Clinical trial NCT01737827
Conditions: Advanced Hepatocellular Carcinoma With c-MET Dysregulation
Keywords: INC280 capmatinib advanced hepatocellular carcinoma c-MET pathway dysregulation
Sponsor: Novartis Pharmaceuticals
Start date: 2013-03-25; Completion date: 2023-05-24
Enrollment: 38 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is to find out if INC280 is safe and has beneficial effects in patients with advanced hepatocellular carcinoma known to have dysregulation of c-MET pathway.

Detailed description:
This study was designed as a Phase II, single arm, open-label, multicenter study to evaluate the safety and efficacy of INC280 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC) who were not eligible for or had disease progression after surgical or locoregional therapies, with c-MET dysregulation.

The study included a Dose-Determining Part and a Dose Expansion Part. Pharmacokinetic and safety profiles of INC280 in the setting of liver dysfunction were determined in the Dose-Determining Part. The Dose Expansion Part started when the appropriate dose for patients with liver dysfunction was determined based on pharmacokinetics (PK) and safety data from the Dose-Determining Part and other INC280 clinical studies. The initial dose of INC280 assessed during the dose expansion part was 600 mg twice daily (BID) administered as capsules of 50 mg. Later during the dose expansion part, a tablet with higher dosage strengths (50 mg, 150 mg, and 200 mg) was developed and introduced to improve the convenience of study drug administration for patients. PK data on INC280 tablet at 400 mg BID from other studies (NCT01324479, NCT01546428 and NCT01610336) showed that systemic exposure to INC280 was in the range of that achieved with the capsule at 600 mg BID.

During the Dose Expansion part of the study, Novartis halted the enrollment in Dec-2016 due to difficulty in identifying patients who met the definition of c-MET high as defined in the inclusion criteria. Patients who were already enrolled and signed the informed consent were allowed to continue in the study according to the protocol. The enrollment halt was not a consequence of any safety concerns.

Arms: arm 1: The protocol consisted of two independent parts (Dose-Determining Part and Dose Expansion Part). Patients were treated with INC280 300 mg twice a day in the Dose-Determining Part. The dose for the Expansion Part could be lower, equal or higher than in the Dose-Determining Part and was determined after the Dose Determining Part at the dose decision analysis.
Interventions: intervention 1: INC280
Intervention descriptions: intervention 1: INC280 was administered orally on a continuous twice a day (BID) dosing schedule, from Day 1 until Day 21 of each 21-day cycle. INC280 was initially supplied as hard gelatin capsules and subsequently also as film-coated tablets.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
INC280
Protocol CINC280X2201 / NCT01737827
A Phase II, open label, single arm, multicenter study of 
INC280 administered orally in adult patients with advanced 
hepatocellular carcinoma
Document type
Amended Protocol Version
EUDRACT number
2012-003758-10
Version number
v06 (Clean)
Development phase
II
Document status
Final
Release date
16-May-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 15-Feb-2012


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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................6
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................11
Protocol summary:.............................................................................................................12
Amendment 6 (16-May-2022)...........................................................................................14
Amendment 5 (04-Aug-2017)...........................................................................................17
Amendment 4 (31-Mar-2016) ...........................................................................................19
Amendment 3 ....................................................................................................................20
Amendment 2 ....................................................................................................................23
Amendment 1 ....................................................................................................................26
1
Background........................................................................................................................28
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............28
1.2
Introduction to investigational treatment...............................................................29
1.2.1
Overview of INC280.............................................................................29
2
Rationale............................................................................................................................34
2.1
Study rationale and purpose...................................................................................34
2.2
Rationale for the study design ...............................................................................34
2.3
Rationale for dose and regimen selection..............................................................35
3
Objectives and endpoints...................................................................................................36
4
Study design ......................................................................................................................38
4.1
Description of study design ...................................................................................38
4.2
Timing of dose decision analyses and design adaptations.....................................40
4.3
Definition of end of the study................................................................................40
4.4
Early study termination..........................................................................................40
4.5
Rationale for public health emergency mitigation procedures..............................41
5
Population..........................................................................................................................41
5.1
Patient population..................................................................................................41
5.2
Inclusion criteria ....................................................................................................41
5.3
Exclusion criteria...................................................................................................42
6
Treatment...........................................................................................................................45
6.1
Study treatment......................................................................................................45
6.1.1
Dosing regimen.....................................................................................45


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6.1.2
Treatment duration................................................................................46
6.2
Dose modifications guidelines...............................................................................46
6.2.1
Starting dose rationale...........................................................................46
6.2.2
Implementation of dose decision analysis.............................................46
6.2.3
Adverse events criteria for dose decision analysis................................47
6.2.4
Dose determining for tablet formulation...............................................48
6.2.5
Dose modification and delay.................................................................48
6.2.6
Follow-up for toxicities.........................................................................57
6.2.7
Anticipated risks and safety concerns of the study drug.......................59
6.3
Concomitant medications ......................................................................................59
6.3.1
Permitted concomitant therapy .............................................................59
6.3.2
Permitted concomitant therapy requiring caution and/or action...........59
6.3.3
Prohibited concomitant therapy ............................................................60
6.4
Patient numbering, treatment assignment or randomization .................................61
6.4.1
Patient numbering .................................................................................61
6.4.2
Treatment assignment ...........................................................................61
6.4.3
Treatment blinding................................................................................61
6.5
Study drug preparation and dispensation...............................................................61
6.5.1
Study drug packaging and labeling.......................................................61
6.5.2
Drug supply and storage........................................................................61
6.5.3
Study drug compliance and accountability ...........................................62
6.5.4
Disposal and destruction .......................................................................62
7
Visit schedule and assessments .........................................................................................62
7.1
Study flow and visit schedule................................................................................62
7.1.1
Molecular pre-screening........................................................................67
7.1.2
Screening...............................................................................................68
7.1.3
Treatment period...................................................................................69
7.1.4
End of treatment visit including study completion and premature 
withdrawal.............................................................................................69
7.1.5
Follow up period ...................................................................................70
7.2
Assessment types...................................................................................................71
7.2.1
Efficacy assessments.............................................................................71
7.2.2
Safety and tolerability assessments.......................................................73
7.2.3
Pharmacokinetics ..................................................................................78
82
8
Safety monitoring and reporting........................................................................................83


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8.1
Adverse events.......................................................................................................83
8.1.1
Definitions and reporting ......................................................................83
8.1.2
Laboratory test abnormalities................................................................85
8.2
Serious adverse events...........................................................................................85
8.2.1
Definitions.............................................................................................85
8.2.2
Reporting...............................................................................................86
8.3
Pregnancies............................................................................................................87
8.4
Warnings and precautions......................................................................................87
9
Data collection and management.......................................................................................88
9.1
Data confidentiality ...............................................................................................88
9.2
Site monitoring ......................................................................................................88
9.3
Data collection.......................................................................................................89
9.4
Database management and quality control............................................................89
10 Statistical methods and data analysis ................................................................................89
10.1
Analysis sets ..........................................................................................................90
10.1.1
Full Analysis Set ...................................................................................90
10.1.2
Safety Set ..............................................................................................90
10.1.3
Per-Protocol Set ....................................................................................90
10.1.4
Dose-determining analysis set...............................................................91
10.1.5
Pharmacokinetic analysis set.................................................................91
10.2
Patient demographics/other baseline characteristics .............................................91
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................91
10.3.1
Study treatment .....................................................................................91
10.3.2
Concomitant therapies...........................................................................92
10.3.3
Compliance ...........................................................................................92
10.4
Primary objective...................................................................................................92
10.4.1
Variable.................................................................................................92
10.4.2
Statistical hypothesis, model, and method of analysis..........................92
10.4.3
Handling of missing values/censoring/discontinuations.......................92
10.4.4
Supportive analyses...............................................................................93
10.5
Secondary objectives .............................................................................................93
10.5.1
Efficacy objective(s) .............................................................................93
10.5.2
Other secondary objectives ...................................................................93
10.5.3
Safety objectives ...................................................................................94
10.5.4
Pharmacokinetics ..................................................................................96
98


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10.7
Interim analysis......................................................................................................98
10.8
Sample size calculation..........................................................................................98
10.9
Power for analysis of key secondary variables....................................................100
11 Ethical considerations and administrative procedures ....................................................100
11.1
Regulatory and ethical compliance......................................................................100
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................100
11.3
Informed consent procedures...............................................................................100
11.4
Discontinuation of the study................................................................................101
11.5
Publication of study protocol and results.............................................................101
11.6
Study documentation, record keeping and retention of documents.....................101
11.7
Confidentiality of study documents and patient records .....................................102
11.8
Audits and inspections.........................................................................................102
11.9
Financial disclosures............................................................................................102
12 Protocol adherence ..........................................................................................................102
12.1
Amendments to the protocol................................................................................102
13 References (available upon request)................................................................................104
14 Appendices ......................................................................................................................107
14.1
Appendix 1: RECIST 1.1.....................................................................................107
14.1.1
Introduction.........................................................................................108
14.1.2
Efficacy assessments...........................................................................108
14.1.3
Definitions...........................................................................................108
14.1.4
Methods of tumor measurement - general guidelines.........................109
14.1.5
Baseline documentation of target and non-target lesions ...................111
14.1.6
Follow-up evaluation of target and non-target lesions........................111
14.1.7
Follow-up & recording of lesions .......................................................111
14.1.8
Determination of target lesion response..............................................113
14.1.9
Determination of non-target lesion response ......................................115
14.1.10
New lesions .........................................................................................116
14.1.11
Evaluation of overall lesion response .................................................116
14.1.12
Efficacy definitions .............................................................................117
14.1.13
Best overall response...........................................................................117
14.1.14
Time to event variables .......................................................................119
14.1.15
Progression-free survival ....................................................................119
14.1.16
Overall survival...................................................................................119
14.1.17
Time to progression.............................................................................119
14.1.18
Time to treatment failure.....................................................................119


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14.1.19
Duration of response ...........................................................................119
14.1.20
Time to response .................................................................................120
14.1.21
Definition of start and end dates for time to event variables ..............120
14.1.22
Handling of patients with non-measurable disease only at baseline...122
14.1.23
Sensitivity analyses .............................................................................123
14.1.24
Data handling and programming rules................................................125
14.1.25
Study/project specific decisions..........................................................125
14.1.26
Treatment and study completion CRFs...............................................125
14.1.27
Study evaluation completion...............................................................126
14.1.28
Medical validation of programmed overall lesion response ...............127
14.1.29
Programming rules..............................................................................127
14.1.30
Calculation of ‘time to event’ variables..............................................127
14.1.31
Incomplete assessment dates...............................................................128
14.1.32
Incomplete dates for last contact or death...........................................128
14.1.33
Non-target lesion response..................................................................128
14.1.34
Study/project specific programming...................................................128
14.1.35
Censoring reason.................................................................................128
14.1.36
References (available upon request) ...................................................129
14.2
Appendix 2: Child-Pugh classification of severity of liver disease.....................130
14.3
Appendix 3: Hepatocellular carcinoma staging systems.....................................131
14.4
Appendix 4: Tables of drugs prohibited and drugs used with caution ................132
14.5
Appendix 5: The Bayesian logistic regression model and dose 
recommendations in hypothetical scenarios........................................................134
14.6
Appendix 6: Cockcroft-Gault formula for GFR estimate....................................141
List of appendices
Appendix 1: Response Evaluation Criteria in Solid Tumors (RECIST 1.1).
Appendix 2: Child-Pugh Classification of severity of liver disease.
Appendix 3: Hepatocellular carcinoma staging systems.
Appendix 4: Guidance on concomitant medications with CYP3A4/5 interactions and gastric 
acid pH modulators interactions.
Appendix 5: The Bayesian logistic regression model and dose recommendations in 
hypothetical scenarios.
Appendix 6: Cockcroft-Gault formula for GFR estimate


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List of figures
Figure 1-1
Signaling and biological functions of the HGF/c-MET pathway .........29
Figure 4-1
Study design..........................................................................................38
Figure 14-1
Probability of qualifying AE according to the weakly informative 
prior distribution in Table 14-11.........................................................135
Figure 14-2
Probability of DLT according to the predictive prior distribution in 
Table 14-15 .........................................................................................138
List of tables
Table 3-1
Objectives and related endpoints ..........................................................37
Table 6-1
Rules for dose recommendation for the Dose Expansion Part..............47
Table 6-2
Criteria for qualifying AEs to be considered for the dose decision 
analysis..................................................................................................47
Table 6-3
Dose-Determining Part study drug dose reductions..............................49
Table 6-4
Dose Expansion Part study drug dose reductions .................................49
Table 6-5
Recommended dosing guidelines for study drug-related toxicities......50
Table 6-6
Follow-up evaluations for selected toxicities........................................55
Table 6-7
Guidelines for the management of hepatitis B reactivation..................56
Table 6-8
Guidelines for the management of hepatitis C reactivation..................56
Table 6-9
Follow-up evaluations for Hepatic Toxicities*.....................................57
Table 7-1
Visit evaluation schedule ......................................................................64
Table 7-2
Visit evaluation schedule (applicable upon local IRB/EC approval 
of protocol amendment 5).....................................................................67
Table 7-3
ECOG Performance status ....................................................................75
Table 7-4
Local clinical laboratory parameters collection plan ............................75
Table 7-5
Timepoints of blood collection for PK assessment during Dose-
Determining Part ...................................................................................80
Table 7-6
Timepoints of blood collection for INC280 PK assessment during 
Dose Expansion Part .............................................................................81
Table 10-1
Noncompartmental pharmacokinetic parameters..................................96
Table 10-2
Design operating characteristics when the number of patients is 25, 
30, 35 and 40, respectively....................................................................99
Table 14-1
Response criteria for target lesions .....................................................113
Table 14-2
Response criteria for non-target lesions..............................................115
Table 14-3
Overall lesion response at each assessment ........................................116
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................123
Table 14-5
Options for event dates used in PFS, TTP, duration of response........123
Table 14-6
Child-Pugh score calculation ..............................................................130


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Table 14-7
Child-Pugh score interpretation ..........................................................130
Table 14-8
Barcelona-Clinic Liver Cancer system ...............................................131
Table 14-9
Prohibited concomitant medications...................................................132
Table 14-10
Permitted concomitant medications requiring caution........................132
Table 14-11
Weakly-informative prior parameters for bivariate normal 
distribution of model parameters ........................................................134
Table 14-12
DLT information (cut-off date 15AUG 2012) from ongoing trial 
INCB28060-101 in patients with advanced malignancies used to 
derive informative prior ......................................................................136
Table 14-13
DLT information (cut-off date AUG2012) from ongoing trial 
INC280X1101 used to derive informative prior.................................136
Table 14-14
DLT information (cut-off date 15AUG 2012) from ongoing trial 
INC280X2102.....................................................................................136
Table 14-15
Posterior (based on data in Table 14-12, Table 14-13 and Table 14-
14) parameters for bivariate normal distribution of model 
parameters for ongoing/previous trials................................................137
Table 14-16
Predictive distribution of model parameters .......................................138
Table 14-17
Prior probabilities of under, targeted and over dosing (derived from 
mixture of priors in Table 14-12.........................................................139
Table 14-18
Possible scenarios in study CINC280X2201 in the Dose-
Determining cohort with 6 evaluable patients ....................................139


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List of abbreviations
AE
Adverse Event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the concentration-time Curve
BCLC
Barcelona-Clinic Liver Cancer
bid
bis in diem/twice a day
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
Cmax
Maximum concentration
CNS
Central Nervous System
CPC
Child-Pugh Classification
CR
Complete Response
CRF
Case Report/Record Form
CRO
Contract Research Organization
CSR
Clinical study report
CT
Computed Tomography
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variance
DCR
Disease Control Rate
DDI
Drug-Drug Interaction
DDS
Dose-Determining Set
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
CMO&PS
Chief Medical Office and Patient Safety
ECG
Electrocardiogram
EGFR
Epidermal growth factor receptor
EOT
End Of Treatment
EWOC
Escalation With Overdose Control
FAS
Full Analysis Set
FISH
Fluorescence in situ hybridization
FSH
Follicular Stimulating Hormone
GFR
Glomerular Filtration Rate
GI
Gastro-intestinal
Hb
Hemoglobin
HBV
Hepatitis B Virus
HCC
Hepatocellular Carcinoma
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C Virus
HGF
Hepatocyte Growth Factor
HIV
Human Immunodeficiency Virus
HV
Healthy volunteer
i.v.
intravenous(ly)


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ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
ILD                         
Immunohistochemistry
Interstitial Lung Disease
INR
International Normalized Ratio
IRB
Institutional Review Board
ITT
Intention-to-treat
LFT
Liver Function Test
LLOQ
Lower Limit Of Quantification
M&S
Modeling and Simulation
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NOAEL
No Observable Adverse Event Effect Level
NRU
Neutral Red Uptake
NSCLC
Non-Small Cell Lung Cancer
NTI
Narrow Therapeutic Index
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Progressive Disease
PET
Positron emission tomography
PFS
Progression Free Survival
PHI
Protected Health Information
PK
Pharmacokinetic(s)
PK/PD
Pharmacokinetic/Pharmacodynamic
PPS
Per Protocol Set
PR
Partial Response
PT
Prothrombin time
qd
once a day
Racc
Accumulation ratio
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
sCr
Serum Creatinine
SD
Stable Disease
Tmax
Time to reach maximum concentration
TTP
Time To Progression
ULN
Upper Limit of Normal
UNK
Unknown
vs
Versus
WBC
White Blood Cells
γGT
Gamma-glutamyl transferase


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q21 days)
Enrollment
Point/time of patient entry into the study; the point at which informed consent 
must be obtained (i.e. prior to starting any of the procedures described in the 
protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This also 
includes approved drugs used outside of their indication/approved dosage, or 
that are tested in a fixed combination. Investigational treatment generally does 
not include other study treatments administered as concomitant background 
therapy required or allowed by the protocol when used in within approved 
indication/dosage
Patient Number (Patient No.)
A unique identifying number assigned to each patient who enrolls in the study
Premature patient withdrawal
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival
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
Study treatment refers to the investigational treatment.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints


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Protocol summary:
Protocol number
CINC280X2201
Title
A phase II, open label, single arm, multicenter study of INC280 administered 
orally in adult patients with advanced hepatocellular carcinoma
Brief title
Study of efficacy and safety INC280 in patients with advanced hepatocellular 
carcinoma.
Sponsor and
Clinical Phase
Novartis
Phase 2
Investigation type
Drug
Study type
Interventional
Purpose and rationale
To find out if INC280 is safe and has beneficial effects in patients with advanced 
hepatocellular carcinoma known to have dysregulation of c-MET pathway.
Primary Objective(s) and
Objective: To estimate overall clinical activity of INC280 in advanced 
hepatocellular carcinoma patients with c-MET dysregulation as measured by 
time to progression.
Secondary Objectives
Objective 1: To further assess the clinical activity of INC280 in advanced 
hepatocellular carcinoma patients with c-MET dysregulation as measured by 
overall response rate, progression free survival, overall survival and disease 
control rate.
Objective 2: To assess the safety and tolerability of INC280 in advanced 
hepatocellular carcinoma patients.
Objective 3: To characterize the pharmacokinetics of INC280 in patients with 
advanced hepatocellular carcinoma.
Study design
Open label, single arm, with a Dose-Determining Part and a Dose Expansion 
Part.
Population
Approximately 56 male or female, at least 18 years old patients with histologically 
or cytologically confirmed advanced HCC with c-MET dysregulation who have 
received no prior systemic therapy. Only patients with Child-Pugh A are included.
Inclusion criteria
Confirmed c-MET pathway dysregulation as defined by: c-MET IHC intensity 
score 3+ in ≥50% tumor cells, or c-MET IHC intensity score 2+ in ≥50% of tumor 
cells and in addition MET gene copy number ≥5 by FISH. MET gene copy 
number ≥5 by FISH and unknown c-MET IHC results or c-MET mutation can be 
enrolled in the study following discussion and agreement with Novartis.
Advanced hepatocellular carcinoma which would not be suitable for treatment 
with locoregional therapies or has progressed following locoregional therapy.
Measurable disease as determined by RECIST version 1.1
Current cirrhotic status of Child-Pugh class A with no encephalopathy
ECOG performance status ≤2


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Exclusion criteria
Received any prior systemic chemotherapy or molecular-targeted therapy for 
hepatocellular carcinoma such as sorafenib
Previous treatment with c-MET inhibitor or hepatocyte growth factor targeting 
therapy
Previous local therapy completed less than 4 weeks prior to dosing and, if 
present, any acute toxicity > grade 1
Known active bleeding (e.g. bleeding from gastro-intestinal ulcers or esophageal 
varices) within 2 months prior to screening or with history or evidence of inherited 
bleeding diathesis or coagulopathy
Clinically significant venous or arterial thrombotic disease within past 6 months
History of acute or chronic pancreatitis, surgery of pancreas or any risk factors 
that may increase the risk of pancreatitis
Investigational and 
reference therapy
INC280 300 mg (capsule) twice a day for the Dose-Determining Part. The dose 
for the Dose Expansion Part will be determined after the Dose-Determining Part.
Efficacy assessments
Tumor response assessment as per RECIST v1.1.
Safety assessments
Physical examination
Vital signs
Weight
ECOG performance status
Clinical laboratory assessments (hematology, biochemistry, urinalysis, 
coagulation, hepatitis B and C markers and pregnancy assessments)
Cardiac monitoring (12-lead ECGs)
Incidence, frequency, and category of qualifying adverse events during the first 
28 days of INC280 treatment in the Dose-Determining Part
Frequency, duration and severity of adverse events
Other assessments
INC280 pharmacokinetics assessment in plasma samples
Data analysis
As the primary analysis, for patients treated at the Expansion Part dose, the 
distribution of time to progression will be estimated using the Kaplan-Meier 
method. The median time to progression and quantiles (along with 95% 
confidence intervals) will be presented. For patients in the Dose-Determining 
Part (who are not treated at the Expansion Part dose), time to progression will be 
listed.
In the Dose-Determining Part, for the safety analysis, a Bayesian Logistic 
Regression Model will be used to recommend the Expansion Part dose. For the 
PK analysis to recommend the Expansion Part dose, systemic clearance of 
INC280 in hepatocellular carcinoma patients from the Dose-Determining Part will 
be compared to patients with normal liver function and the 90% confidence 
interval for the mean ratio of clearance will be reported. A population 
pharmacokinetic model will be used for this pharmacokinetic analysis.
Key words
INC280, advanced hepatocellular carcinoma, c-MET pathway dysregulation


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Amendment 6 (16-May-2022)
Amendment rationale
This amendment has been made to include the following changes:

The definition of end of study has been revised 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 use an alternative 
way to provide study treatment to these patients.
 
 

In order to mitigate the risks of patient safety and data integrity due to public health 
emergency (e.g. COVID-19), language related to risk mitigation procedures has been 
added where applicable.

To align with the latest available safety information, the INC280 dose modification and 
study drug-related toxicity management guideline has been updated to include the 
recommended dose modification and management for ILD/pneumonitis. Additionally, 
the guidance for follow up evaluations of selected toxicities (renal, hepatic) has been 
updated.

To add the duration of the follow-up for pregnancy and newborn.

The list of permitted concomitant therapy requiring caution and/or action and the list of 
prohibited concomitant therapy has been updated according to latest available 
information and in line with other INC280 clinical protocols. 
Study status
As of April 2022, 38 patients have been treated with INC280. All of them have discontinued 
study treatment except for one patient in China who is still receiving treatment with INC280
300 mg BID tablet. The patient is in partial response and has been on treatment for 122 cycles.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
 
 
 
Section 4.3 Definition of end of study: addition of language to account for patients who would 
transfer into another study or an alternative way to continue provision of study treatment.
Section 4.5: new section “Rationale for Public Health Emergency mitigation procedures” added.


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Section 6.2.5 Table 6-5 Recommended dosing guidelines for study drug-related toxicities: 
added dosing modification and toxicity management guideline for ILD/pneumonitis.
Section 6.2.5 Table 6-6 Follow-up evaluations for selected toxicities: updated the CTCAE grade 
threshold for serum creatinine increase that requires weekly monitoring until improvement to ≤ 
CTCAE grade 1 or baseline.
Section 6.2.6 Table 6-9 Follow-up evaluations for hepatic toxicities: added monitoring guidance 
for combined elevations of ALT and/or AST and total bilirubin.
Section 6.3.2 Permitted concomitant therapy requiring caution and/or action: updated with 
addition of new classes of drugs.
Section 6.3.3 Prohibited concomitant therapy: drugs with known risk of TdP were removed and 
added clarification regarding the prohibited use of live vaccines during the study and up to 30 
days from the last dose of INC280.
Section 6.5.3.2 Study drug accountability: added clarification on return or destruction of unused 
study treatment, drug labels and packaging.
Section 7.1 Study flow and visit schedule: added a paragraph to allow that alternative methods 
of providing continuing care may be implemented by the Investigator during a Public Health 
emergency situation.
Section 7.1.3 Treatment period: added references to Definition of end of study and Criteria for 
premature patient withdrawal sections.
Section 7.1.4.1 Criteria for premature withdrawal: addition of language to specify that patients 
who transfer to another study or to use an alternative way to continue provision of study 
treatment will complete end of treatment procedures.
Section 7.1.5 Follow-up period: addition of language to specify that patients who transfer into 
another study or an alternative treatment option to continue provision of study treatment will 
not complete the safety, disease progression and survival follow-up.
Section 7.2.2 has been revised to include a reference to study visits during public health 
emergency.
Section 8.2.2 has been revised to indicate that SAE and follow-up should be reported to 
Novartis immediately, without delay and under no circumstances later than 24h after obtaining 
knowledge of the event/follow-up.
Section 8.3 Pregnancies: clarification added about duration of pregnancy and newborn follow-
up.
 
 
Section 14.4 Appendix 4 Tables of drugs prohibited and drugs used with caution: amended 
Table 14-9 with new class of drugs, made new Table 14-11.


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Other minor changes and corrections are made throughout the protocol for consistency and/or 
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.
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 5 (04-Aug-2017)
Amendment rationale
In order to alleviate the burden for patients, the primary purpose of this amendment is to reduce 
assessments, while maintaining access to study treatment and monitoring safety.
The enrollment of this study has been halted since 25-Dec-2016 due to difficulty in identifying 
patients who met the eligibility criteria of the study. An interim database lock for the primary 
data analysis was performed on 14-Mar-2017. Since then two patients are ongoing in China and 
both have been on treatment for over 30 cycles at dose level of 400 mg BID tablet. One of the 
patients has achieved complete response and the other partial response. As of the cut-off date 
for the primary CSR, one patient had reported episodes of grade 2 lipase increases which were 
suspected to be study treatment-related. No suspected treatment-related AEs≥ Grade 2 have
been reported in the second ongoing patient. 
An additional dose reduction level is added for the tablet formulation in this protocol 
amendment based on information from other INC280 studies, indicating that 200 mg BID tablet 
can achieve target inhibition in patients. 
INC280 150 mg tablets are also introduced in this protocol amendment to facilitate the dosing 
schedule of 300 mg BID in case of dose reduction. INC280 is currently supplied as tablets of 
50 mg and 200 mg. As the 50 mg tablets will not be extended after expiry date, 150 mg tablets 
will be supplied for clinical use upon the availability and regulatory approval. 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
List of Abbreviations: Added CMO&PS, Chief Medical Office and Patient Safety.
Section 6.1.1 is updated to include the addition of 150 mg strength of the tablet formulation. 
Section 6.2.5 and table 6-4 are updated in the dose modification schedule for INC280 tablet 
formulation.
Section 7 has been updated as follows: 

Table 7-2 has been added to introduce new assessment schedules. 

Section 7.2.2 has been amended to reduce safety assessments and to inform that no cardiac 
assessments are required by the protocol.

Section 7.2.3 has been amended to inform that no pharmacokinetics assessments are 
required by the protocol.


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


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Amendment 4 (31-Mar-2016)
Amendment Rationale
To optimize the management of liver toxicities and be consistent across the different INC280 
studies, this protocol amendment provides additional guidance to investigators for the 
management of liver toxicities and specifically work-up guidelines for potential Drug Induced 
Liver Injury (DILI) cases, which were implemented based on the previously described single 
case of a serious, unexpected, possibly related adverse event of abnormal liver function tests 
(LFTs) that met the lab criteria of Hy’s Law. Patients with increased AST/ALT and total 
bilirubin values that may be indicative of potential DILI, should be considered as clinically 
important events; therefore, specific guidance for actions to be taken on the study treatment (e.g. 
discontinuation) and for monitoring of LFTs have been implemented and clarified.
Furthermore, other updates are being implemented in this protocol amendment as described 
below:
The dose modification guidelines for elevations in amylase and lipase have been updated to 
optimize the management of such toxicities and be consistent across the different INC280 
studies.
In addition, based on new PK data it is suggested that the concomitant use of Proton Pump 
Inhibitors (PPIs) is unlikely to impact the efficacy of INC280, therefore the PPI restriction can 
be removed from this protocol for patients requiring PPI gastric protection treatment. Moreover, 
requirements on other acid reducing agents (gastric acid modulators and H2 receptor 
antagonists) can also be removed.
The list of medications prohibited or used with caution has also been updated based on the latest 
internal DDI guidance and has been modified to include drugs with known risk of causing QTc 
prolongation.
To ensure consistency of patient selection across all investigational sites, molecular pre-
screening for cMET pathway dysregulation is restricted to central laboratory testing only. This 
change will not affect the conduct of the study since to date no patients had been enrolled based 
on local pre-screening results.
 
 
Other minor clarification changes have been made and are included in the list of changes below.


