Conditions: Carcinoma, Hepatocellular
Keywords: Carcinoma, Hepatocellular MSC2156119J Sorafenib Recommended Phase 2 dose
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 117
Healthy volunteers: no

Brief summary:
This is an open-label, integrated, Phase 1b/2 trial to determine the recommended Phase 2 dose (RP2D) and to evaluate the efficacy, safety, and pharmacokinetic of MSC2156119J as first-line treatment versus sorafenib in subjects with MET+, Barcelona Clinic Liver Cancer (BCLC) Stage C, systemic treatment naive advanced hepatocellular carcinoma (HCC) and Child-Pugh class A liver function.

Detailed description:

Arms:
arm 1: Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. arm 2: Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. arm 3: Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. arm 4: Participants randomized to receive Tepotinib recommended Phase 2 dose (RP2D) determined from Phase 1b over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. arm 5: Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Interventions: intervention 1: Tepotinib 300 mg intervention 2: Tepotinib 500 mg intervention 3: Tepotinib 1000 mg intervention 4: Tepotinib intervention 5: Sorafenib
Intervention descriptions: intervention 1: Participants received Tepotinib 300 milligram (mg) orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. intervention 2: Participants received Tepotinib 500 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. intervention 3: Participants received Tepotinib 1000 mg orally once daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal intervention 4: Participants randomized to receive Tepotinib recommended Phase 2 dose (RP2D) determined from Phase 1b over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal. intervention 5: Participants randomized to receive Sorafenib 400 mg orally twice daily over a 21-day cycle until disease progression, intolerable toxicity or participant withdrawal.

Protocol document:
Prot_000.pdf: 
MSC2156119J (tepotinib)
Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with 
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Clinical Trial Protocol
Clinical Trial Protocol Number
EMR200095-004
Title
A Multicenter, Randomized, Phase Ib/II Trial to 
Evaluate the Efficacy, Safety, and 
Pharmacokinetics of MSC2156119J as 
Monotherapy Versus Sorafenib in Asian Subjects 
with MET+ Advanced Hepatocellular Carcinoma 
and Child-Pugh Class A Liver Function
Short Title: Efficacy, Safety, and PK of 
MSC2156119J in Asian Subjects with HCC
Phase
Ib/II
Coordinating Investigator
Sponsor
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany
Medical Responsible: 
EMD Serono, Inc.
45A Middlesex Turnpike
Billerica
MA 01821
United States of America
Tel: 
Fax: 
Clinical Trial Protocol Version
19 May 2017/Version 4.0, Amendment No. 4.0
Replaces Version
24 June 2016/Version 3.0
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
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published or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2017 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Signature Page
Protocol Lead responsible for designing the clinical trial:
I approve the design of the clinical trial.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function
Medical Responsible
Institution
EMD Serono, Inc.
Address
45A Middlesex Turnpike
Billerica
MA 01821
United States of America
Telephone number
Fax number
E-mail address
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Coordinating Investigator 
I agree to conduct the clinical trial in accordance with this clinical trial protocol and in compliance
with Good Clinical Practice and all applicable regulatory requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree
Function
Institution
Address
Telephone number
Fax number
E-mail address
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Further Sponsor Responsible Persons
Biostatistician
Name
Function
Institution
Merck-Serono (Beijing), Pharmaceutical R&D Co., Ltd.
Telephone number
Fax number
E-mail address
Clinical Trial Leader
Name
Function
Institution
Merck-Serono (Beijing), Pharmaceutical R&D Co., Ltd.
Telephone number
Fax number
E-mail address
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Principal Investigator Signature
Trial Title
A Multicenter, Randomized, Phase Ib/II Trial to 
Evaluate the Efficacy, Safety, and Pharmacokinetics
of MSC2156119J as Monotherapy Versus Sorafenib 
in Asian Subjects with MET+ Advanced 
Hepatocellular Carcinoma and Child-Pugh Class A 
Liver Function
Clinical 
Trial 
Protocol 
Version/Date
19 May 2017/Version 4.0
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that:
! I understand and will conduct the trial according to the clinical trial protocol, any approved 
protocol amendments, ICH Good Clinical Practice (ICH Topic E6 GCP) and all applicable 
Health Authority requirements and national laws.
I understand that some Health Authorities require the Sponsors of clinical trials to obtain and 
supply, when required, details about the Investigators’ ownership interests in the Sponsor or 
Investigational Medicinal Product and information regarding any financial ties with the Sponsor. 
The Sponsor will use any such information that is collected solely for the purpose of complying 
with the regulatory requirements. I therefore agree to supply the Sponsor with any necessary 
information regarding ownership interest and financial ties (including those of my spouse and 
dependent children), and to provide updates as necessary.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic qualifications
Position (job title)
Address of Institution
Telephone number
Fax number
E-mail address
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Table of Contents
Signature Page .....................................................................................................................3
Table of Contents.................................................................................................................7
Table of In-Text Tables .....................................................................................................11
Table of In-Text Figures....................................................................................................11
List of Abbreviations .........................................................................................................12
1
Synopsis..............................................................................................16
2
Sponsor, Investigators, and Trial Administrative Structure ...............35
2.1
Sponsor ...............................................................................................35
2.2
Trial Administrative Structure............................................................35
2.2.1
Safety Monitoring Committee............................................................35
2.2.2
Independent Data Monitoring Committee..........................................36
2.2.3
Independent Review Committee.........................................................36
3
Background Information.....................................................................36
3.1
Hepatocellular Carcinoma ..................................................................36
3.2
c-Met...................................................................................................37
3.3
MSC2156119J ....................................................................................37
3.3.1
Nonclinical Evaluation .......................................................................37
3.3.2
Clinical Experience.............................................................................38
3.4
Rationale for the Current Trial ...........................................................40
3.5
Risk-Benefit Evaluation......................................................................41
4
Trial Objectives ..................................................................................42
4.1
Primary Objectives .............................................................................42
4.2
Secondary Objectives .........................................................................42
4.3
Exploratory Objectives .......................................................................43
5
Investigational Plan ............................................................................43
5.1
Overall Trial Design and Plan ............................................................43
5.2
Discussion of Trial Design .................................................................47
5.2.1
Inclusion of Special Populations ........................................................48
5.3
Selection of Trial Population..............................................................48
5.3.1
Inclusion Criteria ................................................................................48
5.3.2
Exclusion Criteria...............................................................................49
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5.4
Criteria for Randomization/Initiation of Treatment with the 
Investigational Medicinal Product......................................................52
5.5
Criteria for Subject Withdrawal..........................................................52
5.5.1
Withdrawal from the Trial..................................................................52
5.5.2
Replacement of Discontinued Subjects ..............................................53
5.5.3
Withdrawal from Trial Therapy..........................................................53
5.6
Premature Discontinuation of the Trial ..............................................54
5.7
Definition of End of Trial...................................................................54
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................55
6.1
Description of Investigational Medicinal Product..............................55
6.2
Dosage and Administration ................................................................55
6.2.1
Dose Escalation Assessment Process .................................................56
6.2.2
Definition of DLT...............................................................................57
6.2.3
MTD/RP2D Definition Process..........................................................59
6.2.4
Criteria for Additional Treatment Cycles...........................................59
6.2.5
Dose Adjustment and Missed Dose....................................................60
6.2.6
Intrasubject Dose Escalation...............................................................61
6.3
Assignment to Treatment Groups.......................................................62
6.4
Other Drugs to be used in the Trial ....................................................62
6.5
Concomitant Medications and Therapies ...........................................62
6.5.1
Permitted Medicines...........................................................................62
6.5.2
Non-Permitted Medicines...................................................................63
6.5.3
Other Trial Considerations .................................................................64
6.6
Packaging and Labeling......................................................................66
6.7
Preparation, Handling and Storage.....................................................66
6.8
Investigational Medicinal Product Accountability.............................66
6.9
Assessment of Investigational Medicinal Product Compliance .........67
6.10
Method of Blinding.............................................................................67
6.11
Emergency Unblinding.......................................................................67
6.12
Treatment of Overdose .......................................................................67
6.13
Medical Care of Subjects after the End of Trial.................................68
7
Trial Procedures and Assessments......................................................68
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7.1
Schedule of Assessments....................................................................68
7.1.1
Informed Consent ...............................................................................68
7.1.2
Screening Period.................................................................................69
7.1.3
Treatment Period ................................................................................70
7.1.4
End of Treatment Visit .......................................................................74
7.1.5
Post-Treatment Follow-Up Visit ........................................................75
7.1.6
Survival Follow-up Assessments........................................................76
7.2
Demographic and Other Baseline Characteristics ..............................76
7.3
Assessment of Efficacy.......................................................................78
7.4
Assessment of Safety..........................................................................79
7.4.1
Adverse Events ...................................................................................80
7.4.2
Pregnancy and In Utero Drug Exposure.............................................85
7.4.3
Laboratory Assessments .....................................................................85
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............88
7.5
Pharmacokinetics................................................................................89
7.5.1
Body Fluids.........................................................................................90
7.5.2
Pharmacokinetic Calculations ............................................................90
7.7
Other Assessments..............................................................................93
8
Statistics..............................................................................................94
8.1
Sample Size ........................................................................................94
8.2
Randomization....................................................................................94
8.3
Endpoints............................................................................................95
8.3.1
Primary Endpoints ..............................................................................95
8.3.2
Secondary Endpoints ..........................................................................95
8.3.3
Safety Endpoints.................................................................................96
8.3.4
Further Endpoints of Interest..............................................................96
8.4
Analysis Sets.......................................................................................97
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8.5
Description of Statistical Analyses.....................................................99
8.5.1
General Considerations.......................................................................99
8.5.2
Analysis of Primary Endpoints.........................................................101
8.5.3
Analysis of Secondary Endpoints.....................................................102
8.5.4
Safety Analyses ................................................................................106
8.6
Interim Analysis................................................................................106
9
Ethical and Regulatory Aspects........................................................107
9.1
Responsibilities of the Investigator ..................................................107
9.2
Subject Information and Informed Consent .....................................107
9.3
Subject Identification and Privacy....................................................108
9.4
Emergency Medical Support and Subject Card................................109
9.5
Clinical Trial Insurance and Compensation to Subjects...................109
9.6
Independent Ethics Committee or Institutional Review Board........109
9.7
Health Authorities.............................................................................110
10
Trial Management.............................................................................110
10.1
Case Report Form Handling.............................................................110
10.2
Source Data and Subject Files..........................................................110
10.3
Investigator Site File and Archiving.................................................111
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................112
10.5
Changes to the Clinical Trial Protocol..............................................112
10.6
Clinical Trial Report and Publication Policy....................................112
10.6.1
Clinical Trial Report.........................................................................112
10.6.2
Publication........................................................................................113
11
References.........................................................................................114
12
Appendices .......................................................................................116
Appendix A:
Scoring System for Met Immunohistochemistry..............................117
Appendix B:
Child-Pugh System ...........................................................................118
Appendix C:
Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1......119
Appendix D:
Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) ........................................................................................129
Appendix E: 
New York Heart Association (NYHA) Criteria ...............................130
Appendix F: 
FACT Hepatobiliary Symptom Index 8 ...........................................131
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Appendix G: 
Functional Assessment of Cancer Therapy – Hepatobiliary ............132
Appendix H:
Phase Ib Schedule of Dosing and Assessments................................137
Appendix I:
Phase II Schedule of Dosing and Assessments.................................140
Appendix J:
Blood Sampling Schedule and Blood Volumes for PK, 
..................................................................144
Appendix K:
Barcelona Clinic Liver Cancer Staging Classification.....................146
Table of In-Text Tables
Table 1:
Monitoring of Subjects According to Baseline Virology Status ........65
Table 2:
Hepatitis B Virus and Hepatitis C Virus Reactivation .......................65
Table 3:
Hematology Assessments...................................................................86
Table 4:
Biochemistry Assessments .................................................................87
Table 5:
Coagulation Assessments ...................................................................87
Table 6:
Urinalysis Assessments ......................................................................88
Table 7:
Hepatitis B Virus Serology Panel.......................................................88
Table 8:
Clinical and Biochemical Measurements for Child-Pugh 
Classification ....................................................................................118
Table 9:
Barcelona Clinical Liver Cancer Staging Classification ..................146
Table of In-Text Figures
Figure 1:
Phase Ib Design (“3+3” Dose Escalation Cohorts) ............................45
Figure 2:
Phase II Randomization Scheme ........................................................46
Figure 3:
Treatment Duration.............................................................................47
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List of Abbreviations
Abbreviation
Definition
AASLD
American Association for the Study of Liver Diseases
AE
Adverse event
AESI
Adverse events of special interest
AFP
Alpha-fetoprotein 
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AUC
Area under the curve
AUC0-t
Area under the curve from time zero to time t
AUC0-tau
Area under the curve within 1 dosing interval
AUC0-Q
Area under the curve from time zero to infinity following last 
administration
AUCextra
Area under the curve extrapolated from Clast/Rz
BCLC
Barcelona Clinic Liver Cancer
BCRP
Breast cancer resistance protein
BUN
Blood urea nitrogen
Cav
Average plasma concentration within 1 dosing interval
c-Met
Mesenchymal-epithelial transition factor
CI
Confidence interval
CL
Total body clearance of drug
Clast
Calculated plasma concentration at the last sampling time point 
at which the measured plasma concentration is at or above the 
lower limit of quantification
CL/f
Apparent clearance
Cmax
Maximum concentration 
Cmin
Observed minimum plasma concentration
CNS
Central nervous system
CR
Complete response
CrCl
Creatinine clearance
CRO
Contract research organization
CT
Computed tomography
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Abbreviation
Definition
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation (%)
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGFR-TKI
Epidermal growth factor receptor-tyrosine kinase inhibitor
FACT-HP
Functional assessment of cancer therapy-hepatobiliary
FDA
Food and Drug Administration
FDG-PET
Fludeoxyglucose positron emission tomography
FIM
First-in-man
FHSI-8
FACT Hepatobiliary Symptom Index 8
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
GGT
Gamma-glutamyl transpeptidase
HBeAg
Hepatitis B e antigen
HBsAb
Hepatitis B surface antibodies
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HGF
Hepatocyte growth factor
HIV
Human immunodeficiency virus
HR
Hazard ratio
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemical/immunohistochemistry
IMP
Investigational medicinal product
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Abbreviation
Definition
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
ITT
Intent-to-treat
IVRS
Interactive voice response system
Rz
Area under the curve terminal phase rate constant 
LLQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MFI
Mean fluorescence intensity
mITT
Modified intent-to-treat
MOP
Manual of Operations
mRECIST
Modified RECIST
MRI
Magnetic resonance imaging
MTD
Maximum tolerated dose
NCI
National Cancer Institute
NYHA
New York Heart Association
OCT1
Organic cation transporter 1
OR
Overall response
OS
Overall survival
PCR
Polymerase chain reaction
Pd
Pharmacodynamic
PD
Progressive disease
PET
Positron emission tomography
PFS
Progression-free survival
P-gp
P-glycoprotein
PK
Pharmacokinetic
PoC
Proof of concept
PP
Per protocol
PR
Partial response
PRO
Patient reported outcomes
PS
Performance Status
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Abbreviation
Definition
PT
Prothrombin time
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase II dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable disease
SEM
Standard error of the mean
SMC
Safety monitoring committee
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Half-life
TEAE
Treatment emergent adverse event
tmax
Time to maximum concentration
TTP
Time to progression
TTSP
Time to symptomatic progression
ULN
Upper limit of normal
Vss/f
Apparent volume of distribution at steady state
Vz
Volume of distribution associated to the terminal phase
Vz/f
Apparent volume of distribution associated to the terminal phase
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1
Synopsis
Trial title
A Multicenter, Randomized, Phase Ib/II Trial to Evaluate 
the 
Efficacy, 
Safety, 
and 
Pharmacokinetics 
of 
MSC2156119J as Monotherapy Versus Sorafenib in 
Asian Subjects with MET+ Advanced Hepatocellular 
Carcinoma and Child-Pugh Class A Liver Function
Short Title: Efficacy, Safety, and PK of MSC2156119J in 
Asian Subjects with HCC
Trial number
EMR200095-004
Sponsor
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany
Phase
Ib/II
Trial under IND
yes
no
FDA "covered trial"
yes
no
Trial centers/countries
Phase Ib: Selected sites in mainland China, South Korea, 
and Taiwan.
Phase II: Approximately 45 to 55 sites in mainland China, 
South Korea, Taiwan, and other Asian countries
Planned trial period
(first enrollment-last subject 
out)
September 2013 to March 2018
Trial objectives
Primary Objectives
Phase Ib
! To confirm the recommended Phase II dose (RP2D) of 
MSC2156119J administered orally once daily at a 
21-day cycle in subjects with advanced hepatocellular 
carcinoma (HCC) and Child-Pugh class A liver 
function. The target RP2D in HCC subjects is the RP2D 
as determined in the global first-in-man (FIM) trial, i.e., 
500 mg once daily
Phase II
! To evaluate efficacy as measured by time to progression 
(TTP) of MSC2156119J as monotherapy in the first-line
treatment compared with sorafenib in subjects with 
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MET+ advanced HCC and Child-Pugh class A liver
function
Secondary objectives
Phase Ib
! To characterize the single and multiple dose 
pharmacokinetics (PK), preliminary antitumor activity,
and biochemical response of MSC2156119J in Asian 
subjects with HCC and Child-Pugh class A liver 
function
Phase II
! To evaluate the safety and tolerability of MSC2156119J 
versus sorafenib
! To evaluate antitumor activity of MSC2156119J versus 
sorafenib
Exploratory objectives will be assessed in Phase Ib and 
Phase II for subjects with available baseline and 
on-treatment biopsies and/or blood samples, and/or 
available patient reported outcome (PRO) data. 
 
 
 
 
 
 
 
 
Trial design and plan
Phase Ib will be an open label, single arm trial at selected 
sites in mainland China, South Korea, and Taiwan. 
The classical “3+3” design will be applied for sites in 
South Korea and Taiwan, with a dose escalation phase and 
a dose confirmation phase. In addition and separate from 
the “3+3” trial cohorts, up to 3 subjects will be enrolled in 
a separate cohort at selected sites in mainland China.
Phase II will be a randomized, open label, active
controlled trial to evaluate the efficacy, safety, and PK of 
MSC2156119J as first-line treatment versus sorafenib in 
subjects with MET+, Barcelona Clinic Liver Cancer 
(BCLC) Stage B or C, systemic treatment naive advanced 
HCC and Child-Pugh class A liver function. Phase II is 
planned to be conducted at 45 to 55 sites in mainland 
China, South Korea, Taiwan, and other Asian countries.
Subjects will receive either MSC2156119J once daily (at 
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the RP2D determined from Phase Ib) or 400 mg sorafenib 
twice daily until disease progression, intolerable toxicity 
or consent withdrawal from the trial.
Planned number of subjects
Phase Ib: Up to 21 subjects, including up to 18 subjects 
from South Korea and Taiwan following a “3+3” dose 
escalation method and up to an additional 3 subjects from 
the mainland China sites.
Phase II: Approximately 140 subjects were planned to be 
randomized on a 1:1 basis to receive MSC2156119J or 
sorafenib. The sponsor subsequently decided to stop 
prescreening/enrollment after 40 TTP events (assessed by 
an IRC) or on 15 August 2017, whichever occurs first. 
Schedule of visits and 
assessments
Screening period
The subject must sign a main informed consent form 
(ICF) before any trial procedures are performed. In 
Phase II, subjects must also sign the prescreening and 
clinical screening ICF. 
In Phase II, subjects
will undergo a Molecular 
Prescreening period and a Clinical Screening period. 
MET status will be confirmed
during Molecular 
Prescreening. Clinical Screening must be completed 
within 14 days prior to the initiation of study treatment, 
and will include laboratory parameters (including serum 
pregnancy 
test 
if 
applicable), 
medical 
history, 
concomitant medication/procedure, and tumor imaging to 
check subject eligibility.
Treatment Period
MSC2156119J 
(Phase Ib 
and 
Phase II) 
will 
be 
administered once daily over a 21-day cycle and sorafenib 
(Phase II) will be administered twice daily over a 21-day 
cycle, which may repeat until disease progression (as 
determined by the investigator), intolerable toxicity, or 
withdrawal from the trial.
For Phase Ib, scheduled visits during the treatment period 
will occur on Days 1, 2, 8, and 15 of Cycle 1; Days 1, 8, 
and 15 of Cycle 2; and Day 1 of Cycles U 3. For Phase II, 
scheduled visits during the treatment period will occur on 
Days 1, 8, and 15 of Cycle 1; Days 1 and 8 of Cycle 2; 
and Day 1 of Cycles U 3.
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At each scheduled visit during the treatment period, 
physical examination/weight, vital signs (except as noted 
below), hematology, coagulation, chemistry, adverse 
events (AEs), and concomitant medication/procedure
assessments will be performed. Subjects with a known 
history or evidence of viral hepatitis infection at baseline 
will be monitored throughout the treatment period. 
Additional assessments will be performed as described 
below.
Cycle 1, Day 1
On Cycle 1, Day 1 of Phase Ib, the following 
assessments/treatment 
administrations 
will 
occur: 
dispensing of study drug; 12-lead electrocardiogram 
(ECG); serial PK blood samples; pretreatment tumor 
biopsy (excluding fine needle aspiration and cytology 
samples; optional, will be collected after subjects have 
signed a separate ICF); 
 
 
 
The following assessments will be performed only if 
screening/last assessments were performed > 7 days prior 
to Day 1: Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS); urinalysis; and serum alpha-
fetoprotein (AFP).
Assessments for Cycle 1, Day 1 of Phase II include all 
assessments in Phase Ib with the following changes: 
randomization by interactive voice response system; 
 
 
 FACT Hepatobiliary Symptom Index 8 (FHSI-
8); and PRO (Functional assessment of cancer therapy-
hepatobiliary [FACT-HP]).
Cycle 1, Day 15
On Cycle 1, Day 15 of Phase Ib, the following 
assessments/treatment administrations will occur: tumor 
biopsy (excluding fine needle aspiration and cytology 
samples; optional, will be collected after subjects have 
signed a separate ICF); 12-lead ECG; and serial PK blood 
samples.
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Assessments for Cycle 1, Day 15 of Phase II include all 
assessments in Phase Ib except for PK blood samples, 
postdose 12-lead ECG, and vital signs.
Cycle 2, Day 1
Assessments for Cycle 2, Day 1 of Phase Ib include all 
assessments from Cycle 1, Day 1 as defined above, with 
the following changes: 12-lead ECG at predose only; no 
tumor biopsy; and no PK and 
 blood samples.
Assessments for Cycle 2, Day 1 of Phase II include all 
assessments from Cycle 1, Day 1, with the following 
exceptions:
no randomization by interactive voice 
response system; no tumor biopsy; and no 
 blood 
sample.
 
