the outer part of the label from the packaging and affix it to 
the source document (Drug Label Form) for that patient’s unique patient number. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but will not supply information about 
the patient.
6.7.2
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, INC280 and PDR001 should be stored according to 
the instructions specified on the drug labels and in the current Investigator’s Brochures.
6.7.3
Study drug compliance and accountability
6.7.3.1
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.


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Study treatment will be administered to the patient by the study site staff. Compliance will be 
assured by administration of the study treatment under the supervision of Investigator or his/her 
designee.
6.7.3.2
Study drug accountability
The Investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment according to local institutional drug accountability processes. Drug 
accountability will be noted by the field monitor during site visits and at the completion of the 
study.
At study close-out, and, as appropriate during the course of the study, the Investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the completed 
drug accountability log to the Novartis monitor or to the Novartis address provided in the 
Investigator folder at each site.
6.7.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 and Table 7-2 list all of the assessments and indicate with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. 
No eCRF will be used as a source document. 
Screening evaluations must be performed ≤ 21 days of Cycle 1 Day 1 except for the pregnancy 
test which is to be performed within 3 days prior to the first dose of study treatment. 
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 the first dosing day. 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 (for Phase Ib and II). The time 
window for tumor biopsies may be longer than 21 days.  
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of +/- 3 days is allowed (with the exception of the 150 days safety 
follow-up visit and survival follow-up contact, for which a visit window of +/- 7 days is 
allowed). If the infusion of PDR001 is delayed, the start of the next cycle will be shifted 
accordingly. On PK collection days the windows are provided in Section 7.2.3.2.
Radiological assessments must be performed +/- 7 days of the scheduled date of the assessment.


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Table 7-1
Visit evaluation schedule
Screening 
Phase
Treatment Phase
Follow-Up
Visit name
Category
Protocol Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles
End of treatment
Safety F/U6
Disease 
Progression F/U
Survival F/U
Day of cycle
-21 to     -1
1
2
3
4
8
11
15
1
15
1
2
3
4
8
11
15
Obtain Informed 
Consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion 
criteria
D
5.2 and 
5.3
X
Medical History
D
7.1.1.2
X
Diagnosis and extent 
of cancer
D
7.1.1.2
X
Prior antineoplastic 
therapy
D
7.1.1.2
X
Prior/concomitant 
medications
D
7.1.1.2
X
Continuous until the 30 day safety follow-up6
Physical examination
S
7.2.2.1
X
X
X
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
Performance status
D
7.2.2.4
X
X
X
X
X
Child Pugh status
D
7.2.2
X
To be assessed every 12 weeks after baseline
X


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Screening 
Phase
Treatment Phase
Follow-Up
Visit name
Category
Protocol Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles
End of treatment
Safety F/U6
Disease 
Progression F/U
Survival F/U
Day of cycle
-21 to     -1
1
2
3
4
8
11
15
1
15
1
2
3
4
8
11
15
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
Hepatitis markers
D
7.2.2.5.8
X
X
X
X
X
HIV
D
7.2.2.5.8
X
Coagulation
D
7.2.2.5.3
X
Urinalysis
D
7.2.2.5.4
X
If clinically indicated
Thyroid function
D
7.2.2.5.5
X
X
X
X
X
X
Hepatotoxicity tests
D
6.3.3.2
If clinically indicated
Cytokines 
(IFN-γ; IL-6) for safety
D
7.2.2.5.6
X
In case of a suspected cytokine release syndrome
Pregnancy test in 
serum
D
7.2.2.5.9
X
X
X
X
X
Pregnancy test in 
urine
S
7.2.2.5.9
X
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.5
X6
X
X


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Screening 
Phase
Treatment Phase
Follow-Up
Visit name
Category
Protocol Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles
End of treatment
Safety F/U6
Disease 
Progression F/U
Survival F/U
Day of cycle
-21 to     -1
1
2
3
4
8
11
15
1
15
1
2
3
4
8
11
15
Tumor evaluation 
(CT/MRI) as per 
RECIST 1.1 and as 
per irRC.
7.2.1
X
Every 2 cycles from Cycle 3 Day 1 up to Cycle 11 Day 1, then every 3 cycles until progression of disease 
per irRC or patient withdrawal. 
For disease progression f/u, every 6 weeks until 42 weeks, then every 12 weeks until progression of disease 
per irRC, withdrawal of consent or lost to follow-up.
EOT: If a scan was not conducted within 30 days prior to end of study treatment.
Alpha Fetoprotein
D
7.2.2.5.7
X
Alpha Fetoprotein to be done coincidentally with tumor scan – Phase II only
ECG
D
7.2.2.6.1
X
X
X
X
X
X
Adverse events
D
8
Continuous
Collection of newly 
obtained  tumor 
sample
D
7.2.4
X
X2
Collection of newly 
obtained  tumor 
sample at progression
D
7.2.4
Optional sample collected upon disease progression, for patients who had a 
response to treatment (as determined by the investigator).
Study Drug 
administration 
D
6.1.1
PDR001 i.v. every 3 weeks; INC280 p.o BID
PK sampling INC280 
Phase Ib and II
D
7.2.3.2
X
X
X
X3
PK sampling PDR001 
Phase Ib
D
7.2.3.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X3
X
PK sampling PDR001 
Phase II
D
7.2.3.3
X
X
X
X
X
X
X
X
X
X3
X


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Screening 
Phase
Treatment Phase
Follow-Up
Visit name
Category
Protocol Section
Screening
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles
End of treatment
Safety F/U6
Disease 
Progression F/U
Survival F/U
Day of cycle
-21 to     -1
1
2
3
4
8
11
15
1
15
1
2
3
4
8
11
15
Survival contact
D
7.1.5
X
2 Anytime from 6-9 weeks after Cycle 1 Day 1 and at disease progression for patients who had a response (optional). 
3 Cycles 4-6 only and at disease progression.
4 Every 12 weeks (cycle 7, 11, 15 etc.) 
6 Safety evaluations for 150 days after the last dose of study treatment with contacts at 30-, 90- and 150-day. After initiation of new antineoplastic therapy, only 
AEs/SAEs suspected to be related to study treatment will be collected. Pregnancy tests every month until the 150-day safety follow-up; can be performed at home or a 
local doctor’s office if the patient is not coming to the clinic. Concomitant medications collected until the 30-day safety follow-up or the start of new antineoplastic 
therapy, whichever occurs first. 
For Japan only, patients enrolled in Phase I are required to be hospitalized during Cycle 1.


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7.1.1
Screening
The study IRC/IEC approved ICF must be signed and dated before any screening procedures 
are performed, except for laboratory and radiological evaluations performed as part of standard 
of care.
In the phase Ib and phase II part, cMET will be assessed retrospectively. If a patient is 
considered eligible with regards to the main inclusion/exclusion criteria, the Investigator or 
designee should complete the Patient Allocation Form and send it to Novartis (Phase Ib only). 
The tumor samples can be submitted for analysis as formalin fixed tumor sample or FFPE block 
prepared from multiple passes (3-6) of a core needle tumor biopsy. For details of sample quality 
requirements refer to the [INC280X2108 Laboratory Manual]. For details refer to Section 7.2.4.
The allocation of patients to treatment in phase II (INC280 in combination with PDR001 or 
PDR001 single agent) will be done by NIRT.
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1 and Table 7-2. Screening assessments must be 
repeated if performed outside of the specified screening window (Section 7.1).
7.1.1.1
Information to be collected on screening failures
A patient who signed the ICF but failed to be started on treatment for any reason will be 
considered a screen failure. The screening failure reason will be entered on the Screening Phase 
Disposition eCRF Page.
The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for screen failure patients. Molecular results will be collected and reported for all 
patients, including screen failures. No other data will be entered into the clinical database for 
those patients, unless the patient experienced a SAE during screening (see Section 8 for SAE 
reporting details).
7.1.1.2
Patient demographics and other screening/baseline characteristics
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments, prior medication, procedures, significant non-drug therapies, Hepatitis B and C 
status and any other assessments that are done for the purpose of determining eligibility for 
inclusion in the study. 
7.1.2
Treatment period
A treatment cycle is defined as 21 days for the purposes of scheduling procedures and 
evaluations. Please refer to Table 7-1 for details of the timing of required assessments and 
Section 7.1 for visit windows.
Patients will be treated until they experience unacceptable toxicity, progressive disease per irRC 
and/or treatment is discontinued at the discretion of the Investigator or the patient, as described 
in Section 7.1.5 and Section 4.3. Patients should not discontinue treatment based on progressive 


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disease per RECIST v1.1, unless the Investigator confirms that the patient is not benefiting from 
treatment.
Patients who have disease progression and have evidence of clinical benefit, such as disease 
shrinkage at other sites or symptomatic improvement, may continue treatment with INC280 
combined with PDR001 or PDR001 single agent. In addition, PDR001/INC280 treatment may 
be temporarily interrupted to permit local therapy for symptomatic metastases. Patients who 
continue on treatment after disease progression should discontinue study treatment once they 
are no longer deriving benefit as assessed by the Investigator.
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, 
at which time all of the assessments listed for the End of Treatment (EOT) visit will be 
performed. An End of Treatment Phase Disposition CRF page should be completed, giving the 
date and reason for stopping the study treatment.
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 must make every 
effort (e.g. telephone, e-mail, letter) to determine the primary reason for this decision and 
record this information in the patient’s chart and on the appropriate eCRF page. 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 should discontinue study treatment for a given patient if, on balance, he/she
believes that continuation would be detrimental to the patient’s well-being.
Study treatment may be discontinued under the following circumstances:

Adverse event

Lost to follow-up

Physician’s decision

Progressive disease per irRC (not per RECIST)

Study terminated by Novartis

Subject/guardian decision

Protocol deviation
Patients must be withdrawn if any of the following occur:

Death

Pregnancy
Patients who discontinue study treatment should undergo as soon as possible and within 14 days 
of the last dose of study drug or within 14 days of the decision to discontinue study treatment,
an End of study Treatment (EOT) visit and then be discontinued from the study (please refer to 
Table 7-1 and Table 7-2 for list of assessments to be performed).  If the decision to discontinue 
the patient occurs at a regular scheduled visit, that visit may become the EOT visit rather than 
having the patient return for an additional visit. An End of Treatment Phase Disposition eCRF 
page should be completed, giving the date and reason for stopping the study treatment. End of 


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treatment/Premature withdrawal visit is not considered as the end of the study. The Investigator 
must also register the patient’s discontinuation from study treatment in NIRT.
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Section 7.1.5. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone calls, e-mail, letter) should be 
made to contact them as specified in Section 7.1.6. If a patient discontinues study treatment, but 
continues study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments. At that time, the reason for study completion 
should be recorded on the Post Treatment Disposition eCRF page.
Patients who transfer to another clinical study or an alternative treatment option to continue 
provision of study treatment will perform the end of treatment procedures. 
7.1.3.1
Replacement policy
Phase Ib dose escalation part:
Patients will not be replaced on study. However, if a patient is considered to be non-evaluable 
for the Dose Determining Set (DDS), enrollment of a new patient to the current cohort will be 
considered if there is less than the required number of evaluable patients. Enrollment of new 
patients may be considered until at least the minimum number or at most the maximum number 
of evaluable patients is achieved within the cohort. Minimum and maximum numbers of 
evaluable patients per cohort are defined in Section 6.2.3.
Phase II part:
During the phase II part no replacements will be needed.
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, e-mail, 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 efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
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Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
Lost to follow-up: For subjects whose status is unclear because they fail to appear for study 
visits without stating an intention to discontinue or withdraw, the investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the subject, e.g., dates 
of telephone calls, registered letters, etc. A subject should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.
7.1.5
Follow-up period
All patients must have safety evaluations for 150 days after the last dose of PDR001 and 30 
days after the last dose of INC280 (in case PDR001 has been discontinued > 120 days before). 
The evaluations can be done either by telephone call or visit. During the 150-day safety follow-
up for PDR001, the patient should be contacted for the 30-, 90- and 150-day safety follow-up. 
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. Data collected 
should be added to the Adverse Events eCRF pages, the antineoplastic therapies since 
discontinuation of study treatment eCRF page and the Concomitant Medications eCRF page. 
For female patients of child bearing potential, a pregnancy test will be performed at the time 
points listed in Table 7-1.
Patients who discontinue study treatment for any reason other than death, disease progression 
per irRC, lost to follow-up, consent withdrawal, start of new anti-cancer therapy or study 
termination, should also return for tumor evaluation assessments (disease progression follow-
up: every 6 weeks until week 42, then every 12 weeks until progression of disease per irRC or 
lost to follow-up) and should not be considered withdrawn from the study until 80% of the 
patients enrolled in the phase II part have completed survival follow-up period (minimum 18 
months after the first dose of treatment) or discontinued the study for any reason. 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.
Upon completion of the 150-day/30-day safety follow-ups (noted above) or disease progression 
follow-up, patients will be followed for survival every 3 months +/- 1 week (can be done by 
telephone call) until death or until the end of the study is reached, unless they withdraw consent 
or are lost to follow-up.
Antineoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period.


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For patients who transfer to another clinical study or an alternative treatment option to continue 
provision of study treatment, as described in Section 4.3, the follow-up for safety, disease 
progression and survival will not be performed.
7.1.6
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the Investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient (e.g. dates of telephone calls, e-mail, 
letters). A patient should not be considered lost to follow-up until due diligence has been 
completed. Patients lost to follow-up should be recorded as such on the appropriate Disposition 
eCRF page.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be assessed locally according to the two following criteria:
1. RECIST v1.1 (based on Appendix 1, Eisenhauer et al 2009).
2. irRC (Appendix 2, based on Wolchok et al 2009 and Nishino et al 2013).
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.
Patients will not be withdrawn from the study due to progressive disease per RECIST v1.1, 
unless the Investigator confirms that the patient is not benefiting from treatment. Please refer to 
Appendix 1 and Appendix 2 for further details.
The imaging assessment plan is presented in Table 7-2.
Table 7-2
Disease assessment plan
Procedure
Screening
During Treatment/Follow-up
CT or MRI
with contrast enhancement
(Chest, Abdomen, Pelvis)
Mandated
During treatment starting on Cycle 3 
Day 1, every 2 cycles until cycle 11 day 
1, and then every 3 cycles until 
progression of disease per irRC or 
patient withdrawal.
Follow-up for progression: Every 6 
weeks until week 42, then every 12 
weeks until progression of disease per 
irRC or lost to follow-up. 
EOT: If a scan was not conducted within 
30 days prior to end of study treatment. 
Brain CT or MRI with contrast
If brain metastases are 
suspected
If disease was detected at baseline, or if 
clinically indicated


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Screening assessments
Imaging assessments will be performed at screening within 21 days of start of treatment (Day
-21 to Day -1 prior to Cycle 1 Day 1). 
Any imaging assessments already completed during the regular work-up of the patient within 
21 days prior to start of treatment, including before signing the study ICF, can be considered 
as the screening images for this study. Any imaging assessments obtained after randomization
cannot be considered screening images. The assessments required at screening are indicated in 
Table 7-2.
If a patient is known to have a contraindication to CT intravenous (i.v.) contrast media or 
develops a contraindication during the study, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen 
and pelvis should be performed.
If brain metastases are suspected at screening, 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. 
Any potentially measurable lesion that has been previously treated with radiotherapy should 
be considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable
lesion. 
Chest X-rays and ultrasound should not be used to measure tumor lesions.
Post-screening imaging assessments
Imaging assessments as described in Table 7-2 should be performed using the same imaging 
modality used at screening, irrespective of study treatment interruption or actual dosing.   
Imaging assessments for response evaluation will be performed every 6 weeks (+/- 7 days) after 
screening.
Additional imaging assessments may be performed at any time during the study at the 
Investigator’s discretion to support the efficacy evaluations for a patient, as necessary. Clinical 
suspicion of disease progression at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment.
Each lesion that is measured at screening 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 i.v. contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
v1.1 (Appendix 1).


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7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, hepatitis markers, Child Pugh status, 
thyroid function, pregnancy, ECG, as well as collecting of the (S)AEs at every visit. For details 
on SAE collection and reporting, refer to Section 8.
7.2.2.1
Physical examination
Physical examination will be performed according to Table 7-1. 
At Screening and Cycle 1 Day 1, prior to PDR001 infusion and/or INC280 intake, a complete 
physical examination will be performed and will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph 
nodes, extremities and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
From Cycle 1 Day 8 onwards, a short physical examination will be performed. A short physical 
exam will include the examination of general appearance, vital signs (blood pressure [BP] and 
pulse) and body sites as directed by symptoms.
Significant findings that were present prior to the signature of the study ICF must be included 
in the Medical History eCRF page. Significant new findings that begin or worsen after informed 
consent must be recorded on the Adverse Event eCRF page.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing and 
as indicated in Table 7-1 as per institutional standards. Vital signs should be assessed in the 
same position throughout the study. 
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 in centimeters (cm) or inches and body weight (to the nearest 0.1 kilogram [kg] or to the 
nearest 0.1 pound in indoor clothing, but without shoes) will be measured as indicated in 
Table 7-1 as per institutional standard.
7.2.2.4
Performance status
ECOG performance status will be assessed according to Table 7-3 and as indicated in Table 7-1.
Table 7-3
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours


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Grade
ECOG Status
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
Note: Grade 5 (death) was removed from this table. This information will be collected on a separate eCRF.
7.2.2.5
Laboratory evaluations
All laboratory parameters assessed for safety purposes will be evaluated locally. Refer to 
Table 7-4 for a summary of the parameters to be evaluated according to Table 7-1. Samples for 
these parameters will be collected prior to the dosing of study medication.
More frequent evaluations may be performed at the Investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments.
Novartis will be provided with a copy of the laboratory certification and tabulation of the normal 
ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, Novartis must be provided with a copy 
of the certification and a tabulation of the normal ranges from that laboratory. 
Table 7-4
Local/Central clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, White blood cells with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Chemistry
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, 
Chloride, Sodium, Potassium, Creatinine, Glucose, Serum amylase, Serum lipase, 
Creatinine clearance
Magnesium, Inorganic Phosphate, Total Bilirubin (also measure direct and indirect 
bilirubin if total bilirubin is grade > 1), Blood Urea Nitrogen (BUN) or Urea
Tests for 
hepatotoxicity follow-
up (if clinically 
indicated)
LFTs: albumin, ALT, AST, GGT, total bilirubin, direct and indirect bilirubin, ALP, ALP 
fractionated (quantification of isoforms – if feasible at study sites)
Refer to Section 6.3.3.2 for laboratory tests required in case of potential DILI cases
Coagulation
Prothrombin time (PT), Prothrombin time (quick test) or International normalized ratio 
[INR]), activated partial thromboplastin time (APTT)
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific 
Gravity, White Blood Cells)
Hepatitis markers
HBV-DNA, HBsAg, HBcAb, HBsAb, HCV RNA-PCR
Virology 
HIV
Thyroid
Free T4, TSH
Cytokines*
Gamma-Interferon (γ-IFN), Interleukin-6 (IL-6)
Tumor marker
Alpha Fetoprotein (AFP)
Pregnancy
Serum and/or urine samples only for women of childbearing potential
*Will be done centrally.
7.2.2.5.1 Hematology
Hematology panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1.