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Changes to the protocol
Section 1.2.1.2.2 Clinical efficacy has been updated based on newly available clinical data.
Section 1.2.1.2.3 Clinical Pharmacokinetics has been updated with new PK data for INC280.
Section 4.1, 5.1 and 7.1.1: Language allowing patients to enter clinical screening with local 
molecular pre-screening test results have been removed.
Section 5.3 the exclusion criteria 21: Prohibition of treatment with medications that are known 
CYP2C9, CYP2C19 and CYP2C8 substrates with narrow therapeutic index has been revised 
based on DMPK/CP data for INC280.
Section 5.3 the exclusion criteria 22: Prohibition of treatment with proton pump inhibitors has 
been revised based on new PK data.
Section 6.2.5, Table 6-5: The recommended dose modifications for INC280 have been updated 
for hepatic toxicities and elevations in amylase or lipase.
Table-6.6: Follow-up evaluations for selected toxicities has been updated for hepatic toxicity. 
Table 6-9 has been added for follow-up evaluations for selected hepatic toxicities. Table 7-3 
has been updated to include the required laboratory evaluations for such cases.
Section 6.2.6.1: has been added for follow up on potential drug-induced liver injury (DILI) 
cases.
Sections 6.3.2 and 6.3.3: Permitted concomitant therapy requiring caution and/or action and 
prohibited concomitant therapy and Table 14-9, Table 14-10 in Appendix 4: These sections 
have been updated based on the latest internal DDI guidance and to include drugs with known 
risk of causing QTc prolongation. Additional updates have been made based on new PK data 
to remove restrictions on acid reducing agents (proton pump inhibitors, gastric acid modulators 
and H2 receptor antagonists).
Section 8.1.1 and Section 8.2.2.: have been revised to include language for the electronic 
reporting of SAEs
IRB/IEC
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.
Amendment 3
Amendment rationale
This protocol amendment provides additional information and guidance to investigators for the 
management of liver toxicities. After the cut-off date of the current INC280 Investigator’s 
Brochure (28-Sep-2014), a female patient experienced a serious, unexpected, possibly related 
adverse event of abnormal liver function tests during treatment with a combination of INC280 


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and gefitinib while enrolled in the CINC280X2202 study. This adverse event (AE) met the lab 
criteria of Hy’s Law and the hepatotoxicity could not be attributed solely to either drug alone 
or to the combination. Therefore, clarifications in the dose modification guidelines in case of 
liver toxicity and updated rules with regards to study treatment discontinuation for events that 
meet the Hy’s Law criteria are added.
Furthermore, other updates are being implemented in this protocol amendment as described 
below:
Based on the preclinical data which suggest photosensitization potential for INC280, 
precautionary measures against ultraviolet exposure are being included in this amendment, in 
addition to the information provided in the current Investigator’s Brochure.
The contraception period is being revised based on the half-life of INC280 estimated from the 
recent studies. Recent pharmacokinetic (PK) data from 3 healthy volunteer (HV) studies 
(CINC280X2103, CINC280X2107 and CINC280A2101) showed that when sampling PK up to 
72 hr, the terminal half-life (T1/2) is longer than the apparent half-life estimated from cancer 
patients, with the mean terminal T1/2 from HV studies ranged 11.7-19 hr. Therefore, the 
contraception period for INC280 is extended to 7 days.
A statement that imaging data may be collected for possible central review has been added.
INC280 tablet at 400 mg bid has been evaluated in CINC280X2102, CINC280X1101 and 
CINC280X2202 studies. Preliminary PK data showed that the mean AUC and Cmax at steady-
state following administration of INC280 tablets at 400 mg bid was higher than that following 
capsules at 600 mg bid (recommended phase II dose [RP2D] in the CINC280X2102 study), but 
in the range considering the coefficient of variability (CV%). Based on the tablet PK and safety 
data from these studies, the dosage of INC280 at 400 mg bid in tablet has been declared as 
RP2D in CINC280X2102 study. Therefore, 400 mg bid is determined to be the dose of tablet 
formulation in the dose expansion part of this study. When the INC280 tablet formulation is 
available, patients who are newly enrolled may start at INC280 400 mg bid tablet treatment. 
Patients who have been treated with INC280 600 mg bid capsules, in compliance with the local 
regulation, may switch at the beginning of the next scheduled visit to INC280 400 mg bid tablet 
treatment.
The information of the study formulation (capsule or tablet) have been added throughout the 
document to increase clarity.
Changes to the protocol
Section 1.2.1.2.1 has been updated with the most recent information based on the current 
Investigator’s Brochure (edition 5.2) including the description of the event of abnormal liver 
function tests meeting the criteria of Hy’s Law.
Section 5.3, exclusion criteria #27 and #28 have been revised to update the duration of the 
contraception period.
Section 6.1.1 tablets at 100 mg strength have been added.
Section 6.1.1.1 has been updated by adding the instruction during treatment and precautionary 
measures against ultraviolet exposure.


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Section 6.2.4 has been updated with the available information of studies with INC280.
Section 6.2.5, Table 6-4, the dose reductions in the expansion part have been updated with the 
actual dose.
Section 6.2.5, Table 6-5, the recommended dose modifications for INC280 in case of hepatic 
toxicities have been updated.
Section 6.2.7 has been updated to increase consistency and clarity.
Section 7.2.1 has been modified by adding possible central imaging review process.
Section 7.2.2.5.6, the status of post-menopausal and not of childbearing potential has been 
modified to be consistent with that in the exclusion criteria.
Section 14.4, tables of drugs prohibited and drugs used with caution have been updated based 
on the latest update from the Oncology Clinical Pharmacology Drug-Drug Interaction Database 
(released date: Apr-2015).
IRB/IEC
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs)/
Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.


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Amendment 2
Amendment rationale
The main purpose of this amendment is to update the definition of c-MET positivity as inclusion 
criteria based on the recent preliminary data from the ongoing clinical studies with INC280.
As of 21 March 2014, in the CIN280X2102 study, 3 out of 6 patients (50%) had a confirmed 
partial response (PR); all patients had high c-MET status by immunohistochemistry (IHC) (IHC 
intensity score 3+ ≥50% of tumor cells) or fluorescence in situ hybridization (FISH) (Bang et 
al 2014).
Moreover, as of 21 March 2014, in the combination study (CINC280X2202) of INC280 plus 
gefitinib, all responders had high c-MET status (analyzed by IHC or FISH) (Wu et al 2014).
As of 21 August 2014, in this CINC280X2201 study of INC280 single agent with hepatocellular 
carcinoma (HCC) patients, 1 PR and 2 confirmed stable diseases (SDs) were reported out of 5 
patients whose tumors where c-MET high (IHC intensity score 3+ ≥50% of tumor cells) in 
preliminary efficacy (not validated). Hepatocyte growth factor (HGF) overexpression has been 
described in almost all liver tissue samples adjacent to HCC tumors (TCGA HCC provisional 
data, .cbioportal.org/), but in the clinical setting this stimulation alone seems not sufficient for 
driving the tumor growth especially when the c-MET tumor expression is medium/low.
Based on these preliminary clinical data on the antitumor activity of INC280 as a single agent 
in NSCLC and HCC patients and in combination with gefitinib in NSCLC patients, the 
definition of the c-MET positive status in the inclusion criteria in this study will be updated as 
follow:

c-MET IHC intensity score 3+ in ≥50% of tumor cells

or c-MET IHC intensity score 2+ in ≥50% of tumor cells only if they have in addition 
MET gene copy number ≥5 as detected by FISH

or MET gene copy number ≥5 by FISH and unknown c-MET IHC results

or c-MET mutation can be enrolled in the study following discussion and agreement with 
Novartis
Among the total number of 50 patients as originally planned in the dose expansion part, around 
25 to 40 patients can be expected to have the c-MET positive status with the planned enrollment, 
which can provide reasonable operating characteristics.
Additional modifications have been made:
Clinical safety data including serious adverse events (SAEs) have been updated in Section 
1.2.1.2.1.
 
 
 


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Renal function will be monitored more carefully by adding creatinine clearance (calculated or 
directly measured) in the blood chemistry panel since some patients experienced increased 
blood creatinine and/or renal failure in this HCC study (CINC280X2201).
The prohibited medications and herb/food supplements have been updated for clarification in 
Section 5.3. Restrictions to the concomitant usage of herb/food supplements are added to 
prevent potential interactions with INC280 treatment.
Study update: The dose-determining part with the dose level of 300 mg bid in capsule 
formulation has completed and the dose expansion part has started since December 2013. As of 
01 September 2014, 14 patients have been enrolled in the dose expansion part and have been 
treated with INC280 600 mg bid in capsule formulation.
Changes to the protocol
Section 1.2.1.2 has been updated with newly available clinical data. Clinical safety, efficacy 
and clinical pharmacokinetics of INC280 have been amended respectively in sections 1.2.1.2.1, 
1.2.1.2.2 and 1.2.1.2.3.
Section 4.1 sample size related language has been updated to be consistent with updated Section 
10.8.
Section 5.2 the inclusion criteria of c-MET pathway dysregulation has been redefined: c-MET 
pathway dysregulation confirmed by c-MET IHC intensity score 3+ in ≥50% of tumor cell or 
by c-MET IHC intensity score 2+ in ≥50% of tumor cell and MET gene copy number ≥5 by 
FISH. Patients with MET gene copy number ≥5 by FISH and unknown c-MET IHC results or 
c-MET mutation can be enrolled in the study following discussion and agreement with Novartis.
Section 5.3 the prohibited medications and herb/food supplements have been updated for 
clarification.
Section 5.3 the exclusion criteria of biochemistry have been modified by adding the criteria of 
creatinine clearance.
Section 6.2.4 dose determining for tablet formulation has been modified for clarification of the 
data use from other clinical studies with IN280.
Section 6.2.5 has been updated by adding exceptional situations that study treatment may 
continue even if the patient experienced one of the treatment stopping rules.
Section 6.3.2 and Section 6.3.3 have been modified for clarification of the use of herbal 
medications and food products.
Section 7.1 Table 7-1 has been updated based on modifications in Section 7.2.2.6.
Section 7.1.4 and Section 7.1.4.1 exceptional situations of continuance of the study treatment
have been added.
Section 7.2.2.1 and Section 7.2.2.2 the “pre-dose” restriction of physical examination and vital 
signs in Day 1 of Cycle 2 and subsequent cycles have been removed.


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Section 7.2.2.5 has been modified by adding creatinine clearance in the blood chemistry panel 
as it is required for the exclusion criteria.
Section 7.2.2.6 ECGs matched with the PK blood collection will be added and be centrally 
evaluated by an independent reviewer.
Section 7.2.3 and Table 7-5 have been updated by adding PK blood collections at 2 hours post-
morning dose in Cycle 2 and Cycle 3.
Section 7.2.3.1 PK blood collection procedure has been modified for clarification.
Section 10 analyses of efficacy based on the revised definition of c-MET positive, as introduce 
in Protocol Amendment 2, has been added.
Section 10.4.2 the confidence interval to be presented in the primary analysis of TTP has been 
changed to one-sided 90% to be consistent with sample size justification.
Section 10.8 sample size justification has been updated based on the c-MET positive patient 
population. More technical detail has been provided.
Section 13 the corresponding references have been added.
Section 14.4 Appendix 4 the tables 14-9 and 14-10 have been modified based on the updated 
reference.
Section 14.6 Appendix 6 the calculation method of creatinine clearance (Cockcroft-Gault 
formula) has been added.
Clarification has been made that INC280 capsule was used in the dose-determining part.
Minor editorial changes have been made and typos have been corrected throughout sections.


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Amendment 1
Amendment rationale
The primary purpose of this amendment is to introduce the use of INC280 tablets.
INC280 is currently supplied as capsules of 50 mg. Doses up to 600 mg bid have been tested. 
To improve the convenience of study drug administration for patients, a tablet formulation with 
higher dosage strengths (50 mg and 200 mg) has been developed. A relative bioavailability 
study (INC280X2103) is ongoing to compare the two formulations. If the relative 
bioavailability is comparable, new patients will be treated with tablets and patients still 
benefitting from treatment with capsules may be switched to the tablets. If the exposures are 
significantly different between the two formulations, a dose conversion based on the relative 
bioavailability may be applied.
Additional modifications and updates to the protocol include:
The section covering the preclinical safety of INC280 has been updated to reflect new findings 
obtained from additional toxicity studies which have been conducted since the original protocol 
development. These include the 13-week monkey study, the embryofetal studies in rats and 
rabbits, and photosensitization potential assay evaluation.
 
 
An update to the eligibility criteria for serum creatinine, contraception requirement, permitted 
and prohibited concomitant medication to align with other INC280 protocols and Novartis 
standards.
The data analysis plan has been updated to include the consideration of statistical and PK 
analysis for different study treatment formulations.
Additional editorial changes have been made to sections where previous language was deemed 
inaccurate or ambiguous.
Changes to the protocol
Section 1.2.1.1.3 has been modified by adding new data and findings from preclinical toxicity 
studies.
 
Section 5.3 the typo of exclusion criteria 4 has been amended.
Section 5.3 the exclusion criteria 21 has been amended to exclude patients whose serum 
creatinine are greater than grade 1.
Section 5.3 the exclusion criteria 24 and 25 were amended to update the contraception 
requirement to align with other protocols.
Section 4.1 and Section 6.1.1 tablet formulation and strength have been added, and the usage 
of tablets and capsules has been specified. Moreover, the fasting requirement is now clarified.


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Section 6.2.2 and Table 6-1 have been updated to specify how to adjust dose when decreased 
INC280 exposure is noted during Dose-Determining Part.
Section 6.2.4 has been added to specify the dose determining procedure for INC280 formulation 
change during Dose Expansion Part.
Table 6-5 has been updated for dose modification of serum creatinine increased to align with 
other INC280 protocols.
Table 6-8 has been modified to define the criteria of hepatitis C reactivation.
Section 6.3.2 and Section 6.3.3 and Appendix 4 have been updated to clarify permitted and 
prohibited medication.
Section 7.1 has been modified to define the window day for Day 1 of Cycle 1.
Section 7.1.1.1 and Section 7.1.1.2 have been modified to align with inclusion criteria 1.
Section 7.1.1.3 and Section 7.1.2.1 have been modified to specify the use of Patient Registration 
Form.
Section 7.1.5 has been modified to comply with Novartis Clinical Data Standards.
Section 7.2.1 has been modified to specify the visit window of each tumor assessments.
Section 7.2.4.2.1 has been modified to specify the collection of fresh tumor biopsy is optional.
Section 7.2.5.5.5 has been modified to remove redundant Hepatitis B serology exams on Day 1 
of every cycle from Cycle 2 and EOT.
Section 10 and Section 10.5.3.3 and Section 10.7 have been updated to include the consideration 
of statistical analysis for the change of study treatment formulation.
Section 
10.4.3 
has 
been 
modified 
to 
clarify 
how 
to 
handle 
missing 
values/censoring/discontinuations.
Section 10.5.4.1 has been updated to specify the PK analysis method for dose decision.
IRB/IEC
A copy of this amended protocol will be sent to the IRBs/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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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the third 
leading cause of cancer-related death. In 2008, an estimated 748,000 new cases of liver cancer 
occurred and approximately 696,000 people died of this cancer worldwide. Over 80% of HCCs 
occur in developing countries in Sub-Saharan Africa, Southeast Asia, and East Asia, consistent 
with the fact that about three-quarters of HCCs are attributed to chronic Hepatitis B Virus (HBV) 
and Hepatitis C Virus (HCV) infections and are often associated with liver cirrhosis (Ferlay 
2008, Anzola 2004). Other common etiologies include alcohol consumption, nonalcoholic 
steatohepatitis, exposure to carcinogens, and the genetic metabolic diseases such as 
hemochromatosis (El-Serag 2000, Donato 2002, Adams 2005, Turner 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 2008). HCC is resistant to conventional chemotherapy, and is rarely amenable to radiotherapy. 
No single chemotherapy agent or combination has demonstrated convincing survival benefits 
or improvement in quality of life (Ng 2000, Thomas 2009, Simonetti 1997). Some newer 
chemotherapy agents have demonstrated some activity, but have had minimal impact on disease 
stabilizations and overall survival (OS). The 5-year relative survival rate for patients with HCC 
treated with local or systemic treatment is only 7% (Bosch et al 2004).
HCCs are phenotypically and genetically heterogeneous tumors with alteration of multiple 
signaling pathways. Inhibiting multiple targets may be important to optimize and induce durable 
anti-tumor effects (Whittaker et al 2010). Sorafenib, a multikinase inhibitor with anti-
angiogenic, pro-apoptotic and Raf kinase inhibitory activity, was the first targeted agent to show 
a statistically significant improvement in OS for patients with advanced HCC across all regions. 
The results of a phase III randomized placebo-controlled trial (SHARP trial) demonstrated the 
hazard ratio for OS (sorafenib/placebo) was 0.69 (95% CI 0.55-0.87; p=0.0006). Improvement 
in OS for the patients randomized to sorafenib in another phase III sorafenib study in Asia-
Pacific region was consistent with the SHARP trial as indicated by hazard ratio b for survival 
of 0.68 (95% CI, 0.5-0.93; p=0.014). The positive results from sorafenib demonstrated the 
potential for further development of therapeutic agents targeting the molecular pathways 
involved in HCC. However, the observed OS of 6.5 months in the sorafenib group compared 
with 4.2 months in the placebo group for the sorafenib Asia-Pacific study compared to that of 
10.7 months in the sorafenib group vs 7.9 months in the placebo group for the SHARP study 
suggest that the patient population in the Asia-Pacific region presented with more advanced 
disease, the most common etiology being HBV infection (Llovet 2008a, Cheng 2009).
The biological functions of the c-MET-mediated signaling pathway in normal tissues and 
human malignancies have been well documented (Birchmeier 2003, Christensen 2005, 
Liu 2008, Liu 2010) (Figure 1-1). Improved knowledge of oncogenic processes and signaling 
pathways has led to the identification of c-MET pathway as one of the therapeutic targets in 
HCC. Clinical activities have been observed in NSCLC, medullary thyroid cancer, liver cancer 
and other tumor types when c-MET pathway was interfered (Peters 2012, Spiegel 2011, 
Kurzrock 2011, Rimassa 2012, Gherardi 2012, Verslype 2012). Two phase II trials of c-MET 


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inhibitors in the treatment of HCC were reported recently. The phase II trial of tivantinib for 
HCC is the first randomized data in HCC showing OS advantage (HR=0.64; p=0.04) with a 
MET inhibitor and identifying a biological subgroup responding to a target therapy. c-Met 
positive patients treated with tivantinib experienced significant improvement in time to 
progression (TTP), 2.9 months vs 1.5 months, and OS, 7.2 months vs 3.8 months, compared to 
patients who received placebo (Rimassa et al 2012). In another phase II trial of cabozantinib in 
HCC patients, a median progression-free survival (PFS) of 4.2 months, with 2/36 (5%) 
confirmed partial response (PR) was reported. The overall disease control rate (DCR = PR+SD) 
at Week 12 was 68% (Asian subgroup: 73%) (Verslype et al 2012).
Figure 1-1
Signaling and biological functions of the HGF/c-MET pathway
1.2
Introduction to investigational treatment
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 c-MET receptor tyrosine kinase. The proto-oncogene c-
MET, a member of the receptor tyrosine kinase family, encodes the high-affinity receptor for 
hepatocyte growth factor (HGF), the only ligand for the receptor.
In vitro and in vivo data suggest that INC280 possess potent pharmacological activity against 
c-MET and supports its clinical development as a potentially effective oral treatment for human 
cancers.


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Please refer to the [INC280 Investigator’s Brochure] for more detailed information.
1.2.1.1
Non-clinical experience
1.2.1.1.1 Pharmacology summary
INC280 possesses potent inhibitory activity against the c-MET kinase in vitro (IC50 = 0.13 ± 
0.05 nM) and is both ATP competitive and reversible (Liu et al 2011). INC280 is highly specific 
for c-MET with > 10,000-fold selectivity over a panel of 56 other human kinases tested.
Systematic in vitro dose-response proliferation assays on >500 cancer cell lines showed that 
INC280-responsive cancer models are characterized by either strong c-MET overexpression 
due to c-MET gene amplification or by co-expression of c-MET and HGF, leading to autocrine 
activation.
The pharmacokinetic/pharmacodynamic (PK/PD) relationship of INC280 was characterized in 
tumor-bearing mice. These experiments probed the potential of INC280 to inhibit 
phosphorylation of c-MET, as assessed by phospho-c-MET levels in tumors using 
immunohistochemical or ELISA-based methods. In c-MET/HGF-driven xenograft mouse 
tumor models, oral dosing of INC280 demonstrated significant in vivo activity in blocking c-
MET phosphorylation. Oral administration of INC280 at a dose of 3 mg/kg suppressed > 90% 
c-MET phosphorylation for at least 7 hours in a mouse xenograft tumor model and this 
correlated with plasma INC280 levels greater than or equivalent to the human whole blood IC90 
of 71 nM.
Previous experiments indicated that HCC cell lines with high c-MET expression are responsive 
to c-MET inhibition (Zhang et al 2005). These earlier findings were confirmed by testing the 
anti-tumor efficacy of INC280 in the xenograft HCCLM3 model, which expresses very high c-
MET levels due to c-MET amplification. Tumor regression was observed at the dose level of 
5mg/kg/day and c-MET phosphorylation was fully suppressed up to 8 hours after dosing. These 
data indicate that inhibition of c-MET by INC280 could have therapeutic benefit in HCC 
patients in whose tumors c-MET is activated, for example by gene amplification.
More detailed information can be found in the current INC280 Investigator’s Brochure.
Collectively, the data demonstrate that INC280 possesses potent in vitro and in vivo 
pharmacological activity against c-MET. Together with our epidemiological evidence for 
pathway activation (Section 1.1) these data support the clinical development of INC280 as a 
potentially effective oral treatment for hepatocellular carcinoma.
1.2.1.1.2 Nonclinical drug metabolism and pharmacokinetics summary
In preclinical models, INC280 demonstrated high protein binding (>93%) with low apparent 
volume of distribution. INC280 was predominantly metabolized by CYP enzymes and to a 
minor extent by cytosolic molybdenum containing oxidases. The major enzyme involved in 
INC280 metabolism in the liver is CYP3A4. Other enzymes involved include CYP2C9 and 
2C19.
Drug-drug interaction (DDI) potential of INC280 has been investigated in in vitro metabolism 
and transporter systems. INC280 has low potential for CYP3A4 induction. INC280 showed 


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inhibitory potency for CYP1A2, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5. Time-
dependent (irreversible) inhibition by INC280 was observed for CYP1A2 and CYP3A4/5.
Potential drug-drug interaction due to inhibition of CYP1A2, 2C8, 2C9, 2C19 and 3A4/5 is 
possible at clinically relevant doses.
Based on Caco2 in vitro study, DDI with a P-gp substrate is possible at clinically relevant 
INC280 doses (IC50 of 2.9 µM). INC280 displayed inhibition of MDR1/P-gp, MXR/BCRP, 
OATP1B1 and OATP1B3 with IC50 values of 12 µM, 16.4 µM, 6.5 µM and 6.2 µM, 
respectively in LLCPK1, MDCKII and HEK293 uptake assays, indicating INC280 might result 
in an increased uptake of co-mediations transported by ABC and SLC-transporters in the 
gastrointestinal (GI) tract or a decreased elimination into the bile and/or urine at clinical relevant 
doses of INC280.
For more information, please refer to the most updated the current [INC280 Investigator’s 
Brochure].
1.2.1.1.3 Non clinical toxicology summary
Repeat dose toxicity studies conducted revealed the following target organs or systems: kidneys, 
pancreas, central nervous system (CNS), and potentially liver. Additionally, embryofetal 
toxicity / teratogenicity was observed in rats and rabbits, and skin photosensitization potential 
were also identified.
A potential risk of kidney damage was evidenced in the 28-day toxicology study in cynomolgus 
monkeys, where mild-to-moderate deposits of crystalline-like material within the renal 
interstitium and/or tubular lumen were present at the doses of 75 and 150 mg/kg/day. The no 
observable adverse effect level (NOAEL) for the cynomolgus monkey study is 30 mg/kg/day, 
and is associated with an average area under the curve (AUC) of 97.6 µM*hr (total) or 3.28 
µM*hr (unbound) and Cmax of 34.8µM (total) or 1.17µM (unbound).In the 13-week monkey 
study, no evidence of kidney toxicity were observed at the doses tested (up to 75 mg/kg/day)
Clinical and histopathological signs indicative of CNS toxicity were observed in rats only. In 
the 4-week toxicity study, tremors and convulsions upon handling, as well as white matter 
vacuolation in the thalamus were observed at the high dose groups (60 mg/kg/day for females, 
and 120 mg/kg/day for males). At the NOAELs for the CNS toxicity (30 mg/kg/day for females, 
and 60 mg/kg/day for males), the systemic exposure was 144 µM*hr (or 8.0 µM*hr for unbound 
drug). In a follow up 13-week rat study with a 13-week recovery, the CNS effects and similar 
brain lesions were observed, and were shown to be reversible.
A finding common to rat and cynomolgus monkey in the 28-day toxicology studies was the 
increased incidence of pancreatic acinar cell vacuolation and/or apoptosis without inflammation. 
These findings are reversible in both species.
Findings in serum chemistry liver enzymes observed in several different studies in rats and 
monkeys after administration of relatively high doses of INC280 were highly variable, minimal-
to-mild in nature and lacked a clear dose response. The significance of the elevations is 
undetermined and there is no histological correlate within the liver in most studies, with the 
exception of the 13-week monkey study, where minimal to mild subcapsular neutrophilic 
infiltration associated with single cell necrosis in liver (males only, and reversible) was 
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INC280 is not genotoxic. Studies on embryofetal development were conducted in both rats and 
rabbits. Based on the results of the embryo-fetal development studies, INC280 is teratogenic to 
rabbits at ≥5 mg/kg/day, and teratogenic to rats at ≥10 mg/kg/day. Fetal malformations of limb 
muscle and tongue were the major findings in both rats and rabbits. Based on the findings in 
animal studies, INC280 is considered potentially teratogenic to humans.
INC280 tested positive for phototoxicity in an in vitro 3T3 NRU assay. In the follow up in vivo 
study in mice (UV-LLNA), INC280 was also tested positive for photosensitization at the dose 
of 100 mg/kg/day (with NOAEL of 30 mg/kg/day). Based on these results, INC280 is 
considered to have potential for photosentization.
For more information, please refer to the most updated the current [INC280 Investigator’s 
Brochure].
1.2.1.2
Clinical experience
1.2.1.2.1 Clinical safety
As of 28-Sep-2014 (cut-off date of the INC280 Investigator’s Brochure, edition 5.2), a total of 
203 cancer patients have been treated in five clinical trials with INC280 as a single agent and a 
total of 103 cancer patients have been treated with INC280 in 5 different combination therapies 
with anti-cancer agents at various doses and in two formulations, capsule and tablet.
Single agent INC280 is generally tolerable (regardless of the dose), with the majority of the 
reported AEs being of mild or moderate severity (CTCAE grade 1 or grade 2). CTCAE grade 
3 or grade 4 AEs suspected to be related to INC280 in single agent studies (regardless of the 
dose) included hypophosphatemia, peripheral edema, fatigue, increase in AST, ALT, γGT, 
amylase, blood bilirubin and lipase, vomiting, colitis ulcerative, lung infection, nausea, anemia, 
neutropenia, hypophagia, decreased appetite, hypoalbuminemia, maculo-papular rash, 
dehydration and decreased lymphocytes.
In the combination studies, the most frequent AEs suspected to be related to INC280 (regardless 
of the dose) were nausea and vomiting. CTCAE grade 3 and grade 4 AEs suspected to be related 
to INC280 (regardless of the dose) included most frequently: asymptomatic increase in amylase, 
increase in lipase, AST and ALT, nausea and vomiting. One serious adverse event (SAE) with 
fatal outcome, deteriorated cough and dyspnea, has been reported with a suspected causal 
relationship to INC280.
After the cut-off date of 28-Sep-2014, a 
 patient experienced a serious, unexpected, 
possibly related AE of abnormal liver function tests during treatment with a combination of 
INC280 and gefitinib while enrolled in the [CINC280X2202] study. Patient experienced 
concurrent elevations of total bilirubin >2×ULN and ALT/AST >3×ULN with alkaline 
phosphatase (ALP) <2×ULN. The patient permanently discontinued study drugs. The liver 
function alterations were reversible and improved after the discontinuation of both drugs. At 
the time of the follow-up Investigator Notification (IN), the outcome of the AE of abnormal 
liver function tests was reported as completely recovered. This patient met the criteria of Hy’s 
Law and the hepatotoxicity could not be attributed solely to either drug alone or to the 
combination.
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The recommended phase II dose (RP2D) for INC280 as a single agent with capsule formulation 
has been determined to be 600 mg bid. The RP2D of INC280 monotherapy is 400 mg bid in 
tablet formulation. The maximum tolerated dose (MTD) for single agent INC280 has not been 
defined.
1.2.1.2.2 Clinical efficacy
As of 21-March-2014 (clinical data cut-off date), 8 out of 33 (24%) patients in the dose-
escalation part of the single agent INC280 study [CINC280X2102] had stable disease. 
Moreover INC280 showed preliminary anti-tumor activity in the expansion arm of the dose 
escalation part of the study in patients with NSCLC, 3 out of 6 patients had confirmed PR; all 
patients were epidermal growth factor receptor (EGFR) wild type and had high c-MET status 
by IHC or FISH (Bang Y-J et al, 2014). Two of 3 patients had c-MET mutations.
In addition, as of 21-March-2014, in the INC280 plus gefitinib combination study
[CINC280X2202], PRs were seen in 8 out of 46 (17%) evaluable NSCLC patients (6 confirmed
and 2 unconfirmed PR). All responders had high c-MET status (by IHC or FISH): patients with 
MET gene copy number ≥5 by FISH demonstrated an ORR of 40% (n = 8/20) and patients with 
c-MET IHC intensity score 3+ in ≥50% of tumor cells demonstrated an ORR of 33% (n = 7/21). 
No responses have been observed in patients with c-MET IHC intensity score 2+ in ≥50% of 
tumor cells or low MET gene copy number (Wu YI et al, 2014).
As of 28-September-2015, in this CINC280X2201 study of INC280 single agent with HCC 
patients, total 36 patients were enrolled: 8 patients in a dose-determining part (INC280 300mg 
BID) and 28 patients in dose-expansion part (INC280 600mg BID). In expansion patients, 3 
confirmed PRs and 1 SD were reported in preliminary efficacy analysis. All responders have c-
MET high status (IHC 3+, IHC 2+ and cMET gene copy number [GCN] ≥ 5 by FISH, or cMET 
GCN ≥ 5 and unknown IHC). 
1.2.1.2.3 Clinical Pharmacokinetics
As of 28 September 2013, INC280 (capsule) single agent steady state pharmacokinetic (PK)
data are evaluable in a total of 102 patients from three clinical studies. After oral administration, 
INC280 was rapidly absorbed. Median time to peak plasma concentration was reached at 1 to 
4 hours. The apparent elimination half-life of INC280 is short, with an average of 2.3 to 6.4 
hours across studies. The mean plasma exposures (Cmax and AUC) of INC280 were generally 
increased with dose following qd administration up to 600 mg/day, and following bid dosing 
up to 600 mg bid. Upon daily dosing, there was minimal accumulation in all dose cohorts, which 
is in line with the short terminal half-life of INC280. Steady state INC280 exposure is expected 
to be reached by the third day of consecutive dosing.
INC280 exhibited a pH-dependent solubility profile with a low solubility at high pH level. A 
study to evaluate the effect of long acting proton pump inhibitor on the PK of a single dose 
INC280 tablet (600 mg) was completed in healthy volunteers [CINC280A2101]. Daily 
treatment of 20 mg rabeprazole 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. Considering the 
42% and 65% variability in AUC observed in patient single agent studies [CINC280X2102] 
and [CINC280X1101], therefore a decrease of 25% in AUC when administered with PPI is 
considered not significant. The impact on the 12 hour post-dose concentration of INC280 