 
 
 
 
Cycle 2, Day 15
Assessments for Cycle 2, Day 15 of Phase Ib will be the 
same as the assessments for Cycle 1, Day 15, except for 
tumor biopsy, vital signs, 12-lead ECG, and PK blood 
samples.
Cycles ; 3, Day 1
Assessments for Cycles U 3, Day 1 of Phase Ib include all 
assessments from Cycle 1, Day 1, except a tumor biopsy 
will not be taken, and PK and 
 blood samples will not 
be drawn. The second on-treatment blood sample for 
analysis of 
, scheduled for Cycle 3, 
Day 1, can be drawn between Cycle 2, Day 15 and 
Cycle 4, Day 1 (mandatory, Cycle 3 only). In addition, a 
complete tumor assessment of all lesions by radiographic 
or other modality (using response evaluation criteria in 
solid tumors [RECIST v 1.1]) identified at the screening 
visit will be performed predose on, or up to 5 days prior 
to, Day 1 of Cycles 3, 5, 7, 9, 11, 13, and every 4 cycles 
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thereafter until disease progression or trial medication 
discontinuation.
Assessments for Cycles U 3, Day 1 of Phase II include all 
Cycles U3, Day 1 assessments in Phase Ib. In addition, 
viral load of hepatitis B virus (HBV) will be performed 
every 3 cycles for subjects with a known history of 
chronic HBV infection or HBV at baseline, hepatitis C 
virus (HCV) ribonucleic acid (RNA) using polymerase 
chain reaction (PCR) will be performed every 3 cycles for 
subjects with a known history of chronic HCV infection 
or measurable HCV RNA at baseline, FHSI-8 will be 
assessed, FACT-HP will be assessed on Cycle 5, Day 1. 
 
 
End of Treatment Visit
At the subject’s discontinuation of the trial medication 
(due to disease progression [as assessed by the 
Investigator], intolerable toxicity, or withdrawal), the 
following evaluations, which include safety/tumor 
assessment, will be performed: tumor biopsy (excluding 
fine needle aspiration and cytology samples; optional, 
will be collected after subjects sign a separate ICF); 
physical 
examination/weight; 
ECOG 
PS; 
AEs; 
concomitant medication/procedure; vital signs; 12-lead 
ECG; hematology; coagulation; chemistry; urinalysis; 
monitoring of subjects with a known history or evidence 
of viral hepatitis infection at baseline; complete tumor 
assessment of all lesions by radiographic or other 
modality if previous assessment is more than 6 weeks old 
(using RECIST v 1.1); and serum AFP.
Assessments for the end of treatment visit in Phase II 
include all assessments in Phase Ib. In addition, FHSI-8 
and PRO (FACT-HP) will be assessed and blood samples 
for 
 will be performed.
Note: end of treatment ECG and laboratory assessments 
(hematology, coagulation, chemistry, urinalysis, and 
hepatitis markers) are not required for subjects with 
previous ECG and laboratory assessments, respectively, 
within 7 days of the end of treatment visit.
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Post-Treatment Follow-Up Visit
Study drug post-treatment follow-up visit will be 
performed within 30 ± 3 days after the last dose for 
subjects who discontinue the trial medication, even if the 
subject starts a new antineoplastic therapy. The following 
assessments will be performed: AEs; concomitant 
medication/procedure; 
physical 
examination/weight; 
ECOG PS; vital signs; 12-lead ECG; hematology; 
coagulation; chemistry; and urinalysis.
Assessments for the post-treatment follow-up visit in 
Phase II include all assessments in Phase Ib. In addition, 
FHSI-8 will be assessed.
Subjects who are discontinued from the trial due to 
unacceptable toxicity should perform the tumor 
assessment at 6-week intervals until Cycle 13 and 
12-week intervals (4 cycles) after Cycle 13 until disease 
progression, starting a new therapy, or death.
Survival Follow-up Assessments
Survival data (subject survival and anticancer therapies) 
in Phase Ib and Phase II will be collected every 3 months 
(± 2 weeks) after the last dose of study drug. Subjects will 
be contacted by telephone.  
Assessments After 
the Enrollment Stop
Date
(15 August 2017)
Subjects who sign the ICF prior to 15 August 2017 and 
undergo prescreening/screening after the enrollment stop 
date may still be randomized in the trial. Subjects 
receiving study treatment may continue treatment after 
discussion with their Investigator. Subjects who decide to 
continue treatment will continue on their originally 
randomized treatment, at their most recent dose according 
to the protocol. Safety monitoring and data collection will 
continue without modification through to the end of the 
trial.
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Diagnosis and main inclusion 
and exclusion criteria
Inclusion Criteria
For inclusion in the trial, all of the following inclusion 
criteria must be fulfilled:
! Histologically or cytologically confirmed HCC
! Subjects with either intermediate HCC of BCLC Stage
B, who are not eligible for surgical and/or local-regional 
therapies or who have progressive disease (PD) after 
surgical and/or local-regional therapies (note: the 
local-regional therapy must not contain sorafenib), or 
advanced HCC of BCLC Stage C
! Subjects who have disease progression or are intolerant 
to the prior standard treatment for advanced HCC 
(Phase Ib Korean subjects only)
! A tumor biopsy (excluding fine needle aspiration and 
cytology samples) is required for determining MET
status 
(a 
fresh 
pretreatment 
tumor 
biopsy 
is 
recommended but archived tumor sample is acceptable) 
! MET+ status (Phase II only), as determined by the 
central laboratory (Phase Ib retrospectively, Phase II 
for 
subject 
selection)
is 
defined 
as 
mesenchymal-epithelial 
transition 
factor 
(c-Met)
protein overexpression (e.g., moderate [2+] or strong 
[3+]
staining 
intensity 
for 
c-Met 
using 
immunohistochemistry [IHC] in the majority [U 50%] 
of tumor cells) 
! Child-Pugh class A with no encephalopathy according 
to the screening assessment
! Asian male or female, 18 years of age or older
! Measurable disease in accordance with RECIST v 1.1. 
The target lesion that has received previous local 
therapy should not be considered as measurable unless 
clear progression has been documented since the 
therapy (Phase II only)
! ECOG PS of 0 or 1
! Eligible for treatment with sorafenib, as assessed by 
investigators according to the Package Insert and 
clinical judgment (Phase II only)
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! Signed and dated informed consent indicating that the 
subject has been informed of all the pertinent aspects of 
the trial prior to enrollment
! Willingness and ability to comply with scheduled visits, 
treatment plans, laboratory tests, and other trial 
procedures
! Life expectancy judged by the investigator of at least 
3 months
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of 
the following exclusion criteria:
! Prior systemic anticancer treatment for advanced HCC,
including 
targeted
therapy 
(e.g.,
sorafenib), 
chemotherapy, or any other investigational agent 
(Phase II only)
! Prior treatment with any agent targeting the hepatocyte 
growth factor (HGF)/c-Met pathway
! Prior local-regional therapy within 4 weeks prior to 
Day 1 of trial treatment (e.g., major surgery, radiation 
therapy [with the exception of palliative bone-directed 
radiotherapy 
and 
radiotherapy 
administered 
to 
superficial lesions], hepatic arterial embolization, 
transcatheter 
arterial 
chemoembolization, 
chemoembolization, 
radiofrequency 
ablation, 
percutaneous ethanol injection, or cryoablation)
NOTE: palliative bone-directed radiotherapy should be 
within a limited field of radiation and for palliation only; 
it should be a short course, according to local 
institutional 
recommendations, 
and
should 
be
completed at least 7 days prior to the first administration 
of trial treatment
! Prior history of liver transplant
! Laboratory abnormalities defined as follows:
o
Hematological test abnormalities of either 
hemoglobin Z 8.5 g/dL
(without 
transfusion or growth factor support in the 
preceding 
14 days), 
neutrophils < 1.5 × 109/L, 
or 
platelets < 60 × 109/L (without transfusion 
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or growth factor support in the preceding 
7 days)
o
Liver 
dysfunction 
defined 
by 
total 
bilirubin > 3 mg/dL,
or
aspartate 
aminotransferase 
(AST)/alanine 
aminotransferase (ALT) > 5 × upper limit 
of normal (ULN)
o
Renal impairment as evidenced by serum 
creatinine U 1.5 × ULN 
or 
calculated 
creatinine clearance (CrCl) < 60 mL/min 
by Cockcroft-Gault formula (24-hour CrCl 
might be requested by the investigator for 
confirmation, 
if 
calculated 
CrCl 
is < 60 mL/min. In such case, subjects 
with 24-hour CrCl < 60 mL/min should be 
excluded)
o
International normalized ratio (INR) 
> 2.3 (in accordance with the guidance 
that has been modified for Child-Pugh 
classification)
o
Albumin < 28 g/L (without transfusion in 
the preceding 14 days)
! Past or current history of neoplasm other than HCC, 
except for curatively treated non-melanoma skin cancer, 
in situ carcinoma of the cervix, or other cancer 
curatively treated and with no evidence of disease for at 
least 5 years
! Known central nervous system (CNS) or brain 
metastasis that is either symptomatic or untreated
! Medical 
history 
of 
difficulty 
swallowing, 
malabsorption, or other chronic gastrointestinal disease, 
or conditions that may hamper compliance and/or 
absorption of the tested products
! Clinically significant gastrointestinal bleeding within 
4 weeks prior to Day 1 of trial treatment
! Impaired cardiac function, evidenced by any of the 
following conditions: (1) left ventricular ejection 
fraction < 45% on recent echocardiography; (2) serious 
arrhythmia; (3) unstable angina pectoris; (4) congestive 
heart failure New York Heart Association III and IV; (5) 
myocardial infarction within the last 12 months prior to
Day 1 of trial treatment; or (6) pericardial effusion
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! Hypertension uncontrolled by standard therapies (not 
stabilized to Z 150/90 mmHg)
! Subject with a family history of long QT syndrome, or 
who takes any agent that is known to prolong QT/QTc 
interval, or with a marked prolongation of QT/QTc 
interval (e.g., repeated demonstration of a QTc interval 
> 450 msec)
! Known human immunodeficiency virus (HIV) infection
! Subjects who have acute pancreatitis and/or chronic 
pancreatitis, with elevated lipase and/or amylase, 
clinical symptoms, and/or imaging studies that are 
indicative of the diagnosis (Mainland Chinese subjects 
only)
! Known or suspected drug hypersensitivity to any 
ingredients 
of 
sorafenib 
(Phase II 
only) 
and
MSC2156119J
! Female subjects who are pregnant or lactating, or males 
and females of reproductive potential not willing or not 
able to employ a highly effective method of birth 
control/contraception to prevent pregnancy from 
2 weeks before receiving study drug until 3 months after 
receiving the last dose of study drug. A highly effective 
method of contraception is defined as having a low 
failure rate (< 1% per year) when used consistently and 
correctly
! Concurrent treatment with a non-permitted drug
! Substance abuse, other acute or chronic medical or 
psychiatric condition, or laboratory abnormalities that 
may increase the risk associated with trial participation 
in the opinion of the investigator
! Participation in another interventional clinical trial 
within the 28 days prior to Day 1 of trial treatment or 
within a time period that is less than the cycle length for 
the investigational treatment (whichever is shorter), or 
if the subject has any AE caused by the investigational 
treatment that has not recovered to Grade 1 or less.
! Previous anticancer treatment-related toxicities not 
recovered to baseline or Grade 0-1 (except alopecia)
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! Subjects with any concurrent medical condition or 
disease that will potentially compromise the conduct of 
the study at the discretion of the investigators
! Clinically significant third space fluid accumulation 
(despite the use of diuretics), e.g., moderate to large 
ascites requiring tapping or pleural effusion that either 
requires tapping or results in shortness of breath
! Complete occlusion of the major portal vein or vena 
cava due to HCC. (The major portal vein is defined as 
the part of portal vein between the union of the splenic 
and superior mesenteric veins and the first bifurcation 
into the left and right vein)
Investigational Medicinal 
Product: dose/mode of 
administration/dosing schedule
Investigational medicinal product
MSC2156119J, 
3-(1-{3-[5-(1-Methyl-piperidin-4-
ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-1,6-dihydro-
pyridazin-3-yl)-benzonitrile) mono-HCl, monohydrate, is 
supplied as 25 mg and 100 mg film-coated tablets.
Dose/mode of administration/dosing schedule
Phase Ib: For each dose cohort, a fixed dose and 
administration will be applied. The assigned dose of 
MSC2156119J will be administered daily, using 25 mg 
and/or 100 mg film-coated tablets.
For “3+3” dose escalation cohorts, the first dose level will 
be 300 mg once daily, which is 1 level lower than the 
target dose of RP2D (500 mg, once daily) from the FIM 
trial. The second dose level will be 500 mg once daily.
Subjects will take their assigned doses of MSC2156119J 
orally, in the morning approximately at the same time, 
immediately after breakfast, with a full glass of water 
(approximately 200 mL), every day of each 21-day 
treatment cycle. 
Subjects will be instructed to swallow the tablets whole
and to avoid biting or breaking the tablets, or attempting 
to dissolve the tablets in water before taking them.
On days when PK samples are to be drawn, subjects 
should be instructed to attend the clinic in a fasted state, 
with no breakfast and prior to taking the MSC2156119J 
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dose. After a predose PK blood sample is drawn, the 
assigned dose of MSC2156119J
should be taken 
following breakfast. No further food should be consumed 
until 2 hours after the dose (water is allowed).
Phase II: The dose of MSC2156119J will be the RP2D 
determined in Phase Ib.
Subjects who are randomized to MSC2156119J will take 
their assigned dose orally once daily, approximately at the 
same time in the morning, immediately after breakfast 
with a full glass of water (approximately 200 mL), every 
day of each 21-day treatment cycle. 
 
 
 
 
 
 
Reference therapy: dose/mode 
of administration/dosing 
schedule
Subjects who are randomized to sorafenib will take two 
200 mg tablets in the morning and two 200 mg tablets in 
the evening (800 mg total daily dose), on an empty 
stomach 1 hour before or 2 hours after ingestion of food 
with a full glass of water (approximately 200 mL), every 
day of each 21-day treatment cycle. Subjects should be 
instructed to take sorafenib at approximately the same 
times each day.
Planned treatment duration per 
subject
The minimum duration of treatment for each subject is 
1 full 21-day cycle of treatment. Subjects may repeat the 
treatment cycle without limitation as long as no 
unacceptable toxicity or no disease progression is 
documented. 
Primary endpoints
Phase Ib:  
!
Incidence of subjects experiencing at least 1 dose 
limiting toxicity (DLT) within the first treatment cycle 
(i.e., 21 days after the first dose)
!
Incidence and type of other AEs
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Phase II:
!
TTP based on tumor assessment by an IRC. TTP is 
defined as the time (in months) from randomization to 
date of the observation of radiological PD assessed by 
an IRC
Tumor 
assessment 
endpoints
are 
following
RECIST v 1.1.
Secondary endpoints
Phase Ib and Phase II:
!
Progression-free survival (PFS) based on tumor 
assessment by the IRC. PFS time is defined as the time 
(in months) from randomization to either first 
observation of disease progression or occurrence of 
death due to any cause within 84 days of either 
randomization or the last tumor assessment.
!
PFS based on tumor assessment by the investigator. 
PFS time is defined as the time (in months) from 
randomization 
to 
either 
first 
observation 
of 
radiologically confirmed PD by the investigator or 
occurrence of death due to any cause within 84 days 
of either randomization or the last tumor assessment.
!
Overall survival (OS) time. OS time is defined as the 
time (in months) from randomization to the date of 
death.
!
TTP assessed by investigator. TTP is defined as the 
time (in months) from randomization to date of the 
observation of radiological PD assessed by the 
investigator.
!
Time-to-symptomatic progression (TTSP). TTSP is 
defined as the time (in months) from the date of 
randomization to the date of deterioration of 
symptoms assessed by FHSI-8, defined as the total 
score increase by at least 4 points compared with the 
baseline value, or deterioration to ECOG PS of 4. 
!
Objective response (OR) based on tumor assessment
by the IRC. OR is defined as complete response (CR) 
or partial response (PR) as the best overall response 
according to radiological assessments as adjudicated 
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by the IRC from randomization to first occurrence of 
PD. Responses do not require confirmation according 
to RECIST v 1.1.
!
OR based on tumor assessment by the investigator. 
OR is defined as CR or PR as the best overall response 
according to radiological assessments as adjudicated 
by the investigator from randomization to first 
occurrence of PD. Responses do not require 
confirmation according to RECIST v 1.1.
!
Disease control based on tumor assessment by the 
IRC. Disease control is defined as CR, PR, or stable 
disease (SD) as the best overall response according to 
radiological assessments as adjudicated by the IRC 
from the date of randomization to the first occurrence 
of PD. In the case of SD, measurements must have met 
the SD criteria at least once after study entry at a 
minimum interval of 42 days after randomization.
!
Disease control based on tumor assessment by the 
investigator. Disease control is defined as CR, PR, or 
SD as the best overall response according to 
radiological assessments as adjudicated by the 
investigator from the date of randomization to the first 
occurrence of PD. In the case of SD, measurements 
must have met the SD criteria at least once after study 
entry at a minimum interval of 42 days after 
randomization.
!
Drug exposure.
!
Incidence and type of AEs (all grades as per the 
National 
Cancer 
Institute’s 
[NCI]-Common 
Terminology Criteria for Adverse Events [CTCAE]
version 4.0): all treatment emergent adverse events 
(TEAEs), related TEAEs, treatment emergent serious 
adverse events (SAEs), related treatment emergent 
SAEs, TEAEs of NCI-CTCAE (version 4.0) with 
Grade U 3, related TEAEs Grade U 3, and TEAEs 
leading 
to 
temporary/permanent 
treatment 
discontinuation.
!
Incidence and reasons for deaths, including deaths 
within 33 days after the last dose of study drug.
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!
Safety laboratory tests graded by NCI-CTCAE 
(version 4.0).
!
Vital
signs; 
12-lead 
ECG 
changes;
physical 
examinations, including change in body weight; and 
ECOG PS.
Pharmacokinetics
Phase Ib: PK endpoint (for MSC2156119J only): area 
under the curve from time zero to time t (AUC0-t), area 
under the plasma concentration versus time curve within 
1 dosing interval (AUC0-tau), maximum concentration 
(Cmax), average plasma concentration within 1 dosing 
interval (Cav), observed minimum plasma concentration 
(Cmin), time to maximum concentration (tmax), area under 
the curve from time zero to infinity following last 
administration (AUC0-Q), apparent clearance (CL/f), 
apparent volume distribution associated to the terminal 
phase (Vz/f), apparent volume of distribution at steady 
state (Vss/f), area under the curve terminal phase rate 
constant (Rz), and half-life (t1/2) when appropriate.
Exploratory endpoints 
Phase Ib
 
 
 
 
 
 
Phase II
! PRO assessments of MSC2156119J compared with 
sorafenib will be assessed using the FACT-HP 
questionnaire
 
 
 
 
 
 
 
 
o  
 
 
 