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7.2.2.5.2 Clinical chemistry
Clinical chemistry panel outlined in Table 7-4 will be performed as per the assessment schedule 
in Table 7-1.
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 panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1.
7.2.2.5.4 Urinalysis
Abnormal findings will be followed up with a microscopic evaluation and/or additional 
assessments as clinically indicated. A microscopic evaluation (WBC/HPF, RBC/HPF, and any 
other evaluations depending on macroscopic findings) need only to be performed if the 
urinalysis result is significantly abnormal.
Urinalysis will be performed at screening and if clinically indicated.
7.2.2.5.5 Thyroid function 
Thyroid panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1.
7.2.2.5.6 Cytokine analysis
Samples for the cytokine panel outlined in Table 7-4 will be collected at the following time 
points:

Screening/Baseline

On an ad-hoc basis in case a patient has an adverse event suspected to be a cytokine 
release syndrome (Table 7-1). In such case, this assessment should be performed at the 
following time points:
a. within 5 hours (or as soon as possible) after the occurrence of the adverse event,
b. one week after the occurrence of the adverse event. 
Samples for cytokine panel at screening will be stored below -70°C.  The samples will be 
analyzed retrospectively in batches. The analysis of the samples will be done only for patients 
who experienced an adverse event suspected to be a cytokine release syndrome and had follow-
up samples collected.
7.2.2.5.7 Tumor marker
During phase II, alpha fetoprotein (AFP) must be done at screening and matched with the tumor
efficacy evaluation. Refer to Table 7-2 for timepoints.
7.2.2.5.8 Virology
During the screening period, patients must be screened for HIV, HBV and HCV (current or past
history of infection). Careful medical history must be taken for all patients to look for risk


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factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis,
blood transfusions, etc.), and any past or present HBV symptoms (e.g., jaundice, dark urine,
light colored stools, right upper quadrant pain).
Hepatitis B:
At screening, all patients will be tested for:

HBV-DNA level

Hepatitis B surface antigen (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis B surface antibody (HBsAb)
Monitoring for HBV–DNA level on day 1 of every cycle and EOT is required for:

Patients known to have a history of HBV infection, despite a negative viral load test at 
screening (including patients who were treated and are considered ‘cured’)

Patients positive for viral load on HBV-DNA test at screening

Patients positive for any of the serology at screening
Hepatitis C:
At screening, all patients will be tested for quantitative HCV RNA-PCR.
Monitoring for HCV RNA-PCR level on day 1 of every cycle and EOT is required for:

Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including patients who were treated and are considered ‘cured’)

Patients positive for viral load on HCV RNA-PCR test at screening
Virology panel and HIV testing outlined in Table 7-4 will be performed as per the assessment 
schedule in Table 7-1.
7.2.2.5.9 Pregnancy and assessments of fertility
All females of childbearing potential will have a serum pregnancy test at screening/baseline 
and/or within ≤72 hours before first dose of study treatment. During the study, a serum 
pregnancy test should be done at day 1 of each cycle, and at EOT visit.
A urine or serum pregnancy test should be performed every month during and at the end of the 
safety follow-up period. If the patient is not coming to the clinic 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.
In case of positive urine pregnancy testing- additional testing must be performed to confirm 
pregnancy and if confirmed follow reporting requirements as described in Section 8.3.
A positive pregnancy test requires immediate discontinuation of study treatment and 
discontinuation from study. 


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7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12 lead ECG will be performed as per the assessment schedule (Table 7-1 and 
Table 7-5). Blood samples scheduled at the same time point should be taken after the ECGs are 
completed. 
Triplicate ECGs will be done at all timepoints. A PK sample should be collected right after 
every ECG performed.
Table 7-5
12 lead ECG collection plan
Cycle
Day
Time
Screening
-21 to -1
Anytime
1
1
Pre-dose of INC280 treatment
1
1
1h (±5 min) hour post-dose INC280 treatment and prior to 
PDR001 treatment
1
1
1h (±5 min) hour post PDR001 treatment  (end of infusion)
3
1
Pre-dose of INC280 treatment (or PDR001 treatment in phase II 
single agent arm)
3
1
1h (±5 min) hour post INC280 treatment and prior to PDR001 
treatment (not applicable for phase II PDR001 single agent arm) 
3
1
1h (±5 min) hour post PDR001 treatment (end of infusion)
2, 4 and afterwards
1
Pre-dose
EOT
-
Anytime
Unscheduled
-
Anytime
Clinically significant abnormalities present at screening should be reported on the Medical 
History eCRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF page. All eligibility and patient 
management decisions should be made based on the local reading of the ECG.
Triplicate ECGs will be performed at least 5 minutes apart. All ECGs will be independently 
reviewed by a central ECG laboratory. Instructions for the collection and transmission of ECGs 
to the independent reviewer will be provided in the [INC280X2108 ECG Manual].
7.2.3
Pharmacokinetics 
 assessments
Blood samples will be collected from all patients for the analysis of plasma INC280 and its 
major metabolite CMN288, and serum PDR001 concentrations, 
. The 
PK analysis will be performed according to Section 10.5.4.
 
 
 
7.2.3.1
Pharmacokinetic blood collection and handling
The exact date and clock times of drug administration and PK blood draw will be recorded on 
the appropriate eCRF page. If vomiting occurs within 4 hours following INC280 administration 


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on the day of post dose PK blood sampling, the clock time of vomiting should be recorded in 
the DAR PK eCRF page.
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. Refer to the [INC280X2108 Laboratory Manual] for detailed instructions for 
the collection, handling, and shipment of PK samples.
If patients experience a DLT, SAE or an AE leading to the discontinuation of the study 
treatment, an unscheduled PK blood sample should be obtained whenever possible. The date 
and time of the last dose and the time of PK blood draw should be recorded. 
7.2.3.2
Pharmacokinetic sampling for INC280 
PK blood samples for INC280 and CMN288 as outlined in Table 7-6 and Table 7-7. 
Table 7-6
Schedule of blood collection (plasma) for INC280 (BID) PK for patients 
participating in phase Ib
Cycle
Day
Scheduled time (hours)
1
1
0 hr / pre-C1D1 AM dose a
2
1
0 hr / pre-C2D1 AM dose a
2
1
0.5 hr (±5 minutes)
2
1
1 hr (±10 minutes)
2
1
2 hr (±15 minutes)
2
1
4 hr (±30 minutes)
2
1
8 hr (±2 hr)
3
1
0 hr / pre-C3D1 AM dose a
4
1
0 hr / pre-C4D1 AM dose a
5
1
0 hr / pre-C5D1 AM dose a
6
1
0 hr / pre-C6D1 AM dose a
NA
NA
Unscheduled and at the time of progression (per irRC)
a Take samples immediately prior to administration of INC280 
Table 7-7
Schedule of blood collection (plasma) for INC280 (BID) PK for patients 
participating in phase II
Cycle
Day
Scheduled time (hours)
1
1
0 hr / pre-C1D1 AM dose a
2
1
0 hr / pre-C2D1 AM dose a
2
1
1 hr (±10 minutes)
2
1
4 hr (±30 minutes)
2
1
8 hr (±2 hr)
3
1
0 hr / pre-C3D1 AM dose a
4
1
0 hr / pre-C4D1 AM dose a
5
1
0 hr / pre-C5D1 AM dose a
6
1
0 hr / pre-C6D1 AM dose a
NA
NA
Unscheduled and at the time of progression (per irRC)
a Take samples immediately prior to administration of INC280


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7.2.3.3
Pharmacokinetic 
 sampling for PDR001
Blood samples for PDR001 
 analysis will be collected as outlined in Table 7-8 and 
Table 7-9.
If the dosing of Cycle 3 Day 1 is delayed, the PK sampling for the full PK profile should be 
delayed accordingly to match the scheduled time points for Cycle 3 as outlined in Table 7-8 and 
Table 7-9. PK 
 samples will be collected also at the End of Treatment visit and in the 
event of a clinically significant AE (such as infusion reaction/anaphylaxis) 
. 
After the primary clinical study report (CSR) data cut-off date is reached, no additional PK 
 
 samples will be collected for the patients still ongoing on the study. 
Table 7-8
Schedule of blood collection (serum) for PDR001 PK 
 for 
patients participating in phase Ib
Cycle
Day
Scheduled Time Point (h)**
Analytes
1
1
0 hr / pre-C1D1 dose a
mAb 
1
1
1 hr (± 5 min) b
mAb
1
2
24 hr (± 2h)
mAb
1
3
48 hr (± 8h)
mAb
1
4
72 hr (± 8h)
mAb
1
8
168 hr (± 8h)
mAb
1
11
240 hr (± 24h)
mAb
1
15
336 hr (±24h) 
mAb
2
1
504 (±24h) hr / 0 hr pre-C2D1 dose 
a
mAb 
2
1
1 hr (± 5 min) b
mAb
3
1
0 hr / pre-C3D1 dose a
mAb 
3
1
1 hr (± 5 min) b
mAb
3
2
24 hr (± 2h)
mAb
3
3
48 hr (± 8h)
mAb
3
4
72 hr (± 8h)
mAb
3
8
168 hr (± 8h)
mAb
3
11
240 hr (± 24h)
mAb
3
15
336 hr (± 24h) 
mAb
4
1
504 (±24h) hr / pre-C4D1 dose a
mAb 
5
1
0 hr / pre-C5D1 dose a
mAb 
6
1
0 hr / pre-C6D1 dose a
mAb 
EOT
mAb 
Unscheduled and at the time of progression (per irRC)
mAb 
*
 samples are collected together with PK samples.
**PK samples are collected from the arm opposite from infusion site, or alternatively, infusion site will need 
to be flushed with 10 mL of saline. 
a.
Take samples immediately prior to the administration of PDR001
b.
After completion of the infusion.


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Table 7-9
Schedule of blood collection for PDR001 PK 
 for 
patients participating in phase II
Cycle
Day
Scheduled Time Point (h)**
Analytes
1
1
0 hr / pre-C1D1 dose a
mAb 
1
1
1 hr (± 15 min) b
mAb
1
2
24 hr (± 2h)
mAb
1
8
168 hr (± 8h)
mAb
1
15
336 hr (±24h) 
mAb
2
1
504 (±24h) hr / pre-C2D1 dose a
mAb 
2
1
1 hr (± 5 min) b
mAb
3
1
0 hr / pre-C3D1 dose a
mAb 
3
1
1 hr (± 5 min) b
mAb
3
2
24 hr (± 2h)
mAb
3
8
168 hr (± 8h)
mAb
3
15
336 hr (± 24h) 
mAb
4
1
504 (±24h) hr / pre-C4D1 dose a
mAb 
5
1
0 hr / pre-C5D1 dose a
mAb 
6
1
0 hr / pre-C6D1 dose a
mAb 
EOT
mAb 
Unscheduled and at the time of progression (per irRC)
mAb 
*
 samples are collected together with PK samples.
**PK samples are collected from the arm opposite from infusion site, or alternatively, infusion site will need to 
be flushed with 10 mL of saline. 
a.
Take samples immediately prior to the administration of PDR001
b.
After completion of the infusion.
7.2.3.4
Bioanalytics
Bioanalysis for pharmacokinetic 
 assessment will employ the validated assays:
1. The assay to quantify PDR001 will be a validated LCMS. The details of the assay will be 
documented in the [INC280X2108 Laboratory Manual].
2. The assay to quantify and assess the 
 will be a validated homogeneous ELISA. The 
details of the assay will be documented in the [INC280X2108 Laboratory Manual]. 
3. INC280 will be measured in plasma by a validated liquid chromatography-tandem mass 
spectrometry (LC/MS/MS) assay.
 


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7.2.3.5
PK 
 sample handling, labeling, and shipping 
instructions
A total of 3 mL of blood will be collected at specified time points for INC280 and CMN288 
analysis, and another 3 mL of blood for PDR001 analysis. For time points when PDR001 (mAb) 
PK 
 are to be measured, 
 
. Blood samples should be collected from the arm opposite from the investigational 
drug infusion, or from another site. After clotting, the resulting serum will be separated in 
aliquots and will be stored frozen until analysis. Please see the [INC280X2108 Laboratory 
Manual] for detailed instructions about collection, handling and shipment of samples. 
The actual collection date and time of each sample will be entered on the 
Pharmacokinetics/
 Blood Collection eCRF pages.
7.2.4
Biomarkers 
In this study biomarker analyses will be used to investigate the effect of INC280 in combination 
with PDR001 and PDR001 single agent at the molecular and cellular level as well as to 
determine how changes in the markers may relate to exposure and clinical outcomes.  
 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample collection and/or analysis may be omitted at the 
discretion of Novartis.
The sample collection information must be entered on the appropriate sample collection log 
eCRF and requisition form(s). Detailed instructions for the collection, handling, and shipment 
of biomarker samples are outlined in the [INC280X2108 Laboratory Manual].
Table 7-10
Biomarker sample collection plan (tumor/blood samples)
Sample Type
Visit/ Time 
point
Volume
Marker*
Purpose
Tumor samples
Newly obtained tumor 
sample 
Screening
(recommended 
to be collected 
at least 2 
weeks after the 
last dose of 
sorafenib)
6-9 weeks 
after start of 
study 
treatment
Newly obtained 
formalin fixed 
tumor sample in 
ethanol (3-6 
passes)
 
 
 
 
Expression by 
IHC (e.g., CD8, 
PD-L1, 
 
 
 
Pharmacodynamic (PD) 
markers 
 
 


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Sample Type
Visit/ Time 
point
Volume
Marker*
Purpose
At progression 
of disease only 
for patients 
who had a 
response as 
per 
investigator 
assessment
(optional)
 
 
 
Note: On days and time points when biomarker and pharmacokinetic blood samples are being collected, the 
PK sample must be drawn first.
7.2.4.1
Tumor Collection
Collection of evaluable paired (e.g. baseline and on-treatment) tumor samples is critical to
assess the pharmacodynamic effect on the tumor microenvironment of PDR001 single agent or 
in combination with INC280 as described in Table 7-10. Submission of evaluable newly 
obtained tumor samples, at screening and again 6-9 weeks after the start of study treatment, is 
therefore mandated for all patients in the study. An optional tumor sample is requested to be 
collected at disease progression, for patients who had a response as per investigator assessment. 
Exceptions may be made on a case by case basis following a documented discussion with 
Novartis.


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. For additional details about irAE, please refer to Section 6.3.2.
Once the ICF is signed, all AEs per the descriptions below will be captured in the Adverse 
Event CRF.
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 eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History of the patient’s eCRF. Adverse event monitoring should be 
continued for at least 30 days following the last dose of INC280 (in case PDR001 was 
discontinued >120 days before) and 150 days after the last dose of PDR001. After initiation of 
a 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 according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study (but is collected as a seriousness 
criterion); rather, information about deaths will be collected through a Death form.
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:

The severity grade (CTCAE Grade 1-4)

Its duration (Start and end dates)

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)

Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1, 
and which seriousness criteria have been met.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per irRC or as per RECIST), should not be reported as a serious adverse 
event.


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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 eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 AE (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, 

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 
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
Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event.
Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by RECIST or 
irRC. Hospitalization due solely to the progression of underlying malignancy should NOT be 
reported as a serious adverse event.
Clinical symptoms of progression may be reported as adverse events if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study.
Symptomatic deterioration may occur in some patients. In this situation, progression is evident 
in the patient’s clinical symptoms, but is not supported by the tumor measurements. Or, the 
disease progression is so evident that the Investigator may elect not to perform further disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made 
to document the objective progression of underlying malignancy.
If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE.
8.2.2
Reporting
For patients who sign the ICF, SAE collection will start upon signing the ICF. SAEs will only 
be reported if the event is suspected to be causally related to study procedure as assessed by the 
Investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until resolution 
or until clinically relevant improvement or stabilization.   
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
INC280 (in case PDR001 was discontinued >120 days before) and 150 days after the patient 
has stopped PDR001, must be reported to Novartis within 24 hours of learning of its occurrence.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up 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 this 30 days after the last dose of INC280 (in case PDR001 has 
been discontinued >120 days before) and 150 days (after the last dose of PDR001) period should 
only be reported to Novartis if the Investigator suspects a causal relationship to the study 
treatment. If a patient starts a post treatment antineoplastic therapy, then only SAEs suspected 
to be related to study treatment will be reported.
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 


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Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the submission process and requirements for signature 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 INC280 or PDR001 Investigator’s Brochures 
or Package Insert (new occurrence) and is thought to be related to the Novartis study treatment, 
an oncology Novartis Chief Medical Office and Patient Safety (CMO&PS) department 
associate may urgently require further information from the Investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all 
Investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.
8.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. After the mother has provided consent, the newborn will be 
followed-up for 12 months.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS Department. Pregnancy follow-up should be 
recorded on the same form and should include an assessment of the possible relationship to the 
investigational treatment and any pregnancy outcome. Any SAE experienced during pregnancy 
must be reported on the SAE Report Form.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.


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8.5
Data Monitoring Committee
A formal data monitoring board will not be used for this study. This is an open-label, Phase 
Ib/II study in which patients will receive INC280 in combination with PDR001 or PDR001 
single agent. Novartis will have access to the Safety Data on a regular basis. Novartis will host 
Investigator teleconferences on a regular basis during the study. Further, during the phase I part 
of the study Novartis and the Investigators will meet at the end of each treatment cohort to 
discuss and evaluate all of the gathered safety data. At the dose escalation teleconference the 
clinical course (safety information including both DLTs and all CTCAE Grade 2 or higher 
toxicity data during the first two cycles of treatment, and PK data) for each patient in the current 
dose cohort will be described in detail. Updated safety data on other ongoing patients, including 
data in later cycles, will be discussed as well.
Dose escalation decisions will be based on a clinical synthesis of all relevant available data and 
not solely on DLT information. Selection of the actual dose for the next cohort of patients will 
be guided by the BLRM with EWOC and a medical review of relevant clinical, PK and 
laboratory data.  Novartis and the Investigator parties must reach a consensus on whether to 
declare MTD, escalate the dose any further, or whether to de-escalate and/or recruit an 
additional cohort of patients at the current dose level (Section 10.4.2). 
During the phase II part of the study individual patient data will be reviewed on an ongoing 
basis and aggregate safety data and the primary endpoint will be monitored quarterly by the 
study team across the duration of the trial. The data review and analysis will be based on the 
available Investigator reported data in the clinical database at that time (Section 10.7).
8.6
Steering Committee 
A Steering Committee constituted of members of the Translational Clinical Oncology 
Leadership Team will be formed for this study. If the monitoring of the study data requires a 
decision to be taken on the continuation of the study, then the relevant data (e.g., safety data or 
primary analysis and predictive probability of success) will be communicated to the Steering 
Committee for decision making purposes.
9
Data collection and management
9.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research patient to revoke their authorization for use of their PHI.
In the event that a patient revokes authorization to collect or use PHI, the Investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 


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should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an Investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the Investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, administered, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits.
The Investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The Investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated Investigator’s staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
allow modification or verification of the entered data by the Investigator’s 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.


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PK and biomarker (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by a Novartis designated 
laboratory, contracted central laboratories, or local laboratories. ECG data collected during the 
study will be reviewed and processed centrally by a specialist CRO. During the course of the 
study, Novartis may decide to have a central review of the radiological assessments performed. 
In such case, the Investigator’s staff will be instructed on how to send data from these 
radiological assessments to a Contract Research Organization (CRO) for central review when 
needed. Designated investigational site staff will enter the information required by the protocol 
into the appropriate eCRF and/or designated laboratory requisition forms. Field monitors will 
review the eCRFs and laboratory paper requisition forms for accuracy and completeness and 
instruct site personnel to make any required corrections or additions. One copy of the requisition 
form will be forwarded to each analytical laboratory with the respective sample(s) by the field 
monitor or by the designated investigational site staff; and one copy will be retained at the 
investigational site.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated Investigator site staff is 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
For EDC studies, after database lock, the Investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
Data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the Investigator must be submitted to Novartis before publication or 
presentation.
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized with 
respect to demographic and screening characteristics, efficacy and safety observations and 
measurements and all relevant PK and PD measurements using descriptive statistics 
(quantitative data) and contingency tables (qualitative data).
The study data will be analyzed and reported based on all patients’ data of the dose escalation
and phase II parts up to the time when all patients have potentially completed at least nine cycles 
of treatment or discontinued the study. Any additional data for patients continuing to receive 


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study treatment past the data cutoff date for the primary Clinical Study Report (CSR), 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: 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.

For the phase Ib part, cohorts treated with the same combination dose level will be pooled 
into a single treatment group. All summaries, listings, figures and analyses will be
performed by treatment group.