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(defined as trough concentration for BID dosing) was small with ~7% reduction after 
rabeprazole treatment. Preliminary data in NSCLC patients [CINC280X2202] suggested that 
anti-tumor activity is correlated more with Ctrough than AUC and Cmax.
For more information, please refer to the most updated version of the [Investigator’s Brochure].
2
Rationale
2.1
Study rationale and purpose
In view of the challenges in management of HCC, with its high mortality and morbidity as well 
as limited efficacy to the current available therapies, there is an urgent need for better systemic 
therapy for HCC.
c-MET overexpression has been associated with increased vascular invasion, resistance to 
chemo- and radiotherapy, and poor clinical outcome (Farazi 2006, Takami 2007, Boix 1994, 
Suzuki 1994, Kiss 1997, Ueki 1997, Tavian 2000, Akervall 2004, Kaposi-Novak 2006, 
Lal 2005, Liu 2008). Moreover, 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). Interference with the c-MET receptor intracellular sequence has been shown 
to impair HGF induced angiogenesis, suggesting blocking of receptor site may be a therapeutic 
strategy to overcome angiogenesis in cancers (Cantelmo et al 2010). Pathological HGF/c-MET 
pathway deregulation is one of the key events that drive the oncogenesis and tumor maintenance 
of HCC (Whittaker et al 2010).
INC280, a specific c-MET inhibitor, has shown anti-tumor activity in several pre-clinical 
models of HCC that are driven either by c-MET gene amplification or by HGF stimulation. 
Preclinical studies performed at Novartis have shown that HGF overexpression is found in 
almost all liver tissue samples adjacent to HCC tumors and that c-MET is expressed by the 
majority of HCC tumors. Thus, INC280 is an attractive c-MET inhibitor for HCC.
We therefore intend to develop INC280 as a potential treatment option for patients with HCC. 
Based on the available data that demonstrate the involvement of the c-MET pathway in the 
tumorigenesis of HCC, and poor prognosis of the disease, this study will evaluate INC280 in 
patients with advanced HCC with dysregulated c-MET pathway.
The recently reported positive results of c-MET inhibitors in the treatment of HCC provided 
the strongest rationale for the evaluation of c-MET targeted agents in HCC. The phase II trial 
of tivantinib for HCC demonstrated significant improvements in TTP and OS, particularly in 
patients with high MET expression level while the interim data from a phase II trial of 
cabozantinib for HCC reported a median PFS of 4.2 months, with 2 confirmed PR 
(Rimassa 2012, Verslype 2012).
2.2
Rationale for the study design
This study is designed as a Phase II, single arm, open-label, multicenter study to evaluate the 
safety and efficacy of INC280 as first-line treatment in patients with advanced HCC who are 
not eligible for or had disease progression after surgical or locoregional therapies, with c-MET 
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A single arm trial design was chosen, with an estimated TTP based on the sorafenib study in 
Asia-pacific region which enrolled similar patient population (patients with advanced HCC, 
Child Pugh A and no prior systemic therapy), to evaluate the preliminary activity of INC280 in 
advanced HCC as well as enabling an evaluation of the safety, PK, and other parameters 
detailed in Section 10.
TTP is the primary endpoint recommended by the American Association for the Study of Liver 
Diseases (AASLD) expert panel for a Phase II study in HCC. Secondary endpoints include ORR, 
PFS, OS and disease control rate (DCR). Safety of INC280 in patients with advanced HCC, 
especially liver AEs in patients with liver dysfunction associated with underlying viral or 
cirrhotic medical conditions, will be performed to evaluate INC280 exposure in patients with 
liver dysfunction.
This study is designed to include a Dose-Determining Part and a Dose Expansion Part. The 
Dose-Determining Part was designed in order to characterize the PK and safety profiles of 
INC280 in the setting of liver dysfunction, with the aim of identifying the appropriate dose to 
be used for HCC patients before exposing a larger group of patients to INC280 in the Dose 
Expansion Part of this study. The Dose Expansion Part will start when the appropriate dose is 
determined after the dose decision analysis which will be performed at the end of the Dose-
Determining Part and, will also incorporate safety and PK data from other ongoing clinical 
studies (Section 4.1).
2.3
Rationale for dose and regimen selection
In vitro, INC280 is mainly metabolized via liver CYP3A4 enzyme. HCC and underlying liver 
cirrhosis or the presence of liver metastasis may change the drug metabolism and elimination.
Though preliminary analysis didn’t show a difference in INC280 drug exposure in HCC patients 
as compared to patients with other tumor types, predominant metabolism of INC280 via 
CYP3A4 enzyme and the fact that the PK of INC280 has not been studied exhaustively in 
patients with liver dysfunction raised the concern if its PK may be altered in patients with 
hepatic impairment, a major characteristic of the patient population for this study. Thus, the 
issue is to be addressed via a Dose-Determining Part to evaluate the PK and safety of INC280 
in this population and compared with historical data before exposing to a larger group of 
patients in the Dose Expansion Part, who could be treated at the same, a lower or a higher dose 
than the Dose-Determining Part dose, based on the dose analysis decision (Section 4.1 and 
Section 6.2.2).
INC280 300 mg bid (capsule), which is the highest safe dose being evaluated based on the 
clinical experience from other ongoing studies (Section 1.2.1.2), will be used for the Dose-
Determining Part. 300 mg bid is expected to achieve target inhibition. Observed mean Ctrough
concentration on Day15 at 300 mg bid was approximately 13 fold of in vivo IC90. In addition, 
a bid dosing regimen is potentially more appropriate in fast growing tumors than a qd regimen
(Georgieva et al 2012).
The dose and regimen selection for the Dose-Determining Part was based on previous clinical 
experience from ongoing studies. By the cut-off date of August 15, 2012, INC280 was well 
tolerated in human up to 300 mg bid (capsule) (Section 1.2.1.2). A total of six HCC patients 
have been treated at 10 mg qd (n = 1), 50 mg qd (n = 2), 400 mg qd (n = 1) and 100 mg bid (n 


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= 2). The safety profile in HCC patients was similar to patients with other tumor types and no 
major liver toxicity was reported in the ongoing INC280 studies. In an exploratory analysis 
using linear mixed effect model to assess the impact of the disease status on INC280 exposure, 
neither disease status of HCC nor status of liver metastasis was identified as the significant 
covariates. Therefore, it is reasonable to select 300 mg (capsule) bid as an appropriate dose for 
the Dose-Determining Part in HCC patients.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4.
To estimate overall clinical activity of INC280 in advanced HCC 
patients with c-MET dysregulation.
Time to progression (TTP) assessed using RECIST version 1.1 
(Appendix 1)
Secondary
Refer to Section 10.5.
To further assess the clinical activity of INC280 in advanced HCC 
patients with c-MET dysregulation
ORR, PFS, OS and DCR
To characterize the safety and tolerability of INC280 in advanced 
HCC patients.
Safety: AEs, SAEs, changes in hematology and chemistry values, 
vital signs, electrocardiograms (ECGs)
Tolerability: Dose interruptions, reductions and dose intensity
To characterize the pharmacokinetics of INC280 in patients with 
advanced HCC.
Plasma concentration vs. time profiles, plasma PK parameters 
including but not limited to AUC0-t, CL/F, Cmax, Tmax, T1/2 and 
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4
Study design
4.1
Description of study design
This is a Phase II, open label, single arm, multicenter study of INC280 administered orally as 
first-line treatment in patients with advanced HCC. See Figure 4-1 for an overview of the study 
design.
Patients will be enrolled into the study in 2 parts (Dose-Determining and Dose Expansion parts) 
where the first Part will allow the assessment of safety and PK profiles prior to initiating a larger 
second Part.
Figure 4-1
Study design
* The rules for dose recommendation for the Dose Expansion Part will be followed as listed in 
Table 6-1.


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A complete treatment cycle is defined as 21 days of continuous dosing, with the first dose of 
the INC280 defining Day 1 and the last day of a complete treatment cycle being Day 21. In the 
Dose-Determining Part, the qualifying AEs for dose determination will be assessed for the first 
28 days of treatment for comparability to Cycle 1 safety data observed in previous/ongoing 
clinical trials.
Molecular pre-screening
Evidence of dysregulation of c-MET pathway is required in order to begin screening activities.
Evidence can be demonstrated by submission of an archival or a newly obtained HCC tumor 
sample to a central laboratory for analysis. Tissue requirements are found in Section 7.1.1.2.
Patient must sign the molecular pre-screening consent to allow for the collection and submission 
of samples to the central laboratory for analysis.
If the results of the central analysis meet the criteria for c-MET positivity (Section 5.2), the 
patient can proceed with the screening procedures. In exceptional cases, patients with a tumor 
harboring a documented cMET mutation (based on the results of local testing) can be enrolled 
in the study following discussion and agreement with Novartis.
Screening period
When the required c-MET status is known, patients will sign the Main Informed Consent Form 
and will be evaluated against study inclusion and exclusion criteria and safety assessments 
(Table 7-1). Eligible patients will begin study treatment within 14 days of the commencement 
of the screening assessments.
Dose-Determining Part
During the Dose-Determining Part, at least six patients will be enrolled and treated with INC280 
at 300 mg bid (capsule). Safety, full PK profiles of INC280 on Cycle 1, Days 1, 2, 15 and 16, 
predose PK samples on Cycle 2 Day 1 and Cycle 3 Day 1, demographics and other baseline 
characteristics will be collected in these patients (Section 7.1.2.3, Section 7.2.2 and 
Section 7.2.3).
A dose decision analysis based on safety and PK data will be conducted when patients from 
Dose-Determining cohort have completed 28 days treatment and data from at least 6 patients 
are evaluable for the dose-determining set (DDS) (see Section 10.1). The analysis will be guided 
by the medical review of available clinical, laboratory, and PK data, as well as the 
recommendation from the Bayesian Logistic Regression Model (BLRM) (see Section 6.2.2 for 
details on the decision process).
Novartis and the principal investigators will have a dose decision meeting to discuss and 
evaluate the data. At this meeting, Novartis and the principal investigators must reach consensus 
on the dose level to be used in the Dose Expansion Part. Novartis will prepare minutes from 
this meeting and circulate them to each investigator for comments prior to finalization. The 
Expansion Part dose will be communicated to all investigators in writing.


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Patients in the Dose-Determining Part who have not experienced a dose reduction will be 
allowed to switch to the confirmed Expansion Part dose, if different from the Determining Part 
dose, under consultation from the Investigator with Novartis.
Dose Expansion Part
Once the Expansion Part dose has been confirmed, approximately 50 patients in total will be 
enrolled, among which around 25 to 40 patients will have the c-MET positive status as specified 
in the inclusion criteria (Section 5.2).
Detailed information on all patients will be collected and reported (see Section 10 for details).
Follow-up
All patients will be followed-up as described in Section 7.1.5. At minimum, patients must 
complete the safety follow-up assessments 30 days after the last dose of the study treatment.
All patients will be followed until progressive disease (PD), death or withdrawal of consent 
regardless of any drug discontinuation. All patients will be followed for OS for a duration of at 
least 6 months after last patient first dose.
4.2
Timing of dose decision analyses and design adaptations
The safety and PK analysis will be conducted when at least six patients enrolled in the Dose-
Determining Part become evaluable for the DDS.
4.3
Definition of end of the study
The end of study will be the earliest occurrence of one of the following:

completion of the survival follow-up period and the Study Phase Completion page for the 
last patient treated with INC280 

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 are transferred to that clinical study and all 
discontinued patients have completed the safety follow-up period. The follow-up for 
disease progression and survival will not be performed or pursued (See Section 7.1.5)
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study by an alternative way, to patients who, in the opinion of the investigator, are 
still deriving clinical benefit.
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 and the same assessments should be performed 
as described in Section 7.1.4 for a prematurely withdrawn patient. The Investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The Investigator will be responsible for 
informing IRBs and/or IECs of the early termination of the study.


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4.5
Rationale for public health emergency mitigation procedures
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures to ensure patient safety and trial 
integrity may be implemented; such procedures are listed in relevant sections of the study 
protocol. Notification of the public health emergency should be discussed with Novartis prior 
to implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate.
5
Population
5.1
Patient population
Adult patients with histologically or cytologically confirmed advanced HCC which is not 
amenable to surgical resection or other loco-regional therapy and who have received no prior 
systemic therapy, are eligible. Child-Pugh classification (CPC) will be used to assess the 
severity of impaired hepatic function in patients with liver cirrhosis. Only patients with Child-
Pugh A (5-6 point liver function) are included since more severe liver function impairment 
renders study patients prone to liver decompensation from underlying cirrhosis or reactivation 
of chronic hepatitis B viral infection potentially leading to uninterpretable study data based on 
heterogeneity and causality in exposure, mortality, and AEs.
Evidence of c-MET expression must be documented through central laboratory testing (see 
Section 7.1.1 for further details). Patients enrolled in this study are not permitted to participate 
in additional parallel investigational drug or device studies. The investigator or designee must 
ensure that only patients who meet all the following inclusion and none of the exclusion criteria 
are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Patients with confirmed c-MET pathway dysregulation at pre-screening as defined by:

c-MET IHC intensity score 3+ in ≥50% of tumor cells

or c-MET IHC intensity score 2+ in ≥50% of tumor cells only if they have in addition 
MET gene copy number ≥5 as detected by FISH

or MET gene copy number ≥5 by FISH and unknown c-MET IHC results

or c-MET mutation can be enrolled in the study following discussion and agreement 
with Novartis
2. Written informed consent must be obtained prior to any screening procedures.
3. Patients aged ≥ 18 years (male or female).
4. Patients with advanced (unresectable and/or metastatic, stage C based on Barcelona-Clinic 
Liver Cancer (BCLC) staging classification) hepatocellular carcinoma which would not be 
suitable for treatment with loco-regional therapies or have progressed following 
locoregional therapy such as surgical resection, percutaneous hepatic arterial 
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5. At least one tumor lesion meeting measurable disease criteria as determined by RECIST 
v1.1. 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.
6. Current cirrhotic status of Child-Pugh class A (5-6 points) (Appendix 2), with no 
encephalopathy. Slight ascites controlled by diuretics is permitted in this study.
7. Availability of a representative tumor tissue specimen (archival tumor tissue is allowed) at 
pre-screening.
8. ECOG performance status ≤ 2.
9. 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. Received any prior systemic chemotherapy or molecular-targeted therapy for HCC such as 
sorafenib.
2. Previous local therapy completed less than 4 weeks prior to the dosing and, if present any 
related acute toxicity > grade 1.
3. Previous treatment with a c-MET inhibitor or HGF targeting therapy.
4. Previous treatment with yttrium-90 spheres.
5. Patients with any other malignancies within the last 3 years before study start, except for 
adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer.
6. History of HCC tumor rupture.
7. Patients who have signs/symptoms attributable to portal hypertension and have not been 
assessed with upper GI endoscopy to rule out high-risk of variceal bleeding. If varices are 
identified that require intervention (banding), patient will not be eligible until varices 
adequately treated.
8. Patients with known active bleeding (e.g. from GI ulcers, esophageal varices) within 2 
months prior to baseline/screening visit or with history or evidence of inherited bleeding 
diathesis or coagulopathy.
9. Clinically significant (CTC grade 3 or 4) venous or arterial thrombotic disease within past 
6 months.
10. A history of acute or chronic pancreatitis, surgery of the pancreas, or any risk factors that 
may increase the risk of pancreatitis.
11. Patients with known brain metastasis or who have signs/symptoms attributable to brain 
metastases and have not been assessed with radiologic imaging to rule out the presence of 
brain metastases.
12. Serious, non-healing wound, ulcer, or bone fracture.
13. History of abdominal fistula, GI perforation, or intra-abdominal abscess within past 6 
months prior to study treatment.
14. Clinically significant third space fluid accumulation (i.e., ascites requiring tapping despite 
use of diuretic or pleural effusion that either required tapping or is associated with 
shortness of breath).


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15. Patients who have undergone major surgical procedure, open biopsy, or significant 
traumatic injury within 4 weeks of the start of protocol treatment
16. History of a bone marrow or solid organ transplant.
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, e.g., infection/inflammation, intestinal obstruction, unable or unwilling to 
swallow medication, social/ psychological issues, etc.
18. Unable to undergo either contrast-enhanced magnetic resonance imaging (MRI) or 
contrast-enhanced computed tomography (CT).
19. Known history of human immunodeficiency virus (HIV) seropositivity. HIV testing is not 
required as part of this study.
20. Receiving treatment with medications that are known strong inhibitors or inducers of 
CYP3A4, and cannot be discontinued 7 days prior to the start of INC280 treatment and 
during the course of the study (refer to Appendix 4).
21. Receiving treatment with medications that are known CYP3A4 or CYP1A2, substrates 
with narrow therapeutic index, and cannot be discontinued before start of study treatment 
(refer to Appendix 4).
22. 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 4. From a PD point of view, this definition includes any health 
authority approved herbal medication for HCC.
23. Have any of the following out-of-range laboratory values:

Hematology

Hemoglobin ≤ 9g/dL (SI Units: 90g/L)

Platelet count < 75 x 109/L

Absolute neutrophil count (ANC) < 1.5 x 109/L

Biochemistry

Total bilirubin > 2 mg/dL

AST/SGOT and/or ALT/SGPT >5 x upper limit of normal (ULN)

Serum creatinine > 1.5 x ULN

Calculated or directly measured creatinine clearance <45 mL/min (refer to 
Appendix 6 for the calculation)

Asymptomatic serum pancreatic amylase > grade 2

Serum amylase grade 1 or grade 2 serum with signs and/or symptoms suggesting 
pancreatic or pancreatic injury (e.g. elevated P-amylase, abnormal imaging 
findings of pancreas, etc)

Serum lipase > ULN

Fasting serum triglyceride level >500 mg/dL
24. Patients who have received any other investigational agents within a period of time that is 
less than the cycle length used for that treatment or equal to 4 weeks (whichever is shorter) 
prior to starting study drug and recovered from any side effects to grade 1 or less.


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25. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test.
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 7 days after permanently discontinuing INC280 medication. 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) 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.

Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device or intrauterine system
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy) or tubal ligation at least 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.
Sexually active males unless they use a condom during intercourse while taking drug and for 7
days after stopping study medication 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.


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6
Treatment
6.1
Study treatment
INC280 will be considered as the investigational treatment or the “study drug” for this study.
6.1.1
Dosing regimen
INC280 will be dosed on a flat scale of mg/day and not individually adjusted by body weight 
or body surface area. Hard gelatin capsules at strength of 50 mg, and film-coated tablets at 
dosage strengths of 50 mg and 200 mg are available. Tablets at 150 mg strength may be also 
provided according to local regulations when available.
During the Dose Expansion Part, the INC280 formulation may be changed from capsule to 
tablet upon its availability.
6.1.1.1
Instructions for administration of INC280
INC280 will be administered orally and continuously on bid dosing schedule. A treatment cycle 
is defined as 21 days in Dose-Determining and Dose Expansion parts.
Except on the days of full PK profiles sampling, patients should be instructed to take their dose 
at approximately the same time each day. The second (evening) dose should be taken 12 (±2) 
hours apart from first morning dose. Patients will self-administer the study medication with a 
glass of water at about the same time every day. Patients will consume another glass of water 
approximately 2 hours after dosing. INC280 should be administered in the fasted state, at least 
1 hour before or 2 hours after a meal. During fasting period, patients can freely drink water. 
Patients should avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice 
and start fruits during the treatment. On the days when PK blood samples are to be collected 
(Section 7.2.3), patients will be instructed to hold their dose of INC280 until arrival at the study 
center. The administration of study treatment will be supervised by the study personnel. The 
same dietary restrictions for dosing will be in place on days with PK sampling.

If vomiting occurs, no attempt should be made to replace the vomited dose. If any 
episodes of vomiting occurred within the first 4 hours of INC280 dosing, on PK sampling
days, exact time of vomiting should be recorded on the appropriate electronic Case Report 
Form (eCRF) besides the AE eCRF.

A missed dose is defined as any time point when a patient forgets to take INC280 within 8 
hours after the planned time of dosing or if a patient forgets to take his/her dose for that 
day. In such cases, the dose should be omitted and the patient should continue treatment 
with the next scheduled dose.

On days when PK 
 blood samples are to be collected after Cycle 2, 
study drug will be administered at the site in the morning.
During the entire 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 sunlamp or tanning bed).


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6.1.2
Treatment duration
All patients will be treated with INC280 administered orally, beginning on Cycle1 Day1. Each 
cycle will have 21 days. All patients will continue to receive INC280 until disease progression 
or unacceptable toxicity occurs, withdrawal of consent, or discontinuation for any other reason.
6.2
Dose modifications guidelines
6.2.1
Starting dose rationale
The selection of the oral dosing schedule had been discussed above Section 2.3.
6.2.2
Implementation of dose decision analysis
To implement dose determination for Dose Expansion Part, the available toxicity information 
(including AEs and laboratory abnormalities that are not qualifying AEs), the recommendations 
from the BLRM, and the available PK 
 information will all be evaluated 
by the Investigators and Novartis study personnel (including the study physician and statistician) 
during dose decision meeting by teleconference. Drug administration at Dose Expansion Part 
may not proceed until the investigator receives written confirmation from Novartis indicating 
that the results of the Dose-Determining Part were evaluated and that it is permissible to proceed 
to the Dose Expansion Part.
For safety analysis: The tolerability of INC280 will be evaluated by the BLRM based on the 
incidence of qualifying adverse events during the first 28 days treatment for which relationship 
to study treatment cannot be ruled out (see Table 6-2 and Section 10.5.3.3 for details). The 
BLRM will recommend the highest dose which is estimated to be tolerable (as per the 
Escalation with Overdose Control (EWOC) criteria). The EWOC criteria mandate that any dose 
that is estimated to have 25% or more chance to be excessively toxic (≥ 33% qualified AE-rate) 
must not be used until more data is available. At time of the analyses, BLRM will include all 
available safety data for INC280 from this study and external trials. See Section 10.5.3.3 for 
details.
For PK analysis: Mean ratio of INC280 systemic clearance will be calculated based on the data 
from HCC patients in the Dose-Determining Part and pooled historical data from cancer patients 
who had normal liver function (NCI-ODWG criteria) (Patel et al 2004). If INC280 exposure in 
Dose-Determining Part is comparable to the historical data, as indicated by mean ratio of the 
systemic clearance, Expansion Part dose will be recommended as recommended phase 2 dose 
(RP2D). If INC280 exposure at Dose-Determining Part dose is higher, Expansion Part dose as 
per PK analysis will be the RP2D proportionally reduced by the decreased mean ratio. If 
INC280 exposure in lead-in Dose-Determining Part is lower, Expansion Part dose as per PK 
analysis will be the RP2D proportionally increased by the increased mean ratio taking into 
consideration the toxicity and feasibility. For details of PK analysis and PK specific criteria for
choosing a dose, please refer to Section 10.5.4.1.
The rules for dose recommendation for the Dose Expansion Part will be followed as listed in 
Table 6-1. The Expansion Part dose can be the same, lower or higher than the Dose-Determining 
Part dose.


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Table 6-1
Rules for dose recommendation for the Dose Expansion Part
Consideration of both safety and PK data 
based on the following scenarios
Recommended Expansion Part Dose
Safety
INC280 exposure (PK 
profile)
Tolerable
Comparable
RP2D/MTD/maximum tested dose that is determined to be 
safe, from dose escalation studies CINC280X1101, 
CINC280X2102 and/or INCB28060-101
Increase in exposure
Proportional reduction of RP2D; if the reduced dose is lower 
than the Dose-Determining Part dose, use the Dose-
Determining Part dose for Dose Expansion Part.
Decrease in exposure
Proportional increase of RP2D by taking into consideration the 
toxicity and feasibility.
Intolerable
Comparable
Highest dose recommended by BLRM safety analysis
Increase in exposure
The lower of the dose following recommendation from PK and 
safety analysis:
- Proportional reduction of the Dose-Determining Part dose
- Highest dose recommended by BLRM safety analysis
Decrease in exposure
Highest dose recommended by BLRM safety analysis
6.2.3
Adverse events criteria for dose decision analysis
As mentioned in Section 4.1 and Section 10.5.3.3, a two-parameter BLRM will be used for the 
safety analysis. This safety analysis (to be performed during the dose decision analysis after the 
Dose-Determining Part as well as to confirm the Expansion Part dose) will be based on data 
(occurrence/ absence) of certain AEs within 28 days treatment. The qualifying AEs are defined 
as an adverse event or abnormal laboratory value that is assessed by the investigator as related 
to therapy with INC280 and unrelated to disease progression, intercurrent illness, or 
concomitant medications and meets any of the criteria in Table 6-2. The qualifying AEs will be 
considered in the safety analysis
Table 6-2
Criteria for qualifying AEs to be considered for the dose decision 
analysis
Toxicity
Any of the following criteria:
Hematology
Any grade 3 hematologic toxicity, lasting for > 7 consecutive days
Grade 3 thrombocytopenia with bleeding
Any grade 4 hematologic toxicity (of any duration)
Febrile neutropenia (ANC 1.0 x 109/L or 1000/mm3 and a single temperature 
of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C (100.4 °F) for more than 
one hour.
Renal
Serum creatinine ≥ grade 3 (≥3.0 x baseline or >3.0 - 6.0 x ULN)
Hepatic
≥ CTCAE grade 3 total bilirubin (> 3 x ULN)
AST or ALT grade 3 (>5.0 -20.0 x ULN) for ≥ 7 consecutive days
AST or ALT grade 4 (>20.0 x ULN)
Reactivation of Hepatitis B or/and C
Pancreas
Asymptomatic ≥ CTCAE grade 3 serum amylase or lipase (>2.0 × ULN) occurring 
for > 14 consecutive days
Symptomatic serum amylase or lipase elevation, medical intervention required
Neurologic
Any neurological abnormality or toxicity ≥ grade 2
Cardiac
≥ CTCAE grade 3


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Toxicity
Any of the following criteria:
Other AEs
Any other AE ≥ grade 3
Grade 3 fatigue, lasting for > 7 consecutive days
Grade 3 nausea, vomiting, diarrhea if in setting of optimal, anti-emetic and anti-
diarrheal therapy
CTCAE version 4.03 will be used for all grading.
Patients may receive supportive care (e.g. transfusion of red blood cells) as per local institutional guidelines.
6.2.4
Dose determining for tablet formulation
A relative bioavailability study in HVs, CINC280X2103 study, was conducted to compare the 
relative bioavailability of INC280 tablet to INC280 capsule. The results of this study showed 
that following a single oral administration of 600 mg INC280 in healthy subjects, both 
formulations had similar Tmax; tablets however provided higher systemic exposures (Cmax 
and AUC) and lower inter-subject variability. The exposure geometric mean ratios (tablet vs. 
capsule) were around 2 to 3. As of 3-Nov-2014, preliminary tablet PK data are available from 
16 patients of tablet cohorts at different doses in various INC280 studies (i.e., 200 and 400 mg 
bid single agent in CINC280X1101 study, 200 mg bid in combination with gefitinib in 
CINC280X2202 study, and 400 mg bid single agent in CINC280X2102 study). INC280 tablet 
showed generally lower inter-subject variability than capsule (CV% typically <50% for tablet, 
whereas >50% for capsule). Based on the limited data, mean AUC and Cmax at steady-state 
following administration of INC280 tablets at 400 mg bid was higher than that following 
capsules at 600 mg bid (RP2D in CINC280X2102 study), but in the range considering the CV%. 
Based on the tablet PK and safety data from these studies, the dosage of INC280 at 400 mg bid
in tablet has been declared as RP2D in CINC280X2102 study, and is further evaluated in 
CINC280X1101 study and CINC280X2202 study. Therefore, 400 mg bid is determined to be 
the dose of tablet formulation in the dose expansion part of this study. When the INC280 tablet 
formulation is available, patients who are newly enrolled may start at INC280 400 mg bid tablet 
treatment. Patients who have been treated with INC280 600 mg bid
capsules, in compliance 
with the local regulation, may switch at the beginning of the next scheduled visit with INC280 
400 mg bid tablet treatment.
6.2.5
Dose modification and delay
For patients who do not tolerate the protocol-specified dosing scheme, dose adjustments and 
interruptions are permitted. All dose modifications should be based on the worst preceding 
toxicity (CTCAE version 4.03). Once a dose reduction has occurred, the dose level may not be 
re-escalated during subsequent treatment cycles with INC280. In addition, in the Dose 
Determining Part, a patient must discontinue treatment with INC280 if, after treatment is 
resumed at a lower dose, the toxicity recurs with the same or worse severity. In the Dose 
Expansion Part, a patient must discontinue treatment with INC280 if, after treatment is resumed 
at the lowest allowed dose (200 mg BID, tablet), the toxicity recurs with the same or worse 
severity. All interruptions or modifications to study drug administration must be recorded on 
the Dose Administration Record eCRF.
If a dose delay of >21 days is required, then the investigational treatment with INC280 must be 
discontinued. Table 6-3, Table 6-4, Table 6-5, Table 6-7 and Table 6-8 provide the guidelines 
to be followed for dose modification of the study drug in the event of toxicities. Included are 


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also instructions for re-initiation of study treatment once sufficient recovery of toxicity is seen. 
Any dosing modifications that are not in accordance with the guidelines in Table 6-3, 
Table 6-4, Table 6-5, Table 6-7 and Table 6-8 (Andrew et al 2010) must be discussed with 
Novartis. Any dose change to the study drug must be recorded on the eCRF. The study visit 
schedule should be followed irrespective of any study drug interruption.
In exceptional situations, study treatment may continue even if there is a dose interruption 
of >21 days or the patient experienced disease progression. The decision to allow for 
continuation of treatment will be made on a case-by-case basis following discussion between 
Novartis and the investigator. Situations that may allow for continuation of treatment include 
the following:

A dose delay of >21 days has occurred but the patient is clearly benefiting from study 
treatment (i.e., SD, PR, or CR) and it is the investigator’s opinion that no safety concerns 
are present.