 
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Statistical methods (includes 
sample size calculation)
Statistical analyses of Phase Ib will be carried out in a 
descriptive manner, whereas Phase II has a confirmatory 
component when analyzing TTP.
Data of Phase Ib will be analyzed after completion of the
dose confirmation phase. Primary statistical analyses will 
be performed using electronic case report form (eCRF) 
data obtained until a clinical cut-off date in Phase II, 
which is determined by the date after the required number 
of events for the primary endpoint has been reported in 
the primary analysis population, i.e., 40 TTP events for 
the modified intent-to-treat (mITT) population in Phase II
or on 15 August 2017, whichever occurs first. The final 
statistical analyses for the Phase II study will be 
performed at approximately 6 months after the last 
subject is first dosed. Determination of MET status is 
planned 
at 
Molecular 
Prescreening 
(Phase Ib 
retrospectively, Phase II for subject selection); rescoring 
will be performed as a quality control measure. The mITT 
population excludes subjects who were randomized but 
for whom, retrospectively, a c-Met status 1+ or ‘not 
assessable’ was detected.
All data required for the calculation of time-to-event will 
be taken from eCRF, but randomization strata will be 
taken as specified in interactive voice/web response 
service.
The DLT population will be used for analysis of Phase Ib. 
Statistical analyses in Phase Ib will be carried out in a 
descriptive manner.
The mITT population will be primarily used in the 
analysis of baseline characteristics and efficacy. Analyses 
on the mITT population will consider subjects’ allocation 
to treatment groups as randomized.
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Selected efficacy analyses will be repeated for the 
intent-to-treat population, the Per Protocol (PP) 
population and for subgroups. In case that the PP 
population includes more than 90% of the mITT 
population, additional efficacy analyses on the PP 
population will be omitted.
The safety population will be considered for safety 
analyses. These analyses will consider subjects as treated.
Unless otherwise indicated, all analyses will be presented 
separately for the 2 treatment groups.
All statistical tests comparing treatment arms will be 
performed two-sided using a significance level of 
` = 10%, unless otherwise specified. If confidence 
intervals (CIs) are to be calculated, they will be two-sided
with a confidence probability of 90%, unless otherwise 
specified.
Sample size
Phase Ib:  
For Phase Ib, the total number of subjects to be enrolled 
in this trial is up to 21. Of these subjects, up to 18 will be 
enrolled based on the “3+3” dose escalation method with
2 dose cohorts: 3 to 6 subjects in the first dose cohort and 
3 to 12 subjects in the second dose cohort (if dose de-
escalation does not occur). In addition, separate from the 
“3+3” dose escalation cohorts, up to 3 subjects will be 
enrolled in the mainland China sites. The final sample size 
will depend on the number of subjects who experience 
DLTs observed at each dose level, the number of dose 
levels explored, the safety data, and the decision from the 
Safety Monitoring Committee (SMC) meeting.
Phase II
For Phase II, the initial sample size planning required
100 TTP events (assessed by an IRC) to ensure 80% 
power with a two-sided significance level of 10% for 
rejecting the null hypothesis of equal treatment effect 
between treatment arms, assuming a true hazard ratio 
(HR) of 0.6. Assuming a median TTP in Asian subjects 
for the sorafenib arm of 2.8 months, an HR of 0.6 
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represents a 1.87 month increase, resulting in a median 
TTP of 4.67 months for the MSC2156119J arm.
A total number of 140 subjects with MET+ HCC were
planned to be randomized on a 1:1 basis to receive 
MSC2156119J or sorafenib.
Prescreening/enrollment
will be stopped
following 
40 TTP 
events
(assessed
by 
an
IRC)
or 
on 
15 August 2017, whichever occurs first. It is expected that 
approximately 90 subjects will be randomized by 
15 August 2017. The
sponsor’s decision to
stop
enrollment is due to business-related considerations not 
related to any safety issues.
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2
Sponsor, Investigators, and Trial Administrative Structure
2.1
Sponsor
Merck KGaA will be the sponsor of this Asian clinical trial of mesenchymal-epithelial 
transcription factor (c-Met) inhibitor MSC2156119J (International Nonproprietary Name: 
tepotinib). The address of the sponsor is shown below:
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany
2.2
Trial Administrative Structure
A detailed administrative structure is in the trial Manual of Operations (MOP).
2.2.1
Safety Monitoring Committee
A Safety Monitoring Committee (SMC) will perform periodic reviews to evaluate the safety of the 
subjects who follow “3+3” dose escalation method in Phase Ib. Details of the safety monitoring 
process will be specified in a dedicated SMC charter.
SMC mandatory members will be identified before trial initiation and will include principal
investigator(s) or coordinating investigator, the medical responsible, pharmacokineticist, and a 
safety representative from the sponsor. Ad hoc members will be consulted as needed and may 
include, but are not restricted to, the biostatistician or the treating investigator in the case of 
particular safety findings. 
Responsibilities of the SMC will include: 
!
Review of all adverse events (AEs) and potential dose-limiting toxicities (DLTs), 
laboratory data, vital signs, and electrocardiogram (ECG) data, with determination of 
how to handle dose escalation and de-escalation and maximum tolerated dose 
(MTD)/Recommended Phase II dose (RP2D) based on their findings.
!
The decision to escalate or de-escalate the investigational medicinal product (IMP), 
MSC2156119J, to a new dose level based on the criteria defined in this protocol for each 
dose regimen.
!
Cohort review meetings to be held after Cycle 1 is completed by a number of subjects in 
a given cohort to discuss outcomes, dose escalation, and determination of the 
MTD/RP2D. The SMC will be responsible for reviewing a full set of safety and available 
pharmacokinetic (PK) data to make any determinations.
!
Ad hoc SMC meetings to address any potential safety concerns.
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!
The decision of whether or not to continue with the MTD/RP2D determined during the 
dose escalation based on ongoing outcomes and findings. 
SMC will only be responsible for evaluating the safety profile of the subjects who follow the “3+3” 
dose escalation method in Phase Ib. SMC will not be responsible for safety evaluation of the 
subjects in the Chinese (Mainland) subject cohort of Phase Ib. Sponsor experts including, but not 
limited to, medical responsible, safety responsible and pharmacokineticist, and the coordinating 
investigator will review the safety profile of the subjects in the Chinese (Mainland) subject cohort, 
if 3 evaluable subjects are enrolled in this cohort. See details in Section 5.1.
2.2.2
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will perform periodic reviews to evaluate 
the safety and efficacy of the subjects participating in Phase II. Details and periodicity of the safety 
monitoring process will be specified in a dedicated IDMC charter.
2.2.3
Independent Review Committee
An Independent Review Committee (IRC) will conduct a blinded review of the images of all 
subjects using the same criteria based on a separate charter outlining details of the review process.
In addition, images will be evaluated by the IRC in accordance with modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) (1).
3
Background Information
3.1
Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer and accounts for more 
than 626,000 new cases per year worldwide (2). Asia carries nearly 78% of the burden of HCC,
with 55% of new cases occurring in mainland China (3, 4). 
Many systemic therapies have been investigated for use in subjects with HCC; however, only 
sorafenib is approved for use in Asian countries, North America, and Europe (5). Sorafenib is not 
widely used in Asia largely due to affordability and unsatisfactory efficacy (6). Although cost 
sharing programs in some countries were successful in expanding usage, lack of long term 
coverage renders this practice unsustainable. In addition, emerging evidence suggests that 
sorafenib may be less tolerated by Asian cancer subjects compared with those of other ethnicities
undergoing treatment in other regions. Hand-foot skin reaction appears to be more frequent in 
Asians, particularly lower-grade reactions. As a result, dose reduction or reduced starting doses of 
sorafenib is common in Asia (7, 8). Even with sorafenib, the overall prognosis of these subjects 
remains very poor, with a median time to progression (TTP) of 2.8 months and a median overall 
survival (OS) of 6.5 months (8). Therefore, effective systemic treatment of advanced stage HCC 
remains a high unmet medical need.
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3.2
c-Met
The c-Met receptor tyrosine kinase is a cell surface receptor capable of mediating pleiotropic 
effects, including cell migration, survival, and proliferation. Its ligand is the hepatocyte growth 
factor (HGF), also known as scatter factor (9). Hepatocyte growth factor binding to the c-Met 
receptor leads to receptor dimerization and autophosphorylation, resulting in the activation of 
intracellular signaling cascades, such as the rat sarcoma/extracellular signal-regulated kinase and 
the phosphoinositide 3-kinase/protein kinase B pathway (10). Under physiological conditions, 
c-Met regulates invasive growth and morphogenesis in multiple embryonic tissues, such as 
muscles, nervous system, bones, and vascular system, and is essential for mammalian 
development. In postnatal life, c-Met signaling has been implicated in wound healing and 
regeneration of damaged organs, in particular the liver (11).
c-Met and HGF have been implicated in carcinogenesis and metastatic tumor progression because 
of their ability to enhance angiogenesis, cancer cell proliferation, migration, and invasion, as well 
as to confer resistance to apoptosis (9, 12). Activating c-Met point mutations and amplification, as 
well as c-Met/HGF coexpression, have been observed in a number of human tumors including 
breast, lung, and gastric carcinomas, glioma, multiple myeloma, and certain sarcomas. Hepatocyte 
growth factor is a critical molecule for hepatocyte regeneration after injury. It is secreted by stellate 
cells and binds to the c-Met receptor. Aberrant activity of c-Met has been described in human 
cancers as a result of c-Met amplification, germline or somatic mutations, transcriptional up-
regulation, or HGF-dependent autocrine loops (13, 14, 15). Dysregulation of c-Met and HGF are 
common in HCC, although the exact role of this pathway in the pathogenesis of HCC is not 
established. Pharmacological interference with the HGF/c-Met axis is considered with increasing 
interest as a promising strategy to inhibit primary tumor growth and metastasis.
3.3
MSC2156119J
MSC2156119J is a potent, highly selective c-Met inhibitor with a favorable PK profile in humans 
allowing once daily dosing. It inhibits growth and induces regressions of HGF-dependent and 
HGF-independent susceptible tumor models and is currently under investigation in an ongoing 
first-in-man (FIM) trial. Refer to the latest Investigator’s Brochure (IB) for further information 
about the nonclinical and clinical programs and Guidance for the investigator.
3.3.1
Nonclinical Evaluation
Nonclinical studies indicate that MSC2156119J is a highly selective adenosine triphosphate 
(ATP)-competitive c-Met inhibitor, which effectively inhibits c-Met signaling in tumors. 
MSC2156119J exhibited marked inhibitory activity on the growth of mouse tumors and of human 
tumor xenografts and frequently led to complete regressions of established tumors. This antitumor 
effect was observed in 2 types of clinically relevant models: 1) tumor cells in which c-Met 
activation was ligand independent, i.e., tumors harboring c-Met amplification or activating 
mutation; 2) tumors in which c-Met and HGF were co-expressed, thereby creating an autocrine 
positive feedback loop. 
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Results of the nonclinical safety pharmacological studies conducted in compliance with the 
International Council for Harmonization (ICH) of Technical Requirements for Registration of 
Pharmaceuticals for Human Use-Guideline 7A/7B suggest a favorable nonclinical safety profile 
of the development compound.
On the basis of presently available results of the animal in vivo and in vitro studies, there are no 
reservations from a toxicological point of view against studying MSC2156119J in cancer subjects.
3.3.2
Clinical Experience
A single-center, non-randomized, open label, dose-escalation, FIM trial (EMR200095-001) to 
explore the safety, tolerability, PK/pharmacodynamics (Pd), and clinical activity of MSC2156119J 
administered under 2 treatment regimens was initiated in December 2009. Eligible subjects have 
advanced solid tumors that were either refractory after standard therapy or unsuitable for available 
therapies. An additional regimen, Regimen 3, was added on 04 April 2012.
The FIM trial started with 2 dosing schedules, each over a 21-day cycle: 
!
Regimen 1: 14 days on, 7 days off (starting dose: 30 mg once daily)
!
Regimen 2: 3 times per week (i.e., Days 1, 3, and 5; starting dose: 30 mg once daily) 
The trial was amended in 2012 to introduce a third regimen:
!
Regimen 3: continuous dosing over the entire 21-day cycle (starting dose 300 mg once 
daily)
Regimen 3, which was introduced in 04 April 2012, is to further improve target inhibition by 
ensuring a constant exposure to the compound. Upon introduction of Regimen 3, Regimen 1 was 
discontinued and dose escalation continues with Regimen 2 and Regimen 3. 
The FIM trial followed a sequential dose escalation “3+3” design. The criteria for dose escalation 
were based on the occurrence of DLTs and Grade 2 clinically relevant AEs. At the MTD/RP2D, 
an expansion cohort of 12 subjects carrying c-Met alterations (e.g., protein overexpression or gene 
mutation/amplification) was to be conducted to consolidate the safety profile, antitumor activity, 
and PK/Pd profile at the MTD/RP2D level.
The last subject-last visit in the FIM trial took place on 08 October 2015 and the Clinical Trial 
Report has been finalized.
 
 
 
 
 
 
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!
 
 
 
 
 
 
 
 
 
 
 
Further details, including data from the completed and ongoing trials, are available in the current 
IB.
3.3.2.1
Clinical Experience in Asian Population
Trial EMR200095-006 is a Phase Ib/II randomized, open-label trial to compare MSC2156119J
plus gefitinib versus chemotherapy (pemetrexed + cisplatin) as second-line treatment in subjects 
with MET+, locally advanced or metastatic non-small cell lung cancer harboring epidermal growth 
factor receptor (EGFR) mutation and having acquired resistance to prior EGFR-tyrosine kinase 
inhibitor (EGFR-TKI) therapy.
 
Preliminary data on the clinical activity of MSC2156119J in combination with gefitinib in this 
trial are outlined in Section 3.3.2 and indicate antitumor activity in subjects who have received 
prior EGFR-TKI therapy. Data also suggest that there may be an increased likelihood of response 
to therapy with increased levels of tumor c-Met expression (16).
 
 
Further details are available in the current IB.
Although exposure in Asian subjects is limited, the safety data available to date continues to justify 
the use of MSC2156119J daily in Asian subjects in the clinical trial setting. 
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3.4
Rationale for the Current Trial
The pathogenesis and progression of HCC are mediated by a number of molecular defects and 
deregulated pathways. Among those, deregulation of c-Met and HGF are common in HCC. The 
presence of a c-Met induced expression signature derived from primary HCC and from liver 
metastases from extra hepatic tumors showed a significant correlation between increased vascular 
invasions and decreased mean survival times. Furthermore, recent results from a randomized
second line Phase II trial in HCC showed that subjects with c-Met overexpressing tumors had a 
worse prognosis compared to the overall population, indicating that c-Met overexpression may be 
a poor prognostic factor in this disease (17).
Based on the results from preclinical studies, tumors in which c-Met and HGF were co-expressed 
create an autocrine positive feedback loop, thereby resulting in tumor cell proliferation and tumor 
growth. In SHARP study subgroup analysis by biomarkers, 491 and 305 subjects had usable 
plasma samples at baseline and at 12 weeks respectively. Subjects with low baseline HGF tended 
to derive greater benefit from sorafenib (OS: 12.4 months in sorafenib arm versus 9.8 months in 
placebo arm, hazard ratio [HR]: 0.69, 95% confidence interval [CI]: 0.53-0.90) than those with 
high HGF concentration (OS: 6.3 months in sorafenib arm versus 5.3 months in placebo arm, 
HR: 1.10, 95% CI: 0.72-1.67) (18). Therefore, there is a high unmet medical need for subjects with 
advanced HCC harboring c-Met dysregulation (17).
At present, proof of concept (PoC) has been established for c-Met inhibition in a spectrum of solid 
tumors through a number of Phase II trials with a variety of c-Met inhibitors (e.g., rilotumumab in 
gastric cancer, onartuzumab in non-small cell lung cancer). Furthermore, subjects with c-Met
alterations appeared more likely to derive benefit than subjects who do not overexpress c-Met. 
Specifically for HCC, several non-selective c-Met inhibitors have entered into Phase II trials. 
Cabozantinib, a c-Met/vascular endothelial cell growth factor receptor 2 inhibitor, demonstrated 
anti-HCC activity in a second-line Phase II trial. Notably, in subjects with MET Dx(+) tumors
(defined as c-Met overexpression by immunohistochemistry [IHC]), improvement in both TTP 
and OS were more pronounced, suggesting that c-Met inhibition holds promise in treating HCC, 
especially in subjects with MET+ tumors. 
This Phase Ib/II randomized, active controlled trial with a safety run-in period is designed to
confirm the RP2D, efficacy and safety of MSC2156119J as monotherapy versus sorafenib in 
MET+ Asian (non-Japanese) subjects with HCC and Child-Pugh class A liver function. The trial
is focused on subjects with Child-Pugh class A liver function because it helps control confounding 
issues of liver failure or death due to underlying chronic liver disease or cirrhosis, hence, treatment 
effect can be better assessed.
The rationale that MSC2156119J as monotherapy is to be compared with sorafenib in the first-line
treatment for advanced HCC with MET+ is as follows:
!
Inhibition of HGF/c-Met signaling has been explored as a therapeutic strategy for advanced 
HCC and subjects with MET Dx(+) had a worse prognosis and derived more benefit from the 
therapeutic strategy by c-Met inhibition;
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!
MSC2156119J is more selective and more potent than other c-Met inhibiting agents, which are 
already tested in HCC Phase II trials (refer to the latest IB);
!
In-house studies indicated that primary liver explants with high levels of HGF/c-Met that are 
derived from treatment naïve Chinese HCC subjects were sensitive towards c-Met inhibition 
by monotherapy with MSC2156119J, which resulted in higher antitumor activity compared to 
sorafenib alone. In contrast, tumors characterized by moderate or low levels of HGF/c-Met 
were not sensitive to MSC2156119J (refer to the latest IB).
Geographical differences in terms of HCC disease and treatment practice are well documented (6).
In clinical trials of sorafenib for advanced HCC, different efficacy outcomes were observed in 
Asian and other subjects. While the relative improvement in median OS was similar (HR for OS 
of 0.68 [95% CI: 0.50-0.93] and 0.69 [95% CI: 0.55-0.87] in Asian and other subjects, 
respectively) the absolute improvement in terms of median OS was 6.5 and 10.7 months in
sorafenib arm in Asian subjects and other subjects, respectively (7, 8).
Possible reasons for these outcomes include variation in genetic and/or epigenetic aberrations 
between different viral etiologies and the propensity for Asian physicians to use local-regional
therapy more aggressively and in later stages, resulting in enrollment of a more advanced subject 
population to trials of systemic therapy. In addition, sorafenib, the only globally approved agent 
with established OS benefit in advanced HCC, seems to have a slightly different safety profile in 
Asian subjects. Therefore, a Phase II trial in first-line MET+ HCC subjects in Asia is justifiable.
The proposed focused first-line Phase II trial in cancer subjects of non-Japanese Asian ethnicities 
will provide the global PoC for MSC2156119J in MET+ HCC; a separate trial in Japanese subjects 
with solid tumors is ongoing (EMR200095-003). In addition, a complementary development 
program in Caucasian subjects with HCC will be conducted in parallel to generate supportive data 
regarding the dose, antitumor activity, safety, and tolerability of MSC2156119J. A positive PoC 
trial together with the data from the trial in Caucasian subjects with HCC will provide the basis 
for a subsequent global Phase III trial in first-line HCC subjects with MET+ tumors versus
sorafenib.
3.5
Risk-Benefit Evaluation
A safety run-in phase in HCC subjects with Child-Pugh class A liver function is included to 
confirm the appropriate dose and to better understand the PK and safety profile in subjects with 
mild impaired liver function who were excluded from the ongoing FIM trial. This approach is in 
line with recommendations by HCC experts (19).
Hepatocellular carcinoma generally develops from chronic liver diseases, mostly cirrhosis. Liver 
dysfunction and associated conditions may alter PK and tolerability (19). It is reasonable to set the 
initial dose level below the RP2D derived from subjects with normal liver function to preserve a 
margin for potential increased exposure. However, exposure of cancer subjects to subtherapeutic
dose levels also should be avoided.
Overall, in the ongoing and completed trials, MSC2156119J was well tolerated (refer to the current
IB). Asymptomatic pancreatic enzyme elevations are an identified risk from clinical studies, and 
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hepatobiliary toxicity and drug-drug interaction with P-glycoprotein (P-gp), breast cancer 
resistance protein (BCRP) and organic cation transporter 1 (OCT1) mediated transport drugs are 
potential risks from nonclinical studies.
Given the unmet medical need and limited treatment options in this indication, as outlined in 
Section 3.1, the overall benefit-risk evaluation remains positive.
A RP2D of 500 mg once daily has been determined. This RP2D is defined as a biologically active 
dose, based on PK/Pd modeling and supported by data on target inhibition from paired tumor 
biopsies, rather than as a safety defined MTD. Therefore, a Phase Ib safety run-in phase titrating 
from only 1 dose level below the RP2D of MSC2156119J (i.e., 300 mg prior to the randomized 
phase) is justified.
This clinical trial will be conducted in compliance with the clinical trial protocol, Good Clinical 
Practice (ICH Topic E6, GCP) and all applicable regulatory requirements.
4
Trial Objectives
4.1
Primary Objectives
The primary objectives are: 
! Phase Ib:
To confirm the RP2D of MSC2156119J administered orally once daily at a 21-day
cycle in subjects with advanced HCC and Child-Pugh class A liver function. The 
target RP2D in HCC subjects is the RP2D as determined in the global FIM trial, i.e.,
500 mg once daily
! Phase II:
To evaluate efficacy as measured by TTP of MSC2156119J as monotherapy in the 
first-line treatment compared with sorafenib in subjects with MET+ advanced HCC 
and Child-Pugh class A liver function
4.2
Secondary Objectives
The secondary objectives are: 
!
Phase Ib: To characterize the single and multiple dose PK, preliminary antitumor activity, and 
biochemical response of MSC2156119J in Asian subjects with HCC and Child-Pugh 
class A liver function
!
Phase II: To evaluate the safety and tolerability of MSC2156119J versus sorafenib
To evaluate antitumor activity of MSC2156119J versus sorafenib
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4.3
Exploratory Objectives
The exploratory objectives are: 
!
 
 
 
!
Phase II: To evaluate patient reported outcomes (PROs) of MSC2156119J compared with 
sorafenib. PROs will be assessed using the Functional Assessment of Cancer 
Therapy-Hepatobiliary (FACT-HP) questionnaire.
 