For the phase II part, all summaries, listings, figures will be presented by study treatment 
for safety and efficacy analyses, unless otherwise specified. 
Study treatments in the phase II part:

Treatment A: PDR001+INC280

Treatment B: PDR001
Note: patients from the phase Ib dose escalation parts and the phase II part will not be pooled 
in any analyses unless otherwise specified.
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, Section 7.1.1.1, collected will not 
be included in analyses, but will be reported in the CSR as separate listings.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of study 
treatment in the phase Ib part, and all patients to whom study treatment has been assigned by 
randomization in the phase II part. According to the intent to treat principle, patients in the 
phase II part will be analyzed according to the treatment they have been assigned to during the 
randomization procedure.
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be classified according to treatment received, where treatment received is defined as:

the treatment assigned if it was received at least once, or

the first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.
The safety set will be the primary population for all safety related endpoints. 
10.1.3
Per-Protocol Set
The Per Protocol Set (PPS) for the phase II part consists of a subset of FAS patients who meet 
the following criteria:

Treatment according to the randomization scheme (see Section 6).


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
Presence of at least one measurable lesion at screening according to RECIST v1.1 as per 
Appendix 1.

Have not been previously treated with PD-1- or PD-L1-directed therapy or any therapeutic 
cancer vaccine.
All protocol deviations leading to exclusion from the PPS will be detailed in the RAP. Patients 
will be classified according to the received treatment.
The PPS will be used in the phase II part of the study only and will define the patients used in 
the sensitivity analysis of the primary endpoint (see Section 10.4.4). If the PPS and the FAS are
identical, then analyses described by the PPS will not be performed.
10.1.4
Dose-determining analysis set (DDS)
Phase Ib part (INC280 in combination with PDR001)
The DDS analysis consists of all patients in the dose escalation part who either meet the 
minimum exposure criterion and have sufficient safety evaluations, or have experienced a DLT 
during cycles 1 and 2. This constitutes an evaluable patient for the determination of MTD.
A patient is considered to have met the minimum exposure criterion if having received two
planned doses of PDR001 and 28 days of INC280 during cycles 1 and 2. Patients who do not 
experience a DLT during the first two cycles are considered to have sufficient safety evaluations 
if they have been observed for ≥42 days following the first dose, and are considered by both 
Novartis and the Investigators to have enough safety data to conclude that a DLT did not occur.
Patients who do not meet these minimum dosing and safety evaluation requirements will be
regarded as ineligible for the DDS and additional patients may be enrolled if required to meet
the minimum cohort size for decision making, as described in Section 6.2.3.
10.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing measurable INC280 and PDR001 PK data. The PAS will be used for all PK 
analyses. 
Note: Some patients’ data may not be adequate for the reliable estimation of some PK 
parameters. These patients will be identified and their PK parameters will be excluded from 
summaries. The criteria of exclusion will be detailed in the RAP.
10.2
Patient demographics/other baseline characteristics
Demographic and other screening data (including disease characteristics) will be listed and 
summarized descriptively by treatment group/study treatment on the FAS.


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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study treatment
For each of INC280 and PDR001, the actual dose and duration in days of treatment as well as 
the dose intensity (computed as actual dose received/actual duration) and the relative dose 
intensity (computed as the ratio of dose intensity to planned dose/planned duration) will be 
listed and summarized by means of descriptive statistics by treatment group/study treatment. 
Categories for relative dose intensity of INC280 or PDR001 will be specified as < 0.5, ≥ 0.5 -
< 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and proportion of patients within 
each category will be presented by treatment group/study treatment.
The reason for discontinuation from treatment will be summarized, and listed along with dates
of first and last dose of INC280 and PDR001, duration of exposure to INC280 and PDR001 and 
date of discontinuation for each patient.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug treatment will be listed by patient and summarized by ATC (anatomical therapeutic 
chemical classification system) term and treatment group/study treatment.
10.3.3
Compliance
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. Protocol deviations will be identified prior to database lock and will be 
listed and summarized by treatment group/study treatment. Compliance to the study drug will 
be assessed by the number of dose reductions and dose interruptions, see Section 10.5.3.6.
10.4
Primary objective
Phase Ib part
To characterize the safety and tolerability of INC280 in combination with PDR001 and identify 
the MTD and/or RP2D.
Phase II part

The primary objective is to compare the anti-tumor effect of INC280 in combination with 
PDR001 vs. PDR001 single agent.
10.4.1
Variable
Phase Ib part

Safety: Incidence of dose limiting toxicities (DLTs) in the first two cycles of treatment. 
Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital 
signs and ECGs

Tolerability: dose interruptions, reductions and dose intensity


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Estimation of the MTD will be based upon the BLRM of the probability of a DLT for patients 
in the DDS.
Phase II part
The primary variable is the Overall Response Rate (ORR), defined as the proportion of patients 
with a best overall response of CR or PR based on local Investigator assessment, as defined in 
RECIST v1.1 (Appendix 1).
Estimation of the true ORR in this part of the study will be based upon the observed overall 
response for patients in FAS, using a Bayesian analysis.
10.4.2
Statistical hypothesis, model, and method of analysis
10.4.2.1 Phase Ib part
For the analysis of safety and tolerability endpoints see Section 10.5.3.
Identification of a recommended dose
Estimation of the MTD of the treatment will be based upon the estimation of the probability of 
dose limiting toxicity (DLT) in cycles 1 and 2 for patients in the DDS. A recommended dose 
below the MTD may be identified based on other safety, clinical, PK, and PD data 
(Section 6.2.3).
Bayesian adaptive approach
The dose escalation will be guided by a Bayesian analysis of DLT data in cycles 1 and 2 for 
INC280 and PDR001. The Bayesian analysis will be based on a model with three parts, 
representing:

Single agent INC280 toxicity

Single agent PDR001 toxicity

Interaction 
Single agent toxicity is modelled using logistic regression for the probability of a patient 
experiencing a DLT against log-dose. The odds of a DLT are then calculated under no 
interaction for the two single agent toxicities, and interaction is accounted for by adjusting these 
odds with an additional model parameter (odds multiplier). Details of the model are given in 
Appendix 3.
Assessment of patient risk
After each cohort of patients, the posterior distribution for the risk of DLT for new patients at 
combination doses of interest will be evaluated. The posterior distributions will be summarized 
to provide the posterior probability that the risk of DLT lies within the following intervals:
Under-dosing:
[0 , 0.16)
Targeted toxicity:
[0.16 , 0.33)
Excessive toxicity:
[0.33 , 1]


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The escalation with overdose control (EWOC) principle
Dosing decisions are guided by the escalation with overdose control principal (Rogatko 2007).  
A combination dose may only be used for newly enrolled patients if the risk of excessive 
toxicity at that combination dose is less than 25%.
Prior distributions
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent INC280 and PDR001 model parameters. The MAP prior for the logistic model 
parameters for this study is the conditional distribution of the parameters given the historical 
data (Spiegelhalter et al 2004, Neuenschwander et al 2010, Neuenschwander et al 2014). MAP 
priors are derived from hierarchical models, which take into account possible differences 
between the studies.
A full description of the application of the MAP approach to derive the prior distributions of 
the single agent INC280 and PDR001 model parameters is given in Appendix 3.  
The prior distribution for the interaction parameter was based upon prior understanding of 
possible drug safety interactions.  This prior allows for the possibility of either synergistic or 
antagonistic interaction, and is fully described in Appendix 3.
Starting dose
The starting dose is INC280 200 mg BID and PDR001 300 mg Q3W (Section 6.2.1).  For this 
dose the prior risk of excessive toxicity is 13.9 %, which satisfies the EWOC criterion.  A full 
assessment of the prior risk to patients is given in Appendix 3.
Incorporation of data from ongoing studies
The dose-DLT information generated from the safety patient cohort of INC280 in combination 
with PD-1 inhibitors in the ongoing study [CEGF816X2201], if available by the time of having 
dose escalation meetings in this study will be incorporated in the model. A direct down-
weighting approach will be used to account for between-trial heterogeneity. Details are
provided in Appendix 3.
Listing of DLTs
DLTs will be listed, and their incidence summarized by primary system organ class and worst 
grade (CTCAE version 4.04).  Listings and summaries will be based on the DDS.
10.4.2.2 Phase II part
Patients in each group are randomized in a 1:1 ratio into either PDR001+INC280 arm or 
PDR001 arm. The randomization is stratified by region: Asian vs. non-Asian. The primary 
efficacy endpoint ORR will be determined per RECIST v1.1 for the primary analysis.
For the primary analysis, a Bayesian logistic regression model with treatment (combination vs. 
single agent), region (Asian vs. non-Asian), and interaction of treatment and region as 
covariates will be applied to provide the inference of ORR. Full details of model 


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parameterization and prior specification are provided in Appendix 3. The ORRs of the 
PDR001+INC280 and PDR001 arms will be compared. If the posterior probability that odds 
ratio (ORR PDR001+INC280 to ORR PDR001) > 1 is greater than 0.8, AND the observed ORR
PDR001+INC280 is at least 10% greater than the observed ORR PDR001, it will be concluded that the 
combination treatment has a superior anti-tumor effect compared to the PDR001 single agent 
treatment.  
The posterior mean of ORR adjusted for stratification factor along with 95% credible interval 
will be provided; the probabilities that the true ORR lies in the following efficacy categories 
will be reported:

[0, 20%) no anti-tumor activity

[20%, 100%] clinically relevant anti-tumor activity
Details of analyses will be provided in RAP. 
10.4.3
Handling of missing values/censoring/discontinuations
Patients in the dose escalation part who are ineligible for the DDS will be excluded from the
primary analysis, although their data will be used for all remaining analyses.
Patients in the phase II part who have BOR of Unknown (UNK) or not assessed (NA) will be
considered as a treatment failure in the primary analysis of ORR. Patients with individual scans 
of UNK or NA will be handled according to RECIST v1.1 (Appendix 1).
10.4.4
Supportive analyses
For the phase II part, the observed ORR and corresponding 95% exact confidence interval 
according to Clopper-Pearson method (Clopper and Pearson 1934) will be provided, and by 
stratum if applicable.
The primary analyses on ORR may be repeated using the PPS. 
In addition, ORR will be determined per irRC (Appendix 2) and analyzed with the statistical 
methods specified for primary analyses using FAS. 
 
Additional analysis may be performed based on cMET status. 
10.5
Secondary objectives
Please refer to Table 3-1 for the secondary objectives. The following subsections describe the
analyses of related secondary objectives.
10.5.1
Key secondary objective(s)
Not Applicable.


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10.5.2
Other secondary efficacy objectives
10.5.2.1 Characterization of efficacy
The BOR, TTP, PFS, DOR, TTR and OS will be analyzed to characterize the efficacy of 
PDR001 in combination with INC280 and as single agent in the phase Ib part and phase II part. 
Tumor response related endpoints will be analyzed based on the local Investigator assessments 
according to RECIST 1.1 and irRC, respectively.
Individual lesion measurements and overall response assessments will be listed by patient and
assessment date. BOR, TTP, PFS, DOR, TTR and OS will be listed by patient. The following 
summaries and analyses will be performed for the phase Ib by treatment group (if at least 10 
patients in a treatment group) and for the phase II part by study treatment where applicable:

BOR will be summarized as observed proportion in each category, and corresponding 
90% exact confidence interval (CI). Tumor volume best change from baseline will be 
presented graphically.

For TTP, PFS and OS, Kaplan-Meier method will be used to estimate the median and 
provide the Brookmeyer-Crowley 95% CI along with a graphical presentation as 
appropriate.

DOR and TTR will be listed by patient. Summaries of DOR may be provided if a 
sufficient number of patients responded.
Any additional analyses of the secondary efficacy endpoints will be described in the RAP.
10.5.3
Safety objectives
Incidence and severity of AEs and SAEs, changes in laboratory values, electrocardiograms and 
vital signs will be used to assess the safety of PDR001 single agent and in combination with 
INC280.
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group for the phase Ib part, and by study treatment and by study treatment in the phase 
II part.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from day of first dose of study medication to 30 days after date of 
last administration of study treatment 
3. post-treatment period: from 31 days after date of last administration 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 study treatment related adverse events will be collected. Select 
summaries of related adverse events will be produced for the combined on-treatment and post-
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10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from screening) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group.
Deaths reportable as SAEs, non-fatal serious adverse events and irAEs will be listed by patient 
and tabulated by type of adverse event and treatment group. 
Specific safety event categories (SEC) may be considered. Such categories consist of one or
more well-defined safety events which are similar in nature and for which there is a specific
clinical interest in connection with the study treatment(s). SEC will be specified in a case
retrieval sheet (CRS) or in the RAP and finalized prior to database lock. For each specified SEC, 
number and percentage of patients with at least one event part of the SEC will be reported.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by Common Terminology Criteria for Adverse Events (CTCAE)
version 4.03, the study’s biostatistical and reporting team will grade laboratory data accordingly. 
For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-missing values 
not graded as 1 or higher. Grade 5 will not be used. For laboratory tests where grades are not 
defined by CTCAE, results will be categorized by the low/normal/high classifications based on 
laboratory normal ranges.
If the lower limits of normal ranges used in CTCAE definitions are missing, then they have to 
be replaced by a clinical meaningful limit.
The following summaries will be generated separately for hematology, biochemistry and 
urinary laboratory tests:

Frequency table for newly occurring on-treatment Grades 3 or 4.

Shift tables using CTCAE Grades to compare baseline to the worst on-treatment value; for 
laboratory tests where CTCAE Grades are not defined, shift tables using the 
low/normal/high/ (low and high) classification to compare baseline to the worst on-
treatment value.

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
Grades and the classifications relative to the laboratory normal ranges.
 
 
10.5.3.4 Other safety data
Any other safety information collected will be listed and notable values will be flagged. Any 
statistical tests performed to explore the data will be used only to highlight any interesting 


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comparisons that may warrant further consideration. Additionally, the following outputs will 
be produced:
ECG

Summary of post-baseline notable ECG values.

Listing of ECG evaluations for patients with at least one abnormality.
Vital signs
Definitions of notably abnormal results will be specified in RAP.

Shift table baseline to worst on-treatment result.
10.5.3.5 Supportive analyses for secondary objectives
Any supportive analyses that are considered appropriate for secondary variables will be 
described in the RAP prior to database lock.
10.5.3.6 Tolerability
Tolerability of the study treatment will be assessed by summarizing the number of dose
interruptions and reductions. Reasons for dose interruptions and dose reductions will be listed 
by patient and summarized. 
10.5.4
Pharmacokinetics
INC280, CMN288 and PDR001 concentration data will be listed and summarized by treatment 
group and time point, and listed by treatment group, patient and time point. Descriptive statistics 
will consist of arithmetic and geometric mean, median, standard deviation, arithmetic 
coefficient of variation (CV), geometric CV, minimum and maximum. Zero concentrations will 
not be included in the geometric mean calculation. Individual concentration-time profiles as 
well as mean concentration-time profile will be plotted when applicable.
Where possible, PK parameters will be determined for all patients by applying 
non-compartmental method(s) using Phoenix WinNonlin version 6.4 or above (Pharsight, 
Mountain View, CA). Derived PK parameters, including but not limited to those listed in 
Table 10-1, will be summarized with the descriptive statistics, arithmetic and geometric mean, 
median, standard deviation, arithmetic CV, geometric CV, minimum and maximum. Only 
median values and ranges will be given for Tmax. Missing data will not be imputed.
Table 10-1
Noncompartmental pharmacokinetic parameters
AUClast
The area under the curve (AUC) from time zero to the last measurable analyte (INC280, 
CMN288 or PDR001) concentration sampling time (tlast) (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (mass x time x 
volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid analyte 
concentration after study drug administration (mass x volume-1)
Tmax
The time to reach maximum (peak) analyte concentration after study drug dose administration 
(time)


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PAS will be used in all pharmacokinetic data analysis and PK summary statistics, as appropriate.
 
 
10.5.4.1 Data handling principles
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.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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.
10.7
Interim analysis
No formal interim analyses are planned.
Phase Ib dose escalation part
The dose-escalation design foresees that decisions based on the current data are taken before
the end of the study. More precisely, after each cohort in the dose escalation part, the next dose 
of INC280 in combination with PDR001 has to be chosen depending on the observed data. 
Details of this procedure and the process for communication with Investigators are provided in 
Section 6.2.3.
10.8
Sample size calculation
Phase Ib dose escalation part
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 
six patients at the MTD/RP2D level, as described in Section 6.2.3. Multiple cohorts may be 
sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients may be 
enrolled at any dose level below the estimated MTD/RP2D for further elaboration of safety and 
pharmacokinetic parameters as required. At least 12 patients are expected to be in the dose 
escalation part. If a recommended phase II dose is identified without determination of the MTD,
fewer than 12 patients may be required.
Phase II part
Sample size is considered for assessment of ORR. A priori the true mean of ORR is assumed 
to be 20% in patient groups treated with PDR001 single agent. It is assumed that the 
combination with INC280 will improve the mean of ORR to 40% . A minimally informative 
unimodal (Neuenschwander et al 2008) beta prior distribution with mean as assumed is then 
specified as following:

PDR001+INC280: ORR PDR001+INC280 ~ Beta(0.67,1)

PDR001: ORR PDR001 ~ Beta(0.25,1)
The ORR of the PDR001 in combination with INC280 treatment will be compared to that of 
the PDR001 single agent treatment. A Bayesian logistic regression model will be used to 
perform this comparison.  The full model will include a covariate for treatment effect, and will 
also explore region effects, and treatment/region interaction.  Here, operating characteristics are 
described under the assumption that there is no region effect, and a simplified logistic regression 
model including only treatment as a covariate is used to provide inference.


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Given 30 patients in each treatment, and under the assumption of 20% ORR for PDR001 single 
agent, the probabilities of success under different assumed scenarios of true ORRs for the 
combination are presented in Table 10-2.

For true ORRs for combination and single agent treatment, of 40% and 20%, respectively, 
the probability to declare superior anti-tumor effect of the combination treatment is 
78.5%.

If the true ORRs of combination and single agent treatment in patients are both 20%, the 
probability to incorrectly declare superior anti-tumor effect of the combination treatment 
is 14.1%.
Table 10-2
Operating characteristics for ORRPDR001+INC280 vs. ORRPDR001
comparison
True ORRPDR001
True ORRPDR001+INC280
Probability of success
(success when Posterior P(Odds(ORR
PDR001+INC280)/Odds(ORR PDR001)>1)>0.80)) & (Observed ORR
PDR001+INC280 – observed ORR PDR001) > 10%)
20%
10%
0.008
20%
0.141
30%
0.433
40%
0.785
50%
0.955
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the Investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the Investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.


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11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their eCRFs.
Novartis will provide to Investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the Investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to the 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 presentations at scientific congress; however there will be no honorarium 
provided for such presentations. 


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


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


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14
Appendices
14.1
Appendix 1: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival and Overall 
Survival (based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Document type:
TA Specific Guideline
Document status:
Version 3.1:
29-Nov-2011
Version 3:0:
19-Oct-2009
Version 2:0:
18-Jan-2007
Version 1:0:
13-Dec-2002
Release date:
29-Nov-2011
List of Contributors
Authors (Version 3.1):
 
 
Authors (Version 3):
 
 
 
Authors (Version 2):
 
 
Authors (Version 1):
 


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown
14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.


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14.1.2.1 Definitions
14.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.1.3.2.8
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

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.


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14.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 14.1.3.2.8.
14.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to 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.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
Investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.


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
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when tumor 
samples are obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, some 
disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, PSA 
for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be integrated 
as non-target disease. If markers are initially above the upper normal limit they must 
normalize for a patient to be considered in complete clinical response when all lesions 
have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 


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organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the eCRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.2.1.1.

Nodal target: See Section 14.1.2.1.1.
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target lesions 
will be calculated and reported as the baseline sum of diameters (SOD). The baseline sum of 
diameters will be used as reference by which to characterize the objective tumor response. Each 
target lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.

Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions not 
fulfilling the criteria for target lesions at baseline. Presence or absence or worsening of 
non-target lesions should be assessed throughout the study; measurements of these lesions 
are not required. Multiple non-target lesions involved in the same organ can be assessed as 
a group and recorded as a single item (i.e. multiple liver metastases). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target 
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the Investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 


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the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement.  This default value is derived from the 5 mm CT slice
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement.  This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness).Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
14.1.2.4.2
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response 
(CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes 
assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as reference 
the baseline sum of diameters.
Progressive Disease 
(PD):
At least a 20% increase in the sum of diameter of all measured target lesions, taking as 
reference the smallest sum of diameter of all target lesions recorded at or after baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline.3
SOD for CR may not be zero when nodal lesions are part of target lesions


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Response Criteria
Evaluation of target lesions
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
Methodology change See Section 14.1.2.2.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the Investigator/radiologist has to decide between the following three 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will 
be determined if there is at least 20% increase in the sum of diameters of all measured 
target lesions, taking as reference the smallest sum of diameters of all target lesions 
recorded at or after baseline with at least 5 mm increase in the absolute sum of the 
diameters). Proper documentation should be available to support this decision. This applies 
to patients who have not achieved target response of CR. For patients who have achieved 
CR, please refer to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.


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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. 
14.1.2.4.3
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-
target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have not 
been assessed or have been assessed using a different method than baseline.
1 Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 


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that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.2.2.
14.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3.
Table 14-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1


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Target lesions
Non-target lesions
New Lesions
Overall
lesion response
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1 This overall lesion response also applies when there are no non-target lesions identified at baseline.
2 Once confirmed PR was achieved, all these assessments are considered PR.
3 As defined in Section 14.1.2.4.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.1.3.1 Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.


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
For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
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.


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Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of Investigator 
overall lesion responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or
PR or SD.
Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
14.1.3.2 Time to event variables
14.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
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Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.
14.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If 
a patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
14.1.3.2.4
Time to treatment failure
This endpoint is often appropriate in studies of advanced disease where early discontinuation is 
typically related to intolerance of the study drug. In some protocols, time to treatment failure 
may be considered as a sensitivity analysis for time to progression. The list of discontinuation 
reasons to be considered or not as treatment failure may be adapted according to the specificities 
of the study or the disease.
Time to treatment failure (TTF) is the time from date of randomization/start of treatment to 
the earliest of date of progression, date of death due to any cause, or date of discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
14.1.3.2.5
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 


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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.
14.1.3.2.6
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.


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
at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.1.3.2.7
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 


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is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.

Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.1.3.2.8
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.1.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.


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For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
14.1.3.2.9
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as addresses 
the issues of missing tumor assessments during the study. For instance, if one or more 
assessment visits are missed prior to the progression event, to what date should the progression 
event be assigned? And should progression event be ignored if it occurred after a long period 
of a patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.1.3.2.7, and using the draft FDA guideline on 
endpoints (Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, April 2005) 
as a reference, the following analyses can be considered:
Table 14-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one 
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more 
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)


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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
=Definitions can be found in Section 14.1.3.2.7.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 
14.1.3.2.7.
=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.
=Definitions can be found in Section 14.1.3.2.7.
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:
Date of previous scheduled assessment (from baseline) is the date when a tumor assessment 
would have taken place, if the protocol assessment scheme was strictly followed from baseline, 
immediately before or on the date of the last adequate tumor assessment.


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In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.1.4
Data handling and programming rules
The following section should be used as guidance for development of the protocol, data 
handling procedures or programming requirements (e.g. on incomplete dates).
14.1.4.1 Study/project specific decisions
For each study (or project) various issues need to be addressed and specified in the protocol or 
RAP documentation. Any deviations from protocol must be discussed and defined at the latest 
in the RAP documentation.
The proposed primary analysis and potential sensitivity analyses should be discussed and 
agreed with the health authorities and documented in the protocol (or at the latest in the RAP 
documentation before database lock).
14.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the Investigator at any time. For patients who are lost to follow-
up, the Investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 14 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Patient/guardian decision

Death

Progressive disease per irRC (not per RECIST)

Study terminated by Novartis
14.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event


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
Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Patient/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by Novartis
14.1.4.4 Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
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 Investigator’s or central 
reader’s opinion does not match the programmed calculated response based on RECIST criteria. 
This may be queried for clarification. However, the Investigator or central reader’s response 
assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the Investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.1.4.5 Programming rules
The following should be used for programming of efficacy results:
14.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.


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14.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.
If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.1.4.5.4
Non-target lesion response
If no non-target lesions are identified at baseline (and therefore not followed throughout the 
study), the non-target lesion response at each assessment will be considered ‘not applicable 
(NA)’.
14.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.4.5.6
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (option 

Death due al, see Table 14-5) to reason other than underlying cancer (only used for TTP 
and duration of response)

Initiation of new anti-cancer therapy 


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*Adequate assessment is defined in Section 14.1.3.2.7. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Novartis decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.1.5
References (available upon request)
Dent S, Zee B, Dancey J, et al (2001) application of a new multinomial phase II stopping rule 
using response and early progression, J Clin Oncol; 19: 785-791.
Eisenhauer E, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumors: revised RECIST guideline (version 1.1). European Journal of Cancer; Vol.45: 228-47.
Ellis S, Carroll KJ, Pemberton K, et al (2008) Analysis of duration of response in oncology 
trials. Contemp Clin Trials 2008; 29: 456-465.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18.
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.


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


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


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


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14.3
Appendix 3: Statistical details of Bayesian regression models, 
priors, design operating characteristics and hypothetical dose 
escalation scenarios
14.3.1
Bayesian logistic regression model specification for dose escalation
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data, and the results of the Bayesian analyses and respective dosing decisions for 
some hypothetical data scenarios.
14.3.1.1
Statistical model
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and an interaction part.
14.3.1.1.1
Single agent parts 
Let (
) be the risk of DLT for INC280 given as a single agent at dose 
 ; 
(
) be the risk of DLT for PDR001 given as a single agent at dose 
. Single agent 
toxicity is modelled using logistic regression for the risk of DLT against log-dose:
INC280:
logit((
) ) = log() +  log(
 400
⁄
)
PDR001:
logit(
) = log() +  log(
 300
⁄
)
where 400mg, 300mg are used to scale the doses of INC280 and PDR001, respectively.  Hence, 
 and  (>0) are the single-agent odds of a DLT at 400mg (bid, total daily dose 800mg) 
and 300mg (q3w), respectively; and   and  (>0) are the increase in the log-odds of a 
DLT by a unit increase in log-dose.
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and an interaction part.
14.3.1.1.2
Interaction
Under no interaction, the risk of a DLT at dose 
 of INC280 and dose 
 of PDR001 is:

 !"(
, 
) = 1 −1 −(
)1 −(
)
To allow for interaction between INC280 and PDR001, an odds multiplier is introduced. The 
risk of DLT for combination dose (
, 
) is then given by:
odds&π !"(
, 
)( = exp() × 
 400
⁄
× 
 300
⁄
) ×
odds &
 !"(
, 
)( ,
where odds() =  (1 −)
⁄
; and ) is the log-odds ratio between the interaction and no 
interaction model at the reference doses. Here ) = 0 corresponds to no interaction, with ) > 0
and ) < 0 representing synergistic and antagonistic toxicity respectively.


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14.3.1.2
Prior specifications 
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single agent parameters log(/012), log(3012) for INC280, log(/456), 
log(3456) for PDR001, and the interaction parameter 7.  A meta-analytic-predictive (MAP) 
approach was used to derive the prior distribution for the single-agent model parameters.
14.3.1.2.1
Prior distribution for the logistic parameters 
Description of the meta-analytic-predictive (MAP) approach
Let 89: and ;9: be the number of patients with a DLT, and the total number of patients at dose 

 in historical trial < (< = 1, … , >).  The corresponding probability of a DLT is 9:.  The model 
specifications for the derivation of the MAP prior are as follows:
89: | 9: ~ Bin(9:, ;9:)
logit(9:) = log(:) + : log
/
DEF
GHI(:), GHI(:) J K, L ~ BVN(K, L),
s = 1, … , >
GHI(∗), GHI(∗) J K, L ~ BVN(K, L)
where 
DEF is the reference dose. The parameters K = (KP, KQ) and L are the mean and 
between-trial covariance matrix for the logistic parameters, the latter with standard deviations
P, Q, and correlation .  The parameters P and Q quantify the degree of between trial 
heterogeneity.  The following priors will be used for these parameters:

normal priors for KP and KQ, 

log-normal priors for P and Q, and 

a uniform prior for .
The MAP prior for single-agent model parameters in the new trial, GHI(∗), GHI(∗), is the 
predictive distribution 
GHI(∗), GHI(∗) J (89:, ;9: ∶< = 1, … , >)
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution. This is implemented using JAGS version 3.4.0. The sample from this 
distribution is then approximated by a mixture of bivariate normal (BVN) distributions.  BVN 
mixtures with increasing numbers of mixture components are fitted to the sample using the 
expectation-maximization (EM) algorithm (Dempster et al 1977, Wu 1983).  The optimal 
number of components of the mixture is then identified using the Akaike information criterion 
(AIC) (Akaike 1974).
Single agent INC280
For the MAP model for INC280, reference dose 
DEF = 400 mg (bid) is used, and data from 
> = 2 historical studies are available.


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Weakly informative normal priors are assumed for KP and KQ, with means corresponding to an 
assumed 50% risk of DLT at the reference dose of 400 mg, and a doubling in dose leading to a 
doubling in the odds of the risk of a DLT, respectively.  Priors for P and Q are assigned such 
that (1) their medians correspond to substantial between trial heterogeneity, and (2) their 
uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander et al 2014).
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 14-7.
Table 14-7
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent INC280 model parameters
Parameter
Prior distribution
KP
N(mean = logit(1/2), sd = 2)
KQ
N(mean = 0, sd=1)
TP
log-normal(mean = 0.5, sd = log(2)/1.96)
TQ
log-normal(mean = 0.25, sd = log(2)/1.96)
U
uniform(-1,1)
Historical data
The dose-DLT data of INC280 single agent in tablet formulation and BID dosing schedule from 
the following clinical studies are considered as the relevant information (Table 14-8) and used 
to derive the prior distribution for the BLRM parameters GHI(), GHI().

CINC280X2102: a Phase I study on adult patients with cMET dependent advanced solid 
tumors. 

CINC280X1101: a Phase I study of INC280 in Japanese adult patients with advanced 
solid tumors. 
The DLT observation window was 4 weeks in both trials. The AE records of the patients did 
not show any events that had occurred during the 5th and 6th weeks post-baseline and met the 
specified DLT criteria.
Table 14-8
Historical dose-DLT data from INC280 single agent clinical studies
Dose in BID (mg) 
Number of evaluable 
patients
Number of DLTs
CINC280X2102
400
4
0
CINC280X1101
200
3
0
400
10
1
Single agent PDR001
The 
prior 
distribution 
of 
PDR001 
single 
agent 
BLRM 
model 
parameters 
GHI(), GHI() is a mixture of two components: a MAP prior, and a high toxicity 
prior, which are mixed with weights (0.8, 0.2). 


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Component 1:
For the MAP model for PDR001, reference dose 
DEF = 300 mg (q3w) is used, and data from 
> = 1 historical studies is available.
Weakly informative normal priors are assumed for KP and KQ, with means corresponding to an 
assumed 50% risk of DLT at the reference dose of 300 mg, and a doubling in dose leading to a 
doubling in the odds of the risk of a DLT, respectively.  Priors for P and Q are assigned such 
that (1) their medians correspond to large between trial heterogeneity, and (2) their uncertainty 
(95% 
prior 
interval) 
cover 
plausible 
between-trial 
standard 
deviations 
(Neuenschwander et al 2014).  
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 14-9. 
Table 14-9
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent PDR001 model parameters
Parameter
Prior distribution
KP
N(mean = logit(1/2), sd = 2)
KQ
N(mean = 0, sd=1)
P
log-normal(mean = 1, sd = log(2)/1.96)
Q
log-normal(mean = 0.5, sd = log(2)/1.96)
U
uniform(-1,1)
Historical data
The dose-DLT data of PDR001 single agent from the following clinical study are considered as 
the relevant information (Table 14-9) and used to derive the prior distribution for the BLRM 
parameters GHI(), GHI().

CPDR001X2101: open label multicenter Phase I/II study of the safety and efficacy of 
PDR001 administered to patients with advanced malignancies.
The DLT observation window in the Phase I dose escalation part of this trial was 4 weeks. The 
6-week AE records of the patients did not show difference from the 4-week data in DLT 
observation. It is assumed that DLT rate is associated with total exposure of PDR00l within the 
observation window, and the average weight of a patient is 80 kg. Then each dose level in the 
historical data dqKw[mg/kg] (K = 2 or 4) can be converted to a flat dose level in a q3w dosing 
schedule, dq3w [mg], using the following method:
dq3w [mg] = dqKw[mg/kg] * 80[kg] / K[week] *3[week].


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Table 14-10
Historical dose-DLT data from PDR001 single agent clinical studies
Dosing 
schedule 
Dose level 
(mg/kg)
Converted to dose level in 
q3w (mg) 
Number of 
evaluable 
patients
Number of DLTs
q2w
1
120
16
0
q2w
3
360
15
0
q2w
10
1200
8
0
q4w
3
180
6
0
q4w
5
300
10
0
Component 2:
To take into account the potential situation that PDR001 in combination is substantially more 
toxic than when administered as single agent, a second high-toxicity prior component with 
vague bivariate normal distribution is added to improve the robustness of the final prior. The 
parameters of this weekly informative prior distribution are described below:

Given the relationship defined in Section 14.3.1, here it is assumed that the odds of DLT 
has dose proportionality, and the median probability of DLT at the reference dose 300 mg 
(q3w) is 0.10. This corresponds to the mean of GHI(Q)
 =0 and the mean of 
GHI(Q)
 = −2.20, which results in the median probability of DLT at 100 mg, 300 mg 
and 900 mg (q3w) are 0.04, 0.09 and 0.25, respectively. 

The standard deviations of GHI(Q)
 and GHI(Q)
 are set to 2 and 1, respectively. 

The correlation between GHI(Q)
 and GHI(Q)
 is set to 0, assuming independence.
14.3.1.2.2
Prior distribution for the interaction parameters
Although no interaction is expected for the two agents, uncertainty remains.  Therefore, a 
normal prior for the log-odds multiplier centered at 0 is used that allows for both synergistic 
and antagonistic toxicity.
-
) is normally distributed, with mean 0, and standard deviation 0.561
-
At the starting dose of 200mg (BID) INC280 in combination with 300mg PDR001 q3w 
the corresponding distribution for the odds ratio has mean 0 and a 97.5th percentile of 
log(3) i.e. 3-fold increase in odds of DLT due to interaction compared to no interaction.
14.3.1.2.3
Summary of prior distributions 
The prior distributions of the model parameters are summarized in Table 14-11. The prior 
distribution of DLT rates are summarized in Table 14-12 and Figure 14-1.


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Table 14-11
Prior distribution for the model parameters
Parameter
mean
Standard deviations
correlation
weight
INC280 single agent model
log(), log() ~ BVN 
(MAP)
(-2.376, 0.06)
(1.053, 1.046)
0.044
1
PDR001 single agent model
log(), log() ~ BVN mixture
  Component 1a (MAP)
(-3.042, -0.496)
(2.246, 1.127)
0.071
0.3504
  Component 1b (MAP)
(-4.151, -0.206)
(1.595, 0.773)
-0.179
0.2824
  Component 1c (MAP)
(-3.768, -0.713)
(1.175, 0.978)
0.107
0.1672
  Component 2 (high-tox)
(-2.197, 0)
(2, 1)
0
0.2
Interaction parameter 
Normal
)
0
0.561
N/A
N/A
Table 14-12
Summary of prior distribution of DLT rates 
INC280
dose (mg)
Prior probabilities that P(DLT) is in 
the interval :
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33,1]
2.5%
50%
97.5%
In combination with PDR001 300 mg
INC280=100
0.735
0.144
0.121
0.143
0.184
0.004
0.072
0.739
INC280=150
0.707
0.164
0.129
0.153
0.185
0.006
0.083
0.745
INC280=200
0.677
0.184
0.139
0.164
0.187
0.008
0.094
0.751
INC280=250
0.645
0.203
0.152
0.175
0.189
0.01
0.106
0.759
INC280=300
0.605
0.226
0.169
0.189
0.192
0.013
0.12
0.77
INC280=350
0.562
0.247
0.192
0.204
0.196
0.016
0.136
0.779
INC280=400
0.51
0.266
0.224
0.223
0.202
0.019
0.156
0.797
INC280=450
0.463
0.269
0.268
0.247
0.214
0.02
0.177
0.823
INC280=500
0.424
0.265
0.311
0.272
0.23
0.02
0.199
0.863


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Figure 14-1
Probabilities of under dosing, target toxicity and excessive toxicity of 
the INC280 dose level (mg, BID) in combination with PDR001 300mg 
q3w
14.3.1.3
Incorporation of data from ongoing studies 
Description of direct down-weighting approach
The dose-DLT information generated from ongoing relevant studies, called co-data, can be 
incorporated into the BLRM using a direct down-weighting method that accounts for between-
trial heterogeneity of data (Neuenschwander et al 2010).
The weight w (0 < w < 1), which will be applied to each patient from one particular study, is 
given by
w =
1
1 + 2;TQ ZQ
⁄
=
1
1 + 2;/;[
∗,
where n is the sample size of this set of  co-data, σ is the “outcome standard deviation” for 
individual observations, and τ is the between-study standard deviation. n[
∗is the maximum
prior effective sample size under infinite historical information. Let σ = 2; τ will be chosen 
depending on the degree of between-study heterogeneity. Table 14-13 provides the values of 
n[
∗and τ corresponding to different levels of between-study heterogeneity given σ = 2. 


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Table 14-13
Specification of the maximum prior effective sample size under 
infinite historical information and the between-study standard 
deviation given the level of between-study heterogeneity
Heterogeneity
^[
∗
_
Small
256
0.125
Moderate
64
0.25
Substantial
16
0.5
Large
4
1
Very large
1
2
Ongoing studies and data
CEGF816X2201c is an ongoing phase II, multicenter, open-label study that includes the 
investigation of INC280 in combination with Nivolumab in adult patients with cMet positive 
non-small cell lung cancer. 
Prior to each dose escalation meeting, the 6-week post-baseline AE data will be reviewed to 
identify the events that potentially meet the DLT criteria defined in this protocol (Section 6.2.4). 
Nivolumab dose level conversion will follow the equation specified for PDR001 in Section 
14.3.1.1.1. The cumulative combination dose-DLT data will then be incorporated into the 
BLRM using the direct down-weighting approach. Let σ = 2 and τ = 1 to cover account for a 
large between-trial heterogeneity.
14.3.1.4
Hypothetical on-study data scenarios
To illustrate the performance of the Bayesian model used to guide dose escalation, hypothetical 
dose escalations scenarios following the provisional dose levels specified in Table 14-14 are 
displayed. In each case, the maximum dose that can be used in the next cohort of patients is 
shown.  This maximum dose is determined using the model based assessment of the risk of 
DLT in future patients and the dose escalation rules as described in Section 6.2.3. In practice a 
dose below the maximum might be chosen based on additional safety, PK or PD information 
(Section 6.2.3).
Table 14-14
Hypothetical dose escalation scenarios 
Scenario
INC280 BID dose
Number of 
Next INC280 BID dose level
(mg)
(PDR001 300mg 
q3w fixed)
patients
DLTs
Dose 
(mg)
Median 
P(DLT)
P(excessive 
toxicity)
1
200
3
0
400
0.114
0.097
2
200
3
1
200
0.168
0.197
3
200
3
0
400
6
1
400
0.129
0.053


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Scenario
INC280 BID dose
Number of 
Next INC280 BID dose level
(mg)
(PDR001 300mg 
q3w fixed)
patients
DLTs
Dose 
(mg)
Median 
P(DLT)
P(excessive 
toxicity)
4
200
3
0
400
5
2
300
0.165
0.105
5
200
3
0
400
5
2
300
4
0
400
0.184
0.123
6
200
3
1
200
4
0
400
0.162
0.148
7
200
3
1
200
4
0
400
6
1
400
0.161
0.083
8
200
3
1
200
4
1
200
0.189
0.173
9
200
3
1
200
4
1
200
3
0
400
0.210
0.225
10
200
3
1
200
4
1
200
3
0
400
6
1
400 
(MTD)
0.192
0.116
14.3.1.1 Operating characteristics
Scenarios
In order to investigate the performance of the model, 4 hypothetical scenarios are considered:
1. Scenario 1 represents a scenario which is in line with the prior, i.e. the true underlying 
toxicity is set to the median values of the prior.
2. Scenario 2 represents a scenario assuming low toxicity than that of the prior
3. Scenario 3 represents a scenario assuming high toxicity than that of the prior
4. Scenario 4 represents a scenario assuming extremely high toxicity, i.e. the true underlying 
toxicity is set to values between 0.4 and 0.5. 