A patient with disease progression may be allowed to continue study treatment if it is in 
the best interest of the patient to continue treatment. Examples of situations that may allow 
for continuation of therapy include cystic lesions, mixed responses, and new brain 
metastases that are treatable with stereotactic radiotherapy or surgery.
Table 6-3 and Table 6-4 describe respectively for the Dose-Determining Part and Dose 
Expansion Part, the starting dose and the study drug dose modification to be followed in case 
of study drug related toxicities. For each patient in Dose Expansion Part treated with INC280 
tablets, a maximum of 2 dose level modifications is allowed after which the patient must be 
discontinued from treatment. The lowest dose allowed, 200 mg BID in tablets is expected to be 
pharmacologically active, as the observed steady state plasma trough concentrations 
( [CINC280X1101], [CINC280X2202], n=6) were above the concentration associated with full 
cMET inhibition in xenograft mice models (EC90, 120 nM total concentration).
Table 6-3
Dose-Determining Part study drug dose reductions
Dose level
Dose and schedule (capsule)
Increment from previous dose
-1
200 mg bid
-33% of starting dose
0
300 mg bid
Starting dose for Dose-Determining Part
Table 6-4
Dose Expansion Part study drug dose reductions
Dose level
Dose and schedule (capsule)
Increment from previous dose
−1
450 mg bid (capsule)
−25% of starting dose
0
600 mg bid (capsule)
Starting dose for Expansion Part
Dose level
Dose and schedule (tablet)
Increment from previous dose
−2
200mg bid (tablet)
-50% of starting dose
−1
300 mg bid (tablet)
−25% of starting dose
0
400 mg bid (tablet)
Starting dose for Expansion Part


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Table 6-5
Recommended dosing guidelines for study drug-related toxicities
Recommended dose modifications of INC280
Worst toxicity CTCAE v4.03 grade
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosing
Hematologic
ANC decreased (Neutropenia)
Grade 1 ( LLN - 1500/mm3 or LLN – 1.5x109/L)
Maintain dose level
Grade 2 (< 1500 - 1000/mm3 or <1.5 – 1.0x109/L)
Maintain dose level
Grade 3 (< 1000 - 500/mm3 or < 1.0 – 0.5x109/L)
Discontinue dose until resolved to ≤ grade 1 or baseline, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (< 500/mm3 or < 0.5x109/L)
Discontinue dose and patient from study treatment.
Febrile neutropenia
ANC 1.0 x 109/L or 1000/mm3 and a single 
temperature of >38.3°C (101 °F) or a sustained 
temperature of >=38 °C (100.4 ° F) for more than one 
hour.
Discontinue dose until resolved, then:
If resolved in ≤ 7 days, then resume treatment at 1 dose level. If resolved in > 7 days, then discontinue 
dose and patient from study treatment
Platelet count decreased (Thrombocytopenia)
Grade 1 or 2 (< LLN – 50x109/L)
Maintain dose level
Grade 3 (<50 – 25x109/L)
Discontinue dose until resolved to ≤ grade 1 or baseline, then:
If resolved in ≤7 days, then maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
Grade 4 (<25x109/L)
Discontinue dose until resolved to ≤ grade 1 or baseline, then 1 dose level
Renal
Serum creatinine
Grade 1 (> ULN – 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 - 3.0 x ULN)
Discontinue dose until resolved to ≤ grade 1 or baseline, then maintain dose level. Patients will be 
instructed to increase their fluid intake until resolution to ≤ grade 1 or baseline.
Grade 3 or 4 (3.0 x ULN)
Discontinue dose until resolved to ≤ grade 1 or baseline, then resume treatment at 1 dose level. Patients 
will be instructed to increase their fluid intake until resolution to ≤ grade 1 or baseline.
If grade 4 event recurs at any point during participation, discontinue study treatment.


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Recommended dose modifications of INC280
Worst toxicity CTCAE v4.03 grade
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosing
Hepatic
Isolated Total Bilirubina
Grade 1 (> ULN – 1.5 x ULN)
Maintain dose level with liver function tests (LFTs)* monitored 
Grade 2 (>1.5 - 3.0 × ULN)
Omit/delay dose until resolved to ≤ grade 1 or baseline, then:
If resolved in ≤ 7 days, maintain dose level
If resolved in > 7 days, 1 dose level
Grade 3 (> 3.0 - 10.0 x ULN)
Omit/delay dose until resolved to ≤ grade 1 or baseline, then:
If resolved in ≤ 7 days, 1 dose level
If resolved in > 7 days, discontinue patient from study treatment
Grade 4 (> 10.0 x ULN)
Discontinue dose and patient from study treatment.
Isolated AST or ALT
Grade 1 or 2 (> ULN - 5.0 x ULN)
Maintain dose level with liver function tests (LFTs)* monitored 
Grade 3 (> 5.0 – 20.0 x ULN)
Omit/delay until resolved to ≤ grade 1 or ≤grade 2 if grade 2 elevation at baseline, then:
If resolved in ≤ 7 days, maintain dose level of INC280
If resolved in > 7 days, ↓ 1 dose level of INC280
Grade 4 (>20.0 x ULN)
Discontinue dose and patient from study treatment.


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Recommended dose modifications of INC280
Worst toxicity CTCAE v4.03 grade
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosing
Combinedb elevations of AST or ALT, and Total Bilirubin
For patients with normal baseline ALT and AST and total 
bilirubin value:
AST or ALT >3.0xULN combined with total bilirubin >2.0 
x ULN without evidence of cholestasisc
OR
For patients with elevated baseline AST or ALT or total 
bilirubin value:
[AST or ALT>2x baseline AND > 3.0 xULN] OR [AST or 
ALT > 8.0 xULN] combined with [total bilirubin >2x 
baseline AND >2.0 xULN
Discontinue study treatment 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. Refer to Section 6.2.6 for additional follow-up evaluations 
as applicable.
Reactivation of HBV or HCV
Please refer to Table 6-7, Table 6-8.
*LFTs include albumin, ALT, AST, GGT, total bilirubin (fractionated [direct and indirect] if total bilirubin > 2.0 x ULN) and ALP (fractionated [quantification of isoforms], if 
alkaline phosphatase > 2.0 x ULN). Refer to Section 6.2.6 for additional follow-up evaluations.
Pancreaticd
Asymptomatic grade 1 or 2 amylase or lipase increased 
(>ULN – 2.0 x ULN)
Maintain dose level
Asymptomatic grade 3 or greater amylase or lipase 
increased (> 2.0 - > 5.0 x ULN)
Omit/delay dose until resolved to ≤ G2, then:
If resolved in ≤ 7 days, maintain dose level
If resolved in > 7 days, then ↓ 1 dose level
Asymptomatic grade 4 (> 5.0 x ULN)
Discontinue does and patient form study treatment
Symptomatic elevations of any grade
Discontinue does and patient form study treatment


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Recommended dose modifications of INC280
Worst toxicity CTCAE v4.03 grade
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosing
Neurologic
Any Neurological Toxicity
Grade 2
Discontinue study treatment.
Neurological assessments must be repeated at least twice a week until resolution to < CTCAE grade 1. 
Unscheduled MRI and gadolinium enhanced T1 imaging may also be conducted to evaluate patients for 
intramyelinic edema like lesions, brain metastases and other unanticipated CNS occurrences. An EEG may 
be performed to monitor for physiological changes in brain activity.
Cardiac
Cardiac general
Grade 1 or 2
Maintain dose level
Grade 3
Discontinue dose until resolved to ≤ grade 1, then 1 dose level
Grade 4
Discontinue dose and patient from study treatment
ILD / 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.
Grade 1
Interrupt INC280 during diagnostic workup for ILD/Pneumonitis. 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.
If it recurs after resumption of study drug, permanently discontinue INC280.


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Recommended dose modifications of INC280
Worst toxicity CTCAE v4.03 grade
Recommended dose modifications any time during a cycle of therapy, including intended day of 
dosing
Grade 2
Mandatory: Interrupt INC280 dose during diagnostic workup for ILD/pneumonitis 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, INC280 may be restarted following these guidelines:
· If resolves to ≤ Grade 1 in ≤ 7 days reduce study drug 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 INC280. Treat with IV steroids as clinically indicated. Oxygen therapy 
as indicated
Other adverse events
Grade 1 or 2
Maintain dose level
Grade 3
Discontinue dose until resolved to ≤ grade 1, then 1 dose level
Grade 4
Discontinue study treatment
a 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 of INC280, and continue treatment at the discretion of the Investigator
b “Combined” defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total bilirubin and 
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 the treatment either at the same dose or at one dose lower if meeting a criterion for dose reduction
c “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
d A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any ≥ Grade 3 of amylase 
or lipase.


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Table 6-6
Follow-up evaluations for selected toxicities
Toxicity
Follow-up evaluation
Hematology
If febrile neutropenia of any duration occurs, the patient must be followed until resolution.
If ≥ CTCAE grade 3 hematologic toxicity occurs, the parameter must be repeated at least 
twice a week until resolution to ≤ CTCAE grade 1 and then at least weekly until either 
initiation of retreatment or until stabilization.
Renal
If serum creatinine ≥ CTCAE grade 2 has been demonstrated, this parameter must be 
repeated at least twice a week until resolution to ≤ CTCAE grade 1 or baseline, and then at 
least weekly until either initiation of re-treatment or until stabilization. Patients will be 
instructed to increase hydration until resolution to ≤ CTCAE grade 1 or baseline.
Hepatic
In case of isolated elevations in total bilirubin, AST or ALT, additional follow-up evaluations 
are recommended as outlined in Table 6-9.
Pancreatic
If serum amylase or serum lipase ≥ CTCAE grade 3, follow until resolution to grade 2 or 
less.
Neurologic
If any neurological abnormality or toxicity ≥ grade 2 has been demonstrated, neurological 
assessments must be repeated at least twice a week until resolution to ≤ CTCAE grade 1. 
Unscheduled MRI and gadolinium enhanced T1 imaging may also be conducted to 
evaluate patients for intramyelinic edema like lesions, brain metastases and other 
unanticipated CNS occurrences. An EEG may also be performed to monitor for 
physiological changes in brain activity.
Cardiac
Monitor toxicity until resolution to grade 1 or baseline. If applicable, monitor 
electrocardiograms (ECGs) twice weekly until normalization or stabilization.
Non-laboratory
Patients who experience non-laboratory DLTs must be evaluated at least once a week 
following demonstration of the toxicity until resolution of the toxicity to allow for re-
treatment, until stabilization of the toxicity, or until study completion.


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Table 6-7
Guidelines for the management of hepatitis B reactivation
HBV-DNA
OR HBsAg
in baseline 
result
Definition of 
reactivation
Treatment
+
Increase of 1 log 
in HBV-DNA
relative to 
baseline HBV-
DNA value
Provide antivirus treatment *
AND
Interrupt study drug administration until:
≤baseline HBV-DNA levels
If resolution occurs within ≤21 days, study drug should be restarted at one 
dose lower, if available (see Table 6-2 and Table 6-3 for dose level 
available).
If the patient is already receiving the lowest dose of study drug according 
to the protocol, the patient should restart at the same dose after resolution.
If resolution occurs >21 days, patients should discontinue study drug but 
continue antiviral therapies at least 4 weeks after last dose of study drug.
-/ HBsAb (+)
(with no prior 
history of 
vaccination 
against HBV 
or HBcAb(+)
New 
appearance of 
measurable 
HBV-DNA
Provide antivirus treatment*
AND
Interrupt study drug administration until resolution:
≤undetectable (negative) HBV-DNA levels
If resolution occurs within ≤21 days, study drug should be restarted at one 
dose lower, if available (see Table 6-2 and Table 6-3 for dose level 
available).
If the patient is already receiving the lowest dose of study drug according 
to the protocol, the patient should restart at the same dose after resolution.
If resolution occurs >21 days, patients should discontinue study drug but 
continue antiviral therapies at least 4 weeks after last dose of study drug.
*Antivirus treatment will be provided under discretion of investigator according to local clinical practice.
All reactivations of HBV are to be recorded as grade 3 (CTCAE version 4.03 Infections and 
infestations/Hepatitis viral), unless considered life threatening by the investigator, in which case they should be 
recorded as grade 4. Date of viral reactivation is the date on which the rise or reappearance of HBV-DNA 
criteria was recorded.
Table 6-8
Guidelines for the management of hepatitis C reactivation
HCV Reactivation*
For patients with baseline results :
Detectable HCV – RNA
Discontinue INC280
Reactivation is defined as :
ALT elevation to 5x ULN
Increase of 1 log in HCV-RNA relative to baseline 
HCV-RNA value
For patients with baseline results :
Knowledge of past hepatitis C infection with no 
detectable HCV – RNA
Discontinue INC280
Reactivation is defined as :
New appearance of detectable HCV – RNA
* All reactivations of HCV are to be recorded as grade 3 (CTCAE Version 4.03 - Infections and 
infestations/Hepatitis viral), unless considered life threatening by the investigator, in which case they should be 
recorded as grade 4. Date of viral reactivation is the date on which the rise or reappearance of HCV-RNA (and 
ALT) criteria was recorded.


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6.2.6
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed up at least once a week (or more frequently if 
required by institutional practices, or if clinically indicated) for 4 weeks, and subsequently at 
approximately 4-week intervals, until resolution or stabilization of the event, whichever comes 
first. Appropriate clinical experts should be consulted as deemed necessary. All patients must 
be followed up for AEs and SAE for 30 days following the last doses of INC280.
Table 6-9
Follow-up evaluations for Hepatic Toxicities*
Toxicity
Follow-up evaluation 
Isolated total bilirubin elevation
CTCAE Grade 1
Monitor LFTs per protocol or more frequently if clinically indicated
CTCAE Grade 2
Weekly monitoring of LFTs, or more frequently if clinically indicated, 
until resolved to ≤ 1.5 x ULN
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
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 week
Isolated AST/ALT elevation
CTCAE Grade 2
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
CTCAE Grade 3 -For 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
CTCAE Grade 3
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
CTCAE Grade 4
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 elevations in ALT and/or AST with concurrent total bilirubin increase, in the absence of cholestasis 
or hemolysis


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Toxicity
Follow-up evaluation 
Combined elevations of AST or ALT 
and total bilirubin
After discontinuing the patient from INC280 permanently, repeat core 
LFTs as soon as possible, preferably within 48 hr 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 hepatic toxicities. Refer to Table 6-5 for dose 
modifications required for applicable toxicities.
6.2.6.1
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as: ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc.

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.


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
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.
6.2.7
Anticipated risks and safety concerns of the study drug
Based upon the preclinical data set for INC280, the clinical experience from the three ongoing 
INC280 single agent studies, the overall risk-benefit assessment of INC280 is considered 
favorable. The AEs that have been reported, irrespective of relationship to study drug, have 
been manageable and generally mild or moderate in severity. As of the cut-off date of August 
15, 2012, there have been no SAEs or fatal events with a suspected causal relationship with 
INC280. For further information, please refer to the current version of the [Investigator’s 
Brochure].
6.3
Concomitant medications
6.3.1
Permitted concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies CRF.
Patients are permitted to use the following medications while taking INC280:

Antivirus medications to manage HBV or HCV infection and/or prevent reactivation (e.g. 
lamivudine); supportive care.

Medications to prevent or treat nausea or vomiting.

Anti-diarrheal medications (e.g., loperamide) for patients who develop diarrhea.

Growth factors for low hemoglobin levels (should only be used if hemoglobin is less than 
10g/dL and the patient is symptomatic).

Pain medication to allow the patient to be as comfortable as possible.

Localized radiotherapy and treatment with bisphosphonates for pre-existing, painful bone 
metastases is permitted only if evidence of radiological progression is not present.

Nutritional support or appetite stimulants (e.g. megestrol).

Oxygen therapy and blood products or transfusions.
6.3.2
Permitted concomitant therapy requiring caution and/or action
Medications, herbal remedies and food products that are moderate inducers or inhibitors of 
CYP3A4 are not prohibited but should be administered with caution. 
The following medications should be used with caution when concomitantly used with INC280 
treatment in this study:

Strong CYP3A inhibitors: Coadministration of INC280 with a strong CYP3A inhibitor 
(itraconazole) increased INC280 AUCinf by 42%. There was no change in INC280 Cmax. 


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Closely monitor patients for adverse reactions during coadministration of INC280 with 
strong CYP3A inhibitors.

Moderate CYP3A inducers: Simulations using physiologically-based pharmacokinetic 
(PBPK) models predicted that coadministration of INC280 with the moderate CYP3A 
inducer efavirenz (600 mg once daily for 20 days) would result in a 44% decrease in 
INC280 AUC0-12h and 34% decrease in Cmax at steady-state compared to administration of 
INC280 alone. Caution should be exercised during concomitant use of INC280 with 
moderate CYP3A inducers. Use an alternative medication with no or minimal potential to 
induce CYP3A during coadministration with INC280.

CYP1A2 substrates with narrow therapeutic index (NTI): INC280 is a moderate 
CYP1A2 inhibitor. Coadministration of INC280 increased sensitive CYP1A2 probe 
substrate (caffeine) AUCinf by 134%. Avoid coadministration of INC280 with CYP1A2 
substrateswhere minimal concentration changes may lead to serious adverse reactions. If 
coadministration is unavoidable, decrease the CYP1A2 substrate dosage in accordance 
with the approved prescribing information.

P-gp and BCRP substrates: Coadminstration of INC280 increased P-gp substrate 
(digoxin) exposure (AUCinf and Cmax by 47% and 74%, respectively) and BCRP substrate 
(rosuvastatin) exposure (AUCinf and Cmax by 108% and 204%, respectively). Avoid 
coadministration of INC280 with P-gp and BCRP substrates where minimal concentration 
changes may lead to serious adverse reactions. If coadministration is unavoidable, 
decrease the P-gp or BCRP substrate dosage in accordance with the approved prescribing 
information.

Proton pump inhibitor : Coadministration of INC280 with proton pump inhibitor 
(rabeprazole) decreased INC280 AUCinf by 25% and Cmax by 38%. Exercise caution 
during concomitant use of INC280 with proton pump inhibitors.
H2-receptor antagonists and antacids: As an alternative to proton pump inhibitors, H2-
receptor antagonist or antacid can be taken. INC280 should be administered at least 3 hours 
before or 6 hours after an H2-receptor antagonist. INC280 should be administered at least 2 
hours before or 2 hours after an antacid.
Refer to Appendix 4 for a list of the medications that require caution when concomitantly used 
with INC280.
6.3.3
Prohibited concomitant therapy
INC280 is moderately metabolized by CYP3A4 in vitro. Strong inhibitors or inducers of 
CYP3A4/5 (including medications, herbal remedies and food products) shall be discontinued 7 
days prior to the start of INC280 treatment and are prohibited during the course of the study. 
INC280 is an irreversible inhibitor of CYP1A2 and CYP3A4/5. All agents that are metabolized 
mainly by CYP1A2 or CYP3A4/5 and have a narrow therapeutic window are prohibited during 
this study.
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 INC280 treatment.


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The use of live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, 
yellow fever, varicella, TY21a typhoid vaccines) is not allowed during the study and up to 30 
days from the last dose of INC280 treatment. 
The prohibited medications are listed in Appendix 4.
6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient No. consists of the Center
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the first informed consent form, the patient is assigned to the next sequential 
Patient No. available to the investigator.
6.4.2
Treatment assignment
The assignment of a patient to a particular treatment will be coordinated by the sponsor.
This is an open-label, non-randomized, single arm, multicenter study.
6.4.3
Treatment blinding
This is an open label study.
6.5
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 and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF.
6.5.1
Study drug packaging and labeling
The study medication packaging has a two-part label. Site personnel will add the patient number 
on the label. Immediately before dispensing the package to the patient, site personnel will detach 
the outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique patient number.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and batch number but no information 
about the patient.
6.5.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 


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site personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified on the drug labels and in the [Investigator’s Brochure].
6.5.3
Study drug compliance and accountability
6.5.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
6.5.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all used and unused study 
treatment, packaging, drug labels, and a copy of the completed drug accountability log to the
Novartis monitor or to the Novartis address provided in the investigator folder at each site.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation.
In case that unexpected circumstances interfere with the patient’s compliance and/or protocol 
procedures, the visits can be rescheduled within a ±3-day window except for Day 1 of Cycle 1 
unless otherwise specified in any other section of this protocol. There is -1 day window for all 
evaluations scheduled on Cycle 1 Day 1 except for the PK sampling.
No CRF will be used as a source document.
Following approval by Authorities of protocol amendment 5, the ongoing patients will follow 
a reduced schedule of safety and efficacy assessments as detailed in Table 7-2. The assessments 
in Table 7-1 will no longer be applicable. The table indicates which assessments produce data 


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to be entered into the clinical database (D) or remain in source documents only (S) (“Category” 
column).
Other assessments may be performed at the Investigator’s discretion following standard of care 
at the site.
As per Section 4.5, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowed by local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) can replace on-site study visits, for 
the duration of the disruption until it is safe for the participant to visit the site again.


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Table 7-1
Visit evaluation schedule
Category
Protocol 
Section
Molecular
pre-screening
Screening
Cycle 1
Cycle 2
≥Cycle 3
End of
treatment
(EOT)
Follow-up (FU)
Disease 
progression
30-day 
follow-up
Survival
Every 3 
Weeks
Day of cycle(D)
-14 to 
-1
1
2
15
16
1
8
1
Obtain molecular pre-
screening informed 
consent
D
7.1.1.1
X
c-MET screening on fresh 
or archival tumor biopsy
D
7.1.1.2
X
Obtain Informed Consent
D
7.1.2
X
Patient history
Demography
D
7.1.2.3
X
X
Inclusion/
exclusion criteria
D
5.2 &
5.3
X
Relevant medical 
history/current medical 
conditions, etiology of 
HCC
D
7.1.2.3
X
Diagnosis, extent and 
stage of HCC
D
7.1.2.3
X
Child-Pugh and BCLC 
classification
D
7.1.2.3
X
Prior antineoplastic 
therapy
D
7.1.2.3
X
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
Weight / Height
D
7.2.2.3
X
X
X
X
X


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Category
Protocol 
Section
Molecular
pre-screening
Screening
Cycle 1
Cycle 2
≥Cycle 3
End of
treatment
(EOT)
Follow-up (FU)
Disease 
progression
30-day 
follow-up
Survival
Every 3 
Weeks
Day of cycle(D)
-14 to 
-1
1
2
15
16
1
8
1
ECOG performance status
D
7.2.2.4.
X
X
X
X
X
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
Biochemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
Urinalysis
D
7.2.2.5.3
X
X
Coagulation
D
7.2.2.5.4
X
X
X
X
X
Hepatitis markers
D
7.2.2.5.5
X
X
X
X
Serum Pregnancy
D
7.2.2.5.6
X
X
Urinary Pregnancy
D
7.2.2.5.6
X
X
Tumor Response 
Assessment per RECIST–
i.e., CT/MRI
D
7.2.1
X(-21 
to -1)
X
X
(every other 
cycle starting 
C4D1)
X
X (every 
6 
weeks)
12-lead ECG
D
7.2.2.6
X
X
X
X
(Cycle 3 only)
X
Blood for PK Profile –
Dose-Determining Part
7.2.3.1
X
X
X
X
X
X
(Cycle 3 only)
Blood for PK Profile –
Dose Expansion Part
D
7.2.3.1
X
X
X
X
(Cycle 3 only)


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Category
Protocol 
Section
Molecular
pre-screening
Screening
Cycle 1
Cycle 2
≥Cycle 3
End of
treatment
(EOT)
Follow-up (FU)
Disease 
progression
30-day 
follow-up
Survival
Every 3 
Weeks
Day of cycle(D)
-14 to 
-1
1
2
15
16
1
8
1
Antineoplastic therapy 
after discontinuation of 
study drug
D
7.1.5
X
X
Study Drug Administration
D
7.1.3
Twice Daily
AEs
D
8
X
X
Continuous
X
Prior/concomitant 
medications
D
6.3
X
Continuous
X
Survival contact
D
7.1.5
X


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Table 7-2
Visit evaluation schedule (applicable upon local IRB/EC approval of 
protocol amendment 5)
Category
≥Cycle 3 
(every 12 
weeks) 
End of
treatment
(EOT)
Follow-up (FU)
Disease 
progression
30-day 
follow-up
Survival
(every 12 
Weeks)
Day of 
cycle(D)
1
Physical 
examination
S
X
X
Hematology
D
X
X
Biochemistry*
D
X
X
Coagulation
D
X
X
Hepatitis 
markers
D
X
X
Tumor 
Response 
Assessment 
per RECIST–
i.e., CT/MRI
D
X
X
X (every 12 
weeks)
Antineoplastic 
therapy after 
discontinuation 
of study drug
D
X
X
Study Drug 
Administration
D
Twice Daily
AEs
D
X
X
Concomitant 
medications
D
X
X
Survival 
contact
D
X
* Albumin, ALP, ALT (SGPT), AST (SGOT), amylase, creatinine, lipase, total bilirubin, direct bilirubin are 
mandatory for each visit. The additional parameters may be measured at the discretion of the investigator.
7.1.1
Molecular pre-screening
7.1.1.1
Molecular pre-screening informed consent
Molecular pre-screening consent must be obtained from all patients to permit the collection, 
shipment and testing of archival or fresh tumor sample prior to the planned clinical screening.
7.1.1.2
c-MET pre-screening on fresh or archival biopsy
To be eligible to participate in this study, evidence of c-MET pathway dysregulation in HCC 
patients must be available. Tumor biopsy samples (archival or fresh tumor samples) must be 
submitted to a Novartis designated central laboratory for molecular pre-screening.
Please refer to Section 7.2.4.1 for the collection of tumor samples.


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7.1.1.3
Eligibility for clinical screening
When the patient is considered eligible for clinical screening, the investigator or designee 
should complete the Patient Registration Form and send it to Novartis.
7.1.2
Screening
The clinical screening period starts once a patient has provided written informed consent to 
participate in the study and ends on the day of study entry. Screening assessments have to be 
done within 14 days prior to the first dose of INC280. Patients’ demographics and other 
characteristics data to be collected include: general demography, relevant medical 
history/current medical conditions, diagnosis of HCC, extent of cancer (using BCLC staging 
classification-Appendix 3) for study eligibility evaluation, and prior antineoplastic therapies 
(medication, radiation and surgery), CPC (Appendix 2), physical examination, height and 
weight, vital signs, ECOG performance status, cardiac assessment, safety laboratory 
assessments including hematology, biochemistry, coagulation and pregnancy tests. Other 
assessments will include the special laboratory assessments such as hepatitis markers. Clinical 
and radiological tumor assessment by RECIST (Appendix 1) should be conducted preferably 
within 1 week (7 days) prior to the first dose of the study drug; however tumor assessments up 
to 3 weeks (21 days) prior to the first dose will be acceptable. During screening, the disease 
must be staged. The tumor assessment made during the screening phase will provide the 
baseline tumor measurements, which will be used to determine future responses and/or 
progression. A complete list of screening evaluations is provided in the visit of assessments 
table (Table 7-1).
7.1.2.1
Eligibility screening
When the patient is considered eligible for study treatment, then the investigator or designee 
should complete the Patient Registration Form.
7.1.2.2
Information to be collected on screening failures
Patient who signed an Informed Consent Form but failed to begin taking INC280 for any reason 
will be considered a screen failure. Patients who signed a molecular pre-screening ICF but who 
did not meet the molecular pre-screening criteria, and those patients who did not meet screening 
eligibility criteria will be considered as screening failures. The data from all screening failure 
will be handled in the same manner.
The molecular pre-screening failure or screening failure information will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a SAE during the Screening Phase (see Section 8 for SAE reporting details). For 
molecular pre-screening failures, only SAEs possibly related to a study procedure will be
reported (i.e., SAEs that are assessed as not related will not be reported).