 
 
 
 
5
Investigational Plan
5.1
Overall Trial Design and Plan
Design
Phase Ib will be an open label, single arm trial at selected sites in mainland China, South Korea, 
and Taiwan.
The classical “3+3” design will be applied for sites in South Korea and Taiwan, with a dose 
escalation phase and a dose confirmation phase. In addition and separate from the “3+3” trial 
cohorts, up to 3 subjects will be enrolled in a separate cohort at selected sites in mainland China.
Phase II will be a randomized, open label, active controlled trial to evaluate the efficacy, safety, 
and PK of MSC2156119J as first-line treatment versus sorafenib in subjects with MET+, 
Barcelona Clinic Liver Cancer (BCLC) Stage B or C, systemic treatment naive advanced HCC 
and Child-Pugh class A liver function. Phase II is planned to be conducted at 45 to 55 sites in 
mainland China, South Korea, Taiwan, and other Asian countries.
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Phase Ib
“3+3” Dose Escalation Cohorts
Phase Ib follows the classical “3+3” design, with a dose escalation phase and a dose confirmation 
phase. The criteria for dose escalation are based on the occurrence of DLTs and safety data; the 
definition of DLTs is provided in Section 6.2.2. 
A SMC composed of sponsor representatives (trial physician, drug safety responsible, PK expert) 
and the principal investigator(s) will be responsible for making the decision of dose escalation, 
dose de-escalation, or expansion of enrollment at the same dose level. The decision will be made
after all subjects in the preceding cohort have completed the first cycle of treatment and all safety 
data from Cycle 1 of the cohort under evaluation, as well as potential DLTs have been fully 
evaluated.
The first dose level will be 1 dose level lower than the target RP2D, which is 300 mg once daily.
The second dose level and target RP2D is 500 mg once daily, which was determined as the RP2D 
in the FIM trial. 
After the initial 3 subjects have completed Cycle 1 at the first dose level (300 mg) and have been 
fully followed up for potential DLTs, a SMC meeting will be held to evaluate the safety of 
MSC2156119J and to determine next step (see Figure 1). Depending on the safety observed, the 
next step will be enrollment of additional 3 subjects at 300 mg or enrollment of 3 subjects at 
500 mg (i.e., dose escalation to the target RP2D). A SMC meeting will be held after extension of 
the first dose level to 6 subjects or/and after the initial 3 subjects at the second dose level are 
observed. 
Once 3 subjects have completed 1 cycle at the second dose level (500 mg), and depending on the 
safety observed, the next step will be enrollment of an additional 9 subjects at 500 mg to confirm 
the RP2D, enrollment of an additional 3 subjects at 500 mg for further assessment, or dose 
de-escalation to a dose level less than 500 mg. In addition, recruitment will be stopped and an ad 
hoc SMC meeting will be convened if U 33% of subjects experience a DLT. The criteria for dose
escalation, de-escalation, or expansion of enrollment at the same dose are described in 
Section 6.2.1.
At the target RP2D, the safety and PK profile will be assessed in a total of 12 subjects to confirm
the RP2D in Asian subjects with advanced HCC.
The sponsor may decide to assess doses higher than the target RP2D (i.e., doses > 500 mg once 
daily), doses lower than the first dose level (i.e., doses < 300 mg once daily), or doses between 
300 mg and 500 mg once daily based on the newly updated information and available safety and 
PK data in order to determine the appropriate biologically active dose that will be used in Phase II. 
A new RP2D, which may be higher or lower than target RP2D (i.e. 500 mg once daily), may be 
recommended by SMC. In this case, up to 12 subjects may be required to confirm the new RP2D, 
and the “3+3” method will be followed.
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Figure 1:
Phase Ib Design (“3+3” Dose Escalation Cohorts)
Up to 18 subjects in 2 dose cohorts will be enrolled in Phase Ib following the “3+3” 
dose-escalation method (up to 6 subjects enrolled in the first dose cohort and up to 12 subjects 
enrolled in the second dose cohort). The final sample size depends on the number of subjects who 
experience DLTs, the safety and PK data at each dose level, and the decision from the SMC based 
on DLTs and other safety data.
Chinese (Mainland) Subject Cohort
Up to an additional 3 subjects will be enrolled in the mainland China sites separately. The subject(s)
will be tested at 300 mg once daily. The aim of this cohort is to provide initial and preliminary 
data of the safety and PK of MSC2156119J in mainland Chinese subjects. The safety data from 
the mainland Chinese subject(s) will not be used for DLT evaluation and/or RP2D/MTD 
determination.
The first subject will be followed up for at least 21 days for safety assessment purpose. If the 
participating investigator and the coordinating investigator see no potential safety concerns from 
the first subject, the participating investigator and the coordinating investigator may recommend 
to close enrollment of this mainland Chinese subject cohort and inform the sponsor accordingly. 
All subjects in this cohort will be evaluated with the same criteria as the other subjects in this 
Phase Ib trial. Subjects who are not fully evaluable for safety will be replaced (see Section 5.5.2). 
If the first subject in this cohort experiences an event listed in Section 6.2.2 of the protocol and if 
this event is classified as related to MSC2156119J, then additional 2 evaluable subjects at the same 
dose level may be recruited for further safety evaluation. The participating investigator and the 
coordinating investigator are required to provide a justified reason to the sponsor for expansion of 
the cohort or discuss with the sponsor for a final decision.
The safety evaluation should be based on a full safety and available PK data review of 21 days
after the first dose has been administered. After a follow-up of at least 21 days for the last subject, 
the sponsor experts and the coordinating investigator will assess the safety profile of all enrolled 
subjects.
Phase II
Subjects will receive either MSC2156119J once daily (at the RP2D determined from Phase Ib) or 
400 mg sorafenib twice daily until disease progression (as determined by the investigator), 
MSC2156119J
300 mg
MSC2156119J 
500 mg (proposed)
Dose escalation phase 3+3
Dose confirmation phase 3+9
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intolerable toxicity, or consent withdrawal from the trial (see Figure 2). The dose-modification 
guideline in this trial for MSC2156119J is described in Section 6.2.5. Dose modification for 
sorafenib is at the discretion of the investigators based on the clinical circumstance, taking 
references to the Package Insert. Approximately 140 subjects with MET+ HCC were planned to
be randomized on a 1:1 basis to receive MSC2156119J or sorafenib. The assessment for safety
profile will be performed by the IDMC in Phase II, as described in Section 8.6.
Figure 2:
Phase II Randomization Scheme
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; R, randomized; Sora, sorafenib.
NOTE: Approximately 70 subjects will be randomized in each arm.
a.
Subjects who are not eligible for surgical and/or local-regional therapies or who have progressive disease after surgical 
and/or local-regional therapies only.
Treatment Duration
MSC2156119J (Phase Ib and Phase II) will be administered once daily over a 21-day cycle and 
sorafenib (Phase II) will be administered twice daily over a 21-day cycle. The minimum duration 
of treatment for each subject is 1 full cycle of treatment, i.e., 21 days, unless the subject
discontinues treatment prematurely. Subjects who withdraw from Phase Ib may be replaced, as 
described in Section 5.5.2. Subjects who withdraw from Phase II will not be replaced. Subjects 
who do not show signs of disease progression and who tolerate the treatment during the Cycle 1
are allowed to repeat the treatment cycle without limitation, as long as no unacceptable toxicity or 
no disease progression is documented. The treatment with MSC2156119J or comparator must end 
when the subject experiences disease progression or unacceptable toxicity (see Figure 3).
Treatment duration is summarized in Figure 3.
R
1:1
MSC2156119J
70 subjects
Sorafenib
70 subjects
! BCLCa Stage B 
or C
! Sora Naïve
! Child-Pugh A
MET+
1
st
line
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Figure 3:
Treatment Duration
Abbreviations: DLT, dose-limiting toxicity; IMP, investigational medicinal product.
NOTE: IMP (i.e., MSC2156119J) is administered once daily (Phase Ib and Phase II); sorafenib is administered twice 
daily (Phase II).
5.2
Discussion of Trial Design
This trial was designed based on the safety, tolerability, and PK data observed in the FIM trial in
subjects with solid tumors (see Section 3.5).
In the completed FIM trial, MSC2156119J has a favorable safety profile. A RP2D of 500 mg once 
daily has been determined, based on PK/Pd modeling and supported by data on target inhibition 
from paired tumor biopsies, rather than as an MTD based on safety signals; there were no DLTs 
at the RP2D. Therefore, a Phase Ib safety run-in phase titrating from only 1 dose level below the 
RP2D (300 mg) prior to the randomized phase is justified.
The stepwise dose escalation scheme allows the safety and tolerability of each dose level to be 
evaluated before subjects are exposed to a higher dose level. The starting dose of 300 mg 
MSC2156119J once daily corresponds to 1 dose level lower than the RP2D of 500 mg once daily 
in the FIM trial. Doses exceeding 500 mg once daily will be explored only if there is a reasonable 
concern that the dose of 500 mg might not be biologically active in Asian subjects and the safety 
and/or PK data do not preclude further dose escalation.
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Rationale for treatment regimen
Continuous once daily administration of MSC2156119J for 21 consecutive days was determined, 
after consideration of nonclinical data and the FIM trial, as the most appropriate treatment regimen 
for this trial. 
The definition of the RP2D (i.e., 500 mg) was based on the following criteria and considerations 
(see the latest IB):
1.
Based on the results from a nonclinical PK/Pd and tumor growth model, the analysis of target 
inhibition phospho-c-Met in on-treatment subject biopsies, and from a population PK model, 
the 500 mg once daily dose achieves target inhibition U 95% and results in sufficiently high 
steady state (trough) exposure levels in U 90% of subjects to induce activity in tumors with 
varying degrees of sensitivity to c-Met inhibition. Further support for this recommendation 
can be found in the latest IB.
2.
The SMC evaluated results from an expanded cohort of 14 subjects that were treated with 
500 mg MSC2156119J once daily administered over a 21-day cycle. No DLTs were 
observed in the 12 evaluable subjects. Of the 2 subjects who were not evaluable, 1 subject
was replaced due to the AE of Grade 2 bacteremia (assessed by the investigator as not related 
to MSC2156119J) and the other subject was replaced due to disease progression.
3.
The 500 mg once daily dose is, therefore, considered to be safe and in the biologically active 
range and will be used as the target dose level (i.e., RP2D) in subsequent clinical trials with 
MSC2156119J.
5.2.1
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
5.3.1
Inclusion Criteria
For inclusion in the trial, all of the following inclusion criteria must be fulfilled:
1. Histologically or cytologically confirmed HCC
2. Subjects with either intermediate HCC of BCLC Stage B, who are not eligible for 
surgical and/or local-regional therapies or who have progressive disease (PD) after 
surgical and/or local-regional therapies, or with advanced HCC of BCLC Stage C. See 
Appendix K
NOTE: local-regional therapy MUST NOT contain sorafenib
3. Subjects who have disease progression or are intolerant to the prior standard treatment 
for advanced HCC (Phase Ib Korean subjects only)
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4. A tumor biopsy (excluding fine needle aspiration and cytology samples) is required for 
determining MET status (a fresh pretreatment tumor biopsy is recommended but 
archived tumor sample is acceptable). 
5. MET+ status (Phase II only), as determined by the central laboratory (Phase Ib 
retrospectively, Phase II for subject selection) is defined as c-Met
protein 
overexpression (e.g., moderate [2+] or strong [3+] staining intensity for c-Met using 
IHC in the majority [U 50%] of tumor cells) (see
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6
Appendices
6. Appendix A)
NOTE: the main purpose of the Phase Ib trial is to determine the RP2D, safety, and 
PK profile of MSC2156119J in HCC subjects, therefore, MET+ status is not an 
eligibility criterion for Phase Ib
7. Child-Pugh class A (see Appendix B) with no encephalopathy according to the 
screening assessment
8. Asian male or female, 18 years of age or older
9. Measurable disease in accordance with Response Evaluation Criteria in Solid Tumors 
(RECIST v 1.1). The target lesion that has received previous local therapy should not 
be considered as measurable unless clear progression has been documented since the 
therapy (Phase II only) (see Section 8.3 and Appendix C)
10. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
(see Appendix D)
11. Eligible for treatment with sorafenib, as assessed by investigators according to the 
Package Insert and clinical judgment (Phase II only)
12. Signed and dated informed consent indicating that the subject has been informed of all 
the pertinent aspects of the trial prior to enrollment
13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory 
tests, and other trial procedures
14. Life expectancy judged by the investigator of at least 3 months
6.1.1
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. Prior systemic anticancer treatment for advanced HCC, including targeted therapy 
(e.g., sorafenib), chemotherapy, or any other investigational agent (Phase II only)
2. Prior treatment with any agent targeting the HGF/c-Met pathway
3. Prior local-regional therapy within 4 weeks prior to Day 1 of trial treatment 
(e.g., major surgery, radiation therapy [with the exception of palliative bone-directed 
radiotherapy and radiotherapy administered to superficial lesions], hepatic arterial 
embolization, 
transcatheter 
arterial 
chemoembolization, 
chemoembolization, 
radiofrequency ablation, percutaneous ethanol injection, or cryoablation)
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NOTE: palliative bone-directed radiotherapy should be within a limited field of 
radiation and for palliation only; it should be a short course, according to local 
institutional recommendations, and should be completed at least 7 days prior to the 
first administration of trial treatment
4. Prior history of liver transplant
5. Laboratory index at baseline:
!
Hemoglobin Z 8.5 g/dL (without transfusion or growth factor support in the 
preceding 14 days)
!
Neutrophils < 1.5 x 109/L
!
Platelets < 60 x 109/L (without transfusion or growth factor support in the 
preceding 7 days)
!
Total bilirubin > 3 mg/dL
!
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 5 x upper 
limit of normal (ULN)
!
Renal impairment as evidenced by serum creatinine  1.5 x ULN, or calculated 
creatinine clearance (CrCl) < 60 mL/min by Cockroft-Gault formula (24-hour
CrCl might be requested by the investigator for confirmation, if calculated CrCl 
is < 60 mL/min. In such case, subjects with 24-hour CrCl < 60 mL/min should 
be excluded)
CrCl (mL/min) =
[140 – age (year) x weight (kg)]
{x 0.85 for female subjects}
72 x serum creatinine (mg/dL)
!
International normalized ratio (INR) > 2.3 (in accordance with the guidance that 
has been modified for Child-Pugh classification; see Appendix B)
!
(Criterion has been deleted by amendment)
!
Albumin < 28 g/L (without transfusion in the preceding 14 days)
6. Past or current history of neoplasm other than HCC, except for curatively treated non-
melanoma skin cancer, in situ carcinoma of the cervix, or other cancer curatively 
treated and with no evidence of disease for at least 5 years
7. Known central nervous system (CNS) or brain metastasis that is either symptomatic 
or untreated
8. Medical history of difficulty swallowing, malabsorption, or other chronic gastrointestinal 
disease, or conditions that may hamper compliance and/or absorption of the tested 
products
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9. Clinically significant gastrointestinal bleeding within 4 weeks prior to Day 1 of trial 
treatment
10. (Criterion has been deleted by amendment)
11. Impaired cardiac function:
!
Left ventricular ejection fraction < 45% on recent echocardiography (Note: a 
screening left ventricular ejection fraction assessment without history of 
congestive heart failure is not required unless clinically indicated.)
!
Serious arrhythmia
!
Unstable angina pectoris
!
Congestive heart failure New York Heart Association (NYHA) III and IV 
(see Appendix E)
!
Myocardial infarction within the last 12 months prior to Day 1 of trial treatment
!
Pericardial effusion
12. Hypertension uncontrolled by standard therapies (not stabilized to Z 150/90 mmHg)
13. Subject with a family history of long QT syndrome, or who takes any agent that is 
known to prolong QT/QTc interval, or with a marked prolongation of QT/QTc interval 
(e.g., repeated demonstration of a QTc interval > 450 msec)
14. Known human immunodeficiency virus (HIV) infection
15. Subjects who have acute pancreatitis and/or chronic pancreatitis, with elevated lipase 
and/or amylase, clinical symptoms, and/or imaging studies that are indicative of the 
diagnosis (Mainland Chinese subjects only).
16. Known or suspected drug hypersensitivity to any ingredients of sorafenib (Phase II 
only) and MSC2156119J
17. Female subjects who are pregnant or lactating, or males and females of reproductive 
potential not willing or not able to employ a highly effective method of birth 
control/contraception to prevent pregnancy from 2 weeks before receiving study drug
until 3 months after receiving the last dose of study drug. A highly effective method 
of contraception is defined as having a low failure rate (< 1% per year) when used 
consistently and correctly.
18. Concurrent treatment with a non-permitted drug
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19. Substance abuse, other acute or chronic medical or psychiatric condition, or laboratory 
abnormalities that may increase the risk associated with trial participation in the 
opinion of the investigator
20. Participation in another interventional clinical trial within the 28 days prior to Day 1 
of trial treatment or within a time period that is less than the cycle length for the 
investigational treatment (whichever is shorter), or if the subject has any AE caused 
by the investigational treatment that has not recovered to Grade 1 or less
21. Previous anticancer treatment-related toxicities not recovered to baseline or Grade 0-1 
(except alopecia)
22. Subjects with any concurrent medical condition or disease that will potentially 
compromise the conduct of the study at the discretion of the investigators
23. Clinically significant third space fluid accumulation (despite the use of diuretics), e.g., 
moderate to large ascites requiring tapping or pleural effusion that either requires 
tapping or results in shortness of breath
24. Complete occlusion of the major portal vein or vena cava due to HCC. (The major 
portal vein is defined as the part of portal vein between the union of the splenic and 
superior mesenteric veins and the first bifurcation into the left and right vein)
6.2
Criteria for Randomization/Initiation of Treatment with the 
Investigational Medicinal Product 
The inclusion and exclusion criteria will be checked during Molecular Prescreening (confirmation 
of cMET status in Phase II only) and Clinical Screening. Eligible subjects will be enrolled prior to 
the initiation of MSC2156119J or sorafenib treatment and after verification that the subject fulfils 
all inclusion criteria without meeting any of the exclusion criteria.
6.3
Criteria for Subject Withdrawal
6.3.1
Withdrawal from the Trial
Subjects are free to discontinue the trial at any time without giving a reason. A subject must be 
discontinued in the event of withdrawal of consent.
If a subject fails to attend scheduled trial assessments, the investigator must determine the reasons 
and the circumstances as completely and accurately as possible.
In case of premature withdrawal from the trial, every effort should be made to complete the 
investigations scheduled for the last visit, focusing on the most relevant assessments. In any case, 
the appropriate electronic case report form (eCRF) section must be completed.
In case of withdrawal from the trial, it must be clearly stated if the subject is also withdrawing 
their consent from the post-treatment follow-up and survival assessments, which include the 
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collection of data on tumor assessment (if without documented PD), safety, survival and 
subsequent anticancer therapy.
6.3.2
Replacement of Discontinued Subjects
Subjects withdrawn in Phase Ib may be replaced if they are not fully evaluable for the assessment 
of the primary endpoints. “Not fully evaluable” is defined as:
!
Subjects who discontinue the trial prematurely during Cycle 1 for reasons other than a DLT. 
Such reasons could include, for example, withdrawal of consent, not meeting the eligibility 
criteria, noncompliance with follow up, early disease progression, or unrelated AEs.
!
Subjects who do not receive at least 80% (i.e., 17 treatment days) of planned cumulative doses 
of MSC2156119J during Cycle 1, for reasons other than AEs related to MSC2156119J or 
DLTs.
Subjects withdrawn in Phase II will not be replaced.
6.3.3
Withdrawal from Trial Therapy
The subject must be withdrawn from the IMP or sorafenib in the event of any of the following:
!
Therapeutic failure (i.e., oncologic emergency due to serious tumor progression or serious side 
effect) requiring urgent additional therapy
!
AEs if:
o
discontinuation of trial medication is desired or considered necessary by the 
investigator and/or the subject
o
dose delay time is more than 21 consecutive days at the lowest dose, as defined in 
Section 7.2.5
!
Pregnancy
! Use of a non-permitted concomitant drug, as defined in Section 7.5.2, where the predefined 
consequence is withdrawal of the trial therapy
!
Noncompliance with administration of the trial therapy, as defined in Section 7.2.5;
!
Documented progression of the disease
!
Initiation of any other anticancer treatment (including radiotherapy, surgery, or hormonal 
therapy)
If subjects withdraw without documented disease progression, e.g., due to clinical deterioration or 
AEs, every effort should be made to document objective progression even after discontinuation of 
treatment.
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6.4
Premature Discontinuation of the Trial
The whole trial may be discontinued prematurely in the event of any of the following:
! New information leading to unfavorable risk-benefit judgment of MSC2156119J, e.g., due to
o Evidence of inefficacy
(Note: evidence of inefficacy may arise from this trial or from other trials).
o Safety findings that preclude further continuation of the trial
(Note: unfavorable safety findings may arise from clinical or nonclinical examinations, e.g., 
toxicology).
!
Sponsor’s decision that continuation of the trial is unjustifiable for medical or ethical reasons
!
Poor enrollment making completion of the trial within an acceptable time frame unlikely
!
Discontinuation of development of MSC2156119J
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs) 
will be informed about the discontinuation of the trial in accordance with applicable regulations.
The whole trial may be terminated or suspended upon request of Health Authorities.
6.5
Definition of End of Trial
The end of the trial was defined as when 80% of the subjects either die or drop-out of the trial. 
Subjects who are on active treatment with MSC2156119J (or sorafenib) at the time of end of the 
trial will be offered further treatment with MSC2156119J (or sorafenib if reimbursement is not 
available in participating countries) and assessments as appropriate in case a potential benefit from 
further treatment is seen. However, under certain circumstances, subjects may be given the 
opportunity to participate in a rollover trial or the sponsor may terminate the trial early.
The sponsor will stop prescreening/enrollment following 40 TTP events (assessed by an IRC) or 
on 15 August 2017, whichever occurs first. Subjects who sign the Informed Consent Form (ICF)
prior to 15 August 2017 and undergo prescreening/screening after the enrollment stop date may 
still be randomized in the trial. Subjects who are currently receiving treatment may continue 
treatment after discussion with their Investigator. If the subject decides to continue treatment, they 
will continue on their originally randomized treatment, at their most recent dose according to the 
protocol. Safety monitoring and data collection will continue without modification through to the 
end of the trial.
7
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term “Investigational Medicinal Product” refers to the investigational drug undergoing trial, 
i.e., MSC2156119J (International Nonproprietary Name: tepotinib).
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7.1
Description of Investigational Medicinal Product
MSC2156119J, 
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-benzyl}-6-oxo-
1,6-dihydro-pyridazin-3-yl)-benzonitrile) mono-HCl, monohydrate, is supplied as 25 mg and 
100 mg film-coated tablets.
 