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Table 14-15
True underlying probabilities of DLT for different scenarios
INC280 
(mg)
(with 
PDR001 
300mg)
100
150
200
250
300
350
400
450
500
DLT rate
Scenario1 
(prior): 
0.072
0.083
0.094
0.106
0.120
0.136
0.156
0.177
0.199
Scenario 
2 (low 
tox):
0.049
0.057
0.065
0.073
0.083
0.095
0.110
0.125
0.142
Scenario 
3 (high 
tox):
0.134
0.153
0.172
0.192
0.214
0.239
0.270
0.301
0.390
Scenario 
4
(extremely 
high tox):
0.41
0.42
0.43
0.44
0.45
0.46
0.47
0.48
0.49
Simulation details
1000 trials were simulated for each scenario and the total minimum number of DLT to control 
the declaration of MTD was fixed to one. For the simulated escalation, the next dose selected 
is the one maximizing the probability of the true DLT rate being in the targeted toxicity interval 
(16%, 33%] whilst fulfilling the EWOC criterion.
The starting dose was chosen as 200mg INC280 in combination with 300mg PDR001. PDR001 
dose is fixed. 
Dose escalation continued until MTD was identified, that is, the following conditions were met:

At least 6 patients have been treated at the dose and

The dose satisfies one of the following conditions:

The posterior probability of targeted toxicity at this toxicity at this dose exceeds 50% 
and is the highest among potential doses, or

A minimum of 12 patients have already been treated on the trial.
Otherwise, a trial could stop before MTD declaration if all dose levels did not satisfy the EWOC 
criterion or the maximum number of patients defined below had been treated.
The number of patients to treat was defined as:

Minimum cohort size: 3

Minimum of patients treated: 12

Maximum number of patients treated: 60


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Simulation results
Metric to assess operating characteristics
Operating characteristics are reviewed based on the simulation results under the three scenarios. 
The metrics reviewed are:
1. Average proportion of patients receiving a target dose on study (I).
2. Average proportion of patients receiving a dose with true P(DLT) ≥ 33% on study (II).
3. Average proportion of patients receiving a dose with true P(DLT) < 16% on study (III).
4. Probability of recommending a target dose as the MTD (correct final decision) (IV).
5. Probability of recommending a dose with true P(DLT) ≥ 33% as the MTD (patient risk) 
(V).
6. Probability of recommending a dose with true P(DLT) < 16% as the MTD (VI).
7. Probability of stopping a trial before declaring MTD because all doses levels are too toxic
(Stopped).
Operating characteristics
Table 14-16 below summarizes the operating characteristics of the design under the four
scenarios. 
Table 14-16
Simulation results
Scenario
I
II
III
IV
(Target 
MTD)
V
(Overdose 
MTD)
VI
(Under-dose 
MTD)
Stopped
(all too 
toxic)
1
0.389
0
0.611
0.754
0
0.209
0.037
2
0
0
1
0
0
0.981
0.019
3
0.867
0.109
0.024
0.687
0.147
0.005
0.161
4
0
1
0
0
0.131
0
0.869
The simulation operating characteristics presented show that the combination model performs 
well under the hypothetical scenarios investigated.
Scenario 4 displays the results of the simulation of high toxicity at all dose levels. Results of 
the simulation should be interpreted with caution as this simulation does not allow for dose 
escalation decisions taken outside of the model as defined in Section 6.2.3.2. In particular, if 2 
patients experiencing a DLT at a previously untested dose, recruitment to that cohort will cease 
and either the next cohort will be enrolled at a lower dose, or the dose escalation will end if no 
dose is identified as safe by the BLRM. For this reason, the scenario is considered liable to 
overestimate the number of patients that would be treated on a trial in which all doses are overly 
toxic. Even with this limitation, it is notable that the average proportion of patients expected to 
be treated on trial is low, and the model correctly identifies in a high proportion of cases (86.9%) 
that the dose escalation should be stopped.


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14.3.2
Bayesian logistical model for the primary analysis of ORR
Main model
A Bayesian logistic regression model with treatment (combination vs. single agent), region 
(Asian vs. non-Asian), and interaction of treatment and region as covariates will be applied to 
the primary analysis. The main model is described explicitly as following:
logit(ORR) = α + β1*treatment + β2*region + β3*treatment*region
with α, β1, β2, and β3 the model parameters. 
Prior specification
A priori the following assumptions are made:

No region effect regardless of treatment

No treatment effect differentiated by region (i.e. no region-treatment interaction) 

ORR = 20% in patients treated with PDR001 single agent

The odds ratio (ORRPDR001+INC280 to ORRPDR001) is 2
Then weakly informative normal priors are assumed for the model parameters with the means 
corresponding to the above information, and standard deviations 5:

α ~ N(logit(0.2), 5)

β1 ~ N(exp(2), 5)

β2 ~ N(0, 5)

β3 ~ N(0, 5)
Inference summary
Posterior mean, SD, 2.5%, 50% and 97.5% quantiles of each model parameter (or its 
transformation as appropriate) will be provided. 
Based on the main model, if the posterior probability of either exp(β2)>1 or exp(β2)<1 is greater
than 0.8, it is considered as the evidence of region effect. If the posterior probability of either 
exp(β3)>1 or exp(β3)<1 is greater than 0.8, it is considered as the evidence of interaction 
between region and treatment.
Analysis with evidence of region-treatment interaction
If there is evidence of interaction between region and treatment, ORR will be summarized by 
region. If for a region the posterior probability that odds ratio (ORR PDR001+INC280 to ORR
PDR001) >1 (i.e. exp(β1)>1) is greater than 0.8, AND the observed ORR PDR001+INC280 is at least 
10% greater than the observed ORR PDR001, it will be concluded that the combination treatment 
has a superior anti-tumor effect compared to the PDR001 single agent treatment in the patients 
from this region. 
The ORRs will be estimated and summarized by treatment and by region. The posterior mean
and 95% credible interval of ORRPDR001+INC280 and ORRPDR001 for each region will be provided, 
respectively. The posterior probabilities of ORR in the following efficacy intervals will be 
calculated:

[0, 20%) no anti-tumor activity


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
[20%, 100%] clinically relevant anti-tumor activity
The means and 95% credible intervals of treatment effect in odds ratio for each region will be 
provided.
Analysis without evidence of region-treatment interaction
If there is no evidence of interaction between region and treatment, an analysis with all patients 
using the following model (with prior distributions specified above) should be applied:
logit(ORR) = α + β1*treatment + β2*region
Posterior mean, SD, 2.5%, 50% and 97.5% quantiles of each model parameter (or its 
transformation as appropriate) will be provided.
If the posterior probability that odds ratio (ORR PDR001+INC280 to ORR PDR001) >1 (i.e. exp(β1)>1) 
is greater than 0.8, AND the observed ORR PDR001+INC280 is at least 10% greater than the 
observed ORR PDR001, it will be concluded that the combination treatment has a superior anti-
tumor effect compared to the PDR001 single agent treatment. 
The ORRs will be estimated and summarized by treatment and by region. The posterior mean 
and 95% credible interval of ORRPDR001+INC280, ORRPDR001 will be provided. The posterior 
probabilities of each ORR in the following efficacy intervals will be calculated:

[0, 20%) no anti-tumor activity

[20%, 100%] clinically relevant anti-tumor activity
The means and 95% credible intervals of treatment effect in odds ratio (i.e. exp(β1)) and the 
region effect in odds ratio (i.e. exp(β2)) will be provided.
Analysis without evidence of region effect and region-treatment interaction
If there is evidence of neither region effect nor interaction between region and treatment, an 
analysis with all patients using the following model (with prior distributions specified above) 
should be applied:
logit(ORR) = α + β1*treatment
Posterior mean, SD, 2.5%, 50% and 97.5% quantiles of each model parameter (or its 
transformation as appropriate) will be provided.
If the posterior probability that odds ratio (ORR PDR001+INC280 to ORR PDR001) >1 (i.e. exp(β1)>1) 
is greater than 0.8, AND the observed ORR PDR001+INC280 is at least 10% greater than the 
observed ORR PDR001, it will be concluded that the combination treatment has a superior anti-
tumor effect compared to the PDR001 single agent treatment. 
The ORRs will be estimated and summarized by treatment. The posterior mean with 95% 
credible interval of ORRPDR001+INC280 and ORRPDR001 will be provided. The posterior 
probabilities of each ORR in the following efficacy intervals will be calculated:

[0, 20%) no anti-tumor activity

[20%, 100%] clinically relevant anti-tumor activity
The mean and 95% credible interval of treatment effect in odds ratio (i.e. exp(β1)) will be 
provided.


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Appendix 4: Recommended management algorithms for 
suspected toxicities
These general guidelines for management of toxicities (Postow et al 2015 - supplementary 
appendix) constitute guidance to the Investigator and are not intended to substitute institutional 
standard of care practice. The guidance applies to all agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated. 
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The 
oral equivalent of the recommended IV doses may be considered for ambulatory patients with 
low-grade toxicity. The lower bioavailability of oral corticosteroids should be taken into 
account when switching to the equivalent dose of oral corticosteroids. 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended. 
The frequency and severity of the related adverse events covered by these algorithms will 
depend on the immuno-oncology agent or regimen being used.


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Skin Adverse Event Management Algorithm
Grade of 
Rash 
(NCI CTCAE v4)
Management
Follow-up
Grade 1-2
Covering  = 30% 
body surface area 
(BSA)*
Grade 3-4
Covering >30% BSA; 
Life threatening 
consequences*
• Symptomatic therapy (e.g. antihistamines, 
topical steroids)
• Continue I-O therapy per protocol
• Delay or discontinue I-O therapy per 
protocol
• Consider skin biopsy
• Dermatology consult
• 1.0-2.0 mg/kg/day IV methylprednisolone 
IV or IV equivalent
If persists > 1-2 weeks or recurs:
• Consider skin biopsy
• Delay I-O therapy per protocol
• Consider 0.5-1.0 mg/kg/day methylprednisolone IV or 
oral  equivalent. Once improving , taper steroids over 
at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume I-O therapy per 
protocol
If worsens:
• Treat as Grade 3-4
If improves to Grade 1:
• Taper steroids over at least 1 month and add 
prophylactic antibiotics for opportunistic infections
• Resume I-O therapy per protocol
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical 
improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
*Refer to NCI CTCAE v4 for term-specific grading criteria.
Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. 


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


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Appendix 5: Prohibited concomitant medication for patients in 
INC280 + PDR001 combination arm
If a medication is listed in Table 14-17 and Table 14-18/Table 14-19, more stringent practice 
shall be applied (that is, the medication shall be prohibited as in Table 14-17)
Table 14-17
Drugs prohibited while on study 
Mechanism of Interaction
Drug Name
Strong CYP3A4 inducer
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampin, mitotane, St. John's wort (Hypericum perforatum)
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”.
This may not be an exhaustive list, will be updated periodically.
Note: If a medication is listed more than once, the more stringent practice shall be applied (that is, the medication 
shall be prohibited).


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14.6
Appendix 6: Concomitant medication to be used with caution for 
patients in the INC280 + PDR001 combination arm 
Table 14-18
Drugs with a known risk of torsades de pointes
TdP Risk
Generic names
Known
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levosulpiride, methadone, moxifloxacin, ondansetron, 
oxaliplatin, papaverine HCl (intra-coronary), pentamidine, pimozide, 
procainamide, propofol, quinidine, roxithromycin, sevoflurane, sotalol, 
sulpiride, sultopride, terlipressin, terodiline, thioridazine, vandetanib
Check crediblemeds.org/healthcare-providers/drug-list for the most updated list. 
This may not be an exhaustive list, will be updated periodically.
Table 14-19
Drugs to be used with caution while on study 
Mechanism of Interaction
Drug Name
Strong CYP3A inhibitor
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), indinavir/ritonavir, 
tipranavir/ritonavir, ritonavir, cobicistat, indinavir, ketoconazole, 
troleandomycin, telaprevir, danoprevir/ritonavir, elvitegravir/ritonavir, 
saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, voriconazole, mibefradil, 
clarithromycin, posaconazole, telithromycin,  grapefruit juice, conivaptan, 
nefazodone, nelfinavir, idelalisib, boceprevir, atazanavir/ritonavir, 
darunavir/ritonavir 
CYP1A2 substrate with NTI
theophylline, tizanidine
CYP2C9 substrate with NTI
Phenytoin, warfarin
CYP2C19 substrate with NTI
(S)-mephenytoin
P-gp substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, apremilast, 
aprepitant, atorvastatin,  azithromycin, boceprevir, bosentan, carvedilol, 
caspofungin, ceritinib, citalopram, colchicine, cyclosporine, dabigatran, 
digoxin, docetaxel, domperidone, doxepin, doxorubicin, eribulin, everolimus, 
fentanyl, fexofenadine, fidaxomicin, fluvastatin, fosamprenavir, gatifloxacin, 
idelalisib, iloperidone, indacaterol, irbesartan, lacosamide, lapatinib,
levetiracetam, levofloxacin, linagliptin, linezolid, loperamide, losartan, 
maraviroc, mirabegron, moxifloxacin, nadolol, naloxegol, nateglinide, 
nevirapine, nintedanib, olodaterol, paclitaxel, pantoprazole, paroxetine, 
pazopanib, proguanil, posaconazole, pravastatin, quinidine, ranolazine, 
ritonavir, riociguat, risperidone, rivaroxaban, saquinavir, silodosin, 
simeprevir, simvastatin, sirolimus, sitagliptin, sofosbuvir, sorafenib,
tacrolimus, telaprevir, tenofovir, ticagrelor, tipranavir, tolvaptan, topotecan, 
umeclidinium, valsartan, vardenafil, vincristine, voriconazole, 
BCRP substrates
atorvastatin daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, paritaprevir, pitavastatin, rosuvastatin, irinotecan, 
ethinylestradiol, simvastatin, sofosbuvir, sulfasalazine, tenofovir, topotecan, 
venetoclax
H2-receptor antagonists
ranitidine, nizatidine, famotidine, cimetidine
Proton pump inhibitor
esomeprazole, pantoprazole, Omeprazole, pantoprazole, lansoprazole, 
esomeprazole, rabeprazole, dexlansoprazole


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Mechanism of Interaction
Drug Name
Antacids
aluminum hydroxide, aluminum carbonate, calcium hydroxide, calcium 
carbonate, bismuth subsalicylate
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum (v01, 
2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University School of 
Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of Washington’s 
Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”.
This may not be an exhaustive list, will be updated periodically.
NTI: narrow therapeutic index.
Note: If a medication is listed more than once, the more stringent practice shall be applied (that is, the medication 
shall be prohibited).


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14.7
Appendix 7: Child-Pugh classification of severity of liver disease
Child-Pugh classification system
The CPC is used to assess the severity of impaired hepatic function in patients with liver 
cirrhosis (Child and Turcotte 1964, FDA guidance 2003). In general, it is used to determine the 
risk to a patient with regard to the treatment(s) (e.g. surgery, transplant, medication), and, to 
suggest the perceived survival of the patient over a period of time.
Hepatocellular carcinoma patients who have Child-Pugh grade A score (5 - 6 points) at the 
baseline screening are eligible for participating in Study [CINC280X2201], provided that the 
patients meet all other eligibility criteria.
Calculation and interpretation for Child-Pugh scores
The severity of liver disease is based on the CPC criteria, which will be calculated based on 
clinical findings and laboratory results during the screening period. Five variables are 
considered (severity of ascites, hepatic encephalopathy, abnormality in serum bilirubin, serum 
albumin and clotting times).A score (between 1 and 3) is accordingly assigned to each of these 
factors (Table 14-20). The sum of the scores provides the Child-Pugh score, which corresponds 
to a Child-Pugh grade (or Child’s grade) of A, B or C (Table 14-21).
Table 14-20
Child-Pugh score calculation
Variables
Points assigned
Units
1
2
3
Total Bilirubin
< 2 (<34)
2-3 (34-50)
> 3 (>50)
mg/dL (µmol/L)
Serum Albumin
> 35 (>3.5)
28-35 (2.8-3.5)
<28 (<2.8)
g/L (g/dL)
PT (or INR)
< 4 (< 1.7)
4-6 (1.7-2.30)
> 6 (>2.30)
sec (no unit)
Ascites
Absent
Slight
Moderate
no unit
Hepatic Encephalopathy*
None
Grade 1-2
Grade 3-4
no unit
*Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
*Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves
*Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
*Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
*Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity
Table 14-21
Child-Pugh score interpretation
Severity (grade)
Child-Pugh Score
A
5 - 6
B
7 - 9
C
10 - 15
14.7.1
References (available upon request)
Child CG, Turcotte JG (1964). Surgery and portal hypertension. In: The liver and portal 
hypertension. Edited by CG Child. Philadelphia: Saunders:50-64
FDA Guidance for industry (2003). Pharmacokinetics in patients with impaired hepatic 
function: study design, data analysis, and impact on dosing and labeling

SAP_001.pdf: 
Clinical Development
INC280 (capmatinib), PDR001
CINC280X2108 / NCT02795429
A phase Ib/II, open-label, multi-center study of INC280 in 
combination with PDR001 or PDR001 single agent in 
advanced hepatocellular carcinoma
Statistical Analysis Plan (SAP)
Author:
Document type:
SAP Documentation
Document status:
Final version 1.0, Amendment 1
Release date:
10-May-2021
Number of pages:
51
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted 
(Current)
26-
Aug-
2016
Prior 
to 
DB 
lock
Creation of 
final 
version 1.0
N/A - First version
NA
10-
May-
2021
Prior 
to 
DB 
lock
Creation of 
the 
Amendment 
1 
of 
the 
final 
version 1.0
This version will be used 
for the CSR
Structural update and various 
changes in wording,  in order 
to align with the TCO SAP 
template (SAP_TCO_V3.0). 
Corrections and additions to 
reflect the latest amended 
protocol 
version 
(v5.0).
Wording 
added 
for 
the 
managment of the COVID-19 
situation.