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7.1.2.3
Patient demographics and other baseline characteristics
Data collected will include general patient demographics, relevant medical history and current 
medical confirmations, diagnosis and extent of tumor (BCLC staging classification), CPC and 
details of prior and current anti-neoplastic treatments.
7.1.3
Treatment period
INC280 will be dosed continuously on 21-day (3 calendar weeks) cycles beginning on Day 1 
of cycle 1. A treatment cycle is defined as 21 days (3 calendar weeks) for the purposes of 
scheduling procedures and evaluations. There will be no scheduled break between cycles.
Cycles begin on Day 1 of Cycle 1. Visits will occur on Days 1, 2, 15, and 16 of Cycles 1. Days 
1 and 8 of Cycles 2. Beginning with Cycle 3 Day 1, scheduled visits will occur every 21 days.
Patients will be treated until one of the following criteria is met:

Documented disease progression according to RECIST (Appendix 1)

Unacceptable/intolerable toxicity

Death or discontinuation from study treatment for any other reason as described in 
Section 7.1.4.1 and Section 4.3.
Safety and efficacy monitoring should continue as per visit schedule (see Table 7-1 and 
Table 7-2). Dose adjustments of study drug (reduction, interruption or) according to safety 
findings will be allowed. Tumor assessments will be performed at screening, C2D1(±7 days), 
then on Day 1 (±7 days) of every other cycle after C2D1 until disease progression. PR and 
Complete Response (CR) should be confirmed at the next scheduled tumor assessment (and no 
sooner than 4 weeks after the initial response).
7.1.4
End of treatment visit including study completion and premature 
withdrawal
An EOT visit should be conducted within 14 days of the last dose of study drug or within 14 
days of the decision to permanently discontinue study drug. If the patient discontinues from the 
study at a scheduled visit, the EOT assessment can be performed on that day. An End of 
Treatment Phase Completion eCRF page should be completed to include the date and reason 
for discontinuing INC280.
If the patient experiences INC280 dose delay >21 days (refer to Section 6.2.5 for exceptional
situations), the EOT assessment should be performed within 30 days of the last dose of INC280.
7.1.4.1
Criteria for premature patient withdrawal
Patients may voluntarily withdraw from the study or be withdrawn from it at the discretion of 
the investigator at any time. Patients may be withdrawn from the study if any of the following 
occur:

AE(s)

Lost to follow-up

Non-compliance with study treatment

Physician decision


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
Pregnancy

Progressive Disease (refer to Section 6.2.5 for exceptional situations)

Protocol deviation

Study terminated by sponsor

Technical problems

Patient/guardian decision

Death
Patients who transfer into another study or an alternative way to continue provision of study 
treatment will perform the end of treatment procedures.
7.1.4.2
Replacement policy
Dose-Determining Part :
Patients will not be replaced on study. However, if a patient is considered as non-evaluable for 
the DDS, enrollment of new patients may be considered until at least the minimum number of 
6 evaluable patients is achieved within the Dose-Determining Part.
Dose Expansion Part:
During the Dose Expansion Part, no replacements will be needed.
7.1.5
Follow up period
30-day follow up
All patients must have safety evaluations for 30 days after the last dose of study treatment.
Patients lost to follow up should be recorded as such in the source documents. For patients who 
are lost to follow-up, the investigator 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.
Disease progression follow up
Any patient who discontinues from INC280 for any reason (except for death, disease 
progression, lost to follow-up, or study termination) will continue to have tumor assessments 
performed every 6 weeks in the follow-up period until disease progression or start of new 
anticancer therapy. Patients who withdraw consent to take study treatment but still agree to be 
followed will continue to have all protocol-specific procedures.
Survival follow up
Upon completion of the 30-day follow up or disease progression follow up, all patients, except 
those who died, withdrew consent for follow-up as a result of patient decision or were lost of 
follow-up, will be followed for survival every 3 weeks until death or at least 6 months after last 
patient first dose.


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For patients who transfer to another clinical study or an alternative way 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.
7.2
Assessment types
7.2.1
Efficacy assessments
Evidence of clinical efficacy will be evaluated based on radiographic tumor assessments. Tumor 
response will be evaluated using RECIST version 1.1. (See Appendix 1 for complete details) 
including the additional modifications described later in this section.
Tumor assessments are required for screening purposes to determine baseline disease at study 
entry. Both measurable and non-measurable lesions must be assessed and target lesions 
identified at the baseline visit. Scans performed within 21 days of treatment start can be used 
as the baseline assessments.
Schedule of tumor assessments
The scheduled tumor assessments are as follows:

At screening (preferably 7 days prior to 1st dose, however, scans within 21 days of 1st dose 
are acceptable).

Day 1 (± 7 days) of every other cycle starting from C2D1, (i.e C2D1, C4D1, C6D1, etc).

At the EOT if a scan was not conducted within 30 days prior to EOT.
Tumor assessments at baseline/screening
The following tumor assessments are to be performed at baseline/screening:

Chest, abdomen and pelvis CT or MRI scan, including dual-phase imaging of the entire 
liver

Brain CT or MRI scan (only if clinically indicated to exclude CNS metastases)

If bone metastases are suspected, a whole body bone scan (e.g., Tc99m bone scan, NaF 
positron emission tomography (PET) or whole body bone MRI). Any skeletal lesions 
identified on the bone scan at baseline that are not visible on the chest, abdomen and 
pelvis CT or MRI scan, should be imaged with localized CT, MRI or x-ray at baseline.

Color photography if skin lesions are present (it is recommended to include a ruler to 
estimate the size of the lesion).
Tumor assessments after baseline/screening
The following tumor assessments are to be performed after baseline/screening:

Chest, abdomen (including dual-phase imaging of the entire liver), pelvis CT or MRI scan

Any skeletal lesions identified at baseline that are not visible on the chest and/or abdomen 
and/or pelvis CT or MRI scan, should be imaged with localized CT, MRI or x-ray at 
subsequent visits. Whole body bone scans need not be repeated after baseline unless 
clinically indicated


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
Color photography if skin lesions were identified at baseline (it is recommended to include 
a ruler to estimate the size of the lesion).

Additional tumor assessments may be performed if there is symptomatic evidence 
suggesting the possibility of disease progression based on clinical symptoms or physical 
exam.
PR and CR should be confirmed at the next scheduled tumor assessment (and no sooner than 4 
weeks later).
Chest x-ray or ultrasound should not be used for tumor response assessments in this study.
All patients discontinuing from the study for PD must have their disease progression 
documented by radiologic evaluation. In cases of clinically-evident disease progression, all 
efforts should be made to perform a radiologic evaluation.
Methods of tumor assessments
All scans should be performed with intravenous (i.v.) contrast administration. If a patient cannot 
tolerate i.v. contrast for either CT or MRI at baseline, the patient may not participate in the 
study. If a patient develops a contraindication to CT i.v. contrast during the study, MRI 
(preferably with i.v. contrast if tolerated) may be performed instead. CT without i.v. contrast is 
not recommended unless MRI cannot be performed.
The same method of assessment and the same technique should be used throughout the study 
to characterize each identified and reported lesion at baseline and during follow-up.
It is mandatory to obtain dual-phase imaging of the liver throughout the study (if there is liver 
involvement at baseline). Every effort should be made to time the contrast administration so 
that high-quality arterial-phase imaging is obtained throughout the liver on the first run, and 
high-quality portal venous-phase imaging is obtained throughout the liver on the second run. 
The timing of the contrast administration should also be kept consistent across timepoints for a 
patient.
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 oral and intravenous contrast media and 
provided acquisition of a dual-phase CT scan, as previously described.
Reporting and recording of tumor assessments
Each center should have a designated radiologist responsible for the interpretation of scans and 
the response evaluation according to RECIST 1.1 (Appendix 1). Preferably, a single radiologist 
should perform all evaluations for an individual patient.
Tumor assessments will be recorded in the eCRF RECIST pages.
All patients should have at least one measurable lesion on contrast enhanced CT or contrast 
enhanced MRI per RECIST 1.1(Appendix 1).
Tumor assessments during follow-up
If study drug discontinuation is not due to disease progression, death, lost to follow-up, or 
starting a new cancer therapy, patients will continue to have tumor assessments every 6 weeks 


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(±7 days), until the patient has documented disease progression, begins a new cancer therapy 
(if started before disease progression was documented) or until the completion of study 
evaluation for any other reason. Tumor assessments during the follow-up phase should be 
scheduled from the last scans.
Central assessment
In addition to local radiological assessments, Novartis may collect imaging data for storage and 
possible future central review by a Novartis designated central imaging contract research 
organization (CRO). The radiologist performing the reading at the central imaging CRO would 
remain blinded to the results of the local assessment and to the treatment the patient has received. 
Investigator sites may be requested to submit results of any cytological evaluations performed 
during the study (e.g., to investigate ascites or pleural/pericardial effusions) along with the 
radiological studies to the central imaging CRO. Additionally, the central imaging CRO may 
collect information regarding baseline conditions like prior loco-regional therapies (e.g., 
surgical resection, percutaneous hepatic arterial embolization, radiofrequency ablation,
percutaneous interventional therapy, etc.) directly from the sites to be made available to the
central reader.
7.2.2
Safety and tolerability assessments
Safety will be monitored using the following assessments: safety labs, 12-lead ECG, physical 
examination, vital sign, height and weight, ECOG performance status, laboratory evaluations, 
liver function assessment, 
 HBV and HCV testing. In addition, AEs and concomitant 
medications will also be collected at every visit. For details on AE collection and reporting, 
refer to Section 8.
All safety assessments performed on Cycle 1 Day 1 pre-dose will provide the baseline safety 
assessments. For safety assessments not carried out on Cycle 1 Day 1 prior to dosing, screening 
assessment will be used as baseline.
Following approval of protocol amendment 5, assessments for vital signs, height and weight, 
performance status are not required by the protocol.
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur for safety monitoring and discussion of the patient´s health 
status until it is safe for the patient to visit the site again.
7.2.2.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological assessments.
A complete physical examination must be performed:
!
Screening
!
Cycle 1 Day 1 pre-dose
!
Day 15 of Cycle 1
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
Day 1 and 8 of Cycle 2

Day 1 of Cycle 3 and subsequent cycles

EOT
Information about the physical examination must be present in source documentation at the 
study site.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF.
7.2.2.2
Vital signs
Vital signs (blood pressure, pulse and body temperature) will be obtained in the same position, 
either sitting or supine, as appropriate prior to any blood collection. Vital signs are usually taken 
with the physical examination but may be taken within a window period of ± 72 hours from the 
physical examination.
Vital signs will be performed at:

Screening

Cycle 1 Day 1 pre-dose

Day 15 of Cycle 1 (blood pressure and pulse only)

Cycle 2 Day 1

Day 8 of Cycle 2 (blood pressure and pulse only)

Day 1 of Cycle 3 and subsequent cycles

EOT
Additional results from vital sign evaluations should be recorded on the appropriate 
Unscheduled visit eCRF page.
7.2.2.3
Height and weight
Height in centimeters (cm) will be measured and recorded at the screening visit only.
Body weight (to the nearest 0.1 kilogram) will be measured in indoor clothing and without 
shoes; weight will be measured and recorded:

Screening

Day 1 of all cycles (before first dose on Cycle 1 Day 1)

EOT
Additional results from weight evaluations should be recorded on the appropriate unscheduled 
visit eCRF page.


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7.2.2.4
Performance status
ECOG performance status will be documented at:
!
Screening
!
Day 1 of all cycles (before first dose on Cycle 1 Day 1)
!
EOT
Assessment of ECOG Performance Status will be performed on the scheduled day, even if study 
medication is being held.
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 self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
7.2.2.5
Laboratory evaluations
The local site laboratory will be used for the following standard clinical laboratory assessments: 
hematology, chemistry, coagulation, urinalysis and serum pregnancy test. All analyses for these 
tests will be performed locally and the results will be based on local laboratory normal ranges.
Creatinine clearance will be calculated using Cockcroft-Gault formulation for Glomerular 
Filtration Rate (GFR) estimation (Appendix 6).
Table 7-4
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Complete blood count, including total White blood cells (WBC) with differentials 
(neutrophil count), hemoglobin (Hb), hematocrit, platelet count.
Chemistry
Albumin, ALP, ALT (SGPT), AST (SGOT), Amylase, Bicarbonate, Calcium, Chloride, 
Creatinine, glucose, lipase, inorganic phosphorus, magnesium, potassium, sodium, Direct
Bilirubin, Total Bilirubin, Total Cholesterol, Total Protein, Triglycerides, Blood Urea 
Nitrogen (BUN) or Urea, Uric Acid.
Urinalysis
Macroscopic Panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, pH, Protein, Specific Gravity, Urobilinogen)
Microscopic Panel (Red Blood Cells, WBC, Casts, Crystals, Bacteria, Epithelial cells)
Coagulation
Prothrombin time (PT) or International normalized ratio (INR)
Hepatitis markers
HBV-DNA, HBsAg, HBcAb, HBsAb, HCV RNA-PCR
Tests for 
hepatotoxicity follow-
up (if clinically 
indicated for 
INC280)
LFTs: albumin, ALT, AST, GGT, total bilirubin, direct and indirect bilirubin, ALP, ALP 
fractionated (quantification of isoforms)
Creatine kinase, prothrombin time (PT)/INR
Testing for acute hepatitis A, B, C or E infection, other hepatotropic viral infection and 
autoimmune hepatitis as clinically indicated (refer to Section 6.2.6.1)
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7.2.2.5.1 Hematology
Hematological tests will be performed at:

Screening

Cycle 1 Day 1, before first dose, unless screening samples were collected within 72 hours 
prior to the Cycle 1 Day 1 visit.

Day 15 of Cycle 1

Days 1 and 8 of Cycle 2

Day 1 of Cycle 3 and subsequent cycles

EOT
More frequent hematology testing may also be performed as medically necessary. Additional 
results from unscheduled hematology lab evaluations should be recorded on the appropriate 
Unscheduled Visit eCRF.
In the event of ≥ grade 3 hematological toxicities that require study drug dose modifications or 
interruptions, hematological tests must be repeated until recovery to the baseline value or ≤ 
grade 1.
7.2.2.5.2 Clinical chemistry
Clinical chemistry will be performed at:

Screening

Cycle 1 Day 1, before first dose, unless screening samples were collected within 72 hours 
prior to the Cycle 1 Day 1 visit

Day 15 of Cycle 1

Day 1 and 8 of Cycle 2

Day 1 of Cycle 3 and subsequent cycles

EOT
More frequent clinical chemistry testing may also be performed as medically necessary. 
Additional results from unscheduled clinical chemistry lab evaluations should be recorded on 
the appropriate Unscheduled Visit eCRF.
In the event of ≥ grade 3 clinical chemistry toxicities that require study drug dose modifications 
or interruptions, clinical chemistry tests must be repeated until recovery to the baseline value 
or ≤ grade 1 ( refer to Table 6-5)
7.2.2.5.3 Urinalysis
Urinalysis will be performed at screening and EOT visit.
Microscopic urinalysis will be performed only if macroscopic urinalysis result is abnormal.
7.2.2.5.4 Coagulation
The same coagulation test (PT or INR) will be used at each time point where the evaluation is 
conducted.


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A coagulation profile must be performed:

Screening

Cycle 1 Day 1, before first dose, unless screening samples were collected within 72 hours 
prior to the Cycle 1 Day 1 visit

Day15 of Cycle 1

Day 1 of Cycle 3 and subsequent cycles

EOT
7.2.2.5.5 Hepatitis markers assessments
During the screening period, all patients must be screened for HBV and HCV (current or past 
history of infection). Careful medical history must be taken for all patients to look for risk 
factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, 
blood transfusions, etc.), and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light colored stools, right upper quadrant pain).
Hepatitis B:
At screening, all patients will be tested for:

HBV-DNA level

Hepatitis B surface antigen (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis B surface antibody (HBsAb)
Monitoring for HBV –DNA on Day 1 of every cycle from Cycle 2 and EOT is required for:

Patients known to have a history of HBV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’)

Patients positive for viral load on HBV DNA-PCR test at screening.

Patients positive for any of the serology at screening.
Hepatitis C:
All patients will be tested for quantitative HCV RNA-PCR at the screening visit.
Monitoring for HCV RNA-PCR levels of Day 1 of every cycle from Cycle 2 and EOT is 
required for:

Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’)

Patients positive for viral load on HCV RNA-PCR test at screening.
7.2.2.5.6 Pregnancy and assessments of fertility
All females of childbearing potential should have a serum pregnancy test (hCG) performed ≤ 
72 hours prior to the first administration of INC280 and at EOT visit.
In addition, a urinary pregnancy test should be completed Day 1 at Cycle 2 and on Day 1 of 
subsequent cycles.


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Women who are of non-childbearing potential do not require a pregnancy test, but must fulfill 
the conditions for the non-childbearing status given in Section 5.3.
Please refer to Section 8.4 for information on reporting any pregnancies that occur while the 
patient is on study.
7.2.2.6
Cardiac assessments
12-lead ECGs will be performed in triplicate, separated by 1 minute. ECGs will be transmitted 
to a central laboratory and reviewed by an independent reviewer. Any original ECG not 
transmitted to a central laboratory will be forwarded for central review. At screening, ECGs 
will be performed locally. ECGs will be performed at the following timepoints:
Local laboratory
!
Screening
Central laboratory
!
Cycle 1 Day 1 pre-morning dose and at 2 hours post-morning dose
!
Cycle 2 Day 1 pre-morning dose and at 2 hours post-morning dose
!
Cycle 3 Day 1 pre-morning dose and at 2 hours post-morning dose
!
EOT
!
As clinically indicated
For local laboratory, interpretation of the tracing must be made by a qualified physician and 
documented on the ECG CRF page. Each ECG tracing should be labeled with the study number, 
patient initials (where regulations permit), patient number, date, and kept in the source 
documents at the study site. Clinically significant abnormalities present when the patient signed 
informed consent should be reported on the Medical History eCRF page. Clinically significant
findings must be discussed with the Novartis Medical Monitor prior to enrolling the patient in 
the study. New or worsened clinically significant findings occurring after informed consent 
must be recorded on the Adverse Events eCRF page.
Following local IRB/EC approval of protocol amendment 5, no cardiac assessments are 
required by the protocol.
7.2.3
Pharmacokinetics
During the Dose-Determining Part, full PK blood samples of INC280 will be collected on Days 
1, 2, 15 and 16 of Cycle 1 and trough concentrations will be collected on Cycle 2, Day 1 and 
Cycle 3, Day 1 (Table 7-5). The rationale to collect full PK profiles during Cycle 1 is to closely 
monitor potentially increased exposure of INC280 in HCC patients who usually have impaired 
liver function.
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During the Dose Expansion Part of the study, sparse PK samples will be collected for all patients
based on a sparse “window” sampling scheme on Cycle 1, Days 1 and 15. In addition, blood 
samples of pre-morning dose and at 2 hours post-morning dose will be collected on Cycle 2 
Day 1 and Cycle 3 Day1 to match central triplicate ECG collection for potential exposure-QT 
analysis (Table 7-6).
For Dose-Determining Part and Dose Expansion Part, an additional PK sample will be taken 
with post treatment tumor biopsy (within 30 min after tumor biopsy completion).
Following approval of protocol amendment 5, no pharmacokinetic assessments are required by 
the protocol.


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7.2.3.1
Pharmacokinetic blood collection and handling
Table 7-5
Timepoints of blood collection for PK assessment during Dose-
Determining Part
PK 
sample 
No
Cycle
Day
Scheduled time 
relative to 
dosing
Description
Dose 
Reference 
ID
Blood 
volume
1
1
1
0 h a
Pre-dose
1
3 mL
2
0.5 h (± 5 min)
Post-dose
1
3 mL
3
1 h (± 10 min)
Post-dose
1
3 mL
4
2 h (± 15 min)
Post-dose
1
3 mL
5
4 h (± 20 min)
Post-dose
1
3 mL
6
6 h (± 30 min)
Post-dose
1
3 mL
7
8 h (± 30 min)
Post-dose
1
3 mL
8
2
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
1 Day 2
2/3002d
3 mL
9
15
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
1Day 15
3/3003d
3 mL
10
0.5 h (± 5 min)
Post-dose
3
3 mL
11
1 h (± 10 min)
Post-dose
3
3 mL
12
2 h (± 15 min)
Post-dose
3
3 mL
13
4 h (± 20 min)
Post-dose
3
3 mL
14
6 h (± 30 min)
Post-dose
3
3 mL
15
8 h (± 30 min)
Post-dose
3
3 mL
16
16
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
1 Day 16
4/3004d
3 mL
17
2
1
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
2 Day 1
5/3005d
3 mL
18
3
1
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
3 Day 1
6/3006d
3 mL
Total volume
54 mL
2001+ b
Unscheduled
Unspecified
NA
3 mL
1001
1
Coinciding with tumor biopsy c
NA
3 mL
All measurement times are relative to dose of INC280 unless otherwise specified.
a Take PK sample immediately prior to the morning administration of INC280.
b Sample numbers for any unscheduled blood collection for INC280 will start with 2001, and then coded by 
2002, 2003 etc.
c PK sample should be collected within 30 min after tumor biopsy completion.
d The first Dose Reference ID is for the current dose, while the second Dose Reference ID is for last dose the 
subject received prior to the collection of the PK sample.


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Table 7-6
Timepoints of blood collection for INC280 PK assessment during 
Dose Expansion Part
PK 
sample 
No
Cycle
Day
Scheduled time 
relative to 
dosing
Description
Dose 
reference 
ID
Blood 
volume
101
1
1
0 h a
Pre-dose
101
3 mL
102
2 h (± 1 h)
Post-dose
101
3 mL
103
6 h (± 2 h)
Post-dose
101
3 mL
104
12 h (± 3 h)
Post-dose
101
3 mL
105
15
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
1 Day 15
102/5001d
3 mL
106
2 h (± 1 h)
Post-dose
102
3 mL
107
6 h (± 2 h)
Post-dose
102
3 mL
108
12 h (± 3 h)
Post-dose
102
3 mL
109
2
1
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
2 Day 1
103/5002d
3 mL
111
2 h (± 1 h)
Post-dose
103
3 mL
110
3
1
0 h a
Sample will be collected prior 
to the morning dose of Cycle 
3 Day 1
104/5003d
3 mL
112
2 h (± 1 h)
Post-dose
104
3 mL
Total volume
36 mL
7001+ b
Unscheduled
Unspecified
NA
3 mL
6001
1
Coinciding with tumor biopsy c
NA
3 mL
All measurement times are relative to dose of INC280 unless otherwise specified.
a Take PK sample immediately prior to the morning administration of INC280.
b Sample numbers for any unscheduled blood collection for INC280 will start with 7001, and then coded by 
7002, 7003 etc.
c PK sample should be collected within 30 min after tumor biopsy completion.
d The first Dose Reference ID is for the current dose, while the second Dose Reference ID is for last dose the 
subject received prior to the collection of the PK sample.
Detailed instructions for the processing, handling, storage and shipment of the PK samples will 
be provided in a separate laboratory manual at the time of study initiation.
The exact collection date and time of all samples must be documented on the PK blood 
collection CRF pages. The date and exact time of drug administration as well as the date and 
exact time of blood sampling must be recorded on the CRF.
All blood samples will be taken by either direct venipuncture or venous catheter or indwelling 
cannula inserted in a forearm vein. 3 mL blood will be drawn per sample at series time points
Samples should be processed to obtain plasma and labeled as detailed in the [Laboratory 
Manual]. All samples should be stored frozen at −70°C within 90 minutes of venipuncture at 
the site until sample shipment.


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7.2.3.2
Analytical method
Concentration of INC280 will be measured in plasma by a validated liquid chromatography-
tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 1 ng/mL. Any 
results below the LLOQ and missing samples will be labeled accordingly. 
 


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8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An AE 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 patients whose c-MET status is unknown and who sign the molecular pre-screening ICF, 
AEs which occur after signature of this consent will only be captured if they meet the definition
of serious as outlined in Section 8.2 and are reported to be causally related with study 


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procedures (e.g. an invasive procedure such as biopsy). Once the main study ICF is signed, all 
AEs per the descriptions below will be captured in the AE CRF.
Patients whose c-MET status is known will sign the main study ICF.
Abnormal laboratory values or test results occurring after informed consent constitute AEs 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).
AEs that begin or worsen after informed consent should be recorded in the AEs CRF. 
Conditions that were already present at the time of informed consent should be recorded in the 
Medical History page of the patient’s CRF. AE monitoring should be continued for at least 30 
days (or 5 half-lives, whichever is longer) following the last dose of study treatment. AEs 
(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 AE.
AEs will be assessed according to the Common Terminology Criteria for AEs (CTCAE) version 
4.03.
If CTCAE grading does not exist for an AE, 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 criteria; rather, information about deaths will 
be collected though a Death form.
The occurrence of AEs should be sought by non-directive questioning of the patient (subject) 
during the screening process after signing informed consent and at each visit during the study. 
AEs also may be detected when they are volunteered by the patient (subject) during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each AE should be evaluated to determine:
1. The severity Grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a SAE is defined as in Section 8.2.1, and which seriousness 
criteria have been met.
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded on the AE CRF.
Once an AE 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 


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any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a SAE.
AEs 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 AE 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 AEs CRF. Whenever possible, a diagnosis, rather 
than a symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory 
abnormalities that meet the criteria for AEs 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 AE, 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 AE, should not be reported as 
AEs. A Grade 3 or 4 event (severe) as per CTCAE does not automatically indicate a SAE unless 
it meets the definition of serious as defined below and/or as per investigator’s discretion. A dose 
hold or medication for the lab abnormality may be required by the protocol in which case the 
lab abnormality would still, by definition, be an AE and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
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 SAEs:

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


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
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a SAE
8.2.2
Reporting
For patients with unknown c-MET status and who sign the molecular pre-screening ICF, SAE 
collection will start upon signing the molecular pre-screening ICF. SAEs will only be reported 
if the event is suspected to be causally related to a study procedure as assessed by the 
investigator (e.g. an invasive procedure such as biopsy). SAEs will be followed until resolution 
or until clinically relevant improvement or stabilization. If the main ICF is not signed 
(molecular screen failure), SAE collection ends 30 days after the last study related procedure.
For patients with known c-MET status who sign the main study ICF, SAE collection starts at 
time of main study informed consent whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis immediately, without undue delay, but 
under no circumstances later than within 24 hours of learning of its occurrence (Note: if more 
stringent, local regulations regarding reporting timelines prevail).
Any SAEs experienced after this 30 days period (or 5 half-lives, whichever is longer) should 
only be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment. Recurrent episodes, complications, or progression of the initial SAE must be reported 
as follow-up to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours Novartis. Detailed instructions 
regarding the submission process and requirements for signatures are to be found in the 
investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report i.e. reported to 
Novartis immediately, without undue delay, but under no circumstances later than within 24 
hours of learning of its occurrence (Note: if more stringent, local regulations regarding reporting 
timelines prevail). 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.


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS)department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification, 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.
Pregnancy follow up in this study will end after birth or after any adverse pregnancy outcome 
associated with the end of the pregnancy. In case of live birth the newborn will be followed up 
until 12 months of age to detect any developmental issue or abnormality that would not be seen 
at birth. Pregnancy outcomes should also be collected for the female partners of any males who 
received 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 Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. Pregnancy outcomes 
should be collected for the female partners of any males who took study treatment in this study. 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
mother.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (subject initials and exact 
date of birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated Contract Research Organization (CRO)) will review the protocol and 
CRFs with the investigators and their staff. During the study, the field monitor will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the CRFs, the 
adherence to the protocol to Good Clinical Practice, the progress of enrollment, and to ensure 
that study treatment is being stored, dispensed, and accounted for according to specifications. 
Key study personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information recorded on CRFs must be traceable to source documents in the patient's file. The 
investigator must also keep the original signed informed consent form (a signed copy is given 
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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the eCRF. The eCRFs have been built using fully validated 
secure web-enabled software that conforms to 21 CFR Part 11 requirements, Investigator site 
staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs and, allow modification or 
verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. This includes clinical 
data from safety assessments but also all information as described in the protocol regarding PK, 
 imaging, etc.
9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and AEs will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
PK 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
All statistical analysis will be performed under the direction of Novartis personnel. Any data 
analysis carried out independently by the investigator should be submitted to Novartis prior to 
publication or presentation.
Data will be summarized using descriptive statistics (continuous data) and/or contingency tables 
(categorical data) for demographic and baseline characteristics, efficacy measurements, safety 
measurements, and all relevant PK
measurements.


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The study data will be analyzed and reported based on all patients’ data of the Dose-
Determining and Dose Expansion parts up to the time when all patients have potentially 
completed at least six cycles of treatment or discontinued the study. Any additional data for 
patients continuing to receive study treatment past the data cutoff date for the primary CSR, as 
allowed by the protocol, will be reported once all patients have discontinued the study 
(Section 4.3).
If the dose used in the Dose-Determining and Dose Expansion parts is the same, patients will 
be pooled into a single treatment group within all analyses unless otherwise specified. If the 
dose used in the Dose-Determining and Dose Expansion parts differ, then patients will be 
reported by part.
Additionally, analyses of efficacy data may be presented separately for patients meeting the 
revised definition of c-MET positive, as introduced in Protocol Amendment 2; i.e. MET gene 
copy number ≥5 by FISH with c-MET IHC intensity score +2 in ≥50% of tumor cells or 
unknown, or c-MET IHC intensity score +3 in ≥50% of tumor cell, or c-MET mutation.
All data collected for patients in the Dose-Determining part will be reported at the initial Dose-
Determining dose level, irrespective of whether a patient undergoes intra-patient escalation to 
a higher dose level.
The statistical analyses will take into account the study treatment formulation as appropriate.
Details of the statistical analysis and data reporting will be provided in the Novartis Report and 
Analysis Plan (RAP) document finalized prior to database lock.
10.1
Analysis sets
All analysis sets will be identified prior to database lock.
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of INC280. 
The FAS will be used for all listings of raw data. Unless otherwise specified the FAS will be 
the default analysis set used for all analyses.
10.1.2
Safety Set
The Safety Set includes all patients from the FAS who have received at least one dose of 
INC280 and had at least one valid post-baseline safety assessment.
Please note: A “no” to indicate that the patient had no AEs (on the AE eCRF) constitutes a 
valid safety assessment.
10.1.3
Per-Protocol Set
The per-protocol set (PPS) consists of all patients in the FAS who are in compliance with the 
protocol in the following ways:

diagnosis corresponds to that defined in inclusion criteria

stage of disease corresponds to that defined in inclusion criteria

prior treatment corresponds to that defined in inclusion criteria


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Patients will be evaluable for efficacy if they have at least one response assessed differently 
from ‘unknown’ or ‘not assessed’ under RECIST (Appendix 1). A patient who discontinued the 
study prior to being evaluated for the primary efficacy variable for a reason(s) other than AE, 
PD or death will not be included in the per-protocol set.
10.1.4
Dose-determining analysis set
The DDS consists of all patients from the safety set (who are in the Dose-Determining Part) 
who either meet the minimum exposure criterion and have sufficient safety evaluations (as 
determined by the Investigators and Novartis), or who have experienced a qualifying AE during 
the first four weeks of treatment (see Table 6-2).
A patient is considered to have met the minimum exposure criterion at a dose level if they 
receive INC280 at the planned dose, BID for at least 21 days within the first four weeks of 
treatment (≥75% planned administration). Patients who do not experience a qualifying AE 
during the first four weeks are considered to have sufficient safety evaluations if they have been 
observed for ≥ 28 days following the first dose, and are considered by both the Sponsor and 
Investigators to have enough safety data to conclude that a qualifying AE did not occur.
10.1.5
Pharmacokinetic analysis set
The PK analysis set (PAS) consists of all patients set who have at least one sample providing 
evaluable PK data.
The PAS will be used for summaries of PK data (tables and listings) as well as for listings of 
derived parameters.
Note: patients will be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of the analysis.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively for all patients in the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
10.3.1
Study treatment
The actual dose and duration in days of INC280, as well as the dose intensity (computed as the 
ratio of actual dose received and actual duration) and the relative dose intensity (computed as 
the ratio of dose intensity and planned dose received/planned duration) will be listed and 
summarized by means of descriptive statistics in the clinical study report (CSR). Categories for 
relative dose intensity of INC280 will be specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 


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- < 1.1 and ≥1.1. The number and proportion of patients within each category will be presented 
by treatment, for cycle 1 alone and for overall treatment duration. The FAS will be used.
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 term by means of 
contingency tables. The FAS will be used.
10.3.3
Compliance
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized.
10.4
Primary objective
The primary objective of this study is to estimate the overall activity of INC280 in advanced 
HCC patients with c-MET dysregulation. Please refer to Table 3-1 for the primary objective.
10.4.1
Variable
TTP, as per local assessment, is defined as the time from the date of baseline evaluation to the 
date of the first documented radiological confirmation of disease progression or death due to 
underlying cancer (RECIST v1.1). If a patient has not had the event at the date of analysis cut-
off or when he/she received any further anti-neoplastic therapy, TTP will be censored at the 
time of the last adequate assessment before the cut-off date.
10.4.2
Statistical hypothesis, model, and method of analysis
The primary TTP analysis will include all patients in the FAS (on an Intention-to Treat (ITT) 
basis) with patients classified according to the treatment group they were assigned to at baseline 
(Dose-Determining Part or Expansion Part dose).
For patients in the Dose-Determining Part, TTP will be listed along with overall response.
For patients treated at the Expansion Part dose, the distribution of TTP will be estimated using 
the Kaplan-Meier method. The median TTP and quantiles (along with one-sided 90% 
confidence intervals) will be presented. The Kaplan-Meier curve will be presented graphically. 
TTP rate estimates (along with one-sided 90% CI) at 3 months, 6 months, 9 months and 1 year 
will presented, as given by the Kaplan-Meier analysis.
10.4.3
Handling of missing values/censoring/discontinuations
If a patient has not experienced a radiological disease progression or death due to underlying 
cancer, TTP will be censored at the date of the last adequate tumor assessment, defined as the 
date the last tumor assessment with overall lesion response of CR, PR or SD which was made 
before a censoring reason occurred, or the date of first dose of INC280 if no post-baseline 
assessments are available (See RECIST v1.1).