 
 
 
. All excipients used are of compendial grade. Supplier’s certificates show 
that there is no transmissible spongiform encephalopathy risk.
7.2
Dosage and Administration
Phase Ib
For each dose cohort, a fixed dose and administration will be applied. The assigned dose of 
MSC2156119J will be administered daily, with 25 mg and/or 100 mg film-coated tablets.
For “3+3” dose escalation cohorts, the first dose level will be 300 mg once daily, which is 1 level 
lower than the target dose of RP2D (500 mg, once daily) from the FIM trial. The second dose level 
will be 500 mg once daily.
Subjects will take their assigned doses of MSC2156119J orally, in the morning approximately at 
the same time, immediately after breakfast, with a full glass of water (approximately 200 mL), 
every day of each 21-day treatment cycle.
Subjects will be instructed to swallow the tablets whole and to avoid biting or breaking the tablets, 
or attempting to dissolve the tablets in water before taking them.
On days when PK samples are to be drawn, subjects should be instructed to attend the clinic in a 
fasted state, with no breakfast prior to taking the MSC2156119J dose. After a predose PK blood 
sample is drawn, the assigned dose of MSC2156119J should be taken following breakfast. No 
further food should be consumed until 2 hours after the dose (water is allowed).
Phase II
The dose of MSC2156119J will be the RP2D determined in Phase Ib.
Subjects who are randomized to MSC2156119J will take their assigned dose orally once daily,
approximately at the same time in the morning, immediately after breakfast with a full glass of 
water (approximately 200 mL), every day of each 21-day treatment cycle.
Subjects who are randomized to sorafenib will take two 200 mg tablets in the morning and 
two 200 mg tablets in the evening (800 mg total daily dose), taken on an empty stomach 1 hour 
before or 2 hours after ingestion of food with a full glass of water (approximately 200 mL), every 
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day of each 21-day treatment cycle. Subjects should be instructed to take sorafenib at 
approximately the same times each day.
On days when PK samples are to be drawn, subjects should be instructed to attend the clinic in a 
fasted state, with no breakfast and prior to taking the MSC2156119J dose. After a predose PK 
blood sample is drawn, the assigned dose of MSC2156119J should be taken following breakfast. 
No further food should be consumed until 2 hours after the dose (water is allowed).
7.2.1
Dose Escalation Assessment Process
The trial will adopt the sequential “3+3” dose escalation design. Two sequential dose cohorts of 
escalated dose levels (300 mg and 500 mg) with 3 subjects in each cohort will be conducted.
If  33% of subjects experience a DLT in the second dose cohort (500 mg), the next step will 
depend on the decision of the SMC based on the rules described below.
After 3 subjects at a given dose level have completed Cycle 1 (21 days), new enrollment to this 
trial will be paused and a full safety data set (all AEs, laboratory data, ECG data, and vital signs) 
and available PK data will be submitted to the SMC, which evaluates the data and confirms the 
DLT incidence. The details of this process will be described in the SMC Charter.
Decisions on dose escalation are based on the occurrence of DLT and the safety and PK data (see 
Section 7.2.2) during the Cycle 1 (21 days) and the decision criteria are as follows:
For the first dose cohort (300 mg):
!
If no subject experiences a DLT during Cycle 1 (21 days), dose escalation will proceed 
to the higher dose cohort (500 mg)
!
If 1 subject out of the first 3 experiences a DLT during Cycle 1 (21 days), 3 additional 
subjects will be enrolled at the same dose (300 mg)
o
If none of the additional 3 subjects experiences a DLT; dose escalation will proceed 
to the higher dose cohort (500 mg)
o
If 1 or more of the additional subjects experience a DLT, no additional subjects 
will be enrolled and the trial will be discontinued, unless there is evidence to 
support for further exploration of the potentially biologically active doses lower 
than 300 mg under the decision from the sponsor
!
If 2 or more subjects out of the first 3 experience DLT during Cycle 1 (21 days), no 
additional subjects will be enrolled and the trial will be discontinued, unless there is 
evidence to support for further exploration as specified above
If the SMC sees a potential safety concern from the AEs data other than DLT at the first dose 
cohort, 3 additional subjects may be enrolled at the same dose level under the decision from the 
SMC meeting. 
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For the second dose cohort (500 mg):
!
If no subject out of the first 3 experience DLT during Cycle 1 (21 days), 9 additional 
subjects will be enrolled at the same dose cohort (500 mg)
!
If 1 subject out of first 3 experience DLT during Cycle 1 (21 days), 3 additional subjects 
will be enrolled at the same dose cohort (500 mg)
o If none of the additional 3 subjects experiences a DLT; 6 additional subjects will 
be enrolled at the same dose cohort (500 mg) to have a total of 12 subjects
o If 1 or more of the additional 3 subjects experience a DLT, no additional subjects 
will be enrolled at this dose level, the next step will depend on the decision of the 
SMC
!
If 2 or more subjects out of the first 3 experience DLT during Cycle 1 (21 days), the 
next step will depend on the decision of the SMC
7.2.2
Definition of DLT 
The period of DLT observation is during Cycle 1 (21 days) for each subject. 
Using the National Cancer Institute’s (NCI)-Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0, DLT is defined as any of the following toxicities at any dose level and 
judged to be related to the trial treatment by the investigator and/or the sponsor:
!
Grade 4 neutropenia for more than 7 days
!
Grade U 3 febrile neutropenia for more than 1 day
!
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with non-traumatic bleeding
!
Grade U 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal 
treatment
!
Grade U 3 any non-hematological AE, except the aforementioned gastrointestinal events and 
alopecia; however, a DLT is defined specifically for the following cases:
o
Grade U 3 liver AE requiring a recovery period of more than 7 days to the baseline or to 
Grade 1 (or less) (This criterion is not limited to the liver function tests. Other liver AE 
e.g., jaundice or hepatic encephalopathy suggestive of liver failure should be also 
considered.)
o
Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis, either based 
on clinical or radiological signs will be considered as DLT. An isolated lipase and/or 
amylase elevation of  Grade 3 without clinical or radiological evidence of pancreatitis 
will not be classified as DLT. (For related topics, see below “Asymptomatic Pancreatic 
Enzyme Elevation”)
AEs assessed by the investigators to be exclusively related to the subject’s underlying disease or 
medical condition/concomitant treatment are not considered as DLT.
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Asymptomatic Pancreatic Enzyme Elevation
If an asymptomatic lipase/amylase elevation of Grade  3 occurs during Cycle 1, the subject will 
undergo clinical evaluation for the presence of signs and symptoms typical of acute pancreatitis 
and for other risk factors for pancreatitis. In addition, a computed tomography (CT) scan and/or 
magnetic resonance imaging (MRI) of the abdomen will be performed to assess the pancreas. The 
sponsor (or delegate) will be notified of the outcome of the CT/MRI. Dosing with MSC2156119J 
will continue during the evaluation period unless the clinical evaluation indicates pancreatitis. 
However, the continuation of MSC2156119J for the subject will be individually discussed with 
the sponsor (or delegate) on a subject by subject basis.
All cases of asymptomatic pancreatic enzyme elevations of Grade  3 will be reported as Adverse 
Event of Special Interest (AESI) (see Section 8.4.1.1) to the sponsor (or delegate) in an expedited 
fashion. 
If there are no clinical or radiological signs indicative of pancreatitis, dosing with MSC2156119J 
will continue and the pancreatic enzyme elevation occurring during Cycle 1 will not be classified 
as DLT. 
Asymptomatic lipase/amylase elevations may occur during or beyond Cycle 1, and 3 different 
scenarios are forecasted:
!
Persistent asymptomatic lipase/amylase elevation at the same grade of Grade  3
!
Recurrent asymptomatic elevation of Grade  3, after an initial Grade  3 elevation with 
subsequent resolution
!
Asymptomatic lipase/amylase elevation of Grade  3 with persistent elevation at the same 
grade, followed by subsequent further increase in grade
In all cases, the subject will undergo clinical evaluation for the presence of signs and symptoms 
typical of acute pancreatitis and for other risk factors for pancreatitis. A gastrointestinal consult 
should be requested and additional investigations (e.g., repeated abdominal CT scan) should be 
considered, as appropriate. The case will be discussed with the sponsor (or delegate). Treatment 
with MSC2156119J may be continued during the evaluation period, at the discretion of the treating 
physician and depending on the circumstances of the individual case. 
If there is no clinical or radiological evidence of pancreatitis, treatment with MSC2156119J should 
be continued, particularly if there may be a potential benefit from treatment for the individual 
subject. Evaluation of potential clinical benefit will be based on evidence from the literature, 
preclinical models and/or current experience with MSC2156119J in the subject or other subjects 
with this tumor type. Otherwise, treatment with MSC2156119J should be discontinued.
7.2.3
MTD/RP2D Definition Process
For determination of the MTD/RP2D of MSC2156119J in Asian subjects, relevant data for the 
primary endpoint will be presented to the SMC.
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MTD
In the “3+3” dose escalation method, the MTD is defined as the next lower dose than the dose at 
which a DLT occurs in > 1 out of 3 or U 2 out of 6 subjects. This trial will also apply this method. 
For molecularly targeted oncology drugs in oncology, it may not always be possible or necessary 
to determine an MTD. 
RP2D
The FIM trial specified that the SMC could recommend an RP2D if it was not possible or necessary 
to reach an MTD in a given regimen on the basis of the review of the cumulative safety, PK, Pd,
and clinical data. The definition of an RP2D is then based on the following criteria and 
considerations:
(A)
Preclinical PK/Pd model
Establishment of a nonclinical PK/Pd model that will link plasma concentrations, target inhibition 
and antitumor activity in c-Met dependent xenograft models, and that will determine expectations 
for an active dose range in human.
(B)
Review of human PK data
Review of human PK data to determine at what dose level the active dose range will be reached in 
 90% of subjects.
7.2.4
Criteria for Additional Treatment Cycles
Subjects will repeat the 21-day treatment cycle after completion of Cycle 1 if the disease is not 
progressing.
To qualify for continued treatment beyond Cycle 1, all of the following criteria must be fulfilled:
!
A subject does not show evidence of disease progression
!
A subject and the investigator consider it is in the subject’s best interest to continue treatment
!
A subject does not meet any of the criteria for withdrawal in Section 6.3.
Once the treatment with MSC2156119J beyond Cycle 1 is initiated, the subject can repeat the 21-
day treatment cycle without limitation, as long as all the criteria above remain fulfilled.
7.2.5
Dose Adjustment and Missed Dose
Missed doses of trial treatment will not be made up unless the subject is seen to vomit the entire 
tablet immediately after administration of the study drug. An administration time delay Z 12 hours 
compared to the scheduled administration time is permitted; however, if the time delay is 
> 12 hours, study drug should not be administered on the current day. In Phase Ib and Phase II, 
subjects who miss more than 21 consecutive days of trial treatments for non-medical reasons are 
considered non-compliant and should be withdrawn from trial treatments (see Section 6.3.3).
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As for dose adjustment, subjects will remain on their starting dose of MSC2156119J throughout 
the trial with the exception of dose modification due to tolerability (applicable for Phase Ib and 
Phase II). 
Subjects who miss more than ~20% of doses planned during Cycle 1 (i.e., 4 days) for reasons other 
than adverse drug reactions or DLTs will not be fully evaluable for the assessment of the primary 
endpoints of Phase Ib; these subjects will be replaced for assessment of DLT. The overall safety 
assessment will be performed based on the full data set from all subjects who take at least 1 dose 
of MSC2156119J.
Subjects are permitted to undergo dose modification to ensure MSC2156119J is well tolerated at 
the scheduled dose levels. For the Phase II study, a one-level dose schedule will be applied for 
dose modification, i.e., to the next dose level lower than the RP2D. If a subject still does not tolerate 
the permitted lower dose, the subject will be withdrawn from the study. Assuming that the RP2D 
is 500 mg daily, the lower dose strength to adjust to in case of toxicity is 300 mg. The maximum 
permitted continuous dosing delay time is 21 days.
AEs assessed by the investigators to be exclusively related to the subject’s underlying disease or 
medical condition/concomitant treatment are not applied for the guideline of dose modification.
The following dose modification guideline for MSC2156119J is recommended. However the 
investigators could otherwise modify the dosage based on clinical circumstances on a case by case 
basis. Under such circumstance, the investigators should notify the sponsor case by case and 
provide the reason to the sponsor.
Under the following circumstances, the dose should be interrupted temporarily until AEs recover
to Grade 1 (or less) or baseline. Subjects can be rechallenged at the next lower dose level; the dose 
should be stopped as soon as the investigator becomes aware of the following AEs:
!
Grade 4 neutropenia for more than 7 days
!
Grade U 3 febrile neutropenia for more than 1 day
!
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding
!
Grade U 3 uncontrolled nausea/vomiting and/or diarrhea despite adequate and optimal 
treatment for more than 3 days
!
Grade U 3 non-hematological AE, except the aforementioned gastrointestinal events and 
alopecia; however, the following cases are specifically defined:
o
Grade U 3 liver AE requiring a recovery period of more than 7 days to the baseline 
or to Grade 1 (or less)
o
Grade  3 lipase and/or amylase elevation with confirmation of pancreatitis (for 
related topics, see below “Asymptomatic Pancreatic Enzyme Elevation”)
!
Recurrence of Grade U 2 AEs after rechallenging at the same dose level despite adequate and
optimal treatment
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Under the following circumstances, the dosing could be continued with adequate and optimal 
supportive treatment:
!
Grade 1 AE
!
Grade 2 AE that could be tolerated well
!
Asymptomatic lipase and/or amylase elevation, i.e., without confirmation of pancreatitis
In the event of a subject experiencing Hepatitis B virus (HBV) or Hepatitis C virus (HCV) 
reactivation (see Section 7.5.3.1), the following dose modification guidelines should be followed:
! HBV reactivation:
o
Provide antiviral treatment and/or adjust current antiviral treatment
o
Interrupt MSC2156119J until HBV DNA resolves to Z baseline levels

If resolution takes longer than 21 days, discontinue MSC2156119J

If resolution is within 21 days, MSC2156119J can be resumed at a 
minus 1 dose level
! HCV reactivation: Discontinue MSC2156119J
For the other circumstances not outlined aforementioned, the dose could be interrupted
temporarily (for a maximum of 21 days) until recovery to Grade 1 (or less) or baseline and the 
same dose could be restarted after recovery. The dose should be stopped as soon as the 
investigator becomes aware of the AE.
The investigators should modify the dose of sorafenib based on the clinical circumstance, taking 
references to the description in the Package Insert. The Package Insert will be provided as a 
separate document. The permitted maximum time for continuous dose interruption of sorafenib is 
also 21 days. 
7.2.6
Intrasubject Dose Escalation
Intrasubject dose escalation is not allowed in this trial and each subject will stay on the assigned 
dose level (except for dose modification due to tolerability) throughout his/her treatment period 
unless there is a considerable reason to allow intrasubject dose escalation. Any intrasubject dose 
escalation must be agreed by the sponsor.
7.3
Assignment to Treatment Groups
Subject allocation
Phase Ib is a single arm trial to be conducted at selected sites in mainland China, South Korea, and 
Taiwan. Subjects will be assigned sequentially to the available dose cohort.
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Phase II is a randomized trial to be conducted at 45 to 55 sites in mainland China, South Korea, 
Taiwan, and other Asian countries. Randomization will be performed centrally by using an 
interactive voice response system (IVRS).
Subject Number
Subject numbers will be composed of 16 digits:
!
The first 9 digits will represent the trial number
!
The next 3 digits will represent the site number
!
The last 4 numbers will be the sequential order in which subjects are enrolled into the trial by 
signing the main ICF (beginning with 0001)
Subject numbers will not be reassigned to other subjects or reused in this trial. If a subject is 
replaced, the replacement will be enrolled with a unique subject number.
7.4
Other Drugs to be used in the Trial
In addition to the treatment with MSC2156119J, commercially available sorafenib is also to be 
administered to the subjects during the course of the Phase II. Sorafenib will be supplied as red, 
round film coated tablet, containing 200 mg sorafenib (as the tosylate) and the following 
excipients: iron oxide red, titanium dioxide, sodium laurylsulfate, magnesium stearate, 
hypromellose, cellulose microcrystalline, macrogol, and crosscarmellose sodium; however, the 
actual appearance and composition of the product may depend on the respective marketed product 
sourced for the participating countries.
7.5
Concomitant Medications and Therapies
7.5.1
Permitted Medicines
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary for the subjects’ welfare and will not interfere with the trial medication may be given at 
the investigator’s discretion.
The investigator will record all concomitant medications taken by the subject during the trial, from 
the date of signature of the main informed consent, in the appropriate section of the eCRF.
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration and indication of each drug.
The following are permitted:
!
Oral antivirals for chronic hepatitis are permitted before and during the study. The prescription 
of these agents for subjects with chronic hepatitis during the study is recommended based on 
the clinical guidelines
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!
Ongoing interferon therapy for hepatitis started before screening is permitted
!
Concomitant medications that have a narrow therapeutic window and are known to be 
transported by P-gp (e.g., rivaroxaban, apixaban, ranolazine, talinolol, digoxin), BCRP (e.g., 
rosuvastatin), or OCT1 are permitted, but should be used with caution (refer to 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/default.htm for examples of in vitro, in vivo, and clinical substrates for P-gp 
and BCRP)
!
Concomitant medications that are known to inhibit P-gp (e.g., itraconazole, telaprevir, 
clarithromycin, ketoconazole, and conivaptan) are permitted but should be used with caution
(refer 
to 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/default.htm for examples of clinical inhibitors for P-gp and BCRP)
!
Supportive treatment, e.g., bisphosphonates, agents for improving appetite, if initiated prior to
Day 1 of trial treatment, it is allowed to continue. Change in dose/schedule on study is 
discouraged. Initiation of biphosphates with prophylactic purpose during study treatment 
should be avoided.
7.5.2
Non-Permitted Medicines
Any additional concomitant therapy that becomes necessary during the trial and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration, and indication of each drug.
The following are not permitted during the trial:
!
Drug(s) for which the package insert/Summary of Product Characteristics includes a 
contraindication for P-gp (e.g., dabigatran, aliskiren, colchicine), BCRP, and/or OCT1 
inhibiting 
drugs 
must 
not 
be 
combined 
with 
MSC2156119J
(refer 
to 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/default.htm
for examples of clinical inhibitors for CYP3A-mediated 
metabolisms)
!
Drug(s) that are known to induce P-gp and thereby may decrease the efficacy of MSC2156119J
(e.g., avasimibe, carbamazepine, phenytoin, rifampin, St John’s Wort)
(refer to 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIntera
ctionsLabeling/default.htm
for examples of clinical inhibitors for CYP3A-mediated 
metabolisms)
!
Initiation of new interferon therapy
!
Traditional Chinese Medicine with an approved anticancer indication
!
Any other cancer therapy, including chemotherapy or local regional treatments, with any 
investigational product other than the MSC2156119J and sorafenib, as defined in this protocol
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!
Prophylactic granulocyte colony-stimulating factor or granulocyte macrophage colony-
stimulating factor
!
Experimental or systemic anticancer therapy, except for localized radiotherapy for pain control 
provided the localized radiotherapy does not compromise tumor assessments of target lesions
Use of non-permitted medicines for any reason must result in withdrawal of the subject from this
trial.
7.5.3
Other Trial Considerations
7.5.3.1
Guidelines for Subjects with Hepatitis B or Hepatitis C
Subjects with concurrent hepatitis B or hepatitis C infection are permitted to participate in the trial, 
provided they meet the eligibility criteria. The safeguards outlined below should be followed in 
order to ensure that subjects with concurrent hepatitis infection receive appropriate monitoring and 
care. See also Section 8.4.3.5.
In order to document baseline virology status, all subjects will undergo the following testing at 
baseline (see Section 8.1.2):
! Hepatitis B virus serology (2 mL serum sample) i.e., hepatitis B surface antigen (HBsAg), 
hepatitis B core antibodies, hepatitis B surface antibodies (HBsAb), hepatitis B e antigen 
(HBeAg) and hepatitis B e antibodies
! Hepatitis B virus DNA (2 mL plasma sample)
! Hepatitis C virus RNA using polymerase chain reaction (HCV RNA-PCR) (2 mL plasma 
sample).
Instructions on sample collection and processing will be provided in the laboratory manual.
Thereafter, HBV DNA, HBV serology, and HCV RNA-PCR will be monitored according to the 
subject’s baseline status and previous HBV/HCV history every 3 cycles during the trial and at the 
end of treatment visit, as shown in Table 1. See also Section 8.1.3.5.
Table 1:
Monitoring of Subjects According to Baseline Virology Status
Subject Status at Baseline
Parameters to be Monitored
Known HBV history (despite negative HBV DNA at Baseline)
HBV DNA and serology
Positive HBV DNA
HBV DNA and serology
Positive HBV serologya
HBV DNA and serology
Known HCV history (despite negative HCV RNA at Baseline)
HCV RNA-PCR
Positive HCV RNA
HCV RNA-PCR
Abbreviations: DNA, deoxyribonucleic acid; HBV, hepatitis B virus; HCV, hepatitis C virus; PCR, polymerase chain reaction; 
RNA, ribonucleic acid.
a.
Except for positive hepatitis B surface antibodies after vaccination.
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If necessary, appropriate antiviral treatment should be provided to subjects prior to the first dose 
of trial treatment and/or during trial treatment (refer to local guidelines and to: American
Association for the Study of Liver Diseases [AASLD] Guidelines for Treatment of Hepatitis B, 
2015 and Hepatitis C Guidance: AASLD-Infectious Diseases Society of America
Recommendations for Testing, Managing, and Treating Adults Infected With Hepatitis C Virus, 
2015).
Hepatitis B Virus and Hepatitis C Virus Reactivation
Hepatitis B virus and HCV reactivation are defined, according to the subject’s baseline virology 
status, as shown in Table 2.
Table 2:
Hepatitis B Virus and Hepatitis C Virus Reactivation
Subject Status at Baseline
Definition of Reactivation
Positive HBV DNA
1 log increase in HBV DNA 
Known history of chronic HBV infection; negative HBV DNA
HBV DNA become measurable
Known history of chronic HCV infection; negative HCV RNA
HCV RNA become measurable
Abbreviations: DNA, deoxyribonucleic acid; HBV, hepatitis B virus; HCV, hepatitis C virus; RNA, ribonucleic acid.
In the event of a subject experiencing HBV or HCV reactivation according to the definition in 
Table 2, the following dose modification guidelines should be followed:
! HBV reactivation
o
Provide antiviral treatment and/or adjust current antiviral treatment
o
Interrupt MSC2156119J until HBV DNA resolves to Z baseline levels

If resolution takes longer than 21 days, discontinue MSC2156119J

If resolution is within 21 days, MSC2156119J can be resumed at a 
minus 1 dose level 
! HCV reactivation: Discontinue MSC2156119J
In addition, HBV or HCV reactivation should be reported as a Grade 3 AE (CTCAE version 4.0 
Infection and Infestation/Hepatitis Viral) unless the investigator considers it is life-threatening, in 
which case a Grade 4 event should be reported (see Section 8.4.1).
7.6
Packaging and Labeling
Packaging and labeling will be in accordance with Manufacture of Investigational Medicinal 
Products (Annex 13, Volume 4), applicable local regulatory requirements, and applicable Good 
Manufacturing Practice (GMP) Guidelines.
MSC2156119J tablets will be supplied in aluminum-aluminum blisters. A blister sheet contains 
tablets of 25 mg and/or 100 mg MSC2156119J suitable to support the dose escalation setting of 
the trial. The blisters will be packed in a suitable carton box which is labeled with (but not limited 
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to) the following required information: trial number, number of tablets per box, storage condition, 
the word “for clinical trial use”, batch number, and the sponsor’s name.
Sorafenib is a marketed product and will be provided by the sponsor.
7.7
Preparation, Handling and Storage
The pharmacy or designee will receive MSC2156119J and sorafenib labeled and packaged 
according to the local regulatory requirements and the storage requirements. MSC2156119J and 
sorafenib are formulated as tablets, and are ready for use. The responsible pharmacist will dispense 
the necessary amount of the MSC2156119J or sorafenib until the next visit to each subject. 
Detailed guidance will be provided from the sponsor in a manual of operations.
The drug supplies will be recorded in a drug inventory and stored in a locked cabinet, protected 
from environmental extremes until used in the trial.
 