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................12
2.2
Analysis Set/ Subject Classification/ Withdrawal of ICF/ Subgroups ..................15
2.2.1
Analysis sets..........................................................................................15
2.2.2
Subject classification.............................................................................17
2.2.3
Withdrawal of Informed Consent..........................................................19
2.2.4
Subgroup of interest ..............................................................................19
2.3
Patient disposition, demographics and other baseline characteristics ...................19
2.3.1
Patient disposition.................................................................................19
2.3.2
Demographic and other baseline characteristics...................................19
2.3.3
Medical History.....................................................................................20
2.3.4
Prior antineoplastic therapy...................................................................20
2.3.5
Diagnosis and extent of cancer .............................................................20
2.3.6
Other......................................................................................................21
2.4
Protocol deviations ................................................................................................21
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................21
2.5.1
Study treatment .....................................................................................21
2.5.2
Prior, concomitant and post therapies...................................................23
2.5.3
Compliance ...........................................................................................23
2.6
Analysis of the primary objective..........................................................................23
2.6.1
Definition of the primary endpoint .......................................................24
2.6.2
Statistical hypothesis, model, and method of analysis..........................24
2.6.3
Handling of missing values/censoring/discontinuations.......................26
2.7
Analysis of key secondary efficacy objective(s) ...................................................27
2.8
Analysis of secondary efficacy objective(s)..........................................................27
2.8.1
Definition of secondary endpoints ........................................................27
2.8.2
Statistical hypothesis, model, and method of analysis..........................29
2.8.3
Handling of missing values/censoring/discontinuation ........................30


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2.9
Safety analyses.......................................................................................................31
2.9.1
Adverse events (AEs)............................................................................31
2.9.2
Adverse events of special interest ........................................................32
2.9.3
Laboratory data .....................................................................................33
2.9.4
Other safety data ...................................................................................35
2.10
Pharmacokinetics analyses ....................................................................................36
2.10.1
Data handling principles .......................................................................37
2.10.2
Data analysis set....................................................................................37
2.10.3
Basic tables, figures and listing.............................................................37
2.11
PD and PK/PD analyses.........................................................................................38
38
38
2.13
Patient-reported outcomes .....................................................................................40
40
40
41
41
41
42
43
2.16
Interim analysis......................................................................................................43
3
Sample size calculation .....................................................................................................43
3.1
Phase Ib part ..........................................................................................................43
3.2
Phase II part ...........................................................................................................43
4
Change to protocol specified analyses ..............................................................................44
4.1
Planned analysis due to COVID-19.......................................................................44
5
Appendix ...........................................................................................................................44
5.1
Imputation rules.....................................................................................................44
5.1.1
Study drug.............................................................................................44
5.1.2
AE date imputaition ..............................................................................45
5.1.3
Concomitant medication date imputation .............................................46
5.1.4
Deaths....................................................................................................47
5.1.5
Other imputations..................................................................................48
5.2
AEs coding/grading ...............................................................................................48
5.3
Laboratory parameters derivations ........................................................................48
5.4
Statistical models...................................................................................................49


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5.4.1
Primary analysis....................................................................................49
5.4.2
Key secondary analysis.........................................................................49
5.5
Rule of exclusion criteria of analysis sets..............................................................49
5.6
Confidence interval for response rate.....................................................................49
5.7
Waterfall graphs.....................................................................................................49
5.8
Kaplan-Meier estimates.........................................................................................50
6
Reference...........................................................................................................................50


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List of abbreviations
AE
AESI
Adverse Event
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate Aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BDM
Biometrics and Data Managment
BID
bis in die / Twice daily
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
CI
Confidence Interval
CR
Complete Response
CRO
Contract Research Organization
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DAR
Dose Administration Record
DBL
Data Base Lock
DDS
Dose-Determining Set
DI
Dose Intensity
DLT
Dose Limiting Toxicity
DMPK
DOR
Drug Metabolism & PharmacoKinetics
Duration of Overall Response
DRL
Drug Reference Listing
ECG
ECOG
Electrocardiogram
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EOT
End of Treatment
EWOC
Escalation with Overdose Control
FAS
Full Analysis Set
HCC
Hepatocellular Carcinoma
HGLT
High Level Group Term
HLT
High Level Term
IB
Investigator’s Brochure
IHC
Immunohistochemistry
ir-
Immune related
irRC
Immune-related Response Criteria


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i.v.
Intravenous
LLOQ
Lower Limit Of Quantification
MAP
Meta-Analytic-Predictive
MedDRA
Medical Dictionary for Regulatory Activities
MTD
Maximum Tolerated Dose
NA
Not Assessed
NMQ
Novartis MedDRA Queries
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamics / Progressive Disease, depending on the context
PDI
Planned Dose Intensity
PDS
Programming Datasets Specifications
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial Response
PT
Preferred Term
Q3W
Every 3 Weeks
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors 
RNA
Ribonucleic Acid
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease / Standard Deviation, depending on the context
SMQ
Standardized MedDRA Queries
SOC
System Organ Class
SSD
Study Specification Document
TBL
Total Bilirubin
TFL
Tables-Figures-Listings
TTP
Time to Progression
TTR
Time to Response
ULN
Upper Limit of Normal
UNK
Unknown
WBC
White Blood Cells
WHO
World Health Organization


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CINC280X2108 that will be presented in the Clinical Study Report (CSR).
The output shells (in-text and post-text) accompanying this document can be found in the 
Tables-Figures-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/RP2D 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 a phase Ib/II, open-label, multi-center study of INC280 in combination with PDR001 or 
PDR001 single agent in advanced hepatocellular carcinoma. Patients will be enrolled into the 
study in two parts, a phase Ib dose escalation part and a randomized phase II part. In the phase 
Ib part of the study, cohorts of patients will be treated with INC280 (orally twice daily), in
combination with a fixed dose of PDR001 (intravenously every three weeks), in a dose 
escalation fashion until the Maximum Tolerated Dose (MTD) is reached or the Recommended
Phase II Dose (RP2D) is established. The phase II part will be opened after the MTD/RP2D is 
declared.
In the phase II part, approximately 60 patients will be enrolled, randomly assigned in a 1:1  ratio,
to two different treatments (see Figure 1-1):

INC280+PDR001, and 

PDR001
Randomization will be stratified by geographical region (Asian vs. non-Asian).
The study data will be analyzed and reported based on all patients’ data of the dose escalation
and phase II parts up to the time when all patients have potentially completed at least nine cycles 
of treatment or discontinued the study.


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Figure 1-1
Study Design
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
Phase Ib part: 
To characterize the safety and tolerability 
of INC280 in combination with PDR001 
and identify the MTD and/or RP2D
Phase II part: 
-
To compare the efficacy of INC280 
in combination with PDR001 vs. 
PDR001 single agent
Phase Ib part:
Safety: Incidence and severity of AEs and SAEs, 
including changes in laboratory values, vital signs 
and ECGs. Incidence of DLT during the first 2 cycles 
of treatment.
Tolerability: Dose interruptions, reductions, and dose 
intensity
Phase II part:
Overall response rate (ORR) per Response 
Evaluation Criteria in Solid Tumors (RECIST v1.1)
Secondary
Phase Ib/II part: To further characterize
the efficacy of INC280 in combination 
with PDR001 and PDR001 single agent
Best overall response (BOR), duration of overall 
response (DOR), time to response (TTR), 
progression-free survival (PFS), time to progression 
(TTP), overall survival (OS), Overall response rate 
(ORR)
Phase II part: To characterize the safety 
and tolerability of INC280 in combination 
with PDR001 and PDR001 single agent
Safety: Incidence and severity of adverse events 
(AEs) and serious adverse events (SAEs), including 
changes in laboratory parameters, vital signs and 
electrocardiograms (ECGs)   
Tolerability: Dose interruptions, reductions and dose 
intensity
Phase Ib/II parts: To characterize the 
pharmacokinetic profile of INC280 in 
combination with PDR001 and PDR001 
single agent    
Plasma/serum PK parameters (e.g., AUC, Cmax, 
Tmax) 
Plasma/serum concentration vs. time profiles


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Objective
Endpoint
Phase Ib/II parts: To assess the 
pharmacodynamic effect of INC280 in 
combination with PDR001 and PDR001 
single agent
TIL characterization & CD8 and PD-L1 protein 
expression
2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis personnel and/or designated CRO(s) using the most 
updated SAS version in the GPS environment, and for Bayesian modeling the most updated R 
and WinBUGS versions. PK parameters will be calculated using non-compartmental methods 
available in Phoenix WinNonlin version 5.2 or later.
The study data will be analyzed and reported (in a primary CSR if final DBL has not occurred)
based on all patients’ data of the dose escalation and phase II parts up to the time when all 
patients have potentially completed at least nine cycles of treatment or have discontinued the 
study. The primary CSR will include all outputs planned within the TFL shells document. Any 
additional data for patients continuing to receive study treatment past the data cutoff date for 
the primary CSR as allowed by the protocol, will be reported at completion of the study as 
defined in Section 4.3 of the protocol. However, only a selection of key outputs for which 
additional data was collected will be provided for the final report.
For each of the analyses, all 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 


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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 data derivation.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these cases, the end date will not be imputed and 
therefore will not appear in the listings.
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.
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect 
will be assessed. 
Data will be summarized with respect to demographic and screening characteristics, efficacy 
and safety observations and measurements and all relevant PK and PD measurements using 
descriptive statistics (quantitative data) and contingency tables (qualitative data).
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables;
a missing category will be included as applicable. Percentages will be calculated using the 
number of patients in the relevant population or subgroup as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum).
The following rules will be followed for reporting results unless stated otherwise: 

For the phase Ib part, cohorts treated with the same combination dose level will be pooled 
into a single treatment group. All summaries, listings, figures and analyses will be
performed by treatment group.

For the phase II part, all summaries, listings, figures will be presented by study arm for the 
efficacy analyses, and by study treatment for safety analyses. Patients from the phase II part 
will be classified according to the study arm to which they were assigned at baseline.
Study treatments in the phase II part:

Treatment A: PDR001+INC280

Treatment B: PDR001
Patients from the phase Ib dose escalation parts and the phase II part will not be pooled in any 
analyses unless otherwise specified.


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2.1.1
General definitions
2.1.1.1
Investigational drug and study treatment
Investigational drug, will refer to the INC280 or PDR001. The terms investigational drug and 
study drug are used interchangeably. For consistency across studies, the term study treatment 
will be used throughout this document.
Investigational treatment will refer to PDR001 in combination with INC280 (i.e. 
PDR001+INC280) or PDR001 as single agent. The term investigational treatment may also be 
referred to as study treatment.  For consistency across studies, the term study treatment will 
be used throughout this document.
2.1.1.2
Date of first/last administration of study treatment
The date of first (last) administration of study drug is derived as the first (last) date when a non-
zero dose of any component of study treatment was administered and recorded on the Dosage 
Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment.
2.1.1.3
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1, if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date, if event precedes the reference start date.
Therefore, the first day of study treatment is study day 1.
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.
Phase Ib part 
The reference date for all assessments (safety, efficacy, pk, etc.) is the start of study treatment. 
Phase II part 
-
The reference start date for safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption, pk etc.) is the start
of study treatment.
-
The reference start date for all other, non-safety assessments (i.e., tumor assessment,
survival time, disease progression, tumor response, ECOG performance status) is the date
of randomization.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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2.1.1.4
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25.
2.1.1.5
Baseline
Baseline is the result of an investigation describing the “true” state of the patient before start of 
study treatment administration.
Phase Ib part
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is taken as “baseline” assessment.
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.
Phase II part
-
For efficacy evaluations, the last non-missing assessment, including unscheduled 
assessments on or before the date of randomization is taken as “baseline” value or “baseline” 
assessment. In the context of baseline definition, the efficacy evaluations also include and
performance status. 
-
For safety evaluations, the last available assessment on or before the date of start of study
treatment is taken as “baseline” assessment.
For pregnancy test, baseline will be within 72 hours before first administration of study 
treatment. 
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). Computation of baseline for ECG are described in  Section 2.9.4.1.
If patients have no value as defined above, the baseline result will be missing.
2.1.1.6
On-treatment assessment/event and observation periods
For all safety reporting the overall observation period will be divided into three mutually 
exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 30 days
following the last administration of study treatment.
3. post-treatment period: from 31 days after date of last administration of study treatment.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 


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baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).
Following last administration of study treatment, AEs (including serious adverse events), and 
new antineoplastic therapies are collected for a period of 150 days. Following start of new 
antineoplastic therapy, only study treatment related AEs will be collected. However, all safety 
data (including those from the post-treatment period) will be listed and those collected during 
the pre-treatment and post-treatment period will be flagged.
2.1.1.7
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-1
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last known date subject alive from Survival 
information page 
Patient status is reported to be alive, lost to 
follow-up or unknown.
Date of consent withdrawal
No condition
Start/End dates from concomitant medications
Non-missing medication term.
Start/End dates from further antineoplastic 
therapy
Non-missing medication/procedure term.
Start/End dates from dosage administration 
record and dosage administration record for PK
Non-missing dose. Doses of 0 are allowed.
- Tumor assessment date
Evaluation is marked as ‘done’.
Laboratory
regnancy test/PK 
collection dates
Sample collection marked as 
‘done’/’performed’/’taken’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status
Start/End dates of AE 
Non-missing verbatim term
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring coming from ‘Survival information’ eCRF. 


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The last contact date will be used for censoring of patients in the analysis of time to event 
endpoints.
2.2
Analysis Set/ Subject Classification/ Withdrawal of ICF/ 
Subgroups
2.2.1
Analysis sets
The number (%) of patients in each of the defined analysis set will be summarized using the 
FAS.
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of study 
treatment in the phase Ib part, and all patients to whom study treatment has been assigned by 
randomization in the phase II part. According to the intent to treat principle, patients in the 
phase II part will be analyzed according to the treatment and strata they have been assigned to 
during the randomization procedure.
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment (i.e. at 
least one dose of PDR001 or INC280). Patients will be classified according to treatment 
received, where treatment received is defined as:

the treatment assigned if it was received at least once, or

the first treatment received if the assigned treatment was never received.
The safety set will be the primary population for all safety related endpoints.
Per Protocol Set 
The Per-Protocol Set (PPS) for the phase II part consists of a subset of FAS patients who meet 
the following criteria:

Treatment according to the randomization scheme.

Presence of at least one measurable lesion at screening according to RECIST v1.1 as per 
Appendix 1 of the protocol.

Have not been previously treated with PD-1- or PD-L1-directed therapy or any therapeutic 
cancer vaccine.

Histologically or cytologically documented locally advanced recurrent or metastatic HCC.

Have received prior systemic sorafenib treatment for HCC with documented progression 
during or after discontinuation of sorafenib treatment, or are intolerant to sorafenib.
The PPS will be used in the phase II part of the study only and will define the patients used in
the sensitivity analysis of the primary endpoint. If the PPS and the FAS are identical, then 
analyses described by the PPS will not be performed.


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Dose-Determining Set
The Dose-Determining Set (DDS) consists of all patients in the dose escalation part who either 
meet the minimum exposure criterion and have sufficient safety evaluations, or have 
experienced a DLT during cycles 1 and 2. This constitutes an evaluable patient for the 
determination of MTD.
A patient is considered to have met the minimum exposure criterion if having received at least 
two planned doses of PDR001 and 28 days of INC280 during cycles 1 and 2. Patients who do 
not experience a DLT during the first two cycles are considered to have sufficient safety 
evaluations if they have been observed for ≥ 42 days following the first dose, and are considered 
by both Novartis and the Investigators to have enough safety data to conclude that a DLT did 
not occur.
Patients who do not meet these minimum dosing and safety evaluation requirements will be
regarded as ineligible for the DDS and additional patients may be enrolled if required to meet 
the minimum cohort size for decision making, as described in Section 6.2.3 of the protocol.
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing measurable INC280 and PDR001 PK data. The PAS will be used for all PK 
analyses.
Note: Some patients’ data may not be adequate for the reliable estimation of some PK 
parameters. These patients will be identified at the time of the analysis and their PK parameters 
will be excluded from summaries.
For a concentration to be evaluable, patients are required to:

take at least one dose of INC280 and/or PDR001

for INC280 PK samples taken on or after Cycle 2 Day 1, take the same dose of INC280 
for at least 3 consecutive days prior to sampling

for INC280 pre-dose samples on or after Cycle 2 Day 1, do not vomit within 4 hours 
after the dosing of INC280 prior to sampling; for all post-dose samples, do not vomit 
within 4 hours after the dosing of INC280

for pre-dose samples taken on or after Cycle 2 Day 1, have the sample collected before 
the next dose administration and at least 9 hours after the last dose administration of 
INC280
The PK parameter analysis for phase Ib part will include 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 primary PK parameter

patient did not vomit within 4 hours after the dosing of INC280 


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
for Cycle 2 Day 1 profile of INC280, patient took the same dose of INC280 for at least 
3 consecutive days prior to sampling

for Cycle 2 Day 1 profile of INC280, patients are required to have the pre-dose sample 
collected before the next dose administration and at least 9 hours after the last dose 
administration of INC280.
 
 
 
 
 
2.2.2
Subject 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 classification rules defined in Table 
2-2.
Table 2-2
Classification based on PDs and non-PD criteria
Analysis set
Protocol deviations leading to 
exclusion (DVSPID)
Non protocol deviation leading to 
exclusion
Full analysis set 
No 
written 
informed
consent 
(OTH01, OTH02)
For Phase Ib part:
No dose of study treatment (in both 
drugs) administered
Safety set
No 
written 
informed
consent 
(OTH01, OTH02)
No dose of study treatment (in both 
drugs for the combination arm) 
administered
Dose-determining 
set
No 
written 
informed
consent 
(OTH01, OTH02)
For Phase Ib part:

Patients had no DLT during 
cycles 1 and 2 
and 

Did not receive at least two 
planned doses of PDR001 and
28 days of INC280 during 
cycles 1 and 2.

Were not followed up for ≥ 42 
days after first dose 


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administration, unless patient 
had a DLT during this period.
Per-protocol set

No written informed consent 
(OTH01, OTH02).

No presence of at least one 
measurable lesion at screening 
according to RECIST v1.1
(INCL10).

Histologically or cytologically 
documented type of indication 
different from locally advanced 
recurrent or metastatic HCC
(INCL03).

Patients previously treated with 
PD-1-
or 
PD-L1-directed 
therapy 
or 
any 
therapeutic 
cancer vaccine (EXCL01).

Patient received prior systemic 
sorafenib treatment for HCC 
with documented progression 
during or after discontinuation 
of sorafenib treatment, or are 
intolerant 
to 
sorafenib 
(INCL06).
For Phase II part only:

Treatment not according to the 
randomization scheme.
PK Analysis Set
No 
written 
informed
consent 
(OTH01, OTH02)
No blood sample providing 
evaluable PK data.


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2.2.3
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.
For more details on withdrawal of informed consent, please refer to Section 7.1.4 of the protocol.
2.2.4
Subgroup of interest
Not applicable.
2.3
Patient disposition, demographics and other baseline 
characteristics
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS.
2.3.1
Patient disposition
The number and percentage of the patients included in the FAS, the ones who are still on 
treatment at the time of the data cut-off, the ones who discontinued the study phases, as well as 
the reason for discontinuation will be presented.
The FAS will be used for the patient disposition summary tables and listings. The following
will be tabulated overall, by treatment or study arm:

Number (%) of patients who are still on-treatment at the time of cut-off (based on non-
completion of the ‘End of Treatment Disposition’ page),

Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment Disposition’ page with discontinuation date and reason entered),

Primary reasons for study treatment discontinuation (based on discontinuation reason
entered in the ‘End of Treatment Disposition’ page),

Number (%) of patients who discontinued from study (based on completion of the ‘End of 
Post Treatment Phase Disposition’ page with discontinuation date and reason entered),

Primary reasons for study evaluation completion (based on discontinuation reason entered 
in the ‘End of Post Treatment Phase Disposition’ page).
2.3.2
Demographic and other baseline characteristics
Demographic and background data including age, sex, child bearing potential, race, ethnicity, 
country, region, height, and baseline weight, ECOG performance status, Child-Pugh 
classification will be listed and summarized by treatment and study arm. Region (Asian, non-
Asian) and age categories (18- <65 years, 65- < 85 years, and ≥ 85 years) will be summarized.


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Additionally, information on prognostic factors as portal vein invasion and evidence of 
Hepatitis B and C on the patients will be presented.
2.3.3
Medical History
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.
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be listed. 
2.3.4
Prior antineoplastic therapy
All prior anti-neoplastic therapy will be listed for medication, radiotherapy, surgery and local 
HCC therapies.
The number (%) of patients who received, separately, any prior anti-neoplastic medication, 
radiotherapy or surgery will be summarized.
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), therapy type at last medication, 
setting at last medication, time (in days) between end of last medication to start of study 
treatment, best response at last medication (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), reason for discontinuation at last medication and time (in months) 
from start of last medication to progression. The last medication is defined based on the last end 
date of all prior regimen components. Prior antineoplastic medications will also be summarized 
by Anatomical Therapeutic Chemical (ATC) class, and preferred term.
The summary of prior anti-neoplastic radiotherapy will include the radiotherapy locations, 
(including all locations recorded for each patient) and the setting at last radiotherapy.
The summary of prior anti-neoplastic surgery will include the time (in months) between the last 
surgery (non-biopsy procedure) to start of study treatment, procedure at last surgery and residual 
disease at last surgery.
2.3.5
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, histological grade, stage at initial diagnosis
(only in the listing), stage at time of study entry, time (in months) from initial diagnosis for
primary site to start of study treatment, time (in months) since most recent recurrence/relapse 
or progression to start of study treatment, time (in months) from initial diagnosis of primary site 
to first recurrence/relapse or progression, current stage of cancer, current extent of disease 
(metastatic sites), types of lesions (target and non-target lesions) at baseline, and disease burden 
at baseline for target lesion.
Note: Presence/absence of target and non-target lesions will be based on the data collected on 
RECIST target/non-target lesion assessment eCRF pages. Metastatic sites will be based on 
diagnosis page.