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The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient.
Other missing data will simply be noted as missing on appropriate tables/listings. The FAS will 
be used.
10.4.4
Supportive analyses
Using the PPS, the TTP analysis may be re-run for patients treated with the Expansion Part dose.
10.5
Secondary objectives
Please refer to Section 3 for the secondary objectives.
10.5.1
Efficacy objective(s)
The efficacy objective of this study is to further assess the clinical activity of INC280 in 
advanced HCC patients with c-MET dysregulation.
The tumor response will be evaluated based on RECIST V1.1., ORR, DCR, PFS and OS in 
patients with advanced HCC will be assessed. ORR is defined as the proportion of patients with 
a best overall response (BOR) of complete response (CR) or PR at any time on study per 
RECIST. DCR is defined as the proportion of patients with a BOR of CR, PR or SD at any time 
on study per RECIST. PFS is defined as the time from date of first study treatment intake to the 
date of the first radiologically documented progression or death due to any cause or initiation 
of new antineoplastic therapy. If a patient has not had an event, PFS is censored at the date of 
last adequate tumor assessment. OS is defined as the time from date of first study treatment 
intake 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 contact.
Individual lesion measurements and overall response (investigator’s assessment) at each 
assessment will be listed by patient and treatment group. BOR will be summarized for all 
patients by treatment group and the observed ORR will be summarized in terms of percentage 
rates with 95% confidence intervals for each treatment group. The Kaplan-Meier estimates of 
OS and PFS distribution functions will be presented graphically. The resulting median OS and 
median PFS and quantile estimates will be provided along with 95% confidence intervals. Rate 
estimates of PFS and OS (along with 95% CI) at 3 months, 6 months, 9 months and 1 year will 
presented, as given by the Kaplan-Meier analysis.
For treatments groups with less than 10 patients, Kaplan-Meier estimates and plots will not be 
presented.
10.5.2
Other secondary objectives
Please refer to Section 10.5.3 for the analyses of safety data.
Please refer to Section 10.5.4 for the analysis of PK data.


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10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
A listing of all AEs will be provided based on the FAS. For all safety analyses, the safety set 
will be used unless otherwise specified.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 31 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
All AEs recorded during the study will be summarized. The incidence of treatment-emergent 
AEs (new or worsening from baseline) will be summarized by primary system organ class, 
severity based on the National Cancer Institute’s Common Terminology Criteria for Adverse 
Events (CTCAE) current edition version 4.03, type of AE, and relationship to the study drug by 
study Part. Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated 
by primary system organ class, type of AE, and study Part.
Qualifying AEs will be separately listed by primary system organ class, worst grade based on 
the CTCAE current edition version 4 and type of AE. The DDS will be used.
Any other information collected (e.g. start/end dates and duration of AE, severity or relatedness 
to study medication) will be listed as appropriate. For patients undergoing intra-patient 
escalation to doses other than their initially received dose level, data up to the first intra-patient 
escalation will be summarized and all post-escalation data will only be listed.
10.5.3.3 Analysis of qualifying AEs within first four weeks of treatment
An adaptive BLRM guided by the EWOC principle will be used to guide the dose 
recommendation for the Dose Expansion Part of the study. Doses available for consideration as 
the Expansion Part dose will be those estimated under the modeling for which the risk that the 
true rate of qualifying AE in the first four weeks of treatment (Table 6-2) exceeds 33% is less 
than 25%. Subsequently, the PK data will be used to assess if the highest of these doses is 
acceptable for use in the Dose Expansion Part, or whether a lower dose is appropriate based of 
increased exposure within the HCC patients.
A two-parameter BLRM will be fitted on the qualifying AE data (i.e. absence or presence during 
the first four weeks of treatment) accumulated throughout the Dose-Determining Part of the 
study. All information currently available about the dose-AE relationships of single agent 
INC280 will be summarized in prior distributions.
The DDS will be used for these analyses.
The dose-toxicity relationship in will be described by the following Bayesian logistic regression 
model:


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logit(π(d)) = log(α) + β log(d/d*),
α>0, β>0,
where logit(π(d))= ln ((d)/(1-(d))), π(d) is the probability of patient experiencing a qualifying 
adverse event within the first four weeks of treatment at dose d (mg BID). Doses are rescaled 
as d/d* with reference dose d*= 400 mg bid (total 800mg/day) of INC280. As a consequence α 
is equal to the odds of toxicity at d*. Note that for a dose equal to zero, the probability of toxicity 
is zero.
The Bayesian approach requires the specification of prior distributions for the model parameters. 
The prior distributions and the process for their derivation based on available pre-clinical data 
are provided in Appendix 5.
Dose recommendation
Dose recommendation will be based on posterior summaries including the mean, median, 
standard deviation, 95%-credibility interval, and the probability that the true AE-rate (as 
defined by Table 6-2) for each dose lies in one of the following categories :

[0,16%] under-dosing

[16%,33%] targeted toxicity

[33%,100%] excessive toxicity
Following the principle of EWOC, at the end of Dose-Determining Part, a range of doses will 
be recommended for the Dose Expansion Part. The highest dose level in that dose range will be 
the highest dose that satisfies the overdose criterion that there is less than 25% chance of 
excessive toxicity. If the recommended Dose Expansion Part dose as per the PK analysis 
(Section 10.5.4.1 and Section 6.2.2) is higher than the dose allowed by the BLRM, the highest 
dose allowed by the BLRM will be used for the Dose Expansion Part. Summaries of the 
posterior distribution of model parameters and posterior distribution of AE rates based on the 
AE data from all patients in the DDS will be presented.
10.5.3.4 Laboratory abnormalities
All laboratory values will be converted into SI units, as appropriate, and the severity grade 
calculated using CTCAE, version 4.03. Parameters for which a grading does not exist will be 
classified into low/normal/high group by means of laboratory normal ranges.
For each laboratory test (e.g. hematology, biochemistry, etc.) a listing of laboratory values will 
be provided by laboratory parameter, patient and treatment group. The frequency of notable lab 
abnormalities will be displayed by parameter, cycle and treatment group. Similarly, the 
frequency of all laboratory abnormalities will be displayed by parameter, worst CTCAE version 
4.03 grade experienced and treatment group. A separate listing will display notable laboratory 
abnormalities (i.e., newly occurring CTC grade 3 or 4 laboratory toxicities). Laboratory data 
will be summarized by presenting grade shift tables for those parameters for which CTCAE 
version 4.03 allows classification. All remaining data will be summarized by presenting shift 
tables based on normal ranges.
Laboratory data will also be displayed by presenting summary statistics of raw data and change 
from baseline values (means, medians, standard deviations, ranges).


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10.5.3.5 Other safety data
Data from other tests (e.g., ECG or vital signs) will be listed, notable values will be flagged, 
and any other information collected will be listed as appropriate. Any statistical tests 
performed to explore the data will be used only to highlight any interesting comparisons that 
may warrant further consideration.
10.5.3.6 Tolerability
Tolerability of study drug will be assessed by summarizing the number of dose interruptions 
and dose reductions by study Part. Reasons for dose interruption and dose reductions will be 
listed by patient and study Part and summarized by Part.
10.5.4
Pharmacokinetics
PAS will be used in all INC280 PK data analysis and PK descriptive statistics.
PK parameters summarized in Table 10-1 will be estimated by non-compartmental analysis of 
individual INC280 plasma concentration versus time data using WinNonlin (WinNonlin 
version 5.2 or above, or Phoenix; Pharsight Corporation, Moutain View, California). 
Descriptive statistics will be calculated for PK parameters by treatment group and scheduled 
days.
Concentration data collected in the Dose Expansion Part will be listed. Summary tables by time 
point (as described earlier) will be presented as well.
Table 10-1
Noncompartmental pharmacokinetic parameters
AUC0-t
The AUC from time zero to time t (t=12 hours dosing interval for twice daily dosing) post 
dose (ng*h/mL)
AUCinf
The AUC from time zero to infinity (ng*h/mL)
AUClast
The AUC from time zero to the last quantifiable concentration point (ng*h/mL)
Cmax
The maximum (peak) observed plasma drug concentration (ng/mL)
Tmax
The time to reach maximum (peak) plasma drug concentration after single dose 
administration (h)
Lambda_z
Terminal elimination rate constant, calculated as the slope of linear regression of the 
terminal phase of the logarithmic concentration-time profile(hr-1)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve. Determined as Ln (2)/Lambda z (h).
CL/F
Apparent drug clearance from the plasma (L/hr), as calculated by dose/AUCinf or 
dose/steady state AUC0-t following extravascular administration.
Vz/F
The apparent volume of distribution during terminal elimination phase (L)
Racc
Accumulation ratio of drug exposure, calculated by AUC0-t on Day 15 divided by AUC0-t on 
Day 1.
10.5.4.1 Dose-Determining Part
PK will be assessed for patients treated in the Dose-Determining Part on Cycle 1, Day 1 and 15. 
Patients with at least one evaluable full PK profile will be included in PK analysis.
Summary statistics (number, arithmetic mean, median, standard deviation, coefficient of 
variance CV(%), geometric mean, geometric CV (%), minimum and maximum) will be 
presented for concentrations of INC280 by nominal time point and treatment dose. Graphics 


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with concentration mean and standard deviation by time point and treatment dose will be 
presented as well.
The following PK parameters from Dose-Determining Part will be summarized:
Cycle 1, Day 1: AUC0-t, Cmax, T1/2, Tmax, CL/F, and Vz/F.
Cycle 1, Day 15: AUC0-t, Cmax, T1/2, Tmax, CL/F, Vz/F and Racc.
PK parameters other than Tmax will be summarized by number, arithmetic mean, standard 
deviation, CV%, median, range (minimum and maximum), geometric mean and geometric 
CV%. Number, median and range (minimum and maximum) will be presented for Tmax.
At the dose decision analysis, systemic clearance of the HCC patients from the Dose-
Determining Part as well as from study CINC280X2102 will be assessed in comparison with
the cancer patients from historical studies (INCB028060-101, CINC280X1101 and 
CINC280X2102) who had normal liver function (NCI-ODWG criteria) using non-
compartmental analysis. 90 percent confidence interval for the systemic clearance mean ratio 
of the two populations will be calculated and compared to the no effect boundary of 80% to 
125%. If 90 percent confidence interval for the mean ratio falls between the no effect boundary, 
it indicates the drug exposure is comparable in the two populations. Recommended Expansion
Part dose (as per PK analysis) will be RP2D. If lower drug clearance is observed in HCC 
patients from the Dose-Determining Part, recommended Expansion Part dose is the RP2D 
proportionally reduced by decreased mean ratio of systemic clearance. For example, if mean 
ratio of systemic clearance is 0.7, which indicates a 30% increase in drug exposure in HCC 
patients from the Dose-Determining Part, recommended Expansion Part dose will be 0.7 times 
RP2D (Section 6.2.2). If INC280 exposure in lead-in Dose-Determining Part is lower, 
Expansion Part dose as per PK analysis will be the RP2D proportionally increased by the 
increased mean ratio taking into consideration of the toxicity and feasibility. Drug exposure of 
the HCC patients from the Dose-Determining Part, including AUC0-t and Cmax will also be 
compared to the historical studies at the same dose level.
In addition, the recommended Expansion Part dose as per PK analysis will not be higher than 
the dose recommended by the safety analysis (Section 10.5.3.3).
10.5.4.2 Dose Expansion Part
Summary statistics (number, arithmetic mean, median, standard deviation, CV(%),geometric 
mean, geometric CV (%), minimum and maximum) will be presented for concentrations of 
INC280 by nominal time point and treatment dose. Graphics with concentration mean and 
standard deviation by time point and treatment dose will be presented as well.


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10.5.4.4 Data handling principles
All concentrations of INC280 below their respective LLOQs (lower limits of quantification) or 
missing data will be labeled as such in the concentration data listings. Concentrations below the 
LLOQ will be treated as zero in summary statistics and for the calculation of PK parameters.
10.7
Interim analysis
No formal interim analysis of the primary efficacy variable (TTP) has been planned. However, 
a safety analysis and PK analysis will be done when at least six patients evaluable for the DDS 
is available at the 300 mg dose level (capsule) in the Dose-Determining Part to evaluate which 
dose level is to be used for the Expansion Part dose (Section 6.2.2).
10.8
Sample size calculation
Dose-Determining Part
It is expected that between 6 and 10 patients will be enrolled in order to obtain data on 
occurrence or absence (within first four weeks of treatment) of qualifying AE (Table 6-2) for at 
least 6 patients evaluable for the DDS.
Dose expansion Part
A total number of 50 patients are planned to be enrolled and treated in the dose expansion part. 
It is expected that 25 to 40 among these patients will have the c-MET high status as specified 
in the inclusion criteria. The following assumptions and design parameters are considered:

in general the median TTP for patients treated with sorafenib has been established to be 
2.8 months (Cheng et al 2009); for the c-MET high patients it has been estimated to be 2.2 
months (Santora et al 2013)

the required improvement to be seen on treatment with INC280 in the Dose Expansion 
Part is an increase in median TTP to approximately 4 months in patients with advanced 


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HCC with high c-MET status and preserved liver function of Child Pugh class A with 5-6 
point

therefore a successful outcome will be indicated by an observed median TTP of ≥4 
months, and a one-sided 90% lower confidence limit for median TTP of ≥2.2 months

It is assumed that on average 1.5 patients are enrolled per month; the primary analysis is 
conducted 6 months after enrolment of the final patient

Data is simulated from the exponential distribution with true mTTP = 2.2, 4, 5 and 6 
months

a 30% risk of loss to follow up per patient per year is assumed ; this corresponds to loss to 
follow up of approximately 15% patients given an assumed true mTTP = 4 months; 
censoring time is simulated from the exponential distribution with rate parameter = -log(1-
0.30)/12
Kaplan-Maier method is used to estimate the median TTPs and provide the Brookmeyer-
Crowley CIs in simulated event data. Table 10-2 presented the expected numbers of observed
events at primary analysis, the probability that the observed mTTP is ≥4 months, the probability 
that the lower limit of one-sided 90% CI is >2.2 months provided the observed mTTP ≥4 months, 
and the probability of study success (i.e. the probability that the lower limit of one-sided 90% 
CI is >2.2 months and the observed mTTP is ≥4 months), given different true values of TTP 
and sample sizes. Therefore, with the planned enrollment, if the true median TTP is 6 months a 
successful outcome is expected with high probability. Conversely, a successful outcome is 
highly improbable if the true median TTP is as low as 2.2 months.
Table 10-2
Design operating characteristics when the number of patients is 25, 
30, 35 and 40, respectively
True TTP (months)
Expected number 
of observed 
events
P(observed mTTP 
≥4m | true TTP)
P (lower CI >2.2m | 
observed mTTP 
≥4m, true TTP)
P (lower CI >2.2m 
and observed 
mTTP ≥4m | true 
TTP)
N = 25
2.2
22
0.01
0.76
0.01
4
19
0.52
0.95
0.49
5
18
0.77
0.97
0.75
6
16
0.90
0.99
0.89
N = 30
2.2
27
0.01
0.81
0.01
4
24
0.50
0.97
0.49
5
22
0.79
0.98
0.78
6
20
0.92
0.99
0.92
N = 35
2.2
31
0.01
0.82
0.00
4
28
0.51
0.98
0.50
5
26
0.81
0.99
0.80
6
24
0.94
1.00
0.93
N = 40
2.2
36
0.00
0.93
0.00


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True TTP (months)
Expected number 
of observed 
events
P(observed mTTP 
≥4m | true TTP)
P (lower CI >2.2m | 
observed mTTP 
≥4m, true TTP)
P (lower CI >2.2m 
and observed 
mTTP ≥4m | true 
TTP)
4
32
0.50
0.99
0.50
5
30
0.82
0.99
0.82
6
28
0.95
1.00
0.95
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent, or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs.


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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 assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 


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documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
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 


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included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days.


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13
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Opinion: Chronic Hepatitis B Virus Infection Screening in Patients Receiving Cytotoxic 
Chemotherapy for Treatment of Malignant Diseases. Journal of Oncology 19: 3199-3202
Park EJ, Lee JH, Yu GY, et al (2010). Dietary and genetic obesity promote liver inflammation 
and tumorigenesis by enhancing IL-6 and TNF expression. Cell, Jan 22;140(2):197-208
Patel H et al (2004). Comparison of Child-Pugh (CP) criteria and NCI organ dysfunction 
working group (NCI-ODWG) criteria for hepatic dysfunction (HD): Implications for 
chemotherapy dosing. Journal of Clinical Oncology, 2004 ASCO Annual Meeting 
Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 6051
Peters, et al (2012). MET: a promising anticancer therapeutic target. Nat. Rev. Clin. Oncol. 9, 
314-326
Rimassa, et al (2012). Tivantinib (ARQ 197) versus placebo in patients (Pts) with 
hepatocellular carcinoma (HCC) who failed one systemic therapy: Results of a randomized 
controlled phase II trial (RCT). J Clin Oncol 30, 2012 (suppl; abstr 4006)
Santoro A, et al (2013). Tivantinib for second-line treatment of advanced hepatocellular 
carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 14: 55Onc


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Simonetti RG, et al (1997). Treatment of hepatocellular carcinoma: a systematic review of 
randomized controlled trials. Ann Oncol 8,117-36
Spiegel, et al ( 2012). The MetLUNG study: A randomized, double-blind, phase III study of 
onartuzumab (MetMAb) plus erlotinib versus placebo plus erlotinib in patients with advanced, 
MET-positive non-small cell lung cancer (NSCLC) J Clin Oncol 30, 2012 (suppl; abstr 
TPS7616
Suzuki K, et al (1994). Expression of the c-MET protooncogene in human hepatocellular 
carcinoma. Hepatology 20: 1231-1236
Takami T, Kaposi-Novak P, Uchida K, et al (2007). Loss of hepatocyte growth factor/c-Met 
signaling pathway accelerates early stages of N nitrosodiethylamine induced 
hepatocarcinogenesis. Cancer Res;67:9844-9851
Tavian D, et al (2000). u-PA and c-MET mRNA expression is co-ordinately enhanced while 
hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. Int J 
Cancer 87: 644-649
Thomas M (2009). Molecular targeted therapy for hepatocellular carcinoma. J Gastroenterol, 
44 [Suppl XIX]:136-141
Turner PC, et al (2002). The role of aflatoxins and hepatitis viruses in the etiopathogenesis 
ofhepatocellular carcinoma: A basis for primary prevention in Guinea-Conakry, West Africa. 
J. Gastroenterol. Hepatol. 17 (Suppl.), S441-S448
Ueki T, et al (1997). Expression of hepatocyte growth factor and its receptor, the c-MET 
proto-oncogene, in hepatocellular carcinoma. Hepatology 25: 619-623
Verslype, et al ( 2012). Activity of cabozantinib (XL184) in hepatocellular carcinoma: Results 
from a phase II randomized discontinuation trial (RDT). J Clin Oncol 30, 2012 (suppl; abstr 
4007)
Whittaker S, Marais R, Zhu AX (2010). The role of signaling pathways in the development 
and treatment of hepatocellular carcinoma. Oncogene, 29, 4989-5005
Wu F, et al (2006). The clinical value of hepatocyte growth factor and its receptor-c-MET for 
liver cancer patients with hepatectomy. Dig Liver Dis,38,490-7
Wu YL, Yang JCH, Kim DW, et al (2014) Safety and efficacy of INC280 in combination 
with gefitinib in patients with EGFR-mutated, MET-positive NSCLC: a single-arm Phase 
Ib/II study. J Clin Oncol 32:5s, (suppl; abstr 8017)
Zhang SZ, et al (2005). Knockdown of c-MET by adenovirus-delivered small interfering 
RNA inhibits hepatocellular carcinoma growth in vitro and in vivo. Mol Cancer Ther, 4, 
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14
Appendices
14.1
Appendix 1: RECIST 1.1
Guidelines for Response, Duration of Overall Response, TTF, TTP, 
Progression-Free Survival and Overall Survival (based on RECIST 1.1)
List of Contributors
Authors (Version 3):
 
Authors (Version 2):
 
Authors (Version 1):
Document type:
TA Specific Guideline
Document status:
Version 3: Final, October 19, 2009
Version 2: January 18, 2007
Version 1: December 13, 2002
20Oct2019
20Oct2019
20Oct2019


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14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.13 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.14 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 14.1.24 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the analysis plan(s) to provide further details needed for programming.
As for a usual Novartis template, comments are written in italic font. The protocol authors must 
take these comments into consideration and provide project or study specific details in the 
protocol. Specifically, definitions highlighted in red must be discussed, defined and then 
documented in the study protocol. Any deviations to the guideline must be clearly specified in 
the protocol with justification.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.
14.1.3
Definitions
14.1.3.1 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 14.1.22.
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.


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
Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ≥10mm and <15mm 
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.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (longest diameter <10 mm with CT scan or pathological lymph nodes with 10 to 
< 15 mm short axis), e.g., blastic bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, 
abdominal masses that are not confirmed and followed by imaging techniques, and cystic 
lesions.
14.1.3.2 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 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 14.1.22.
14.1.4
Methods of tumor measurement - general guidelines
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5mm 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 be allergic to CT contrast or develops allergy 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 (eg. 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.


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
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-PT 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-PT at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.

If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.

Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for objective 
tumor evaluation has not yet been fully and widely validated. Their uses in this specific 
context require sophisticated equipment and a high level of expertise that may only be 
available in some centers. Therefore, the utilization of such techniques for objective tumor 
response should be restricted to validation purposes in specialized centers. However, such 
techniques can be useful in confirming complete pathological response when biopsies are 
obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, 
 LDH and Beta-hCG for testicular cancer) can be integrated 
as non-target disease. If markers are initially above the ULN 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 SD. Under such 
circumstances, the cytologic examination of the fluid collected will permit differentiation 
between response and SD (an effusion may be a side effect of the treatment) or PD (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, 


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documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.1.5
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination) should be at least 10mm in longest 
diameter. See Section 14.1.3.1.

Nodal target: See Section 14.1.3.1.
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 metastasis). Each non-target 
lesion identified at baseline must be followed at each subsequent evaluation and 
documented on eCRF.
14.1.6
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameter 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.
14.1.7
Follow-up & 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 


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evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.
14.1.7.1 Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are patient to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
When a tumor does not disappear completely and shrinks to less than the slice thickness a 
default value should be assigned depending on the slice thickness. With 5 mm contiguous slice 
thickness, the default value will be 5 mm. Similarly, for a 7 mm slice thickness, the default 
value will be 7 mm. Actual measurement should be given for all lesions larger than the default 
value.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
14.1.7.2 Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
If a nodal lesion shrinks to less than the slice thickness a default value should be assigned 
depending on the slice thickness. With 5 mm contiguous slice thickness, the default value will 
be 5 mm. Similarly, for a 7 mm slice thickness, the default value will be 7 mm. Actual 
measurement should be given for all lesions larger than the default value.
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.


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14.1.8
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
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
PR:
At least a 30% decrease in the sum of diameter of all target lesions, taking as reference 
the baseline sum of diameters.
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.
SD:
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10mm in size. In this case, the target lesion response is CR
3. Methodology change See Section 14.1.4.
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 PD

The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 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). Proper documentation should be available to support this decision.

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 
100mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140mm (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.


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
Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes.

Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation.

Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the CRF, the diameter of the “merged lesion” should b 
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 10mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10mm are considered normal a CR for target lesion response 
should be assigned when nodal target lesions shrink to less than 10mm 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 the absolute sum of the remaining 
nodal target lesions increases by at least 5mm and at least one of those remaining 
lesions are at least 10mm in size. i.e. if the short axis of a remaining nodal target 
lesion increases from 5 mm to 10 mm or from 7 mm to 12.5 mm this is called PD, but 
if it increases from 7 mm to 10 mm it does not qualify for PD.
When both nodal and non-nodal lesions are still present there may be rare occasions when a PD 
for target lesion response is primarily due to increases in size of nodal lesions but where the 
target lymph nodes are still all less than 10mm in size. This kind of rare anomaly is acceptable 
since otherwise the rules for determining target lesion response would become too complex.


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14.1.9
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
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)
PD:
Unequivocal progression of existing non-target lesions.1
Incomplete Response/SD:
Neither CR nor PD
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. < 10mm). 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 ‘Incomplete 
response/Stable disease’ unless any of the lesions was not assessed (in which case 
response is UNK) or there is unequivocal progression of the non-target lesions (in which 
case response is PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-
target disease there must be an overall level of substantial worsening in non-target disease 
such that, even in presence of CR, PR or SD in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the 
size of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. Even in cases where there is no measurable disease at baseline, 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. In studies where the overall non-target lesion response is not recorded but 
instead the individual status of individual lesions (Absent, Present or Worsened) is 
determined, if there is unequivocal progression of non-target lesions then at least one of 
the non-target lesions must be assigned a status of “Worsened”. Similarly, an individual 
non-target lesion should only be assigned a “Worsened” status if there is unequivocal 
progression of non-target lesions overall.

Where possible, similar rules to those described in Section 14.1.8 for assigning PD 
following a CR for the non-target lesion response in the presence of non-target lesions 
nodal lesions should be applied.


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14.1.10
New lesions
The appearance of a new lesion is always associated with PD and has to be recorded as a new 
lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion1

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 14.1.11).

A lymph node is considered as a “new lesion” and, therefore, indicative of PD if the 
short axis increases in size to ≥ 10mm for the first time in the study plus 5mm absolute 
increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.4.
14.1.11
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
Incomplete response/SD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1. This overall lesion response also applies when there are no non-target lesions identified at baseline.
2. Once confirmed PR was achieved, all these assessments are considered PR.
3. As defined in Section 14.1.6.
If there are no baseline scans taken at all at baseline then the overall lesion response at each 
assessment should be considered 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.


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In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR depends on this determination, it is recommended that the residual 
lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.12
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.22 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.1.13
Best overall response
The BOR 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 BOR 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 BOR and/or whether these additional 
assessments will be required for sensitivity or supportive analyses. As a default, any 
assessments taken more than 28 days after the last dose of study therapy will not be included in 
the BOR derivation. If any alternative cancer therapy is taken while on study any subsequent 
assessments would ordinarily be excluded from the BOR 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 a 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.
The BOR 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).
If PD in a different follow-up period is considered overall response=’PD’, this must be specified 
in the protocol.


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The protocol should state if discontinuation due to ‘Disease progression’ or death due to study 
indication is considered PD even if this was not accompanied by documentation of PD based 
on tumor measurements. This depends on Phase of the study and the primary endpoint (e.g. 
Phase III studies in which PFS is primary endpoint should consider only documented PD, 
whereas Phase I and II studies may consider all clinical deteriorations PD). The following 
sentence therefore is only applicable if this is specified in the protocol:

Patients with symptoms of rapidly progressing disease without radiologic evidence will be 
classified as progression only when clear evidence of clinical deterioration is documented 
and/or patient discontinued due to ‘Disease progression’ or death due to study indication.

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.
If the patient progressed but continues study medication, further assessments are not considered 
for the determination of BOR.
Note: these cases may be described as a separate finding in the CSR but not included in the 
BOR rate.
The BOR 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 BOR will be based on the sequence of investigator/central blinded 
review/calculated (investigator)/calculated (central) overall lesion responses.


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Specify which determination of BOR will be considered primary (and delete the other terms in 
the text). If a central blinded review is used (e.g. in an open-label study in which response is 
the primary endpoint), the BOR evaluated by the central blinded review will always be 
considered the primary response.
Based on the patients’ BOR during the study, the following rates are then calculated:
ORR is the proportion of patients with a BOR of CR or PR. This is also referred to as ‘Objective 
response rate’ in some protocols or publications.
DCR is the proportion of patients with a BOR 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 PD within 8 weeks of the start 
of treatment.
14.1.14
Time to event variables
14.1.15
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, PFS 
is censored at the date of last adequate tumor assessment.
14.1.16
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 
contact.
14.1.17
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, TTP is censored at the date of last adequate tumor assessment.
14.1.18
Time to treatment failure
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.
14.1.19
Duration of response
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.