 
7.8
Investigational Medicinal Product Accountability
The storage manager at the trial site who will be assigned by the head of the trial site is responsible 
for ensuring accountability for the IMP, including reconciliation of drugs and maintenance of drug 
records.
After the conclusion of the trial contract with the site, the sponsor (or designee) may deliver the 
IMP to the storage manager at the trial site.
!
Upon receipt of IMP, the investigator (or designee) will check for accurate delivery and 
acknowledge receipt by signing (or initialing) and dating the documentation provided by the 
sponsor and returning it to the sponsor. A copy will be retained for the investigator file.
!
The dispensing of the IMP will be carefully recorded on the appropriate drug accountability 
forms provided by the sponsor/contract research organization (CRO) and an accurate 
accounting will be available for verification by the sponsor/CRO monitor at each monitoring 
visit.
!
IMP accountability records will include:
o Confirmation of IMP delivery to the trial site
o The inventory at the site of IMP provided by the sponsor and prepared at the site
o The use of each dose by each subject
o Disposition of unused IMP
o Dates, quantities, batch numbers, expiry dates, and (for IMP prepared at the site) 
formulation, as well as the subjects’ trial numbers
!
The storage manager should maintain records that adequately document:
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o That the subjects were provided the doses specified by the clinical trial 
protocol/amendment(s)
o That all IMP provided by the sponsor was fully reconciled
Unused IMP must not be discarded or used for any purpose other than the present trial. IMP that 
has been dispensed to a subject must not be redispensed to a different subject.
The sponsor/CRO monitor (or delegate) will periodically collect the IMP accountability forms and 
will check all returns (both unused and used containers) before authorizing their destruction by the 
trial site.
7.9
Assessment of Investigational Medicinal Product Compliance
Each subject will record on a diary card the number and dosage of IMP taken daily and the time 
of taking the IMP daily. This diary card will be returned to the investigator site at each visit.
Subjects should be instructed to bring with them to each visit both opened and unopened IMP 
packages, in order to allow the assessment of compliance with trial treatment. The IMP 
administration must be recorded in the eCRF, as applicable.
7.10
Method of Blinding
Not applicable; this is an open label trial.
7.11
Emergency Unblinding
Not applicable.
7.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in the clinical trial 
protocol. Any overdose must be recorded in the trial medication section of the eCRF.
For monitoring purposes, any case of overdose – whether or not associated with an AE (serious or 
non-serious) – must be reported to the sponsor’s Global Drug Safety department in an expedited 
manner using the appropriate reporting form (see Section 8.4.1.4).
In case of an overdose that needs to be treated, the investigator should use his/her clinical judgment 
for the management of the overdose.
7.13
Medical Care of Subjects after the End of Trial
After a subject has completed the trial or has withdrawn early, usual treatment will be 
administered, if required, in accordance with the trial site’s standard of care and generally accepted 
medical practice, and depending on the subject’s individual medical needs.
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8
Trial Procedures and Assessments
Trial periods and assessments apply to both Phase Ib and Phase II, except where noted.
8.1
Schedule of Assessments
A chart of all treatment and assessments is presented in Appendix H (Phase Ib) and Appendix I
(Phase II). Details of the assessments performed are provided in their respective sections.
Assessments are performed on an outpatient basis. However, hospitalization for at least the first 
3 days (Days 1 to 3) of Cycle 1 may be needed. In addition, if clinically indicated, subjects may 
be hospitalized for assessments at the discretion of the investigator.
The AE reporting period for safety surveillance and a concomitant medication/procedure recording 
period begins when the subject first signs the main informed consent and continues through the 
post-treatment period defined in Section 8.1.5.
In the below subsections 8.1.1 to 8.1.6, the assessment schedule other than AEs and concomitant 
medication/procedure are presented.
8.1.1
Informed Consent
Prior to performing any trial assessments not part of the subject’s routine medical care, the 
investigator will ensure that the subject or the subject’s legal representative has provided written 
informed consents according to the procedure described in Section 10.2.
In Phase II, subjects will have a Molecular Prescreening period during which their MET status will 
be determined (see Section 8.1.2). A separate prescreening informed consent is required to permit 
the collection, shipment and testing of archival or fresh tumor samples prior to the planned Clinical 
Screening activities. Demographic data and disease history may also be collected during Molecular 
Prescreening (subject to the provision of informed consent).
8.1.2
Screening Period
During screening, the subject must sign the prescreening (Phase II only) and the main ICF before 
any trial procedures are performed.
Molecular Prescreening (Phase II only)
In Phase II, subjects will have a Molecular Prescreening period prior to Clinical Screening during 
which (subject to the provision of informed consent) their MET status will be determined in order 
to confirm their suitability for the trial, and demographic data and disease history will also be 
collected.
Screening (Phase Ib)/Clinical Screening (Phase II)
The Screening/Clinical Screening period must be completed for all subjects within the 14 days 
prior to the initiation of study treatment. Screening/Clinical Screening will include evaluation of
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laboratory parameters (including serum pregnancy test if applicable), medical history, concomitant 
medication/procedure, and tumor imaging to check subject eligibility, plus demographic data and 
disease history if not already collected at Molecular Prescreening (Phase II only). The laboratory 
analyses for the subject eligibility check during Screening/Clinical Screening will be performed 
by a local laboratory (although a duplicate sample will also be sent to the central laboratory) (see 
Section 8.4.3 for full details).
Assessments for the screening period of Phase Ib include:
!
Eligibility evaluation (review of inclusion/exclusion criteria)
!
Demography (date of birth, gender, race), height
!
Medical history
o
Smoking status and alcohol use
!
Physical examination/weight
!
ECOG PS
!
Vital signs (body temperature, respiratory rate, blood pressure, and heart rate)
!
12-lead ECG
!
Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count, differential, 
and platelet count)
!
Coagulation (prothrombin time [PT], activated partial thromboplastin time [aPTT], and 
international normalized ratio [INR])
!
Chemistry (blood nitrogen urea [BUN], creatinine, AST, ALT, gamma-glutamyl 
transpeptidase [GGT], total bilirubin [including direct fraction if total bilirubin is abnormal], 
lipase, amylase, total protein, albumin, alkaline phosphatase, sodium, potassium, calcium, 
magnesium, and glucose)
!
Urinalysis (dipstick followed by microscopic examination if abnormal results)
!
Hepatitis B virus serology: HBsAg, hepatitis B core antibodies, HBsAb, HBeAg and 
hepatitis B e antibodies
!
Hepatitis B virus DNA (viral load)
!
HCV RNA-PCR
Note: Hepatitis markers (serology and viral load) for HBV and HCV are part of the baseline 
assessments and can be collected either during Screening/Clinical Screening or at Cycle 1 Day 1, 
if not done during Screening/Clinical Screening.
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!
Serum pregnancy test for female subjects of childbearing potential, including those who have 
had tubal ligation
!
Complete tumor assessment of all lesions by radiographic or other modality (using 
RECIST v 1.1). Computed tomography or MRI of the chest, abdomen, and pelvis to evaluate 
disease in these locations. CT/MRI of the head for subjects who are suspected to have CNS 
metastases
!
Serum AFP
Assessments for Phase II include all assessments in Phase Ib plus recording of ethnicity and FACT 
Hepatobiliary Symptom Index 8 (FHSI-8) (see Appendix F). The pretreatment tumor biopsy (fresh 
biopsy or archived material) is mandatory for Phase Ib and Phase II.
8.1.3
Treatment Period
MSC2156119J (Phase Ib and Phase II) will be administered once daily over a 21-day cycle and 
sorafenib (Phase II) will be administered twice daily over a 21-day cycle, which may repeat until 
disease progression (as determined by the investigator), intolerable toxicity, or withdrawal from 
the trial.
For Phase Ib, scheduled visits during the treatment period will occur on Days 1, 2, 8, and 15 of 
Cycle 1; Days 1, 8, and 15 of Cycle 2; and Day 1 of Cycles U 3. Note: the 24-hour postdose PK 
sample from Day 1 and Day 15 are the predose samples from Day 2 and Day 16, respectively. For 
Phase II, scheduled visits during the treatment period will occur on Days 1, 8, and 15 of Cycle 1; 
Days 1 and 8 of Cycle 2; and Day 1 of Cycles U 3.
In Sections 8.1.3.1 to 8.1.3.5, the assessment schedule other than physical examination/weight, 
vital signs, hematology, coagulation, chemistry, AEs, and concomitant medication/procedure are 
presented, as these assessments will be performed at each scheduled visit during the treatment 
period (with the exception of vital signs, as noted below).
In addition, subjects who have a known history of HBV (despite being negative for HBV DNA at 
baseline), or who are positive for HBV DNA at baseline, or have positive HBV serology will 
continue to be monitored for HBV DNA and serology every 3 cycles. Similarly, subjects who have 
a known history of HCV (despite being negative for HCV RNA at baseline) or who are positive 
for HCV RNA at baseline will continue to be monitored for HCV RNA-PCR throughout the trial. 
See Section 7.5.3.1.
8.1.3.1
Cycle 1, Day 1
On Cycle 1, Day 1 of Phase Ib, the following assessments/treatment administrations will occur: 
!
Dispensing of study drug
!
Tumor biopsy (excluding fine needle aspiration and cytology samples). Undergoing paired 
tumor biopsy is not mandatory, but highly recommended for subjects with accessible tumors: 
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the paired tumor biopsy will be performed before the first treatment (i.e., during screening or 
on Cycle 1, Day 1 prior to the first dose of trial treatment), and anytime between Cycle 1, 
Day 15 and the beginning of Cycle 3 (optional, will be collected after subjects have signed a
separate ICF)
!
Triplet 12-lead ECG recordings with 2-minute intervals (± 1 minute) after at least 5 minutes 
rest in supine position at predose (within 60 minutes prior to dose) and 4 hours (± 12 minutes)
postdose. ECGs should be performed within 10 minutes prior to PK sampling at time points 
where both assessments are performed
!
PK blood samples. Samples will be taken predose (within 60 minutes prior to dose) and at 
0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose. Note: the 24-hour postdose sample from Day 1
and Day 15 are the predose samples from Day 2 and Day 16, respectively. Postdose PK 
samples should be taken within ± 5% of the scheduled assessment time, e.g., the 4-hour 
postdose sample should be obtained at 4 hours ± 12 minutes
!
!
The following assessments will be performed only if screening/last assessments were performed 
> 7 days prior to Day 1:
!
ECOG PS
!
Urinalysis (dipstick followed by microscopic examination if abnormal results)
!
Serum AFP
Assessments for Cycle 1, Day 1 of Phase II include all assessments in Phase Ib with the following 
changes:
!
Randomization by IVRS
!
PK blood samples. Samples will be taken predose (within 60 minutes prior to dose) and 4 hours 
postdose in the MSC2156119J arm. At selected sites, PK sampling will be performed predose 
(within 60 minutes prior to dose) and at 1.5, 3.5, and 6.5-8 hours postdose. Postdose PK 
samples should be taken within ± 5% of the scheduled assessment time, e.g., the 4-hour 
postdose sample should be obtained at 4 hours ± 12 minutes
!
FHSI-8
!
PRO (FACT-HP) (see Appendix G)
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8.1.3.2
Cycle 1, Day 15
On Cycle 1, Day 15 of Phase Ib, the following assessments/treatment administrations will occur: 
!
Tumor biopsy (excluding fine needle aspiration and cytology samples). Undergoing paired 
tumor biopsy is not mandatory, but highly recommended for subjects with accessible tumors: 
the paired tumor biopsy will be performed before treatment at screening or on Cycle 1, Day 1
and anytime between Cycle 1, Day 15 and beginning of Cycle 3 (optional, will be collected 
after subjects have signed a separate ICF). A predose PK is recommended to be taken on the 
day of the second biopsy.
!
A single 12-lead ECG recording after at least 5 minutes rest in supine position at predose
(within 40 minutes prior to dose) and triplet 12-lead ECG recordings with 2-minute intervals 
(± 1 minute) at 4 hours (± 12 minutes) postdose. ECGs should be performed within 10 minutes 
prior to PK sampling at time points where both assessments are performed
!
PK blood samples (samples will be taken predose [trough value, within 30 minutes prior to 
dose] and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose). Note: the 24-hour postdose sample 
from Day 1 and Day 15 are the predose samples from Day 2 and Day 16, respectively. Postdose 
PK samples should be taken within ± 5% of the scheduled assessment time, e.g., the 4-hour 
postdose sample should be obtained at 4 hours ± 12 minutes
Assessments for Cycle 1, Day 15 of Phase II include all assessments in Phase Ib except for PK 
blood samples, 4-hour postdose ECG, and vital signs.
8.1.3.3
Cycle 2, Day 1
Assessments for Cycle 2, Day 1 of Phase Ib include all assessments from Cycle 1, Day 1 as 
defined in Section 8.1.3.1, with the following changes:
!
Single 12-lead ECG recording after at least 5 minutes rest in supine position at predose (within 
60 minutes prior to dose) only
!
No tumor biopsy
!
No PK blood sample
!
 blood sample
Assessments for Cycle 2, Day 1 of Phase II include all assessments from Cycle 1, Day 1, with the 
following changes:
!
No randomization by IVRS
!
No tumor biopsy
!
 blood sample
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!
Triplet 12-lead ECG recordings with 2-minute intervals (± 1 minute) after at least 5 minutes 
rest in supine position at predose (within 40 minutes prior to dose) and 4 hours (± 12 minutes) 
postdose. ECGs should be performed within 10 minutes prior to PK sampling at time points 
where both assessments are performed
!
PK blood samples. Samples will be taken predose (trough value, within 30 minutes prior to 
dose) and at 4 hours postdose in the MSC2156119J arm. At selected sites, PK sampling will 
be performed predose (trough value, within 30 minutes prior to dose) and at 2 and 6-8 hours 
postdose. Postdose PK samples should be taken within ± 5% of the scheduled assessment time, 
e.g., the 4-hour postdose sample should be obtained at 4 hours ± 12 minutes
 
 
 
8.1.3.4
Cycle 2, Day 15
Assessments for Cycle 2, Day 15 of Phase Ib will be the same as the assessments for Cycle 1, 
Day 15, as defined in Section 8.1.3.2, except for tumor biopsy, vital signs, 12-lead ECG, and PK 
blood samples.
8.1.3.5
Cycles ; 3, Day 1
Assessments for Cycles U 3, Day 1 of Phase Ib include all assessments from Cycle 1, Day 1, 
except a tumor biopsy will not be taken, and 
 blood samples will not be drawn. 
 