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2.3.6
Other
All data collected at baseline, including prognostic factors for HCC and Child-pugh 
Classification Score, will be listed.
2.4
Protocol deviations
The FAS will be used for the protocol deviation summary tables and listings. The number (%) 
of patients with any CSR-reportable protocol deviation will be tabulated by the deviation 
category (entry criteria not satisfied; wrong treatment or incorrect dose; developed withdrawal 
criteria, but not withdrawn; took an excluded concomitant medication; others). The full list of 
protocol deviations are documented in the Study Specification Document (SSD).
COVID-19 specific protocol deviations will be listed. Details about COVID-19 impact are 
provided in Section 4.1
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.5.1
Study treatment
The safety set will be used for all summaries and listings of study treatment. 
2.5.1.1
Data handling
Imputation rules regarding last and first treatment administration of study drug can be found in 
Appendix, Section 5.1.1.
2.5.1.2
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control, and any combination partner, if applicable:
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment) + 1.
The last date of exposure to study treatment is the latest of the last dates of exposure to 
investigational drug (see Table 2-3). 
Table 2-3
Definition of last date of exposure of study drug
Study drug
Definition of last date of exposure of study drug 
PDR001  
The planned end date of the last cycle in which the last non-zero dose of 
PDR001 was last administered, i.e. the date of PDR001 infusion in the last 
cycle + 20 days
Note:  If the patient died or was lost to follow-up before the derived last date
of exposure, the last date of exposure to PDR001 for this patient is the date 
of death or the date of last contact (see Section 2.1.1), respectively. 
If the derived last date of exposure goes beyond the data cutoff date, it should 
be truncated to the date of data cutoff.


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INC280
Date of last administration of a non-zero dose of INC280.
2.5.1.3
Summary of duration of exposure of investigational drug will include 
categorical summaries (based on clinically meaningful time intervals) 
and continuous summaries (i.e. mean, standard deviation, etc.) using 
appropriate units of time.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 investigational 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 subject is on the study treatment as documented in the Dose Administration eCRF.
For patients who did not take any drug, the actual cumulative dose is by definition equal to zero
for that drug.
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.
2.5.1.4
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).
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 (mg).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg/day)  / PDI (mg/day).
The duration of exposure of the PDR001 considered for the derivation of the DI and the 
RDI will be derived from the start date of study treatment (first dosing date) to the last date of 
exposure to study treatment (see 2.5.1.2), irrespective of date of death, date of last contact and 
cut-off date.
DI and RDI (including categories: < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1) 
will be summarized separately for each of the study treatment components, using the duration 
of exposure of each of the components.
2.5.1.5
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 changed’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration eCRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively. Dose reductions will be derived 
programmatically using the dosing information as described below.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption.
Intermediate interruptions that end up in a non-zero dose administration should not be 
considered dose interruptions.
Dose reduction: A dose change where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered/total daily dose is lower than the 
calculated dose amount based on the prescribed dose. Therefore, any dose change to correct a 
dosing error will not be considered a dose reduction.  Only dose change is collected in the eCRF, 
number of reductions will be derived programmatically  based on the change and the  direction 
of the change.
2.5.2
Prior, concomitant and post therapies
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and
blood transfusions) administered in the study and are recorded in the Concomitant
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system.
Any concomitant therapies starting prior to or after the start of study treatment will be listed.
Imputation rules regarding last and first treatment administration of concomitant therapies can 
be found in Appendix, Section 5.1.3.
2.5.3
Compliance 
Compliance to the study drug is presented by the number of dose reductions, dose interruptions
and the percentage of patients who took a predefined percentage (RDI categories: <0.5, 0.5-
<0.75, 0.75- <0.9, 0.9-<1.1, ≥1.1) of the number of prescribed doses of study treatment. Details 
are provided in Section 2.5.1.
2.6
Analysis of the primary objective
Phase Ib part


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The primary objective of Phase Ib part is to characterize the safety and tolerability of INC280 
in combination with PDR001 and identify the MTD and/or RP2D.
Phase II part
The primary objective of Phase II part is to compare the efficacy of INC280 in combination 
with PDR001 and PDR001 single agent.
2.6.1
Definition of the primary endpoint
2.6.1.1
Phase Ib part
Safety: Incidence of dose limiting toxicities (DLTs) in the first two cycles of treatment. 
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs 
and ECGs.
Tolerability: dose interruptions, reductions and dose intensity.
2.6.1.2
Phase II part
Overall response rate (ORR): is defined as the proportion of patients with a best overall 
response of CR or PR as per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
2.6.2
Statistical hypothesis, model, and method of analysis
2.6.2.1
Phase Ib part
Safety and tolerability
See Section 2.9 for details in safety analysis.
Identification of a recommended dose
Estimation of the MTD of the treatment will be based upon the estimation of the probability of 
DLTs in cycles 1 and 2 for patients in the dose determining set (DDS). 
A recommended dose below the MTD may be identified based on other safety, clinical, PK, 
and PD data.
Bayesian adaptive approach
The dose escalation will be guided by a Bayesian analysis of DLT data in cycles 1 and 2 for 
INC280 and PDR001. The Bayesian analysis will be based on a model with three parts, 
representing:

Single agent INC280 toxicity

Single agent PDR001 toxicity

Interaction 
Single agent toxicity is modelled using logistic regression for the probability of a patient 
experiencing a DLT against log-dose. The odds of a DLT are then calculated under no 
interaction for the two single agent toxicities, and interaction is accounted for by adjusting these 


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odds with an additional model parameter (odds multiplier). Details of the model are given in 
Appendix 3 of the protocol.
Assessment of patient risk
After each cohort of patients, the posterior distribution for the risk of DLT for new patients at 
combination doses of interest will be evaluated. The posterior distributions will be summarized 
to provide the posterior probability that the risk of DLT lies within the following intervals:
Under-dosing:
[0 , 0.16)
Targeted toxicity:
[0.16 , 0.33)
Excessive toxicity:
[0.33 , 1]
The escalation with overdose control (EWOC) principle
Dosing decisions are guided by the escalation with overdose control principal [Rogatko 2007].  
A combination dose may only be used for newly enrolled patients if the risk of excessive 
toxicity at that combination dose is less than 25%.
Prior distributions
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
single-agent INC280 and PDR001 model parameters. The MAP prior for the logistic model 
parameters for this study is the conditional distribution of the parameters given the historical 
data [Spiegelhalter et al 2004, Neuenschwander et al 2010, Neuenschwander et al 2014]. MAP 
priors are derived from hierarchical models, which take into account possible differences 
between the studies.
A full description of the application of the MAP approach to derive the prior distributions of 
the single agent INC280 and PDR001 model parameters is given in Appendix 3 of the protocol.  
The prior distribution for the interaction parameter was based upon prior understanding of 
possible drug safety interactions.  This prior allows for the possibility of either synergistic or 
antagonistic interaction, and is fully described in Appendix 3 of the protocol.
Starting dose
The starting dose is INC280 200 mg BID and PDR001 300 mg Q3W. For this dose the prior 
risk of excessive toxicity is 13.9 %, which satisfies the EWOC criterion.  A full assessment of 
the prior risk to patients is given in Appendix 3 of the protocol.
Incorporation of data from ongoing studies
The dose-DLT information generated from the safety patient cohort of INC280 in combination 
with PD-1 inhibitors in the ongoing study [CEGF816X2201], if available by the time of having 
dose escalation meetings in this study will be incorporated in the model. A direct down-
weighting approach will be used to account for between-trial heterogeneity. Details are
provided in Appendix 3 of the protocol.


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The following reports will be produced based on the DDS:

A heatmap  of posterior probabilities of DLT rate in the excessive toxicity interval will be 
presented in the body of the CSR;

Summary of the DLTs with onset during the evaluation period (dose escalation part only)  
by primary system organ class, preferred term:  recommendations at the time of  database 
lock will be included in the body of the CSR, for each DEM, summary of recommendations 
will be included in Appendix 16.1.9 of the CSR;

Listing of inferential results from the BLRM at the time of dabase lock, will be included in 
Appendix 16.1.9 of the CSR.
2.6.2.2
Phase II part
Estimation of the true ORR in this part of the study will be based upon the observed overall 
response for patients in FAS, using a Bayesian analysis.
Patients in each group are randomized in a 1:1 ratio into either PDR001+INC280 arm or 
PDR001 arm. The randomization is stratified by region: Asian vs. non-Asian. The primary 
efficacy endpoint ORR will be determined per RECIST v1.1 for the primary analysis.
For the primary analysis, a Bayesian logistic regression model with treatment (combination vs. 
single agent), region (Asian vs. non-Asian), and interaction of treatment and region as 
covariates will be applied to provide the inference of ORR. Full details of model 
parameterization and prior specification are provided in Appendix 3 of the protocol. The ORRs 
of the PDR001+INC280 and PDR001 arms will be compared. If the posterior probability that 
odds ratio (ORR PDR001+INC280 to ORR PDR001) > 1 is greater than 0.8, AND the observed ORR
PDR001+INC280 is at least 10% greater than the observed ORR PDR001, it will be concluded that the 
combination treatment has a superior anti-tumor effect compared to the PDR001 single agent 
treatment.  
The posterior mean of ORR adjusted for stratification factor along with 95% credible interval 
will be provided; the probabilities that the true ORR lies in the following efficacy categories 
will be reported:

[0, 20%) no anti-tumor activity

[20%, 100%] clinically relevant anti-tumor activity.
2.6.3
Handling of missing values/censoring/discontinuations
Patients in the dose escalation part who are ineligible for the DDS will be excluded from the 
BLRM analysis, although their data will be used for all remaining analyses.
Patients in the phase II part who have BOR of Unknown (UNK) or not assessed (NA) will be
considered as a treatment failure in the primary analysis of ORR. Patients with individual scans 
of UNK or NA will be handled according to RECIST v1.1 (see Appendix 1 of the protocol).
The tumor assessement data handling rules in Section 5.1.5 will be applied.
Other missing data will simply be noted as missing on appropriate tables/listings.


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2.6.3.1
Supportive analyses
For the phase II, the observed ORR and corresponding 95% exact confidence interval according 
to Clopper-Pearson method [Clopper and Pearson 1934] will be provided for each study arm
overall, and by stratum, if applicable.
The primary analyses on ORR may be repeated using the per-protocol set (PPS), unless FAS 
and PPS are identical.
2.7
Analysis of key secondary efficacy objective(s)
Not applicable.
2.8
Analysis of secondary efficacy objective(s)
Phase Ib/II parts
The secondary objectives of Phase Ib/II parts are:

to further characterize the efficacy of INC280 in combination with PDR001 and PDR001 
single agent

To characterize the pharmacokinetic profile of INC280 in combination with PDR001 and 
PDR001 single agent.

To assess the pharmacodynamic effect of INC280 in combination with PDR001 and 
PDR001 single agent in tumor biopsy.
Phase II part
The primary objective of Phase II part is to characterize the safety and tolerability of INC280 
in combination with PDR001 and PDR001 single agent.
2.8.1
Definition of secondary endpoints
2.8.1.1
Phase I/II parts
2.8.1.1.1 Efficacy of INC280 in combination with PDR001 and PDR001 single agent       
The BOR, TTP, PFS, DOR, TTR and OS will be analyzed using FAS to characterize the 
efficacy of PDR001+INC280 and PDR001 single agent in the phase Ib part and phase II part. 
Tumor response related endpoints will be analyzed based on the local Investigator assessments 
according to RECIST 1.1 and irRC, respectively.
Definitions of the relevant endpoints is given below:

Best Overall Response (BOR): is defined as the best response recorded from the start of 
the study treatment until disease progression/recurrence as defined for RECIST v1.1 and 
irRC. Complete and partial responses must be confirmed by repeat assessments that should 
be performed not less than 4 weeks after the criteria for response are first met. Additionally, 
for irRC, progressive disease should be confirmed in a similar manner.

Overall Response Rate (ORR): see Section 2.6.1.2. 

Time to progression (TTP): 


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
For RECIST v1.1, TTP is defined as the time from the date of randomization/start of 
treatment to the date of the first documented progression per RECIST v1.1 or death 
due to underlying cancer (“study indication” – see Section 5.1.4).

For irRC, TTP is defined as the time from the date of randomization/start of treatment 
to the date of the first documented and confirmed progression per irRC or death due to 
underlying cancer (“study indication” – see Section 5.1.4). 
Progressive disease should be confirmed by a repeat assessment that should be 
performed not less than 4 weeks after the criteria for progression are first met. The date 
of progression will then be the date of the first of these two assessments. 
For patients without a confirmation assessment, and with no subsequent assessments 
of SD, or better, a single assessment will be used as date of progression. 
If a patient has not experienced an  event at the time of the analysis or has started a new 
anticancer therapy, TTP will be censored at the date of the last adequate tumor 
evaluation before the start of a new anticancer therapy, if any.

Progression-free Survival (PFS):

For RECIST v1.1, PFS is defined as the time from the date of randomization/start of 
treatment to the date of the first documented progression per RECIST v1.1 or death due 
to any cause.

For irRC, PFS is defined as the time from the date of randomization/start of treatment 
to the date of the first documented and confirmed progression per irRC or death due to 
any cause. 
Progressive disease should be confirmed by a repeat assessment that should be 
performed not less than 4 weeks after the criteria for progression are first met. The date 
of progression will then be the date of the first of these two assessments. 
For patients without a confirmation assessment, and with no subsequent assessments 
of SD, or better, a single assessment will be used as date of progression. 
If a patient has not experienced an  event at the time of the analysis or has started a new 
anticancer therapy, PFS will be censored at the date of the last adequate tumor 
evaluation before the start of a new anticancer therapy, if any.

Duration of Response (DOR): is defined for responder as the time between the date of first 
documented response (CR or PR) and the date of first documented progression or death due 
to any cause. 
DOR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1).
For irRC, DOR is similarly defined for confirmed irCR or irPR patients.
If progression or death due to any cause has not occurred or patient has started a new 
anticancer therapy, then the patient is censored at the date of last adequate tumor assessment 
before the start of a new anticancer therapy, if any.

Time to Response (TTR): is defined as the time from the date of randomization/start of 
treatment to the date of first documented response (CR or PR, which must be confirmed 
subsequently) for patients who achieved a confirmed CR or PR. All patients in the FAS will 
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Patients who did not achieve a confirmed CR or PR will be censored at the maximum 
follow-up time for patients who had a PFS event (i.e. either progressed or died due to any 
cause), or at the date of last adequate tumor assessment before the start of a new anticancer 
therapy (if any) otherwise.
For irRC, TTR is similarly defined for confirmed irCR or irPR patients.

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, OS time will be censored at the date of last contact.
2.8.1.1.2 Pharmacokinetic profile of INC280 in combination with PDR001 and 
PDR001 single agent
See Section 2.10
2.8.1.1.3 Pharmacodynamic effect of INC280 in combination with PDR001 and 
DR001 single agent in tumor biopsy
See Section 2.14.
2.8.1.2
Phase II part
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, vital 
signs and ECGs.
Tolerability: dose interruptions, reductions and dose intensity
2.8.2
Statistical hypothesis, model, and method of analysis
Tumor response related endpoints will be analyzed based on the local Investigator assessments 
according to RECIST 1.1 and irRC, respectively.
Individual lesion measurements and overall response assessments will be listed by patient and
assessment date. BOR, TTP, PFS, DOR, TTR and OS will be listed by patient. The following 
summaries and analyses will be performed for the phase Ib by treatment group (if at least 10 
patients in a treatment group) and for the phase II part by study treatment where applicable:

BOR is the best response recorded from the start of the treatment until disease 
progression/recurrence. However, any assessments taken more than 30 days after the last 
dose of study therapy will not be included in the BOR derivation. Moreover, if any 
alternative cancer therapy is taken while on study, any subsequent assessments will be 
excluded from the BOR determination.
ORR and corresponding 95% confidence intervals (CIs) based on the exact binomial 
distribution will be presented. Tumor volume best change from baseline will be presented 
graphically.

For TTP, TTR, PFS and OS, a Kaplan-Meier plot will be presented. Median time-to-event 
values (in months) with corresponding 95% CI, 25th and 75th percentiles (Brookmeyer and 
Crowley 1982, Klein and Moeschberger 1997) and Kaplan-Meier estimated probabilities 
(time to event free rates) with corresponding 95% CIs (Greenwood’s formula, Kalbfleisch 
and Prentice 1980) at several time points (3, 6, 12, 18 and 24 months) will be presented. 


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The number (%) and type of events per endpoint and patients censored will also be 
summarized

DOR will be listed for all patients with a response. Summaries of DOR may be provided if 
a sufficient number of patients responded.
For PK see Section 2.10
For PD see Section 2.14.
For safety endpoints see section 2.9.
2.8.3
Handling of missing values/censoring/discontinuation
Patients who have BOR of Unknown (UNK) or not assessed (NA) will be considered as a 
treatment failure in the primary analysis of ORR. Patients with individual scans of UNK or NA 
will be handled according to RECIST v1.1 (see Appendix 1 of the protocol) and irRC (see 
Appendix 2 of the protocol). If any new anticancer therapy is taken while on study, any 
subsequent assessments will be excluded from the BOR determination.
For the analysis of TTP, patients without documented disease progression or death due to 
underlying cancer (“study indication” – see Section 5.1.4) will be censored at the time of last 
adequate tumor assessment documenting non-progression (one of CR, PR, SD) before the start 
of a new anticancer therapy, if any. Patients without any valid post-baseline tumor assessment 
response (one of CR, PR, SD, or PD) will be censored on the date of randomization/start date 
of treatment. Patients who have a PFS event (progression or death due to any cause) after two 
or more consecutive missing assessments from the last valid tumor assessment will be censored 
on the last valid tumor assessment (or on the start date of treatment among those without a 
postbaseline tumor assessment).
For the analysis of PFS, patients without documented disease progression or death due to any 
cause will be censored at the time of last adequate tumor assessment documenting non-
progression (one of CR, PR, SD) before the start of a new anticancer therapy, if any. Patients 
without any valid post-baseline tumor assessment response (one of CR, PR, SD, or PD) will be 
censored on the date of randomization/start date of treatment. Patients who have a PFS event 
(progression or death due to any cause) after two or more consecutive missing assessments from 
the last valid tumor assessment will be censored on the last valid tumor assessment (or on the 
start date of treatment among those without a postbaseline tumor assessment).
For the analysis of DOR, patient without documented disease progression or death due to any 
cause will be censored at the date of last adequate tumor assessment documenting non-
progression (one of CR, PR, SD) before the start of a new anticancer therapy, if any.
DOR apply only to patients with a BOR of confirmed CR or PR (RECIST v1.1) or of confirmed 
irCR or irPR (irRC). 
For the analysis of TTR, patients without confirmed CR or PR will be censored at the maximum 
follow-up time for patients who had a PFS event (i.e. either progressed or died due to any cause), 
or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if 
any) otherwise. All patients in the FAS will be included in TTR calculations.