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The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall 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 TTP.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or an SD the start and end date as well as censoring is defined the same as that for 
TTP.
14.1.20
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 ORRs, since the same kind of selection bias may be introduced as 
described for duration of response in Section 14.1.19. It is recommended that an analysis of all 
patients (both responders and non-responders) be performed whether or not a responders only 
descriptive analysis is presented. Where an inferential statistical comparison is required then all 
patients should definitely be included in the analysis to ensure the statistical test is valid. For 
analysis including all patients, patients who did not achieve a response (which may have to be 
a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS is the worst 
possible outcome as it means the patient that 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 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.
Indicate in the protocol whether a subgroup analysis of responders only will be performed in 
addition to the full population analysis (which should be included as default).
14.1.21
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 


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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
State in the protocol if date of randomization or date of start of treatment is to be used for all 
definitions. For randomized studies specify exactly where the randomization date comes from, 
e.g. from IVRS, or if start of treatment is used as randomization date. For non-randomized 
studies please specify which treatment start date is taken if more than one treatment is to be 
given.
For all “time to event” variables, other than the duration of responses, the randomization/ date 
of treatment start will be used as the start date.
For the calculation of duration of responses 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 PD.
When there is no documentation of radiologic evidence of progression, and the patient 
discontinued for ‘Disease progression’ due to documented clinical deterioration of disease, the 
date of discontinuation is used as date of progression.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.19).
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 corresponds to 9 months.


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
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 contact date from that 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.
14.1.22
Handling of patients with non-measurable disease only at baseline
It is possible that patients with just 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.
The protocol should state clearly whether patients with non-measurable disease only at baseline 
will be allowed into the study. If patients with non-measurable disease only are allowed to be 
enrolled then the statistical section should describe clearly how data from these patients will be 
incorporated into the primary analysis and main analyses of the key secondary endpoints. In 
studies where presence or otherwise of measurable disease is expected to have a relatively large 
impact on the primary endpoint, this factor can even be considered as a stratification factor in 
the randomization process.
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.
For studies which specifically exclude patients with non-measurable disease only at baseline 
the pre-specified analysis plan should describe how to handle data from these types of patients 
if they are enrolled by error. It is recommended for these types of studies that patients with non-
measurable disease identified through the local site evaluation be included in the list of protocol 
violations. However, decisions on exclusion from a per protocol analysis should relate to 
whether the patient has measurable disease according to the primary data source. For example, 
if the primary data source is from a central independent review then patients with non-
measurable disease only according to this central review should be excluded from the relevant 
per protocol analyses.
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.


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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
Incomplete response/SD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.1.6.
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 BOR patients with just non-
measurable disease may be highlighted in an appropriate fashion e.g. in particular by displaying 
the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. Study teams may also want to 
perform sensitivity analyses excluding patients from the analysis of ORR (e.g. possibly as part 
of a per-protocol type analysis). Similar considerations should be given to other endpoints 
which rely on a clear distinction being made between a PR and an SD response.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with just 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
14.1.23
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well is 
addressing 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 analysis 
plan 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 14.1.21, 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 analysis plan
Outcome


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A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next 
scheduled assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly 
one missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or 
more missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. clinical 
progression based on investigator 
claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP 
and duration 
of response)
1.
=Definitions can be found in Section 14.1.21.
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.1.21.
3.
=The rare exception to this is if the patient dies no later than the time of the second scheduled 
assessment as defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.


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Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.1.24
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).
14.1.25
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).
14.1.26
Treatment and study completion CRFs
If study drug is discontinued, the End of Treatment Page is to be completed with a visit date 
reflecting the date the discontinuation decision was made, and with the ‘Last known date patient 
took study drug’ and one of the following reasons:

AE(s)

Abnormal laboratory value(s)

Abnormal test procedure results(s)

Protocol violation

Patient withdrew consent

Lost to follow-up

Administrative problems


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
Death

Disease progression

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
For reasons other than progression (and death) it should be checked if this was not in fact 
progression (especially reasons AEs, Abnormal laboratory value (s), Abnormal test procedure 
result and patient withdrew consent). Also it should be checked if patient withdrew consent 
because of safety issues, in which case reasons AEs, Abnormal laboratory value (s), Abnormal 
test procedure result should be used. In such cases where the reason for discontinuation is AE, 
the adverse event CRF page must be consistent with the EOT reason provided.
All patients who discontinued study drug will be followed for post a treatment evaluation until 
progression or until a new anticancer therapy is initiated. Patients who discontinued study drug 
for reasons other than documented progression, death or lost to follow-up will be followed for 
progression thereafter (patients who withdrew consent might not be followed with regular 
tumor assessments at the study site, but should ideally be followed until progression outside the 
study site). Ideally, all patients who discontinued study drug for progression without 
documented progression will still be followed with regular tumor assessments (e.g. in case of 
central radiology review).If patient withdraws consent, it must be clearly stated if patient is also 
withdrawing consent from post treatment evaluations and/or post treatment follow-up 
assessments. During that evaluation period, usually only tumor measurements (and/or response 
status) and survival data are collected. In some protocols, the subsequent anti-cancer therapies 
may also be recorded.
14.1.27
Study evaluation completion
At the end of the study evaluation period, the study evaluation completion page is filled out 
with the following options:

Patient withdrew consent

Lost to follow-up

Administrative problems (when follow-up for progression has met protocol required 
events, e.g. follow-up stopped at certain number of events or certain time)

Death

New cancer therapy (optional, to be used when follow-up for progression is stopped in this 
case)

Disease progression
Thereafter, patients will be followed for survival using the survival follow-up pages. If 
information on death becomes available for patients who were lost to follow-up or withdrew 
consent, this may also be entered in the database. The reason for death must be documented 
(and will be coded using MedDRA); it must be also stated if death was due to ‘Study indication’ 
or ‘Other’ reason.
In comparative studies with long follow-up period and therefore extended visit schedule, it may 
be useful to collect the survival status at a pre-specified cut-off within a limited timeframe for 
all patients with no documented death. In this case, this requires a contact to be made with the 


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patient or with any reliable source of information on the patient’s status, but not requiring a 
specific visit to be scheduled
Until the specified cut-off point has been reached, the goal is to collect tumor assessments until 
disease progression for all patients regardless of whether the patients are still receiving study 
drug. If patients are not followed for progression, e.g. in a Phase I or II study mainly evaluating 
safety, the evaluation is completed when study drug is completed (in this case only the first 
completion page is used).
14.1.28
Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, data 
review reports will be available to identify assessments for which the investigators’ opinion 
does not match the programmed calculated response based on RECIST criteria. This may be 
queried for clarification. However, the investigator response assessment will never be overruled.
If Novartis elect to invalidate an evaluation of overall lesion response 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.
14.1.29
Programming rules
The following should be used for programming of efficacy results:
14.1.30
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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14.1.31
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 14.1.21). 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.
14.1.32
Incomplete dates for last contact 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.
14.1.33
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)’.
14.1.34
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.35
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-5)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)


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
New cancer therapy added (optional; only if the protocol specified that PFS/TTP will be 
censored at that date)
* Adequate assessment is defined in Section 14.1.21. 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=’Administrative problems’ 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 for censor in case of no baseline assessment.
14.1.36
References (available upon request)
Dent S, Zee (2001). application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009). New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008). Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988). Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000). New Guidelines to Evaluate the Response 
to Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16


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14.2
Appendix 2: 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 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 14-6). 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 14-7).
Table 14-6
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 14-7
Child-Pugh score interpretation
Severity (grade)
Child-Pugh Score
A
5 - 6
B
7 - 9
C
10 - 15
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


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14.3
Appendix 3: Hepatocellular carcinoma staging systems
Staging systems
Clinical staging is crucial for risk stratification during cancer management. For HCC, a number 
of clinical staging systems have been developed mainly from HCC patients of different 
etiologies and extent of disease. The following three staging systems : the BCLC system are 
most widely studied and will be assessed at screening for all patients participating in this study:
For more information on patient eligibility, please refer to the core text of the study protocol.
Barcelona-Clinic Liver Cancer system
The BCLC staging system (Table 14-8) was developed based on the combination of data from 
several independent studies representing different disease stages and/or treatment modalities. It 
includes variables related to tumor stage, liver functional status, physical status and cancer 
related symptoms. (Llovet et al 2008b)
Table 14-8
Barcelona-Clinic Liver Cancer system
BCLC stage
PS
Tumor Features
Liver Function
Stage A* (early HCC)
A1
0
Single < 5 cm
No portal HTN** and normal bilirubin
A2
0
Single < 5 cm
Portal HTN, normal bilirubin
A3
0
Single < 5 cm
Portal HTN, abnormal bilirubin
A4
0
Up to 3 tumors < 3 cm
Child-Pugh class A - B
Stage B (intermediate HCC)
0
Large multinodular
Child-Pugh class A - B
Stage C (advanced HCC)
1 - 2
Vascular invasion or 
extrahepatic spread
Child-Pugh class A - B
Stage D (end-stage HCC)
3 - 4
Any of the above
Child-Pugh class C
* Stages A1, A2, A3 and A4 will be considered “Stage A” for data collection.
** HTN = Hypertension
Only BCLC Stage C HCC patients are eligible for participating in this study, provided that the 
patients meet all other eligibility criteria.
References (available upon request)
Chan S, Mo F, Johnson P, et al (2010). Prospective validation of the CUPI and Comparison 
with other staging systems for hepatocellular carcinoma in Asian population. Journal of 
Gastroenterology and Hepatology, “Accepted Artcle”; doi: 10.111/j.1440-1746.2010.06329.x
Llovet J, Sergio R, Mazzaferro V, et al (2008). Sorafenib in advanced hepatocellular 
carcinoma. N Engl J Med; 359: 378-390
The Cancer of the Liver Italian Program (CLIP) investigators (1998). A new prognostic 
system for hepatocellular carcinoma: a retrospective study of 435 patients. Hepatology; 28(3): 
751-755


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14.4
Appendix 4: Tables of drugs prohibited and drugs used with 
caution
If a medication that is listed in both Table 14-9 and Table 14-10, more stringent practice shall 
be applied (that is, the medication shall be prohibited as in Table 14-9).
Based on available data, INC280 is not expected to have any clinically relevant effect on QTc 
(INC280 Investigator’s Brochure); drugs with known risk of Torsade de Pointes (TdP) were 
therefore removed from the list of INC280 prohibited concomitant medications.
The use of live vaccines is not allowed during the study and up to 30 days from the last dose of 
INC280 treatment. 
Table 14-9
Prohibited concomitant medications
Mechanism of Interaction
Drug Name
Strong CYP3A4 inducer
carbamazepine, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin, rifabutin, rifampin, St. John’s wort
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 (https://drug-
interactions.medicine.iu.edu/Main-Table.aspx), the University of Washington’s Drug Interaction 
Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction Studies”
Table 14-10
Permitted concomitant medications requiring caution
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, eltegravir/ritonavir, 
saquinavir/ritonavir, lopinavir/ritonavir, 
itraconazole, voriconazole, mibefradil, 
clarithromycin, posaconazole, telithromycin, 
grapefruit juice, conivaptan, nefazodone, 
nelfinavir, idelalisib, boceprevir, 
atazanavir/ritonavir, darunavir/ritonavir
Moderate CYP3A inducer
bosentan, dabrafenib, efavirenz, etravirine, 
genistein, modafinil, nafcillin, tipranavir/ritonavir, 
lopinavir, telotristat, thioridazine
CYP1A2 substrate with NTI
theophylline, tizanidine
P-gp substrates 1
afatinib, alfuzosin, aliskiren, alogliptin, 
ambrisentan, apixaban, apremilast, aprepitant, 
atorvastatin, azithromycin, boceprevir, bosentan, 
carvedilol, caspofungin, ceritinib, 
citalopram, colchicine, cyclosporine, dabigatran, 
digoxin, docetaxel, doxepin, doxorubicin, 
eribulin, everolimus, fentanyl, fexofenadine,
fidaxomicin, fluvastatin, fosamprenavir, 
gatifloxacin, idelalisib, iloperidone, indacaterol, 
irbesartan, lacosamide, lapatinib, levetiracetam, 
linagliptin, linezolid, loperamide, losartan, 


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Mechanism of Interaction
Drug Name
maraviroc, mirabegron, moxifloxacin, nadolol, 
naloxegol, nateglinide, nevirapine, nintedanib, 
olodaterol, paclitaxel, pantoprazole, paroxetine, 
pazopanib, phenytoin, posaconazole, 
pravastatin, proguanil, quinidine, ranolazine, 
riociguat, risperidone, ritonavir, rivaroxaban, 
saquinavir, silodosin, simeprevir, simvastatin,
sirolimus, sitagliptin, sofosbuvir, sorafenib, 
tacrolimus, telaprevir, tenofovir, ticagrelor, 
tipranavir, tolvaptan, topotecan, umeclidinium, 
valsartan, vardenafil, vincristine, voriconazole
BCRP substrates 1
atorvastatin daunorubicin, dolutegravir, 
doxorubicin, ethinyl estradiol, hematoporphyrin, 
imatinib, irinotecan, methotrexate, 
mitoxantrone, paritaprevir, pitavastatin, 
rosuvastatin, simvastatin, sofosbuvir, 
sulfasalazine, tenofovir, topotecan, venetoclax
Proton pump inhibitor
Dexlansoprazole, esomeprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole
H2-receptor antagonists
cimetidine, famotidine, nizatidine, ranitidine
Antacids
aluminum carbonate, aluminum hydroxide, 
calcium carbonate, calcium hydroxide, 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 (https://drug-
interactions.medicine.iu.edu/Main-Table.aspx), the University of Washington’s Drug Interaction 
Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, Drug Interaction 
Studies”.This list may not be exhaustive and could be updated periodically. Please refer to the 
above mentioned databases for latest information. NTI: narrow therapeutic index
1 If coadministration with capmatinib is unavoidable and minimal concentration changes of the drug 
listed may lead to serious adverse reactions, decrease dosage in accordance with the approved 
prescribing information.


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14.5
Appendix 5: The Bayesian logistic regression model and dose 
recommendations in hypothetical scenarios
An adaptive Bayesian logistic regression model (with 2 parameters) guided by the escalation 
with overdose control principle will be used to make dose recommendations for the Dose 
Expansion Part at the end of the Dose-Determining Part.
The dose-toxicity relationship will be described by the following logistic regression model:
logit(π(d)) = log(α) + β log(d/d*),
α>0, β>0
where logit(π(d))= ln ((d)/(1-(d))), π(d) is the probability of a patient experiencing a qualifying 
AE within the first four weeks of treatment at dose d (mg BID). Doses are rescaled as d/d* with 
reference dose d*= 400 mg BID (800mg total in a day) of INC280. As a consequence α is equal 
to the odds of toxicity at d*. Note that for a dose equal to zero, the probability of toxicity is zero.
Prior specifications
Prior for (log(α), log(β)):
Step 1: Weakly informative bivariate normal prior for the model parameters (log(),log()) is 
elicited based on prior guesses (medians) from preclinical data and wide confidence intervals 
for the probabilities of DLT at each dose, and can be obtained as follows:

For the purposes of tuning the prior for the model a priori the median DLT rate at 10 mg 
BID is assumed to be low (1%) and the MTD is surmised to be 300 mg BID (33% DLT 
rate) based on preclinical studies (BSA-based projection to human dose). For the 
remaining doses, median DLT rates a priori are assumed linear in the logit-scale as a 
function of log-dose.

Based on the above specified medians for the DLT rate at each dose and wide prior 
confidence intervals, the optimal parameters of the bivariate normal distribution can be 
obtained following the procedure described by (Neuenschwander et al 2008).
The parameters of the weakly informative prior distributions of model parameters and the 
assigned weights are presented in Table 14-11. Figure 14-1 illustrates the resulting prior 
distribution of qualifying AE-rate derived from the prior given in Table 14-11.
Table 14-11
Weakly-informative prior parameters for bivariate normal distribution 
of model parameters
Parameters
Means
Standard deviations
Correlation
log(α), log(β)
(-0.308, 0.011)
(1.835, 0.949)
-0.310


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Figure 14-1
Probability of qualifying AE according to the weakly informative prior 
distribution in Table 14-11
Step 2: Given the weakly informative prior obtained in Step 1 above, data available (at the time 
of developing the study plan of the present trial) from the ongoing trials of INC280 is then used 
to compute a posterior that serves as informative prior. Table 14-12, Table 14-13 and 
Table 14-14 summarizes the information available from the ongoing trial. Because there are 
both qd and bid dosing schedule in the INCB28060-101 trial, when deriving the informative 
priors, a Bayesian logistic regression model with a covariate that represents the dosing schedule 
is used to take the dosing schedule into account. The model parameter for the covariate is γ, 
which is assumed to have a weakly informative normal prior distribution with mean of 0.693 
and standard deviation of 0.541.


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Table 14-12
DLT information (cut-off date 15AUG 2012) from ongoing trial 
INCB28060-101 in patients with advanced malignancies used to derive 
informative prior
Dose
(mg/day)
Regimen
FIH study
(Prot No. INCB28060-101)
No. of evaluable patients
No. of DLT(s)
10
QD
3
0
20
QD
3
0
50
QD
6
1
70
QD
3
0
100
BID
3
0
150
QD
3
0
200
QD
3
0
300
QD
4
0
400
QD
4
0
400
BID
4
0
600
BID
4
0
Table 14-13
DLT information (cut-off date AUG2012) from ongoing trial 
INC280X1101 used to derive informative prior
Dose
(mg QD)
FIH study
(Prot No. INC280X1101)
No. of evaluable patients
No. of DLT(s)
100
3
0
200
3
0
400
3
0
Table 14-14
DLT information (cut-off date 15AUG 2012) from ongoing trial 
INC280X2102
Dose
(mg BID)
FIH study
(Prot No. INC280X2102)
No. of evaluable patients
No. of DLT(s)
100
4
0
The parameters of the informative prior distributions of all model parameters are provided in 
Table 14-15. The weakly informative prior (Table 14-11) was updated using the data in the 
above trials separately to derive the informative priors presented in Table 14-15.


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Table 14-15
Posterior (based on data in Table 14-12, Table 14-13 and Table 14-14) 
parameters for bivariate normal distribution of model parameters for 
ongoing/previous trials
Parameters
Means
Standard deviations
Correlation
log(α), log(β) –
INCB28060-101
(-2.226, -0.393)
(0.825, 0.627)
0.1833
log(α), log(β) –
INC280X1101
(-1.961, 0.406)
(1.286, 0.900)
-0.107
log(α), log(β) –
INC280X2102
(-1.358, 0.476)
(1.476, 0.859)
0.056
Step 3: For the deriving the predictive distribution of the model parameters, the between trial 
variability was captured by the prior distributions of standard deviations of (log(),log()), 
denoted by τ1 and τ2. Both τ1 and τ2 are assumed to follow log-normal distributions with mean 
log(0.70) and standard deviation 0.01, assuming substantial between-trial variability 
(Neuenschwander et al 2010). The resulting prior (see Table 14-16 and Figure 14-2) may be 
updated again (based on new data from [INC280X1101], [INC280X2102] and INCB28060-
101) before the safety analysis at the end of the Dose-Determining Part. If such an update is 
made, the new prior (and the corresponding summary of qualifying AE-rates) will be presented 
in the meeting to discuss dose adjustment for the Dose Expansion Part and will be reported in 
the statistical appendix to the CSR as well.


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Figure 14-2
Probability of DLT according to the predictive prior distribution in 
Table 14-15
Table 14-16
Predictive distribution of model parameters
Parameters
Means
Standard deviations
Correlation
log(α), log(β)
(-1.940, 0.092)
(1.040, 0.926)
0.043


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Table 14-17
Prior probabilities of under, targeted and over dosing (derived from 
mixture of priors in Table 14-12
Dose (mg 
BID)
Prior probabilities that Pr(DLT) is in 
interval:
Mean
Sd
Quantile
0-0.16
0.16-0.33
0.33-1.0
2,5%
50%
97.5%
50
0.953
0.037
0.011
0.036
0.066
0
0.012
0.229
75
0.938
0.048
0.014
0.044
0.073
0
0.018
0.258
100
0.924
0.059
0.017
0.052
0.078
0
0.024
0.283
150
0.893
0.083
0.024
0.067
0.087
0
0.037
0.323
200
0.855
0.113
0.031
0.083
0.095
0.001
0.051
0.358
250
0.809
0.149
0.042
0.1
0.103
0.003
0.067
0.392
300
0.752
0.191
0.057
0.119
0.111
0.008
0.085
0.428
400
0.607
0.276
0.117
0.165
0.134
0.018
0.126
0.527
500
0.48
0.31
0.21
0.218
0.174
0.024
0.168
0.685
Hypothetical dose escalation scenarios
The design should make reasonable decisions during a study based on the observed toxicities. 
After completion of the first 28 days in all evaluable patients in the Dose-Determining Part, the 
decision to adjust the dose will depend on the recommendation of the BLRM per EWOC 
principle and medical review of available clinical and laboratory data.
Some scenarios to illustrate the dose adjustment are listed in Table 14-18 using the 2-parameter 
BLRM. It is assumed that the Dose-Determining Part has exactly 6 evaluable patients. It is also 
assumed that the RP2D from other INC280 studies will be 600mg bid (in practice, the RP2D 
can be different).
Table 14-18
Possible scenarios in study CINC280X2201 in the Dose-Determining 
cohort with 6 evaluable patients
Scenario 
number
Dose History (mg bid) –
Cohort
No. AEs / No. Pat
Dose recommended (mg bid) for Dose 
Expansion Part *
1
300 - 1
0/6
600
2
300 - 1
1/6
500
3
300 - 1
2/6
300
4
300 - 1
3/6
200
5
300 - 1
4/6
100
6
300 – 1
5/6
50 mg bid too toxic
7
300-1
6/6
50mg bid too toxic
* Please note that the recommendation presented in this table is based on the BLRM only. The actual dose will 
be determined after a comprehensive review of all available data, including PK analysis as mentioned in the 
protocol.


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Discussion
The BLRM enables us to incorporate the pre-clinical and clinical information, as well as to 
update the recommended dose based on emergent safety data in the study.
On-study recommendations based on the model are consistent with the clinical decision making 
process regarding the Dose Expansion part dose should be made in conjunction with other 
available clinical information by the Novartis Clinical Trial Team and Study investigators in 
deciding the dose-levels to be tested in the Dose Expansion Part.
References (available upon request)
Neuenschwander B, Capcun–Niggli G, Branson M, et al (2010). Summarizing Historical 
Information on Controls in Clinical Trials. Clin Trials; 7(1): 5-18
Neuenschwander, Branson, Gsponer (2008). Critical aspects of the Bayesian approach to 
Phase I cancer trials. Statistics in Medicine, 27:2420-2439


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14.6
Appendix 6: Cockcroft-Gault formula for GFR estimate
Calculation
a. Indications: Stable kidney function
1. Older patients
2. General screening
b. Male GFR = (140 − age) × (weight) / (sCr × 72)
c. Female GFR = (140 − age) × (weight) × 0.85 / (sCr × 72)
d. Annotation
1. Where GFR is Glomerular Filtration Rate in ml/min
2. Where age is in years
3. Where weight is Lean Body Mass in kilograms
4. Where sCr is Serum Creatinine in mg/dl
e. Efficacy
1. As accurate as 24 hour urine in most cases
2. Exceptions: See 24 hour CrCl indications below
Should be altered in the following: Calculating GFR in specific cohorts
1. Overweight (GFR >25 kg/m2)

Calculate based on adjusted body weight

Adjusted body weight = wtKgIdeal + 0.4 × (wtKgActual - wtKgIdeal)
2. Underweight

Use actual weight

Do not round up to Serum Creatinine (significantly underestimates GFR)
3. Elderly

Do not round up to Serum Creatinine (significantly underestimates GFR)
4. Amputation

Measure 24 hour Creatinine Clearance
Reference
Wallach JB (2007) Interpretation of Diagnostic Tests. 8th ed; Lippincott Williams & Wilkins.

SAP_001.pdf: 
Clinical Development
INC280
CINC280X2201 / NCT01737827
A Phase II, open label, single arm, multi-center study of INC280 
administered orally in adult patients with advanced hepatocellular 
carcinoma
Statistical Analysis Plan (SAP)
Author:
Trial Statistician
Document type:
SAP Documentation
Document status:
Final Amendment 01
Release date:
28-Nov-2022
Number of pages:
26
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP Amendment 1 
  
CINC280X2201
Document History – Changes compared to previous version of SAP
Version
Date
Changes
0.1
08-Dec-2016
Create
1.0
18-Jan-2017
Final version after CTT review
2.0
28-Nov-2022
Updated to align with the Protocol amendment V6.0


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SAP Amendment 1 
  
CINC280X2201
Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................5
1.1
Study design.............................................................................................................5
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical Methods ..............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................8
2.2
Analysis sets ..........................................................................................................10
2.2.1
Subgroup of interest ..............................................................................11
2.3
Patient disposition, demographics and other baseline characteristics ...................11
2.3.1
Patient disposition.................................................................................11
2.3.2
Basic demographic, Prognostic factors for HCC and background 
data........................................................................................................11
2.3.3
Medical History.....................................................................................11
2.3.4
Prior antineoplastic therapy...................................................................12
2.3.5
Diagnosis and extent of cancer .............................................................12
2.4
Protocol deviations ................................................................................................12
2.5
Study treatment......................................................................................................13
2.5.1
Data handling ........................................................................................13
2.5.2
Data analysis .........................................................................................13
2.6
Analysis of the qualifying adverse events within first four weeks of treatment
for dose determination...........................................................................................15
2.7
Analysis of the primary objective..........................................................................16
2.7.1
Primary endpoint...................................................................................16
2.7.2
Statistical hypothesis, model, and method of analysis..........................16
2.7.3
Handling of missing values/censoring/discontinuations.......................16
2.8
Analysis of the efficacy variables..........................................................................17
2.9
Safety analysis .......................................................................................................18
2.9.1
Adverse events ......................................................................................18
2.9.2
Laboratory data .....................................................................................21
2.9.3
Vital signs, weight and physical examinations .....................................21
2.9.4
Electrocardiograms ...............................................................................21
2.10
Pharmacokinetic data.............................................................................................21
2.10.1
Dose-Determining Part..........................................................................22
2.10.2
Dose Expansion Part .............................................................................22
2.10.3
Data handling principles .......................................................................22


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2.11
Patient reported outcomes......................................................................................22
22
23
2.13
Interim analyses.....................................................................................................23
3
Sample size calculation .....................................................................................................23
Dose-Determining Part......................................................................................................23
Dose expansion Part ..........................................................................................................23
4
Change to protocol specified analyses ..............................................................................25
4.1
Handling of missing and partial dates ...................................................................25
5
References .........................................................................................................................26


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CINC280X2201 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 TFL 
shells document. The specifications for derived variable and datasets can be found in the 
Programming Datasets Specifications (PDS) document.
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend.
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., IB updates, abstracts, posters, presentations,
manuscripts and management updates. Data used for these analyses will have a status aligned 
to the database lock guidance.
As Novartis decided to halt the enrollment in the expansion part in December 2016 (enrollment 
halt letter to investigators on 24-Nov-2016), the enrollment to the expansion part was 
permanently halted after 25-Dec-2016 (no patients will be enrolled beyond 25-Dec-2016), the 
study data will be analyzed and reported based on all data in the final Clinical Study Report 
(CSR).
The content of this SAP is based on protocol CINC280X2201 version 6.0.
1.1
Study design
This is a Phase II, open label, single arm, multicenter study of INC280 administered orally as 
first-line treatment in adult patients with advanced hepatocellular carcinoma (HCC). Patients 
will be enrolled into the study in 2 parts (Dose-Determining and Dose Expansion parts) where 
the first part will allow the assessment of safety and PK profiles prior to initiating a larger 
second part.
During the Dose-Determining Part, at least six patients will be enrolled and treated with INC280 
at 300 mg bid in capsule formulation. The dose for the Dose Expansion Part will be determined 
after the Dose-Determining Part.


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1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below. Planned objectives and 
endpoints which will not be considered for analysis in the full CSR are noted in the table below. 


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Table 1-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
To estimate overall clinical 
activity of INC280 in advanced 
HCC patients with c-MET 
dysregulation.
Time to progression (TTP) assessed 
using RECIST version 1.1
Section 2.7
Secondary
To further assess the clinical 
activity of INC280 in advanced 
HCC patients with c-MET 
dysregulation
Overall Response Rate (ORR), 
Progression Free Survival (PFS), 
Overall Survival (OS) and Disease 
Control Rate (DCR)
Section 2.8
To characterize the safety and 
tolerability of INC280 in 
advanced HCC patients.
Safety: Adverse Events (AEs), 
serious AEs (SAEs), changes in 
hematology and chemistry values, 
vital signs, electrocardiograms 
(ECGs)
Tolerability: Dose interruptions, 
reductions and dose intensity
Section 2.9
To characterize the 
pharmacokinetics (PK) of 
INC280 in patients with 
advanced HCC.
Plasma concentration vs. time 
profiles, plasma PK parameters 
including but not limited to AUC0-t, 
AUCinf, Cmax and Tmax
Section 2.10


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2
Statistical Methods
2.1
Data analysis general information
The data will be analyzed by Novartis personnel and/or designated CRO(s) using SAS version 
9.4, and for Bayesian modeling, R version 2.13.2 and Winbugs 1.4.3. PK parameters will be
calculated using non-compartmental methods available in Phoenix WinNonlin version 6.4 or 
above.
The data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant PK 
using descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) for 
quantitative data and contingency tables (frequencies and percentages) for qualitative data.
Demographic and safety data will be summarized and listed by study treatment groups. 
Study treatment groups refer to

INC280 300 mg BID Capsule

INC280 600 mg BID Capsule

INC280 400 mg BID Tablet
Analyses of efficacy data may be summarized by study parts and revised definition of c-MET 
positivity, as introduced in Protocol Amendment 2; i.e. MET gene copy number ≥5 by FISH 
with c-MET IHC intensity score 2+ in ≥50% of tumor cells or unknown, or c-MET IHC 
intensity score 3+ in ≥50% of tumor cell, or presence of c-MET mutation:

Dose Determining

Dose Expansion
o
c-MET high
o
c-MET low
The cMET IHC and FISH analyses were performed through Novartis designated central 
laboratories.
All data collected for patients in the Dose-Determining part will be reported at the initial
Dose-Determining dose level, irrespective of whether a patient undergoes intra-patient
escalation to a higher dose level.
The statistical analyses will take into account the study treatment formulation as appropriate.
The primary and secondary endpoints (refer to Section 1.2) will be performed based on FAS. 
For more information please refer to Section 2.7.1.
2.1.1
General definitions
Study drug and study treatment
Both study drug and study treatment refer to the study compound: INC280.