 
 In 
addition, a complete tumor assessment of all lesions by radiographic or other modality (using 
RECIST v 1.1) identified at the screening visit will be performed predose on, or up to 5 days prior 
to, Day 1 of Cycles 3, 5, 7, 9, 11, 13, and every 4 cycles thereafter until disease progression, 
starting a new anti-tumor therapy, or death. 
Assessments for Cycles U 3, Day 1 of Phase II include all Cycles U 3, Day 1 assessments in 
Phase Ib. 
In addition, HBV DNA, HBV serology, and HCV RNA-PCR will be monitored every 3 cycles 
according to the subject’s baseline status and previous HBV/HCV history (see Section 7.5.3.1), 
FHSI-8 will be assessed, FACT-HP will be assessed on Cycle 5, Day 1.
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8.1.4
End of Treatment Visit
At the subject’s discontinuation of the trial medication (due to disease progression [as assessed by 
the investigator], intolerable toxicity, or withdrawal), the following evaluations, which include
safety/tumor assessment, will be performed:
!
Tumor biopsy to be taken at the time of progression on the last day of drug application
(excluding fine needle aspiration and cytology samples; optional, will be collected after 
subjects sign a separate ICF). Whenever possible, the biopsy taken at progression for 
determination of the MET status should be taken from the progressing lesion, provided that the 
lesion is accessible and there are no medical or safety reasons precluding a biopsy of the 
progressing lesion.
!
Physical examination/weight
!
ECOG PS
!
AEs
!
Concomitant medication/procedure
!
Vital signs (body temperature, respiratory rate, blood pressure, and heart rate)
!
12-lead ECG
!
Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count, differential, 
and platelet count)
!
Coagulation (PT, aPTT, and INR)
!
Chemistry (BUN, creatinine, AST, ALT, GGT, total bilirubin [including direct fraction if total 
bilirubin is abnormal], lipase, amylase, total protein, albumin, alkaline phosphatase, sodium, 
potassium, calcium, magnesium, and glucose)
!
Urinalysis (dipstick followed by microscopic examination if abnormal results)
!
Complete tumor assessment of all lesions by radiographic or other modality if previous 
assessment is more than 6 weeks old (using RECIST v 1.1)
!
Serum AFP
!
!
HBV DNA and serology (subjects with a known history of HBV, or who are positive for HBV 
DNA at baseline, or have positive HBV serology only)
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!
HCV RNA-PCR (subjects with a known history of HCV or who are positive for HCV RNA at 
baseline only)
Assessments for the end of treatment visit in Phase II include all assessments in Phase Ib. In 
addition, FHSI-8 and PRO (FACT-HP) will be assessed.
NOTE: end of treatment ECG and laboratory assessments (hematology, coagulation, chemistry, 
urinalysis, and hepatitis markers) are not required for subjects with previous ECG and laboratory 
assessments, respectively, within 7 days of the end of treatment visit.
8.1.5
Post-Treatment Follow-Up Visit
Study drug post-treatment follow-up visit will be performed within 30 ± 3 days after the last dose 
for subjects who discontinue the trial medication, even if the subject starts a new antineoplastic 
therapy. Subjects who terminated their treatment early will be encouraged to return to the clinic 
for the post-treatment follow-up visit.  If an end of trial visit is not possible, the reason should be 
clearly documented in the subject’s medical record.
The following assessments will be performed:
!
AEs
!
Concomitant medication/procedure
!
Physical examination/weight
!
ECOG PS
!
Vital signs (body temperature, respiratory rate, blood pressure, and heart rate)
!
12-lead ECG
!
Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count, differential, 
and platelet count)
!
Coagulation (PT, aPTT, and INR)
!
Chemistry (BUN, creatinine, AST, ALT, GGT, total bilirubin [including direct fraction if total 
bilirubin is abnormal], lipase, amylase, total protein, albumin, alkaline phosphatase,  sodium,
potassium, calcium, magnesium, and glucose)
!
Urinalysis (dipstick followed by microscopic examination if abnormal results)
Assessments for the post-treatment follow-up visit in Phase II include all assessments in Phase Ib. 
In addition, FHSI-8 will be assessed.
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Subjects who are discontinued from the trial without documented progressive disease, for example, 
due to unacceptable toxicity or clinical deterioration, should perform the tumor assessment at 6-
week intervals until Cycle 13 and 12-week intervals (4 cycles) after Cycle 13 until disease 
progression, starting a new therapy, or death.
8.1.6
Survival Follow-up Assessments
Survival data (subject survival and anticancer therapies) in Phase Ib and Phase II will be collected 
every 3 months (± 2 weeks) after the last dose of study drug. Subjects will be contacted by 
telephone.  
8.2
Demographic and Other Baseline Characteristics
Prior to the first dosing (Cycle 1, Day 1), all subjects will have screening and baseline 
examinations to ensure their eligibility for this trial. Before any examination, they will be informed 
about the trial aims, procedures, and possible risks of MSC2156119J and the investigator will 
ensure that the subject or the subject’s legal representative has provided written informed 
consent(s), according to the procedure described in Section 10.2. 
The following screening and baseline assessments will be performed:
! Demographics 
Demographic data will be collected, including date of birth, race, and gender. Height will also 
be recorded. Ethnicity will be recorded in Phase II only.
! Medical History
The medical history will include: 
o
The starting and ending dates or duration of the medical condition/disease
o
Concomitant illnesses at screening, including chronic diseases or abnormal conditions
o
Previous relevant illnesses
o
Major relevant surgery not related to the cancerous condition, as well as other relevant prior 
procedures
o
Smoking status and alcohol use
! Oncology History 
The oncology history will include: date of diagnosis, tumor type, histological type and location, 
BCLC stage (see Appendix K), staging information at the initial histological diagnosis, 
previous treatments (surgery, radiotherapy) and outcome, current symptoms, and tumor 
involvement at the time of screening.
! Medication History of Oncology
The medication history of oncology will include: the starting and ending dates of previous 
anticancer therapies, the best response to each treatment (including both prescription and over-
the-counter medications) and other relevant tumor-related interventions. 
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! Other treatment History of Oncology
! Tumor Biopsy
Tumor biopsy will be performed as described in Section 8.6.1.
! Tumor Assessment
Tumor imaging assessment will be performed as described in Section 8.3.
! Physical Examination/Weight
A physical examination will be performed as described in Section 8.4.4.1. Weight will also be 
recorded.
! Vital Signs
Vital signs will be recorded as described in Section 8.4.4.2.
! 12-lead ECG
A standard 12-lead ECG will be performed as described in Section 8.4.4.3.
! Pregnancy Test
If applicable, a serum pregnancy test for beta-human chorionic gonadotropin will be 
administered.
! Chest X-ray
A chest X-ray will be performed per institutional standard.
! ECOG PS
The ECOG PS is a value between 0 and 5 assigned by a clinician based on observations of the 
subject's ability to perform common tasks. Thus, 0 signifies normal physical abilities with no 
evidence of disease. Increasing numbers indicate a reduced ability to perform activities of daily 
living, where 5 represents death. Subjects should have a score of < 2 to participate in this trial.
Details are described in Appendix D.
! Blood Samples for 
o
Hematology
o
Biochemistry
o
Coagulation
o
An overview of laboratory assessments is presented in Section 8.4.3. Preparation of blood 
samples are described in the MOP. The amount of blood volume for laboratory assessments is 
shown in Appendix J.
! Urinalysis
Urinalysis assessments are described in Section 8.4.3.4.
! Concomitant medication/procedures
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Concomitant medication/procedures and therapies will be documented as described in 
Section 7.5.
! AEs
AEs (since signature of the main informed consent) will be recorded as described in 
Section 8.4.1.
! Hepatitis markers
! Serum AFP
8.3
Assessment of Efficacy
Tumor Assessment (Tumor Response Assessment)
Tumor assessment will be performed according to RECIST v 1.1 (see Appendix C) locally by the 
Investigators and centrally by an independent radiologist. The baseline tumor assessment is 
scheduled to be performed during the Screening period of Phase Ib (see Section 8.1.2) and during 
the Clinical Screening period of Phase II. 
CT or MRI with contrast enhancement is required for tumor assessment. CT scans are required to 
be with intravenous contrast and to include phases/series of the entire liver, at a minimum, 1) 
hepatic arterial and 2) portal venous. If a subject has a known history of contraindication to CT 
contrast media or develops a contraindication during the trial, a non-contrast CT of the chest and
a contrast-enhanced MRI (if possible) of the abdomen and pelvis are recommended. Contrast-
enhanced MRI of the entire liver should include, at a minimum, 1) hepatic arterial and 2) portal 
venous.
Imaging studies, including CT or MRI of the chest (MRI is not recommended for chest due to 
respiratory artifacts), abdomen, and pelvis must be performed at baseline in order to survey 
metastasis. At baseline, the organs with metastatic disease and target and non-target lesions should 
be documented. CT/MRI of the head for subjects suggestive of CNS metastasis can be performed 
at baseline. The bone scan and/or positron emission tomography (PET) scan could be considered 
for subjects suggestive of bone metastasis at baseline or when suspecting any bone metastasis 
during the study, however X-ray or CT/MRI scan must be used for tumor assessment at the 
baseline and at the subsequent visits. The bone scan or PET could not be used for tumor 
assessment.
At baseline, all subjects should have at least 1 measurable lesion by CT scan or MRI. Any lesion 
that has been subjected to local-regional or surgical therapy should not be considered as 
measurable at baseline unless clear progression has been documented since the therapy. Otherwise,
previously treated lesions will be considered as non-target lesions.
Tumor response evaluations will be assessed by CT or MRI and other modalities at the end of 
every 2 cycles, i.e., every 6 weeks (every 4 cycles after Cycle 13, i.e., every 12 weeks). The 
scheduled 6-week (or 12-week) interval between tumor response evaluations should be maintained 
through the trial regardless of any delay or interruption to trial treatment. Tumor response 
evaluations should include a complete assessment of all target and non-target lesions. In case of 
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symptoms suggestive of symptomatic progression, subjects should be evaluated by imaging
studies thereafter. A CT or MRI must also be performed at the end of treatment (see Appendix I). 
Evaluation of lesions should be based on images obtained by either CT or MRI. The same method 
of assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during the trial. If a chest X-ray indicates metastatic disease while the subject
is enrolled in this trial, a CT of the chest is required for confirmation. It is recommended that, for 
a given subject, the tumor assessment is provided by the same physician or radiologist during the 
study. A change in methodology is defined as a change in contrast use or a change in technique. A 
change in methodology will result in a “Not Assessable” overall lesion response assessment unless 
a definitive response assessment can be justified by the current available information.
All measurements should be recorded in metric notation.
Further guidance and recommendations on image acquisition are provided in the Image 
Acquisition Guidelines.
If subjects discontinue MSC2156119J or sorafenib treatment for a reason other than PD or death, 
tumor assessment will be performed at the end of treatment visit if it has not been done within the 
past 6 weeks, and will be repeated every 6 weeks (± 1 week) until radiological progression per 
RECIST v 1.1, death or start of a new anticancer therapy, whichever occurs first.
Clinical progression, at any time, requires a physical examination and prompt radiological 
confirmation rather than waiting for the next scheduled imaging assessment. If unscheduled 
imaging does not meet progressive disease by RECIST v 1.1, the next scheduled imaging 
assessment should still be performed on time unless the next scheduled imaging assessment is 
within 14 days following the unscheduled imaging.
8.4
Assessment of Safety
The safety profile of MSC2156119J will be assessed through the recording, reporting, and 
analyzing of baseline medical conditions, AEs, 12-lead ECG, physical examination findings 
including vital signs and laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by the subject will be performed 
from the time of the subject’s signature of main informed consent throughout the trial. The 
investigator will report any AEs, whether observed by the investigator or reported by the subject
(see Section 8.4.1.2). The reporting period for AEs is described in Section 8.4.1.3.
8.4.1
Adverse Events
8.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
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abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal product, whether or not considered related to the medicinal product. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The investigator is required to grade the severity/intensity of each AE by referencing the 
NCI-CTCAE, version 4.0 (publication date: 28 May 2009). This is a descriptive terminology that 
can be used for AE reporting. A general grading (severity/intensity; hereafter referred to as 
severity) scale is provided at the beginning of the above referenced document, and specific event 
grades are also provided.
If a particular AE’s severity is not specifically graded by the guidance document, the investigator 
is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following his or her best 
medical judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe
Grade 4 or Life-threatening 
Grade 5 or Death 
According to sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as anemia or neutropenia, 
is considered serious only if the condition meets one of the serious criteria described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as a SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (for example, sudden 
death, unexplained death), the death per se might be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to MSC2156119J
using the following definitions. Decisive factors for the assessment of causal relationship of an AE 
to MSC2156119J include, but may not be limited to, temporal relationship between the AE and 
MSC2156119J, known side effects of MSC2156119J, medical history, concomitant 
medication/procedure, course of the underlying disease, or trial procedures.
Not related: Not reasonably related to MSC2156119J/sorafenib. AE could not medically 
(pharmacologically/clinically) be attributed to MSC2156119J/sorafenib under study 
in this clinical trial protocol. A reasonable alternative explanation must be available.
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Related:
Reasonably 
related 
to 
MSC2156119J/sorafenib. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to MSC2156119J/sorafenib under study 
in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g. on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation or are considered otherwise medically important by the investigator. If 
a laboratory abnormality fulfills these criteria, the identified medical condition (e.g. anemia, 
increased ALT) must be reported as the AE rather than the abnormal value itself.
Serious Adverse Event
A SAE is any untoward medical occurrence that at any dose:
! Results in death
! Is life-threatening
NOTE: The term “life-threatening” refers to an event in which the subject is at risk of death at 
the time of the event; not an event that hypothetically might have caused death if it was more 
severe.
! Requires inpatient hospitalization or prolongation of existing hospitalization
! Results in persistent or significant disability/incapacity
! Is a congenital anomaly/birth defect
! Is otherwise considered as medically important
Note: Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAEs when, based upon appropriate medical judgment, they 
may jeopardize the subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via MSC2156119J
is also considered an SAE, as described in Section 8.4.1.4.
Events that Do Not Meet the Definition of a SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (e.g., an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (e.g., undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
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Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as baseline medical conditions, and are NOT to be considered AEs.
AE/SAEs Observed in Association with Disease Progression 
Progression of the disease/disorder being studied assessed by measurement of lesions on 
radiographs or other methods as well as associated clinical signs or symptoms (including 
laboratory abnormalities) should not be reported as an (S)AE, unless the subject’s general 
condition is more severe than expected for the participant’s condition and/or unless the outcome 
is fatal within the AE reporting period (as defined in Section 8.4.1.3).
AEs of Special Interest 
Subjects might experience asymptomatic elevations in serum pancreatic enzyme (lipase and 
amylase). Such an enzyme elevation of Grade U 3 is considered an AESI in this trial.
When such AESI is not serious, a specific AESI form should be filled at the site and the sponsor 
must be notified immediately (within 24 hours). Reporting process of an AESI should follow the 
same procedure for reporting SAEs (see Section 8.4.1.4). 
Should the AESI be serious, a SAE Report Form instead of the AESI form should be filled and the 
procedure for reporting SAEs (see Section 8.4.1.4) should be followed.
In addition to SAEs, all DLTs will be expeditiously sent by the investigator to the sponsor using 
the AE section of the eCRF.
8.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his/her condition. During the reporting 
period, any unfavorable changes in the subject’s condition will be recorded as AEs, whether 
reported by the subject or observed by the investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs and all nonserious AEs of special interest must be additionally documented and reported 
using the appropriate Report Form as described in Section 8.4.1.4.
It is important that each AE report includes a description of the event, its duration (onset and 
resolution dates and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time), its severity, its causal relationship with the trial treatment, 
any other potential causal factors, any treatment given or other action taken (including dose 
modification or discontinuation of MSC2156119J/sorafenib) and its outcome. In addition, serious 
cases should be identified and the appropriate seriousness criteria documented.
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Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the sponsor.
8.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of main informed consent) and continues through the trial’s 
post-treatment follow-up visit, as defined in Section 8.1.5, regardless of whether the subject starts 
a new antineoplastic therapy prior to the post-treatment follow-up visit. If the post-treatment
follow-up visit was not performed (e.g., the subject could not come back to the site for a visit), a 
telephone contact should be completed and documented for AE assessment.
Any SAE assessed as related to trial treatment must be reported whenever it occurs, irrespective 
of the time elapsed since the last administration of trial treatment.
8.4.1.4
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest and Dose Limiting Toxicities
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the investigator must 
immediately (within a maximum 24 hours after becoming aware of the event) inform the sponsor
or its designee in writing. All written reports should be transmitted using the SAE Report Form, 
which must be completed by the investigator following specific completion instructions. In 
exceptional circumstances, an SAE (or follow-up information) may be reported by telephone. In 
these cases, a written report must be sent immediately thereafter by fax or e-mail. The same 
reporting procedures apply for follow up cases.
Names, addresses, telephone and fax numbers for SAE reporting will be included in the trial 
specific SAE Report Form.
Additional documents may be provided by the investigator, if available (for example, laboratory 
results, hospital report, autopsy report). In all cases, the information provided on the SAE Report 
Form must be consistent with the data about the event recorded in the eCRF.
The investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the sponsor or designee and 
(as applicable) to allow the sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the investigator directly to obtain 
further information or to discuss the event.
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Adverse Events of Special Interest
In the event of a nonserious AESI, the investigator will complete the AESI Report Form and send 
it to the sponsor/designee within 24 hours after becoming aware of the event. Names, addresses, 
telephone and fax numbers for AESI reporting will be included on the Report Form. Serious AESIs 
have to be reported in an expedited manner as SAEs as outlined above.
Dose Limiting Toxicities (Phase Ib)
Each event meeting the criteria of a DLT (see Section 7.2.2) has to be recorded in the eCRF within 
24 hours after becoming aware of the event. Serious DLTs have to be reported in an expedited 
manner as SAEs as outlined above.
8.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particular deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP guidelines, the sponsor/designee will inform the investigator of 
“findings that could adversely affect the safety of subjects, impact the conduct of the trial, or alter 
the IEC’s/IRB’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the sponsor/designee will inform the investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). The investigator should place copies of safety 
reports in the Investigator Site File. National regulations with regard to safety report notifications 
to investigators will be taken into account.
When specifically required by regulations and guidelines, the sponsor/designee will provide 
appropriate Safety reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting by the sponsor is not clearly defined by national or 
site-specific regulations, the investigator will be responsible for promptly notifying the concerned 
IEC/IRB of any Safety reports provided by the sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive 
and with the related Detailed Guidances.
8.4.1.6
Monitoring of Subjects with Adverse Events
AEs are recorded and assessed continuously throughout the study (see Section 8.4.1.3) and are 
assessed for final outcome at the post-treatment follow-up visit. All SAEs and AESIs ongoing at 
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the post-treatment follow-up visit must be monitored and followed up by the investigator until 
stabilization or until the outcome is known, unless the subject is documented as “lost to follow-up.” 
Reasonable attempts to obtain this information must be made and documented. It is also the 
responsibility of the investigator to ensure that any necessary additional therapeutic measures and 
follow-up procedures are performed. 
8.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the investigator as related to trial treatment (e.g., resulting from a 
drug interaction with a contraceptive medication) are considered to be AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 8.4.1.3 must 
be recorded by convention in the AE page/section of the eCRF. The same rule applies to 
pregnancies in female subjects and to pregnancies in female partners of male subjects. The 
investigator must notify the sponsor/designee in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting in Section 8.4.1.4. 
Investigators must actively follow up, document, and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The investigator must notify the sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 8.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from the trial immediately. The sponsor/designee must be notified without delay 
and the subject must be followed as mentioned above.
8.4.3
Laboratory Assessments
Samples will be sent to a central laboratory for analysis, and these values will be entered into the 
eCRF. However, during Screening/Clinical Screening, the laboratory samples taken for the 
purposes of confirming subject eligibility should be reported by a local laboratory. The investigator 
should use the local laboratory results to determine whether the subject meets the eligibility criteria 
and should enter these data into the relevant eCRF page. A duplicate sample should also be sent 
to the central laboratory for analysis and reporting. 
The investigator may also use local laboratory results for safety evaluations and real time 
individual dose adjustments. In the event of any discrepancy between the results of the analyses 
performed by the local and the central laboratories, the investigator will use their discretion to 
determine any appropriate action with regard to the subject. Any repeat testing must be done by 
the central laboratory. 
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It is essential that the sponsor be provided with a list of laboratory normal ranges before shipment 
of the trial medication. Any change in laboratory normal ranges during the trial will additionally 
be forwarded to the sponsor. The amount of blood volume for laboratory assessments is shown in 
Appendix J.
8.4.3.1
Hematology
Hematology assessments for Phase Ib and Phase II are presented in Table 3.
Table 3:
Hematology Assessments
Parameter
Hemoglobin 
Hematocrit
Red blood cell count 
White blood cell count
Differential
Platelet count
8.4.3.2
Biochemistry
Biochemistry assessments for Phase Ib and Phase II are presented in Table 4.
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Table 4:
Biochemistry Assessments
Parameter
Albumin 
Alkaline phosphatase 
Alanine aminotransferase
Amylase 
Aspartate aminotransferase
Blood urea nitrogen 
Calcium 
Creatinine 
Gamma-glutamyl transpeptidase
Glucose 
Lipase 
Magnesium
Potassium
Sodium
Total bilirubin (direct fraction if total bilirubin is abnormal)
Total protein
8.4.3.3
Coagulation 
Coagulation assessments for Phase Ib and Phase II are presented in Table 5.
Table 5:
Coagulation Assessments
Parameter
Activated partial thromboplastin time
International normalized ratio
Prothrombin time
8.4.3.4
Urinalysis
Urinalysis assessments (dipstick) for Phase Ib and Phase II are presented in Table 6. The dipstick 
urinalysis will be followed by microscopic examination if abnormal results.
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Table 6:
Urinalysis Assessments
Parameter
Blood
Glucose
Ketones
Leukocytes
Nitrites
pH
Proteins
8.4.3.5
Hepatitis Markers
Serological investigations (HBV panel) to be performed at baseline (either during 
Screening/Clinical Screening or predose on Cycle 1 Day 1) for Phase Ib and Phase II are presented 
in Table 7. In addition, all subjects will be tested (plasma sample) for HBV DNA and HCV RNA-
PCR. Based on the results of these tests, subjects may be given prophylactic or antiviral treatment 
following the institutional guidelines (see Section 7.5.1).
Table 7:
Hepatitis B Virus Serology Panel
Parameter
HBc antibodies
HBs antibodies
HBs antigen
HBe antigen
HBe antibodies
Abbreviations: HBc, Hepatitis B core; HBe, Hepatitis B e; HBs, Hepatitis B surface
Thereafter, subjects with a known history of HBV (despite being negative for HBV DNA at 
baseline), or who are positive for HBV DNA at baseline, or have positive HBV serology will 
continue to be monitored every 3 cycles for HBV DNA and serology and at the end of treatment 
visit. Similarly, subjects with a known history of HCV (despite being negative for HCV RNA at 
baseline) or who are positive for HCV RNA at baseline will continue to be monitored every 
3 cycles for HCV RNA-PCR and at the end of treatment visit. See Section 7.5.3.1.
8.4.4
Vital Signs, Physical Examinations, and Other Assessments
8.4.4.1
Physical Examinations
The physical examination will be identical to a general medical check-up comprising a whole body 
inspection (general appearance, body height and weight, skin/subcutaneous tissue, head, eyes, ears, 
nose, throat, neck, thyroid, respiratory, cardiovascular, peripheral vascular, lymphatic, lymph 
nodes/immunology, abdomen, musculoskeletal, neurological, and psychiatric), palpation, 
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percussion, and auscultation. Any clinically significant abnormal findings or worsening of 
conditions previously recorded in the medical history must be documented in the eCRF.
8.4.4.2
Vital Signs
Systolic blood pressure, diastolic blood pressure, respiratory rate, and pulse rate (beats per minute) 
will be measured in seated position after 5 minutes resting (for individual subjects, measurements 
at different visits should be taken in the same position). Body temperature will be recorded.
Vital signs should be taken within 30 minutes prior to each 12-lead ECG recording after sitting 
position of 5 minutes. Where ECGs are recorded in triplicate, vital signs only need to be recorded 
once prior to the first ECG recording.
8.4.4.3
Electrocardiogram
A single standard 12-lead ECG will be recorded after the subject has rested at least for 5 minutes 
in a supine position. At least 5 to 7 beats are required for each lead run. 
For time points where both ECGs and PK samples are obtained, 12-lead ECGs should be taken in 
triplicate at 2-minute intervals (± 1 minute), and should be performed within a maximum of 
10 minutes prior to PK sampling. Thus, the triplicate ECGs performed prior to collection of the 
predose trough PK samples must be completed within a maximum of 40 minutes prior to dosing. 
Postdose ECGs should be recorded within ± 5% of the scheduled assessment time, e.g., the 4-hour 
postdose ECG should be recorded within ± 12 minutes of the 4-hour time point. In addition, the 
time of the ECG recordings (relative to dosing) should be recorded. 
Results of the 12-lead ECG recordings will be included in the subject's eCRF.
8.5
Pharmacokinetics
Plasma concentrations of MSC2156119J for all subjects will be examined on Cycle 1, Day 1 and 
Day 15 of Phase Ib (samples will be taken predose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours 
postdose; Note: the 24-hour postdose sample from Day 1 and Day 15 are the predose samples from 
Day 2 and Day 16, respectively).
 
 
 
 
The predose PK sample on Cycle 1 Day 1 may be collected up to 60 minutes predose. Thereafter,
predose (trough) samples should be collected within 30 minutes predose.
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Postdose PK samples should be collected within ± 5% of the scheduled assessment time, e.g., the 
4-hour postdose sample should be collected within ± 12 minutes of the 4-hour time point. In 
addition, the time of the PK sample (relative to dosing) should be recorded.
For both phases, the concentration of MSC2156119J will be determined by a validated liquid 
chromatography-tandem mass spectrometry method. The validation of the method will be 
presented separately.
Details about the sampling and processing procedures, storage, and transportation will be provided 
in a separate laboratory manual. Schedule of dosing is detailed in Appendix H and Appendix I for 
Phase Ib and Phase II respectively. Sampling time points are detailed in Appendix J.
8.5.1
Body Fluids
Blood sampling will be taken as specified in the schedule of assessments (see Section 8.1, 
Appendix H, and Appendix I). Preparation of blood samples is described in the MOP.
Whole blood (2 mL samples) will be collected in ethylenediaminetetraacetic acid-coated tubes and 
may be kept at ambient temperature until centrifuged to prepare plasma. A laboratory manual will 
provide detailed instructions on proper centrifugation, and further processing of samples for 
plasma collection.
The plasma samples for PK must be divided into 2 equal aliquots (A and B). Plasma aliquots A 
will be assigned for analysis of MSC2156119J for calculation of PK parameters. Plasma aliquots B 
will be used as back-up samples.
 