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For the analysis of OS, patient without an event (death) will be censored at the date of last 
contact.
Other missing data will simply be noted as missing on appropriate tables/listing.
2.9
Safety analyses
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE) grading limits or normal ranges as appropriate). 
Other safety data include electrocardiogram and vital signs. 
The Safety set will be used for summaries and listings of safety data with the exception of dose 
limiting toxicities (DLTs) for which the DDS will be used.
For all safety reporting the overall observation period and safety summaries will follow the 
instructions mentioned in section 2.1.1Error! Reference source not found..
2.9.1
Adverse events (AEs)
2.9.1.1
Data handling
Adverse events will be coded using the latest available version of the MedDRA and assessed 
according to the CTCAE version 4.03. If CTCAE grading does not exist for an adverse event, 
the severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will 
be used. CTCAE Grade 5 (death) will not be used in this study (but is collected as a seriousness 
criterion); rather, information about deaths will be collected through a Death form.
2.9.1.2
Data analysis
Adverse Events Summaries
AE summaries will include all AEs occurring during the on-treatment period. All AEs collected 
in the AE eCRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A 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 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the investigational arm
The following AE summaries will be produced by treatment:


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
Overview of adverse events and deaths (number and % of patients who died, with any 
AE, any SAE, any dose reductions/interruptions, AE leading to discontinuation)

AEs by SOC and PT, summarized by relationship (all AEs and AEs related to study 
treatment);

Seriousness (SAEs and non-SAEs)

Leading to treatment discontinuation

Leading to dose interruption/adjustment 

Requiring additional therapy

Leading to fatal outcome

Dose limiting toxicities by  PT
The following listings will be produced:

All adverse events (safety set) 

Adverse events among patients who were not treated (all screened patients)
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed for the safety set, post treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened patients.
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on on-
treatment/treatment-emergent adverse events which are not serious adverse events with an 
incidence greater than 5% and on on-treatment/treatment-emergent SAEs and SAEs suspected 
to be related to study treatment will be provided by SOC and PT on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.9.2
Adverse events of special interest
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound PDR001 and INC280. These groupings are defined using 


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MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 
a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad. For each specified AESI, number and percentage of subjects with at least one 
event of the AESI occurring during on-treatment period will be summarized for each study drug 
separately:

All AESIs 

AESIs suspected to be study drug related

Serious AESIs

AESIs leading to study drug discontinuation

AESIs leading to dose adjustment or study drug interruption

AESIs leading to fatal outcome
All AESIs will be listed for each study drug separately. In addition, a listing of all grouping 
levels down to the MedDRA preferred terms used to define each AESI will be provided for 
each study drug.
2.9.3
Laboratory data
2.9.3.1
CTC grading for laboratory parameters
Laboratory data will be converted into SI units and classified (by Novartis statistical 
programming) into CTC grades according to CTCAE version 4.03. The calculation of 
laboratory CTC grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. The criteria to assign CTC grades are given in 
Novartis internal criteria for CTC 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 is not applicable. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labeled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
2.9.3.2
Imputation rules
See Section 5.3.


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2.9.3.3
Data analysis
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected prior to 
the end date of the on-treatment period (see section 2.1.1.6).
The following summaries will be produced separately for hematology, coagulation, urinary and 
biochemistry parameters (by laboratory parameter and treatment):

Worst post-baseline CTC grade (regardless of the baseline status). Each  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 listings will be produced for the laboratory data: 

Listing of all CTC grade 3 or 4 laboratory toxicities 
All scheduled/unscheduled assessments should be assigned to time windows. In case of multiple 
values per window, the one closest to the planned visit date should be used. If 2 values are 
equidistant to the planned visit date, the selection should be made by selecting the one assessed 
by central (if any) and otherwise - for multiple central assessments - the last value.
Refer to Section 7.2.2 of the protocol for all laboratory parameters that will be summarized.
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 events are defined as those s with concurrent occurrence of AST or ALT > 
3xULN and TBL > 2xULN and ALP < 2xULN in the same assessment sample during the on-


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treatment period. Further medical review has to be conducted to assess potential confounding 
factor such as, liver metastases, liver function at baseline etc.
Renal function parameters
Renal function parameters of interest are Creatinine, Urea or Blood Urea Nitrogen (BUN) and 
the macroscopic panel (dipstick) for Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific 
Gravity, White Blood Cells .
2.9.4
Other safety data
2.9.4.1
ECG and cardiac imaging data
As described in Section Error! Reference source not found., baseline is the last available and 
valid assessment performed or value measured on or before the date of first administration of 
study treatment. Especially for ECG, where study requires multiple replicates per timepoint, the 
average of all these available ECG measurements associated with the baseline assessment will 
be calculated. Scheduled study day 1 pre-dose ECGs will be considered to have been obtained 
prior to study drug administration if dosing time is missing.
Triplicate ECGs will be done at all timepoints. The average of all available measurements 
associated with the nominal time point will be used for the analyses. If a patient has more than 
one ECG assessment associated with a specific post-baseline pre-dose timepoint, the one before 
and closest to the planned timepoint should be used. Scheduled pre-dose ECGs will be
considered to have been obtained prior to study drug administration if dosing time is missing.
For the other timepoints, if a patient has more than one associated assessment, the one closest 
to the planned timepoint should be used; if two assessments are equidistant to the planned 
timepoint, the last assessment associated with the nominal time point will be used for the 
analyses.
A standard 12 lead ECG including PR, QRS, QT, QTcF, QTcB and HR intervals will be 
obtained locally and independently reviewed by a central laboratory. 
The number and percentage of patients with notable ECG values will be presented by treatment 
group. ECG values considered notably abnormal are defined in Table 2-4. 
Table 2-4
Criteria for notable ECG values
ECG parameter
Criteria for notable ECG values
QT, QTcF, QTcB (ms)
o New value of > 450 and ≤ 480 ms 
o New value of > 480 and ≤ 500 ms 
o New value of > 500 ms 
o Increase from baseline of > 30 ms to ≤ 60 ms 
o Increase from baseline of > 60 ms 
HR (bpm)
o
Increase from baseline >25% and to a value >100 bpm
o
Decrease from baseline >25% and to a value <50 bpm
PR (ms)
o
New PR >200 ms
o
Increase from baseline >25% and to a value >200 ms
QRS (ms)
o
New QRS >120 ms


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o
Increase from baseline >25% and to a value >120 ms
A listing of all ECG assessments will be produced by treatment arm and notable values will be 
flagged. In the listing, the assessments collected during the post-treatment period will be flagged.
2.9.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg). 
Vital signs collected during on-treatment will be summarized. The number and percentage of 
patients with notable vital sign values (high/low) will be presented by treatment group. Vital 
sign values considered notably abnormal are defined in Table 2-5.
Table 2-5
Clinically notable changes in vital signs
Clinically notable criteria
Vital sign (unit)
Notable high value
Notable low value
Weight (kg)
increase >= 10% from baseline
decrease  >= 10% from baseline
Systolic blood 
pressure (mmHg)
>=180 with increase from 
baseline of >=20
<=90 with decrease from 
baseline of >=20
Diastolic blood 
pressure (mmHg)
>=105 with increase from 
baseline of >=15
<=50 with decrease from 
baseline of >=15
Pulse rate (bpm)
>=100 with increase from 
baseline of >25%
<=50 with decrease from 
baseline of > 25%
Body temperature
>= 39.1
-
A listing of all vital signs will be produced by treatment arm and notable values will be flagged. 
In the listing, the assessments collected during the post-treatment period will be flagged.
2.9.4.3
Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions by treatment group. Reasons for dose interruption and dose 
reductions will be listed by patient and treatment group and summarized by treatment group. 
Cumulative dose, dose intensity and relative dose intensity of study treatment (see Section 2.5) 
will be also be used to assess tolerability.
2.10
Pharmacokinetics analyses
All PK analyses will be performed for INC280, CMN288 and PDR001 based on the PAS.
PK parameters will be calculated using non-compartmental methods using Phoenix WinNonlin 
version 6.4 or later (Pharsight, Mountain View, CA). 
PK parameters shown in Table 2-6 will be summarized and reported for each analyte. AUClast, 
AUCtau, Cmax, and Tmax are the primary PK parameters. AUCtau will be AUC0-12h for 
INC280 and CMN288, and AUC0-504h for PDR001. Other parameters, including AUCinf 


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(Cycle 1 Day 1 only), T1/2, CL，Racc and Vz are considered secondary parameters for 
PDR001 only.
Table 2-6
Non-compartmental PK parameters
PK parameter
Description
AUClast
The area under the curve (AUC) from time zero to the last measurable analyte 
(INC280, CMN288 or PDR001) concentration sampling time (tlast) (mass x 
time x volume-1)
AUCtau1
The AUC calculated to the end of a dosing interval (tau) at steady-state (mass 
x time x volume-1)
AUCinf 2
The AUC from time zero to infinity (mass x time x volume-1)
Tmax
The time to reach maximum (peak) analyte concentration after study drug dose 
administration (time)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid 
analyte concentration after study drug administration (mass x volume-1)
T1/2 3
Elimination half-life
CL 3
The total body clearance of drug from the plasma (volume x time-1)
Racc3
Accumulation ratio calculated as AUCtau at Cycle 3/AUCtau at Cycle 1
Vz 3
The volume of distribution during the terminal elimination phase
1 AUCtau will be AUC0-12h for INC280 and CMN288, and AUC0-504h for PDR001.
2 AUCinf is for PDR001 at Cycle 1 Day 1 only
3 PDR001 only
2.10.1
Data handling principles
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.
At the time of analysis, concentration data from patient may be removed from the estimation of 
certain PK parameters depending on the number of available blood samples, concomitant 
medications, vomiting, etc. Specific time points 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
2.10.2
Data analysis set
All PK analyses and PK summary statistics will be based on the PAS. Only PK blood samples 
with date and time and for which the last prior dose dates and times are adequately recorded 
will be included in the PK analyses.Patient data may be removed on an individual basis.
2.10.3
Basic tables, figures and listing
All individual plasma drug concentration data will be listed by treatment group, visit, and 
timepoint.


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Descriptive statistics will be presented for all pharmacokinetic parameters, as described in Table 
2-7.
Table 2-7
Descriptive analysis
Parameters
Descriptive statistics
AUC(1) , Cmax, CL, Vz, Racc, T1/2
Mean standard deviation, CV% mean, geometric mean, 
CV% geo-mean, median, minimum, and maximum. 
Tmax
Median, minimum, and maximum.
(1) Includes all AUC parameters
CV% = coefficient of variation (%) = sd/mean*100
CV% geo-mean = sqrt (exp (variance for log transformed data)-1)*100
Zero concentrations will not be included in the geometric mean calculations. Tmax will be 
summarized in terms of median values and ranges. Missing concentrations or PK parameter 
values will not be imputed. A listing of derived PK parameters per patient will be produced by 
treatment group.
Analysis of drug concentrations 
Descriptive statistics for drug concentrations, including n, m (number of non-zero 
concentrations), arithmetic mean, CV% mean, SD, median, geometric mean, CV% geo-mean,
minimum and maximum, will be presented at each scheduled time point by treatment. Zero 
concentrations will not be included in the geometric mean calculation.
The mean (+/- SD) and geometric mean concentration-time profiles by treatment over time will 
be displayed graphically on the linear and semi-log view, for phase Ib only (Cycle 2 Day 1 for 
INC280 and CMN288, Cycle 1 Day 1 and Cycle 3 Day 1 for PDR001).
2.11
PD and PK/PD analyses
The objective is to assess the pharmacodynamic effect of INC280 in combination with PDR001
and PDR001 single agent in tumor biopsy.
The FAS will be used for all biomarker analysis. The expression of the pharmacodynamic 
markers, including CD8 (TIL) and PD-L1 (tumor cells),  will be assessed using paired tumor 
samples at screening/baseline and on-treatment. 
Assessments at screening/baseline and on-treatment and change from baseline of the biomarker 
levels will be listed by patient and summarized (when sample size is sufficient) by treatment 
group using descriptive statistics.


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2.13
Patient-reported outcomes
Not Applicable. 


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Table 2-8
List of biomarkers evaluated and the collection time points
Sample Type
Visit/ Time point
Volume
Marker*
Purpose
Tumor samples
Newly obtained 
tumor sample 
Screening
(recommended
to be collected
at least 2
weeks after the
last dose of
sorafenib)
6-9 weeks
after start of
study
treatment
At progression
of disease only
for patients
who had a
response as
per
investigator
assessment
(optional)
Newly obtained
formalin fixed
tumor sample in
ethanol (3-6
passes)
Expression by
IHC (e.g., CD8,
PD-L1, 
)
Pharmacodynamic (PD)
markers
Note: On days and time points when biomarker and pharmacokinetic blood samples are being collected, thePK 
sample must be drawn first.
2.14.5
Exploratory Data analyses
If deemed necessary, this part of analysis may be described in separate analysis plan 
documentation and displayed external to the main study CSR.


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2.16
Interim analysis
No formal interim analyses was planned.
3
Sample size calculation
3.1
Phase Ib part
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 
six patients at the MTD/RP2D level, as described in Section 6.2.3 of the protocol. Multiple 
cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients 
may be enrolled at any dose level below the estimated MTD/RP2D for further elaboration of
safety and pharmacokinetic parameters as required. At least 12 patients are expected to be in
the dose escalation part. If a recommended phase II dose is identified without determination of 
the MTD, fewer than 12 patients may be required.
3.2
Phase II part
Sample size is considered for assessment of ORR. A priori the true mean of ORR is assumed 
to be 20% in both cMET high and cMET low patient groups treated with PDR001 single agent. 
It is assumed that the combination with INC280 will improve the mean of ORR to 40%. A 
minimally informative unimodal [Neuenschwander et al 2008] beta prior distribution with mean 
as assumed is then specified as following:

PDR001+INC280: ORR PDR001+INC280 ~ Beta(0.67,1)

PDR001: ORR PDR001 ~ Beta(0.25,1)
The ORR of the PDR001 in combination with INC280 treatment will be compared to that of 
the PDR001 single agent treatment. A Bayesian logistic regression model will be used to 
perform this comparison.  The full model will include a covariate for treatment effect, and will 
also explore region effects, and treatment/region interaction.  Here, operating characteristics are 
described under the assumption that there is no region effect, and a simplified logistic regression 
model including only treatment as a covariate is used to provide inference.
Given 30 patients in each treatment, and under the assumption of 20% ORR for PDR001 single 
agent, the probabilities of success under different assumed scenarios of true ORRs for the 
combination are presented in Table 3-1.

For true ORRs for combination and single agent treatment, of 40% and 20%, respectively, 
the probability to declare superior anti-tumor effect of the combination treatment is 78.5%.

If the true ORRs of combination and single agent treatment in patients are both 20%, the 
probability to incorrectly declare superior anti-tumor effect of the combination treatment is 
14.1%.


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Table 3-1Operating characteristics for ORRPDR001+INC280 vs. ORRPDR001 comparison
True ORRPDR001
True ORRPDR001+INC280
Probability of success
(success when Posterior P(Odds(ORR
PDR001+INC280)/Odds(ORR PDR001)>1)>0.80)) & (Observed ORR
PDR001+INC280 – observed ORR PDR001) > 10%)
20%
10%
0.008
20%
0.141
30%
0.433
40%
0.785
50%
0.955
4
Change to protocol specified analyses
In the analysis of vital signs, “shift table baseline to worst on-treatment result” specified in (see 
Section 10.5.3.4 of the protocol) will not be produced. Instead, “number (%) of patients having 
on treatment notable vital sign values” will be provided (see Section 2.9.4.2).Definition of the 
per-protocol analysis set was updated, as this was considered more relevant by the study team.
 
BOR will be summarized using the 95% exact confidence interval and not the 90% described 
in the protocol. Given that 95% confidence intervals will presented in the entire CSR, the 
selection of a 90% only in this case has no reasoning.
Definitions of DOR and TTR were updated in order to be alligned with other relevant studies 
of the same compound. 
Various minor changes were applied in the analysis described in the protocol, as considered 
appropriate by the study team.
All changes were defined in the statistical analysis plan before the data base lock.
4.1
Planned analysis due to COVID-19
The COVID-19 pandemic had minimal impact on this study because at the start of the pandemic, 
the vast majority of subjects had discontinued the study treatment and completed the safety 
follow-up phase. COVID-19 specific protocol deviations will be listed.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:


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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 is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the dose end
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available:
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.
5.1.2
AE date imputaition
A missing AE start date will be imputed using the following logic matrix described in Error! 
Reference source not found..
Table 5-1
Imputation rules for a partially missing AE start date
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
No imputation
No imputation
No imputation
No 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 Error! Reference source not found. 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
01MONYYYY
(B)
Uncertain
TRTSTD+1
(C)
Before treatment start
15MONYYYY
(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.
5.1.3
Concomitant medication date imputation
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 5.1.2). No imputation will be performed for concomitant 
medication end dates.
5.1.3.1
Prior therapies date imputation
Start date
The same rule which is applied to the imputation of AE/concomitant medication start date (see 
Section Error! Reference source not found.) will be used, with the exception that TRTSTD-
1 will be used instead of TRTSTD+1.
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
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.


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End date
No imputation.
5.1.4
Deaths
Due to the fact that the reason of death is inserted as a free text into the database, a wider 
categorization should be applied in order to be able to distinguish the cases where a death is 
considered an event for the endpoints TTP and DOR (namely deaths due to study indication). 
For this wider categorization, the preferred term of the primary reason of death will be used.
The two basic categories will be the following ones:

“Study indication”: for all cases where death is due to underlying cancer. This category 
will include the cases with following preferred terms: 
-
Disease progression
-
Hepatocellular carcinoma

“Other”: for all other cases where death is not due to underlying cancer.
Regarding incomplete death dates, the following imputation rules will be used:  

When only the day of death is missing, then 
death date=max [(01-MMM-YYYY), min (last contact date + 1, cut-off date)]. 

When day and month of death is missing, then 
death date=max[(01-JAN-YYYY, min (last contact date + 1, cut-off date)].
The imputed dates will not appear in the listings


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5.1.5
Other imputations
For date of diagnosis and date of previous progression, when recorded as a partial date, the 
missing day is imputed to the 1st of the month (e.g., DEC2007 imputed to 01DEC2007), and if 
the day and month are both missing then to 1st of January of that year (e.g., 2007 imputed to 
01JAN2007). Such imputed data will not appear in the listings.
For date of 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, and if the overall response at that assessment is 
CR/PR/SD/UNK, 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). 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 previous and following 
assessment are not available, this assessment will not be used for any calculation.
In case there is an entry with a date completely missing (e.g. in tumor assessments, in prior 
therapies, in post-treatment therapies, etc.), no imputation will be performed and the entry will 
be ignored.
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). Grade 5 (death) will not be used 
in this study.
5.3
Laboratory parameters derivations
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. 


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The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.
5.4
Statistical models
5.4.1
Primary analysis
Not Applicable.
5.4.2
Key secondary analysis
Not Applicable.
5.5
Rule of exclusion criteria of analysis sets 
See section 2.2.2.
5.6
Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100(1 − α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ 
with EXACT statement for one-way table [Clopper and Pearson 1934].
5.7
Waterfall graphs
Waterfall graphs will be used to depict anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of target lesions for each patient. 
Note: Patients without any valid assessments to calculate a percentage change from baseline 
value will be excluded from the graphs. Assessments with an unknown overall response will be 
included as long as the sum of diameters of target lesions is correctly computed on the same 
lesions assessed at baseline.
Patients will be ordered in the graph from left (worst change) to right (best change).
1. Bars above the horizontal axis (0%) representing tumor growth,


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2. Bars under the horizontal axis (0%) representing tumor shrinkage.
A special symbol (e.g. ∗) will be added below the bottom of respective bars for confirmed 
RECIST response (CR or PR), with corresponding specificatons in footnote. The total number 
of patients displayed in the graph (n) over the total number of patients in the FAS (N) will be 
shown. The BOR will be shown above each of the displayed bars in the graph. Symbols will be 
used to differentiate groups of interest, i.e. treatment group. A horizontal threshold line at -30% 
will be shown.
5.8
Kaplan-Meier estimates
An estimate of the survival function in each patient group will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG.
Median survival for each treatment group will be obtained along with 90% confidence intervals
calculated from PROC LIFETEST output using the method of [Brookmeyer and Crowley1982]. 
Kaplan-Meier estimates of the survival function with 90% confidence intervals at specific 
time points will be summarized. The standard error of the Kaplan-Meier estimate will be 
calculated using Greenwood’s formula [Collett 1994].
6
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