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Date of first administration of study treatment
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of study treatment was administered as per the Dosage Administration eCRF. 
Date of last administration of study treatment
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of study treatment was administered as per the Dosage Administration eCRF. 
Study day
The study day for safety and efficacy assessments will be calculated as the difference between 
the date of the event (onset date of an event, assessment date etc.) and the start of study treatment 
plus 1. The first day of study treatment is therefore study Day 1. Example: if start of study 
treatment is on 05-Jan-2014 and start date of an adverse event is on 09-Jan-2014 then the study 
day of the adverse event onset is 5. For safety assessments before start of study treatment, the 
study day is negative and derived by (date of event - start date of study treatment). For example: 
if start of study treatment is on 05-Jan-2014 and date of lab measurement is on 02-Jan-2014 
then the study day of the laboratory abnormality is -3. Note, the day of start of study treatment
is Day 1, and the day before the date of first study treatment is Day - 1, not day 0.
Baseline
Baseline is the result of an investigation describing the “true” state of the patient before start of 
study treatment administration.
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, the last available assessment before the treatment start date/time is 
used for baseline.
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline.
If patients have no value as defined above, the baseline result will be missing.
On-treatment assessment/event observation periods
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s first informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 30 days 
after date of last actual administration of any study treatment (including start and stop 
date)
3. post-treatment period: starting at day 30+1 after last administration of study treatment.


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Safety summaries include only data from the on-treatment period with the exception of baseline 
data which will also be summarized where appropriate (e.g. change from baseline summaries). 
In 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).  
However, all safety AE data (including those from the pre-treatment period) will be listed.
2.2
Analysis sets 
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of INC280. 
The FAS will be used for all listings of raw data. Unless otherwise specified the FAS will be 
the default analysis set used for all analyses.
Safety Set
The Safety Set includes all patients from the FAS who have received at least one dose of 
INC280 and had at least one valid post-baseline safety assessment.
Please note: A “no” to indicate that the patient had no AEs (on the AE eCRF) constitutes a 
valid safety assessment.
Per-protocol Set
Not applicable. As the study did not meet the planned enrollment, supportive analysis with PPS 
is no longer of clinical interest.
Dose-determining analysis set
The dose-determining set (DDS) consists of all patients from the safety set (who are in the 
Dose-Determining Part) who either meet the minimum exposure criterion and have sufficient 
safety evaluations (as determined by the Investigators and Novartis), or who have experienced
a qualifying AE during the first four weeks of treatment.
A patient is considered to have met the minimum exposure criterion at a dose level if they 
receive INC280 at the planned dose, BID for at least 21 days within the first four weeks of 
treatment (≥75% planned administration). Patients who do not experience a qualifying AE
during the first four weeks are considered to have sufficient safety evaluations if they have been 
observed for ≥28 days following the first dose, and are considered by both the Sponsor and 
Investigators to have enough safety data to conclude that a qualifying AE did not occur.
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who provide an evaluable PK 
profile. A profile is considered evaluable if all of the following conditions are satisfied:

Subject receives one of the planned treatments

Subjects provides at least one primary PK parameter

Subject did not vomit within 4 hours after the dosing of INC280


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2.2.1
Subgroup of interest
Analyses of efficacy data may be presented separately for patients meeting the revised 
definition of c-MET positive, as introduced in Protocol Amendment 2; i.e. MET gene copy 
number ≥5 by FISH with c-MET IHC intensity score +2 in ≥50% of tumor cells or unknown, 
or c-MET IHC intensity score +3 in ≥50% of tumor cell or presence of c-MET mutation.
The primary and secondary endpoints (refer to Section 1.2) will be performed based on FAS. 
For more information please refer to Section 2.7.1.
2.3
Patient disposition, demographics and other baseline
characteristics
Summaries and listings described in this section will be done by study treatment groups based 
on the FAS.
2.3.1
Patient disposition
The FAS will be used for the patient disposition summary tables and listings. The following
will be tabulated:

Number (%) of patients who are still on-treatment (based on non-completion of the ‘End 
of Treatment 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 complete study evaluation (based on completion of the ‘End 
of Post-treatment follow-up’ page with discontinuation date and reason entered),

Primary reasons for study evaluation completion (based on discontinuation reason entered 
in the ‘End of Post-treatment follow-up’ page),
Treatment/study completion status and the reason for discontinuation from study will be listed, 
along with dates of first and last study drug treatment, duration of exposure to study drug 
treatment and date of discontinuation for each patient.
2.3.2
Basic demographic, Prognostic factors for HCC and background data
Demographic data including age, sex, race, ethnicity, height, baseline weight, body mass index
(BMI), ECOG(WHO) performance status, HBV/HCV at diagnosis, Child Pugh, alpha 
fetoprotein, portal vein invasion at diagnosis and distant metastases at diagnosis will be listed 
and summarized. In addition, child bearing potential and pregnancy test results will be listed, 
and age (18 - <65, 65 - <85, ≥85 years) and weight (<55, 55-<75, ≥75 kg) categories will be 
summarized.
BMI is calculated using the following formulas:

BMI [kg/m2] = weight[kg] / (height[m]**2)
2.3.3
Medical History
Relevant medical history and current medical conditions will be listed using Safety set..


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2.3.4
Prior antineoplastic therapy
Concomitant medications will be coded using the WHO Anatomical Therapeutic Chemical
(ATC) dictionary using the latest version available prior to clinical database lock. 
All concomitant medications will be listed using Safety set, with a flag to differentiate those 
which started more than 30 days after the last study treatment.
2.3.5
Diagnosis and extent of cancer
Diagnosis and extent of cancer will be listed, including all of the information collected in 
eCRF.
2.4
Protocol deviations
All protocol deviations will be finalized before database lock. For the purpose of excluding 
patients from the analysis sets defined in Section 2.2, the protocol deviations and non-protocol 
deviations and severity codes are defined in Table 2-1.
Table 2-1
Protocol deviations and non-protocol deviations
Analysis set
Protocol deviations with ID [severity codes leading to 
exclusion]
Full analysis set
[GCP01] The patient was enrolled and the ICF was not 
signed [511]
Safety set
[PROC01] Patient has had at least one dose of INC280, 
but has no post-baseline safety assessment [2]
Dose-determining set
[PROC04] For patients in dose-determining part: Patient 
did not have sufficient safety assessments by Cycle 2 Day 
8 for the investigator to complete the Dose Decision 
Analysis [16]
[PROC09] For patients in dose determining part: Patient 
did not receive INC280 at the planned dose, BID for at 
least 21 days within the first four weeks of treatment and 
did not experience a qualifying AE during the first four 
weeks [16]
Pharmacokinetic analysis set
[PROC02] Patient has no PK sample collected for INC280
[24]
Other
[COMD01] Patients participate in additional parallel 
investigational drug or device studies [256]
[COMD02] Patient received another anticancer therapy 
other than the study treatments while on the study [256]
[511] exclude from all analysis [2] exclude from safety analysis [16] exclude from dose-
determining set [24] exclude from dose-determining set and pharmacokinetic analysis set 
[256] exclude from date only


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2.5
Study treatment
Summaries and listings described in this section will be done by study treatment groups based 
on the Safety set.
2.5.1
Data handling
2.5.1.1
Data Imputation
The following rule should be used for the imputation of date of last administration (please refer 
to Sections 2.1.1) for a given study treatment:
If the date of last administration is completely or partially missing and the EOT eCRF page is 
available  (prior to any death date or withdrawal of consent date, if available): 
Case 1: The date of last administration is completely missing, and the EOT visit date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date: 
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy  = the year of EOT date and mm < the month of EOT visit:  
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 the start date of that specific record, if the 
imputed date is < start date of that record
Use the start date of that record.
Patients with missing start dates are to be considered missing for study treatment related 
calculations described in  Section 2.5.2 and no imputation will be made. If the date of first 
administration is missing, then the date of last administration should not be imputed.
2.5.2
Data analysis
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity
(RDI) will be summarized for the study treatment. Duration of exposure will be categorized 
into time intervals; frequency counts and percentages will be presented for the number(%) of 
patients in each interval. The number (%) of patients who have dose reductions or interruptions, 
and the reasons, will be summarized by study treatment. 
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced.  
The safety set will be used for all summaries and listings of study treatment.


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2.5.2.1
Duration of exposure to study treatment
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 last dates of exposure to INC280, i.e., a
patient had a permanent discontinuation of the study drug on 06-Jan-2013 after being put on a 
temporary interruption since 01-Jan-2013. In this case the last date of exposure is 31-Dec-2012.
Summary of duration of exposure of study treatment will include categorical summaries (based 
on time intervals: <=3 weeks, 3-<=9 weeks, 9-<=18 weeks and >18 weeks) and continuous 
summaries (i.e. mean, standard deviation etc.) using units of days.
2.5.2.2
Cumulative dose
Cumulative dose of a study drug is defined as the total dose given during the study drug
exposure and will be summarized. 
The planned cumulative dose for the study drug refers to the total planned dose as per the 
protocol up to the last date of study drug administration. The planned cumulative dose is not 
summarized/listed. It is used for relative dose intensity calculations. 
The planned cumulative dose is the planned total daily dose * Duration of exposure to study 
drug (days).
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on the study treatment as documented in the Dose Administration eCRF, 
i.e., 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.
For patients who did not take any drug, the actual cumulative dose is by definition equal to zero
for that drug.
2.5.2.3
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (dosing unit / unit of time) = Actual Cumulative dose (dosing unit) / Duration of exposure 
(unit of time).
For example, for INC280, the dosing unit is mg and actual cumulative dose is 1200 mg, and the 
unit of time is a day and duration of exposure is 18 days, then 
DI (mg/day) = Actual Cumulative dose (mg) / Duration of exposure (day)
= 1200 (mg) / 18 (day) = 66.7 (mg/day)
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (day).
Relative dose intensity (RDI) is defined as follows:


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RDI = DI (mg / day)  / PDI (mg / day).  
DI and RDI will be summarized for the study drug. The RDI will be tabulated using the 
following intervals: <0.5, >=0.5-<0.75,>=0.75-<0.9, >=0.9-<1.1, >=1.1.
2.5.2.4
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized for the study drug. 
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the 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. 
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 considered a dose reduction. Only dose change is collected in the CRF, 
number of reductions will be derived programmatically based on the change and the  direction 
of the change.   
2.6
Analysis of the qualifying adverse events within first four weeks 
of treatment for dose determination
A two-parameter Bayesian Logistic Regression Model (BLRM) guided by the Escalation with 
Overdose Control (EWOC) principle will be used for the safety analysis. This safety analysis 
(to be performed during the dose decision analysis after the Dose-Determining Part as well as 
to confirm the Expansion Part dose) will be based on data (occurrence/absence) of certain AEs 
within the first 28 days treatment. Doses available for consideration as the Expansion Part dose 
will be those estimated under the modeling for which the risk that the true rate of the qualifying 
AE in the first four weeks of treatment exceeds 33% is less than 25%. 
The DDS will be used for these analyses. 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
All information currently available about the dose-AE relationships of single agent INC280 will 
be summarized in prior distributions. More details can be found in CINC280X2201-Protocol-
Appendix 5.


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Dose recommendation will be based on posterior summaries including the mean, median, 
standard deviation, 95%-credibility interval, and the probability that the true rate of qualifying
AEs lies in one of the following categories:

[0,16%] under-dosing

[16%,33%] targeted toxicity

[33%,100%] excessive toxicity
Following the principle of EWOC, at the end of Dose-Determining Part, a range of doses will 
be recommended for the Dose Expansion Part. The highest dose level in that dose range will be 
the highest dose that satisfies the overdose criterion that there is less than 25% chance of 
excessive toxicity. If the recommended Dose Expansion Part dose as per the PK analysis (See 
CINC280X2201-Protocol sections 10.5.4.1.1 and 6.2.2) is higher than the dose allowed by the 
BLRM, the highest dose allowed by the BLRM will be used for the Dose Expansion Part.
Summaries of the posterior distribution of rate of qualifying AEs based on the AE data from all 
patients in the DDS will be presented.
2.7
Analysis of the primary objective
2.7.1
Primary endpoint
The primary variable for analysis is Time to progression (TTP), as per local assessment, is 
defined as the time from the date of baseline evaluation to the date of the first documented 
radiological confirmation of disease progression or death due to underlying cancer (RECIST 
v1.1). If a patient has not had the event at the date of analysis cut-off or when he/she received 
any further anti-neoplastic therapy, TTP will be censored at the time of the last adequate 
assessment.
2.7.2
Statistical hypothesis, model, and method of analysis
The primary TTP analysis will include all patients in the FAS (on an Intention-to Treat (ITT) 
basis) with patients classified according to the treatment group they were assigned to, at baseline 
(Dose-Determining Part or Expansion Part dose).
For patients in the Dose-Determining Part, TTP will be listed along with overall response.
For patients treated at the Expansion Part dose, the distribution of TTP will be estimated using 
the Kaplan-Meier method. The number of censored patients and number of patients with the 
event along with the median TTP and quantiles (along with one-sided 90% confidence intervals) 
at 3 months, 6 months, 9 months and 1 year will be presented. Also, the reason of censoring
will be summarized and listed for each patient.
2.7.3
Handling of missing values/censoring/discontinuations
If a patient has not experienced a radiological disease progression or death due to underlying
cancer, TTP will be censored at the date of the last adequate tumor assessment, defined as the
date the last tumor assessment with overall lesion response of CR, PR or SD which was made


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before a censoring reason occurred, or the date of first dose of INC280 if no post-baseline
assessments are available (See RECIST v1.1).
Other missing data will simply be noted as missing on appropriate tables/listings. The FAS
will be used.
2.8
Analysis of the efficacy variables
Evaluation of anti-tumor activity will be based on local radiologic examinations of overall 
lesion response according to RECIST v1.1 (refer CINC280X2201-Protocol-Appendix 1). The 
variables used to evaluate anti-tumor activity are ORR, DCR, BOR, PFS as per RECIST v1.1
and OS. Summaries and listings described in this section will be done based on the FAS.
Individual lesion measurements, overall lesion response will be listed by patient. ORR, DCR 
and BOR will be summarized (Table 2-2) by study treatment group and by cMET status.
Whereas PFS and OS will be summarized using Full analysis set. 
Individual lesion measurements and overall response (investigator’s assessment) at each
assessment will be listed by patient and treatment group. BOR will be summarized for all
patients by treatment group and the observed ORR will be summarized in terms of percentage
rates with 95% confidence intervals for each treatment group. The Kaplan-Meier estimates of
OS and PFS distribution functions will be presented graphically. The resulting median OS and 
median PFS and quantile estimates will be provided along with 95% confidence intervals. 
Rate estimates of PFS and OS (along with 95% CI) at 3 months, 6 months, 9 months and 1 
year will presented, as given by the Kaplan-Meier analysis.
For treatments groups with less than 10 patients, Kaplan-Meier estimates and plots will not be 
presented.
Table 2-2
Analysis of the efficacy variables
Endpoint
Definition
Analysis
PFS
PFS is defined as the time from date of 
first study treatment intake to the date of 
the first radiologically documented
progression or death due to any cause or 
initiation of new antineoplastic therapy.
The number of censored patients and 
number of patients with the event along 
with the resulting median PFS and 
quantile estimates will be provided 
along with 95% confidence intervals 
using Kaplan Meier method.
OS
OS is defined as the time from date of first  
study treatment intake to date of death 
due to any cause
The number of censored patients and 
number of patients with the event along 
with the resulting median OS and 
quantile estimates will be provided 
along with 95% confidence intervals 
using Kaplan Meier method.


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BOR
The best overall response (BOR) is the 
best response recorded from the start of 
the treatment until disease 
progression/recurrence.
BOR will be summarized as observed 
proportion in each category, and 
corresponding 95% confidence 
intervals (CIs) based on the exact 
binomial distribution will be presented.
Tumor volume best change from 
baseline will be presented graphically
(waterfall graphs).
ORR
Proportion of patients with a best 
overall response of confirmed CR or 
PR at any time on study per
RECIST.
ORR and corresponding 95% 
confidence intervals (CIs) based on the 
exact binomial distribution will be 
presented.
DCR
Proportion of patients with a BOR of CR, 
PR or SD at any time on study per 
RECIST.
DCR and corresponding 95% 
confidence intervals (CIs) based on the 
exact binomial distribution will be 
presented.
2.9
Safety analysis
Summaries and listings described in this section will be done by study treatment groups based 
on the Safety set.
2.9.1
Adverse events
2.9.1.1
Coding of AEs
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. The latest available MedDRA version at the time of the analyses should be used. 
The MedDRA version used should be specified in the footnote of relevant tables.
2.9.1.2
Grading of AEs
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).
2.9.1.3
AE summaries
AE summaries will include all AEs occurring during on-treatment period (Section 2.1.1). All 
AEs collected in the AE (e)CRF page will be listed along with the information collected on 
those AEs e.g. AE relationship to study drug, AE outcome etc. AEs starting during the post-
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 


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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 SOC will be presented alphabetically and the PTs will be sorted within 
primary SOC in descending frequency, based on their frequency in the ‘All Patients’ column.
The following AE summaries will be produced by study treatment group:

Overview of AE

AEs regardless of study treatment relationship by SOC, PT and maximum grade

AEs regardless of study treatment relationship by PT and maximum grade

AEs suspected to be study treatment related by PT and maximum grade

SAEs regardless of relationship to study treatment by PT and maximum grade

SAEs suspected to be study treatment related by PT and maximum grade

Summary of qualifying AE for dose decision analysis (Dose determining part only)

AEs leading to discontinuation of study treatment regardless of relationship to study 
treatment by PT and maximum grade

AEs leading to discontinuation of study treatment suspected to be study treatment related
by PT and maximum grade

AEs requiring dose adjustment/interruption by SOC, PT and maximum grade

AEs requiring additional therapy by SOC, PT and maximum grade
Additionally, for the legal requirements of ClinicalTrials.gov and EudraCT, two required 
tables on on-treatment adverse events which are not serious adverse events with an incidence 
greater than 5% and on on-treatment serious adverse events and SAE suspected to be related 
to study treatment will be provided by system organ class and preferred term on the safety set 
population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if 
at least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SoC and PT.


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2.9.1.4
Adverse events of special interests
An adverse event of special interest (AESI) is a grouping of AEs that are of scientific and 
medical concern specific to Capmatinib. These grouping are defined using MedDRA terms, 
SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high level 
terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) may 
also be used. A NMQ is a customized group of search terms which defines a medical concept 
for which there is no official SMQ available or the available SMQ does not completely fit the 
need. It may include a combination of single terms and/or an existing SMQ, narrow or broad.
For each specified AESI, the number and percentage of subjects with at least one event of AESI 
occurring during on-treatment period will be summarized:

Overview of adverse events of special interest for Capmatinib
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.
Note: From the eCSR, only risk where “Core Safety Risk” = Y should be selected to report 
Adverse events of special interest in the CSR (the available name in GPS, for “Core Safety 
Risk”, is SP).
2.9.1.5
Death
On-treatment deaths will be produced by study treatment group, SOC and PT. All deaths will 
be listed using safety set, post treatment deaths will be flagged.
2.9.1.6
Imputation rules for missing AE date
A missing AE start date will be imputed using the following logic matrix described in Table 2-
3.
Table 2-3
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 2-4 is the legend to the logic matrix shown in Table 2-3 and details the relationship of 
AE start date to study treatment start date.


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Table 2-4
Imputation legend and AE/treatment start date relationship
AE start date relationship
Imputation
(A)
After treatment start or Uncertain
MAX( 01MONYYYY, TRTSTD+1 )
(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.
No imputation will be performed for AE end dates.
2.9.2
Laboratory data
All laboratory values will be converted into SI units, as appropriate, and the severity grade
calculated using CTCAE, version 4.03. Parameters for which a grading does not exist will be
classified into low/normal/high group by means of laboratory normal ranges.
For each laboratory test (e.g. hematology, biochemistry, etc.) a listing of laboratory values
will be provided by laboratory parameter, patient and treatment group. The frequency of
notable lab abnormalities will be displayed by parameter, cycle and treatment group. Similarly,
the frequency of all laboratory abnormalities will be displayed by parameter, worst CTCAE
version 4.03 grade experienced and treatment group. A separate listing will display notable
laboratory abnormalities (i.e., newly occurring CTC grade 3 or 4 laboratory toxicities).
Laboratory data will be summarized by presenting grade shift tables for those parameters for
which CTCAE version 4.03 allows classification. All remaining data will be summarized by
presenting shift tables based on normal ranges.
2.9.3
Vital signs, weight and physical examinations
Vital signs will be listed, notable values will be flagged, and any other information collected 
will be listed as appropriate. 
2.9.4
Electrocardiograms
ECG will be listed, notable values will be flagged, and any other information collected will be 
listed as appropriate. Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions for the study drug. Reasons for dose interruption will be summarized by study 
drug. Cumulative dose, dose intensity and relative dose intensity of study drug (see Section 
2.5.2) will be also be used to assess tolerability.
2.10
Pharmacokinetic data
All PK analyses will be performed based on the PAS. Patient data may be removed on an 
individual basis. Cycle 1 Day 15 pre-dose concentration may be utilized as concentration at 12 
h post-dose for the calculation of AUC0-12,ss of INC280. This is based on the PK principle 
that, steady state concentration is assumed to be the same at the beginning and end of the dose 


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interval, in this case 12 h. Therefore the pre-dose value of the dosing period may be carried 
forward to the end of the 12 h-dosing interval and will be included in the PK merge data.
Descriptive graphical plots of mean (standard deviation) and geometric mean plasma 
concentration at Cycle 1 Day 15 steady-state will be generated by treatment group.
2.10.1
Dose-Determining Part
PK will be assessed for patients treated in the Dose-Determining Part on Cycle 1, Day 1 and
15. Patients with at least one evaluable full PK profile will be included in PK analysis.
Summary statistics (number, arithmetic mean, median, standard deviation, coefficient of
variance CV(%), geometric mean, geometric CV (%), minimum and maximum) will be
presented for concentrations of INC280 by nominal time point and treatment dose. Graphics
with concentration mean and standard deviation by time point and treatment dose will be
presented as well.
The following PK parameters from Dose-Determining Part will be summarized:
Cycle 1, Day 1: AUC0-t, AUCinf, AUClast, Cmax, T1/2, Tlast, Tmax, CL/F, and Vz/F.
Cycle 1, Day 15: AUC0-t, AUCinf, AUClast, Cmax, T1/2, Tlast, Tmax, CL/F, Vz/F and 
Racc.
PK parameters other than Tmax will be summarized by number, arithmetic mean, standard
deviation, CV%, median, range (minimum and maximum), geometric mean and geometric
CV%. Number, median and range (minimum and maximum) will be presented for Tmax.
2.10.2
Dose Expansion Part
Summary statistics (number, arithmetic mean, median, standard deviation, CV(%),geometric
mean, geometric CV (%), minimum and maximum) will be presented for concentrations of
INC280 by nominal time point and treatment dose. Graphics with concentration mean and
standard deviation by time point and treatment dose will be presented as well.
2.10.3
Data handling principles
Zero concentrations will not be included in the geometric mean calculation. Since Tmax is
generally evaluated by a nonparametric method, median values and ranges will be given for this 
parameter.
Missing concentration values will be reported as is in data listings. Concentration values below 
Lower limit of quantitation will be handled as zero in summary statistics, and reported as is in 
data listings. Any missing pharmacokinetic parameter data will not be imputed.
2.11
Patient reported outcomes
Not Applicable.


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2.13
Interim analyses
No formal interim analysis is planned. However the design in the dose determining part of the 
study foresees that decisions based on the current data are taken before the end of the study. 
More precisely, after at least six patients have been enrolled in the dose determining part, the 
dose for dose expansion part will be chosen depending on the observed data. Details of this
procedure and the process for communication with investigators are provided in
CINC280X2201-Protocol-Section 6.2.2.
3
Sample size calculation
Dose-Determining Part
It is expected that between 6 and 10 patients will be enrolled in order to obtain data on 
occurrence or absence (within first four weeks of treatment) of qualifying AE for at least 6 
patients evaluable for the DDS.
Dose expansion Part
A total number of 50 patients are planned to be enrolled and treated in the dose expansion part. 
It is expected that 25 to 40 among these patients will have the c-MET high status as specified 
in the inclusion criteria. The following assumptions and design parameters are considered:

in general the median TTP for patients treated with sorafenib has been established to be 
2.8 months (Cheng et al 2009); for the c-MET high patients it has been estimated to be 2.2 
months (Santora et al 2013)

the required improvement to be seen on treatment with INC280 in the Dose Expansion 
Part is an increase in median TTP to approximately 4 months in patients with advanced 
HCC with high c-MET status and preserved liver function of Child Pugh class A with 5-6 
point

therefore a successful outcome will be indicated by an observed median TTP of ≥4
months, and a one-sided 90% lower confidence limit for median TTP of ≥2.2 months


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
It is assumed that on average 1.5 patients are enrolled per month; the primary analysis is 
conducted 6 months after enrolment of the final patient

Data is simulated from the exponential distribution with true mTTP = 2.2, 4, 5 and 6 
months

a 30% risk of loss to follow up per patient per year is assumed ; this corresponds to loss to 
follow up of approximately 15% patients given an assumed true mTTP = 4 months; 
censoring time is simulated from the exponential distribution with rate parameter = -log(1-
0.30)/12
Kaplan-Maier method is used to estimate the median TTPs and provide the Brookmeyer-
Crowley CIs in simulated event data. Table 3-1 presented the expected numbers of observed
events at primary analysis, the probability that the observed mTTP is ≥4 months, the probability 
that the lower limit of one-sided 90% CI is >2.2 months provided the observed mTTP ≥4 months, 
and the probability of study success (i.e. the probability that the lower limit of one-sided 90% 
CI is >2.2 months and the observed mTTP is ≥4 months), given different true values of TTP 
and sample sizes. Therefore, with the planned enrollment, if the true median TTP is 6 months a 
successful outcome is expected with high probability. Conversely, a successful outcome is 
highly improbable if the true median TTP is as low as 2.2 months
Table 3-1
Design operating characteristics when the number of patients is 25, 
30, 35 and 40, respectively
True TTP 
(months)
Expected 
number of 
observed events
P(observed 
mTTP ≥4m | true 
TTP)
P (lower 
CI >2.2m | 
observed mTTP 
≥4m, true TTP)
P (lower 
CI >2.2m and 
observed mTTP 
≥4m | true TTP)
N = 25
2.2
22
0.01
0.76
0.01
4
19
0.52
0.95
0.49
5
18
0.77
0.97
0.75
6
16
0.90
0.99
0.89
N = 30
2.2
27
0.01
0.81
0.01
4
24
0.50
0.97
0.49
5
22
0.79
0.98
0.78
6
20
0.92
0.99
0.92


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True TTP 
(months)
Expected 
number of 
observed events
P(observed 
mTTP ≥4m | true 
TTP)
P (lower 
CI >2.2m | 
observed mTTP 
≥4m, true TTP)
P (lower 
CI >2.2m and 
observed mTTP 
≥4m | true TTP)
N = 35
2.2
31
0.01
0.82
0.00
4
28
0.51
0.98
0.50
5
26
0.81
0.99
0.80
6
24
0.94
1.00
0.93
N = 40
2.2
36
0.00
0.93
0.00
4
32
0.50
0.99
0.50
5
30
0.82
0.99
0.82
6
28
0.95
1.00
0.95
4
Change to protocol specified analyses
As Novartis decided to halt the enrollment in the expansion part in December 2016, therefore 
the following analyses as per protocol will not be performed due to insufficient data:
 

The sensitivity analyses using PPS
4.1
Handling of missing and partial dates
For patients not known to have died prior to the cut-off date:
All events (e.g. AEs) that started before or on the cut-off date, and with end date missing or 
after the cut-off date will be reported as continuing and unresolved at the cut-off date. For these 
events, the end date will not be imputed.
Calculating duration of e.g. AEs and concomitant medications for patients known to have died 
prior to or on the cut-off date:
AEs and concomitant medications that started before or on the cut-off date, and with end date 
missing or after the cut-off date will have the end date imputed to the date of death. For these 
events, the imputed end date will not appear in the listings.
If imputation of an end date is required to calculate the duration of exposure to study treatment 
(a dose administration record with missing end date, or last date of study treatment is after the 
cut-off date), the end date will be imputed to the cut-off date. The imputed date will be displayed 
and flagged in the listings.


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5
References
Cheng AL, et al (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region
with advanced hepatocellular carcinoma: a phase III randomized, double-blind, placebo
controlled trial. Lancet Oncol 10:25–34
Santoro A, et al (2013). Tivantinib for second-line treatment of advanced hepatocellular 
carcinoma: a randomised, placebo-controlled phase 2 study. Lancet Oncol 14: 55Onc
Neuenschwander, Branson, Gsponer (2008) Critical aspects of the Bayesian approach to
Phase I cancer trials. Statistics in Medicine, 27:2420-2439.
Neuenschwander B, Capcun–Niggli G, Branson M et al (2010) Summarizing Historical
Information on Controls in Clinical Trials. Clin Trials; 7(1): 5-18.Clopper CJ and Pearson ES 
(1934). The Use of Confidence or Fiducial Limits Illustrated in the Case of the Binomial. 
Biometrika.; 26,(4):404-13.
Kaplan, EL and Meier, P (1958). Nonparametric estimation from incomplete observations. 
Journal of the American Statistical Association.;53:457-81.