During this research trial, blood, urine, and tumor tissue samples will be collected for laboratory 
testing. These samples will be collected, prepared and shipped at the site according to the 
laboratory instruction manual for this study. The samples will be shipped via courier to the relevant 
central laboratory “
” located in 
(for samples from outside of China) and 
Beijing (for samples from China), where they will either be analyzed or stored until shipment to 
third party vendors for analysis. 
The eCRF will contain provisions for recording the protocol-specified nominal time of each 
specimen, as well as the actual time and date that the specimen was obtained. Recording of the test 
results in the eCRF is not required.
8.5.2
Pharmacokinetic Calculations
The following PK parameters will be calculated and summarized from the measured individual 
plasma concentrations of MSC2156119J using non-compartmental methods based on frequent PK 
sampling as applied in Phase Ib.
!
Cmax: observed maximum plasma concentration
!
Cmin: observed minimum plasma concentration 
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!
Cav: Average plasma concentration within 1 dosing interval 
!
tmax: time to reach maximum plasma concentration
!
AUC0-t: area under the plasma concentration versus time curve from time zero to the last 
sampling time t at which the concentration is at or above the lower limit of quantification 
(LLQ). AUC0-t will be calculated according to the mixed log-linear trapezoidal rule 
!
AUC0-tau: area under the plasma concentration versus time curve within 1 dosing interval
Further derived PK parameters will be calculated, when appropriate:
!
Rz: apparent terminal rate constant determined by log-linear regression analysis of the 
measured plasma concentrations of the terminal log-linear phase
!
t1/2: apparent terminal half-life, calculated by ln2/Rz
!
AUC0-Q: area under the plasma concentration versus time curve from time zero to infinity. 
AUC0-Q will be calculated by combining AUC0-t and AUCextra. AUCextra represents an 
extrapolated value obtained by Clast/Rz, where Clast is the calculated plasma concentration at the 
last sampling time point at which the measured plasma concentration is at or above the LLQ. 
If the value of AUCextra provides more than 20% of AUC0-Q, this parameter and all related 
parameters (e.g., total body clearance of drug [CL] and volume of distribution associated to 
the terminal phase [Vz]) will be rejected as implausible and not included for further statistical 
analysis.
!
CL/f: apparent body clearance of the drug from plasma, CL = Dose/AUC0-Q
!
Vz/f: apparent volume of distribution associated to the terminal phase, calculated by 
Dose/(AUC0-Q*Rz) 
!
Vss/f: apparent volume of distribution at steady state, CLhMRT
The PK evaluation shall be carried out under the responsibility of the sponsor.
The PK variables will be analyzed descriptively for each treatment and administration separately. 
Descriptive statistics include N, arithmetic mean, geometric mean, standard deviation, standard 
error of the mean (SEM), median, minimum, maximum, and coefficient of variation (CV in %). 
The drug concentration in plasma at each sampling time will be presented on the original scale for 
all subjects who participated in the trial. Values below LLQ will be taken as zero for descriptive 
statistics of concentrations. 
Individual plasma concentration-time profiles (linear and semi-logarithmic scale) will be plotted 
by treatment. Mean plasma concentrations per treatment and administration will be plotted with 
StD using schedule time points. The weight-normalized PK parameters will be calculated if it 
would be appropriate.
Formal statistical hypotheses are not set up. All statistical tests will be performed in an explorative 
way. All analyses will be based on the PK analysis set. Details of the statistical analyses will be 
described in the Statistical Analysis Plan (SAP).
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When appropriate, the determinants of PK variability will be studied using a non-linear mixed 
effects modeling analysis of the sparse-sampling pharmacokinetic data generated in the Phase II
part of this trial, using the software NONMEM. This statistical modeling methodology will allow 
estimation of interindividual PK variability in the population, to calculate estimates of individual 
parameters and to assess quantitative relationships between PK parameters and potential 
influencing factors. Special consideration will be given to age, weight, gender, race, CrCl, total 
bilirubin, and smoking status. However, other covariates will be considered. In an optimal way the 
data will be merged with data from other MSC2156119J trials and the analysis may be reported 
separately as appropriate. 
The PK base model for the HCC population will be developed first based on the frequent PK 
sampling data from Phase Ib. If applicable, the model used will be a one-compartment model. 
Basic PK parameters (clearance, volume of distribution) for each individual subject will be 
estimated with the same statistical methodology. The relationships between parameters and 
covariates will be first explored graphically before inclusion in the statistical model.
The relationship between efficacy measures, safety measures, and PK parameters will be explored 
using graphical methods, correlation, and modeling techniques. The detailed statistical methods 
for the PK analyses will be detailed in a specific SAP.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.
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8.7
Other Assessments
Not planned.
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9
Statistics
9.1
Sample Size
For Phase Ib, the total number of subjects to be enrolled in this trial is up to 21. Of these subjects, 
up to 18 will be enrolled based on the “3+3” dose-escalation method with 2 dose cohorts: 3 to 6 
subjects in the first dose cohort and 3 to 12 subjects in the second dose cohort (if dose de-escalation 
does not occur). In addition, separate from the “3+3” dose escalation cohorts, up to 3 subjects will 
be enrolled in the mainland China sites. The final sample size will depend on the number of 
subjects who experience DLTs observed at each dose level, the number of dose levels explored, 
the safety data, and the decision from the SMC meeting.
For Phase II, the initial sample size planning required 100 TTP events (assessed by an IRC) to 
ensure 80% power with a two-sided significance level of 10% for rejecting the null hypothesis of 
equal treatment effect between treatment arms, assuming a true hazard ratio (HR) of 0.6. Assuming 
a median TTP in Asian subjects for the sorafenib arm of 2.8 months, a HR of 0.6 represents a 
1.87 month increase, resulting in a median TTP of 4.67 months for the MSC2156119J arm. With 
other assumptions: 
!
Accrual period of 12 months and follow-up period of 6 months, 
!
Overall drop-out rate of 17.4%.
A total number of 140 subjects with MET+ HCC were planned to be randomized on a 1:1 basis to 
receive MSC2156119J or sorafenib.
However, due to business-related considerations not related to any safety issues, the sponsor will
stop prescreening/enrollment when 40 TTP events are observed (assessed by an IRC) or 
15 August 2017, whichever occurs first. It is expected that approximately 90 subjects will be 
randomized by 15 August 2017.
9.2
Randomization
Randomization will only occur in Phase II. All eligible subjects will be randomized (1:1 basis) to 
receive MSC2156119J or sorafenib. Randomization will be performed centrally by using an IVRS.
A stratified permuted block randomization procedure will be employed using the following strata:
!
BCLC Stage: Stage B versus Stage C
The purpose of stratification is to ensure an even distribution of the 2 treatment arms within the 
stratum. 
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9.3
Endpoints
9.3.1
Primary Endpoints
The primary endpoints are: 
! Phase Ib:
Incidence of subjects experiencing at least 1 DLT within the first treatment cycle 
(i.e., 21 days after the first dose)
Incidence and type of other AEs
! Phase II:
TTP based on tumor assessment by an IRC. TTP is defined as the time (in months) 
from randomization to date of the observation of radiological PD assessed by an IRC
Tumor assessment endpoints are following RECIST v 1.1 (see Appendix C).  
9.3.2
Secondary Endpoints
The secondary endpoints are: 
!
PFS based on tumor assessment by the IRC. PFS time is defined as the time (in months) from 
randomization to either first observation of disease progression or occurrence of death due to 
any cause within 84 days of either randomization or the last tumor assessment.
!
PFS based on tumor assessment by the investigator. PFS time is defined as the time (in months) 
from randomization to either first observation of radiologically confirmed PD by the 
investigator or occurrence of death due to any cause within 84 days of either randomization or 
the last tumor assessment. 
!
OS time. OS time is defined as the time (in months) from randomization to the date of death.
!
TTP assessed by investigator. TTP is defined as the time (in months) from randomization to 
date of the observation of radiological PD assessed by the investigator.
!
Time-to-symptomatic progression (TTSP). TTSP is defined as the time (in months) from the 
date of randomization to the date of deterioration of symptoms assessed by FHSI-8, defined as 
the total score increase by at least 4 points compared with the baseline value, or deterioration 
to ECOG PS of 4. This is the PRO endpoint.
!
Pharmacokinetics (Phase Ib only): AUC0-t, AUC0-tau, Cmax, Cav, Cmin, tmax, AUC0-Q, CL/f, Vz/f, 
Vss/f, Rz and t1/2 when appropriate.
!
Objective response (OR) based on tumor assessment by the IRC. OR is defined as complete 
response (CR) or partial response (PR) as the best overall response according to radiological 
assessments as adjudicated by the IRC from randomization to first occurrence of PD. 
Responses do not require confirmation according to RECIST v 1.1 (see Appendix C).
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!
OR based on tumor assessment by the investigator. OR is defined as CR or PR as the best 
overall response according to radiological assessments as adjudicated by the investigator from 
randomization to first occurrence of PD. Responses do not require confirmation according to 
RECIST v 1.1 (see Appendix C).
!
Disease control based on tumor assessment by the IRC. Disease control is defined as CR, PR,
or stable disease (SD) as the best overall response according to radiological assessments as 
adjudicated by the IRC from the date of randomization to the first occurrence of PD. In the 
case of SD, measurements must have met the SD criteria at least once after study entry at a 
minimum interval of 42 days after randomization. 
!
Disease control based on tumor assessment by the investigator. Disease control is defined as 
CR, PR, or SD as the best overall response according to radiological assessments as adjudicated 
by the investigator from the date of randomization to the first occurrence of PD. In the case of
SD, measurements must have met the SD criteria at least once after study entry at a minimum 
interval of 42 days after randomization.
9.3.3
Safety Endpoints
The safety endpoints, not including the DLT primary objective (see Section 9.3.1), are:
!
Drug exposure
!
Incidence and type of AEs (all grades as per NCI-CTCAE version 4.0): all treatment emergent 
adverse events (TEAEs), related TEAEs, treatment emergent SAEs, related treatment emergent 
SAEs, TEAEs of NCI-CTCAE (version 4.0) Grade U 3, related TEAEs Grade U 3, and TEAEs 
leading to temporary/permanent treatment discontinuation
!
Incidence and reasons for deaths, including deaths within 33 days after the last dose of study 
drug
!
Safety laboratory tests graded by NCI-CTCAE (version 4.0)
!
Vital signs; 12-lead ECG changes; physical examinations, including change in body weight; 
and ECOG PS
9.3.4
Further Endpoints of Interest
Further endpoints of interest in this trial are: 
!
 
 
 
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!
Phase II: PRO assessments of MSC2156119J compared with sorafenib will be assessed using 
the FACT-HP questionnaire
 
 
 
 
 
 
9.4
Analysis Sets
! All Subjects Set:
The All Subjects Set includes all subjects who have signed the main informed consent 
(i.e., screening failures plus subjects enrolled). 
! DLT Analysis Set (Phase Ib only):
The DLT Analysis Set includes all subjects who experienced a DLT during Cycle 1, or did not 
experience a DLT, and completed at least 80% of planned treatment during the DLT observation 
period (21 days after the first dose administered). Subjects who have been replaced during the 
Cycle 1 or whom belong to the Chinese (Mainland) subject cohort will be excluded from the 
DLT Analysis Set (for replacement criteria, see Section 6.3.2).
! Safety Analysis Set:
The Safety Analysis Set includes all subjects who have received at least 1 dose of 
MSC2156119J or sorafenib. Subjects who were replaced for evaluation of DLT will still be 
included in the Safety Analysis Set, if they are treated at least once (i.e., if the above criterion 
is met). 
! Intent-to-treat (ITT) Analysis Set:
The ITT Analysis Set in the Phase II part of this trial consists of all subjects who were 
randomized to study treatment. Subjects will be allocated as randomized.
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! Modified intent-to-treat (mITT) Analysis Set:
The mITT Analysis Set in the Phase II part of this trial consists of all subjects with MET+ HCC 
who were randomized to study treatment. Subjects will be allocated as randomized.
Determination of MET status is planned at Molecular Prescreening (Phase Ib retrospectively, 
Phase II for subject selection); rescoring will be performed as a quality control measure. 
Subjects with IHC c-Met status 1+ or ‘not assessable’ on re-scoring will be excluded from the 
primary analysis.
The mITT Analysis Set will be used for the primary analysis of tumor activity and efficacy of 
the compound.
! PP Analysis Set:
The PP Analysis Set is defined as all mITT subjects who meet the following criteria:
o Histologically or cytologically confirmed hepatocellular carcinoma
o Correct treatment allocation according to randomization or dose selection
o Measurable or evaluable disease at baseline
o Completed at least 1 cycle of study therapy
o Received only permitted medications or procedures according to this protocol
! Subgroups of Interest:
The following subgroups are considered to be of interest to explore the treatment effect of 
MSC2156119J. Other subgroups may be analyzed as well in an exploratory manner.
o Age: < 65 years versus U 65 years
o Gender: male versus female
o Geographic region: Greater China versus outside of Greater China
o BCLC stage: Stage B versus Stage C
o Type of MET+: overexpression versus amplification (including subjects with co-existing 
amplification and overexpression)
o Vascular invasion and/or extrahepatic spread: presence versus absence
o The underlying disease or medical condition related to etiology: HBV versus Other
o AFP elevation at the baseline: Yes versus No
o Prior local-regional therapy: Yes versus No
o Subjects with a change in IHC c-Met status from 2+ or 3+ to either 1+ or ‘not assessable’, 
based on a re-assessment planned for quality assurance purposes (subgroup of the ITT 
Analysis Set)
! PK Analysis Set:
All subjects who have received at least 1 dose of the MSC2156119J and who have provided at 
least 1 plasma concentration measurement of MSC2156119J after the first dose.
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!
9.5
Description of Statistical Analyses
9.5.1
General Considerations
Statistical analyses will be performed by the Merck Serono Global Biostatistics Department and 
CRO, except for the analysis of PK parameters. The computer program SAS® System (version 9.1 
or higher; SAS Institute, Cary, North Carolina, USA) or R (version 2.10.1 or higher) will be used.
Any subject, who received MSC2156119J but is “not fully evaluable,” will be clearly identified in 
the summaries of subject disposition and in listings. The definition of “not fully evaluable” is 
provided in Section 6.3.2.
Statistical analyses of Phase Ib will be carried out in a descriptive manner, whereas Phase II has a 
confirmatory component when analyzing TTP.
Data of Phase Ib will be analyzed after a follow-up of at least 21 days for the last subject. Statistical 
analyses will be performed using eCRF data in general. Primary statistical analysis of endpoints 
will be performed using eCRF data obtained until a clinical cut-off date in Phase II. The Phase II 
clinical cut-off date is determined by the date after the required number of events for the primary 
endpoint has been reported in the primary analysis population, i.e., 40 TTP events for the mITT 
population (assessed by an IRC) in Phase II, or on 15 August 2017, whichever occurs first. The 
final statistical analyses for the Phase II study will be performed at approximately 6 months after 
the last subject is first dosed.
Safety analyses will be performed according to the as-treated principle. Safety data will be 
descriptively analyzed on the Safety Analysis Set. Adverse events will be coded according to the 
current Medical Dictionary for Regulatory Affairs (MedDRA) and reported by preferred term and 
system organ class. The severity of AEs will be graded using NCI-CTC toxicity grades.
The mITT population will be primarily used in the analysis of baseline characteristics and efficacy.
Analyses on the mITT population will consider subjects’ allocation to treatment groups as 
randomized.
Selected efficacy analyses will be repeated for the ITT population, the PP population and for 
subgroups (see Section 9.4). In case that PP population includes more than 90% of the mITT 
population, additional efficacy analyses on the PP population will be omitted.
In order to provide overall estimates of the treatment effect data will be pooled across centers. The 
factor center will not be considered in statistical models or for subgroup analyses because of high 
number of participating centers and the anticipated small number of subjects randomized in each 
center.
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All statistical tests comparing treatment arms will be performed two-sided using a significance
level of ` = 10%, unless otherwise specified. If CIs are to be calculated, they will be two-sided 
with a confidence probability of 90%, unless otherwise specified.
Continuous variables will be summarized using descriptive statistics, i.e., number of subjects 
(N), mean, median, standard deviation, 25th and 75th percentiles (Q1, Q3), minimum and maximum. 
Confidence intervals will be presented where appropriate.
Qualitative variables will be summarized by means of counts and percentages. Unless otherwise 
stated, the calculation of proportions will be based on the sample size of the population of interest. 
Counts of missing observations will be included in the denominator and presented as a separate
category.
In general, the last measurement prior to or on the day of randomization will serve as the baseline 
measurement.
Details of the statistical analyses will be defined in the SAP.
9.5.1.1
Protocol Violations
All protocol violations, including inclusion/exclusion criteria violations and violations during the 
trial, will be listed, even if they are believed not to influence any of the results. The SMC meetings 
will evaluate potential protocol deviations that could affect the MTD/RP2D determination. The 
definition of protocol deviations will be specified in the SMC’s charter or in the SMC’s SAP.
9.5.1.2
Missing Data
Unless otherwise specified, missing data will not be imputed. For the derivation of new variables 
the following rules will apply:
Incomplete AE-related dates will be handled as follows:
! In case the onset date is completely missing or the onset is in the same year (if the onset year is 
available only) or the onset is in the same month and year (if the day is missing) as start of study 
treatment then the onset date will be replaced by the minimum of start of study treatment and 
AE resolution date.
! In all other cases the missing onset day or onset month will be replaced by 1.
! Incomplete stop dates will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of subject's death. In the latter case, the date of death 
will be used to impute the incomplete stop date.
! In all other cases the incomplete stop date will not be imputed.
For imputing missing parts of dates for the efficacy analyses the missing day in a date will be 
imputed as the 15th of the month, if month and year is documented. This includes also dates of 
start of follow-up therapy. In all other cases missing or incomplete dates will not be imputed if not 
indicated otherwise.
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In individual subject data listings the documented date as given in the eCRF will be reported (e.g.,
__May 2013 in case of day missing, but month and year available). No imputed values will be 
presented in clinical trial report. In all other subject data listings, imputed values will be presented. 
In those listings imputed date of death, last date known to be alive, start of AE, and relationship of 
AE to study treatment will be flagged.
9.5.2
Analysis of Primary Endpoints
9.5.2.1
Statistical Analysis of the Dose Escalation Cohort
The DLT Analysis Set will be used for evaluation of the number of subjects experiencing any 
DLTs at the end of each cohort and for the assessment of the MTD/RP2D.
For final statistical analysis, the number and proportion of subjects in the DLT population who 
experienced DLT during the Cycle 1 of treatment with MSC2156119J will be presented by dose 
level. Subject disposition will be reported for each dose level, and subject profiles will be 
presented. 
Listings and graphics of information which is relevant to the primary endpoint will be prepared 
for the SMC, for the purpose of determination of the MTD/RP2D of MSC2156119J in Asian 
subjects, according to the content agreed and specified in the SMC’s charter.
The MTD/RP2D will be determined as described in Section 7.2.3.
9.5.2.2
Statistical Analysis of Primary Endpoint of Phase II
The primary endpoint of Phase II in this trial is TTP based on tumor assessment by an IRC. TTP 
is defined as the time (in months) from randomization to date of the observation of radiological 
PD assessed by an IRC. Death without radiological progression date will be censored. In subjects 
without a progression date or loss to follow-up at time of analysis, the time between the date of 
randomization and the date of last tumor assessment will be calculated and used as a censored 
observation in the analysis. In principle, all tumor assessment should be considered to determine 
and derive the date of radiological progression.
The primary analysis will test the equality of TTP between treatment groups, based on the mITT 
population, applying two-sided unstratified log-rank test at a significance level of 10%.
The following null-hypothesis is tested:
H0: #A(t) = #B(t) versus H1: #A(t) = #B(t),  % 1,  
where #(t) represents the hazard at time t and  the unknown constant of proportionality of hazards 
in the allocated treatment groups (MSC2156119J and sorafenib).
The HR (including 90% CI) of MSC2156119J compared to sorafenib will be calculated by Cox's 
proportional hazards model.
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Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment arm 
together with a summary of associated statistics (median survival time, 6-month, 12-month 
survival rate estimates and estimates for every 6 months thereafter as applicable) including the 
corresponding two-sided 90% CIs. The CIs for the median will be calculated according to 
Brookmeyer and Crowley, and CIs for the survival function estimates at above defined time points 
will be derived directly from the Kaplan-Meier estimates. The estimate of the standard error will 
be computed using Greenwood's formula.  Comparisons of survival rates will be performed from 
a Z-test using estimates and standard errors derived from the Kaplan-Meier method and 
Greenwood’s formula. 
TTP will be further explored considering the ITT population, the PP population and pre-defined 
subgroups (see Section 9.4).
9.5.3
Analysis of Secondary Endpoints
9.5.3.1
Progression-free Survival
Progression-free survival (assessed by the IRC) time is defined as the time (in months) from 
randomization to either first observation of progression disease or occurrence of death due to any 
cause within 84 days of either randomization or the last tumor assessment. If no progression or 
death is observed at the time of analysis, or if death without previously documented PD is observed 
after more than 84 days of last tumor assessment without progression, the PFS time will be 
censored on the date of last tumor assessment or date of randomization, whatever occurs later. The 
84-day time window represents the time between 2 scheduled tumor assessments.
Treatment groups will be compared based on mITT population, applying two-sided unstratified 
log-rank test at a significance level of 10%.
The same survival analysis methods will be employed as for the primary endpoint, PFS will be 
further explored considering the ITT population, the PP population and pre-defined subgroups (see
Section 9.4).
Progression-free survival based on tumor assessment by the investigator will also be analyzed in 
the same way as described above.
9.5.3.2
Overall Survival
Overall survival will be measured as the time (in months) between the date of randomization and 
the date of death. The analysis will be performed on the basis of the ITT principle on the primary 
analysis population. OS time (in months) is defined as:
(date of death or last date known to be alive – date of randomization + 1) / 30.4375.
For subjects not known to be deceased at time of analysis, the time between date of randomization 
and date of last contact or date of lost to follow-up will be calculated and used as a censored 
observation in the analysis. If this date is after the data cut-off, subjects will be censored at the date 
of data cut-off.
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Treatment groups will be compared based on the mITT population, applying two-sided unstratified 
log-rank test (` = 10%).
OS data will be further explored considering the ITT population, the PP population and predefined 
subgroups (see Section 9.4).
9.5.3.3
Time-to-symptomatic Progression
Time-to-symptomatic progression is defined as the time (in months) from the date of 
randomization to the date of deterioration of symptoms assessed by FHSI-8, defined as the total 
score increase by at least 4 points compared with the baseline value, or deterioration to ECOG PS 
4. The analysis will be performed on the basis of the ITT principle on the primary analysis 
population at time when TTP is statistically analyzed.
Treatment groups will be compared based on the mITT Population, applying two-sided unstratified 
log-rank test (` = 10%).
9.5.3.4
Antitumor Activity
Objective response and disease control will be evaluated based on the mITT population. 
The objective response rate is defined as the proportion of subjects having achieved CR or PR as 
the best overall response according to radiological assessments as adjudicated by the IRC from 
randomization until the first occurrence of PD. Responses do not require confirmation according 
to RECIST v 1.1 (see Appendix C).
The disease control rate is defined as the proportion of subjects having achieved CR, PR, or SD 
as the best overall response according to radiological assessments as adjudicated by the IRC from
randomization until the first occurrence of PD. In the case of SD, measurements must have met 
the SD criteria at least once after study entry at a minimum interval of 42 days after randomization.
Fisher’s exact test will be performed for analysis and will test the following two-sided hypothesis:
H0: j = 1 versus H1: j k 1
where j defines the odds ratio between treatments.
The OR rate and disease control rate will be presented for each treatment group including the 
corresponding 90% Newcombe-Wilson CIs.
Duration of response will be presented descriptively. 
Objective response rate and disease control rate based on tumor assessment by the investigator 
will also be analyzed in the same way as described above. 
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9.5.3.5
Safety and Tolerability
The Safety Analysis Set will be used for summaries of demographic and baseline characteristics, 
as well as for all summaries of safety data (except for DLT analysis).
Safety analyses will be performed according to as-treated principle. Any treatment emergent AEs 
will be summarized, i.e., those events that emergent during treatment having been absent 
pretreatment, or worsen relative to the pretreatment state and with onset dates occurring within the 
first dosing day of study treatment until 33 days after the last dose of study treatment. No formal 
statistical comparisons are planned.
The extent of exposure to MSC2156119J and sorafenib will be characterized by time on treatment
(weeks), cumulative dose, dose intensity, relative dose intensity (actual cumulative dose/planned 
dose), number of dose reductions, and number of dose delays.
AEs will be coded according to the MedDRA. Severity of AEs will be graded using NCI-CTCAE 
(version 4.0) toxicity grade. The incidence and type of AEs, SAEs, study treatment-related AEs 
and SAEs, AEs of Grade U 3 by NCI-CTCAE, study treatment-related AEs of Grade U 3 by NCI-
CTCAE, AEs leading to death, study treatment-related AEs leading to death, and AEs leading to 
temporary/permanent treatment discontinuation will be summarized in total and for each treatment 
group according to MedDRA system organ class and MedDRA preferred terms. Adverse event 
summaries will be prepared for Cycle 1 and the whole treatment period.
All deaths and deaths within 33 days after last dose of study treatment as well as reasons for death 
will be tabulated.
Laboratory results will be classified according to NCI-CTCAE (version 4.0). The worst 
on-treatment grades after the first dose of the study treatment will be summarized. Shifts in toxicity
grades from treatment start to the highest grade will be displayed. Results for variables that were 
not part of the NCI-CTCAE will be presented as below, within and above the normal limits of the 
local laboratory. Only subjects with post-baseline laboratory values will be included in these 
analyses. The last measurement before study treatment will serve as the baseline measurement. 
Descriptive summaries of actual (absolute) laboratory values and changes from baseline will be 
presented. 
Changes in body weight from baseline to measurements during the treatment phase will be 
classified according to the NCI-CTCAE (version 4.0) criteria. The highest change from baseline 
will summarized.
Clinically significant, abnormal findings from 12-lead ECG during treatment phase will be 
descriptively presented.
Changes from baseline to worst on-treatment value will be summarized descriptively for the QTc 
interval (including absolute changes and categorical shifts).
Vital signs (body temperature, heart rate, blood pressure, respiratory rate) recorded at baseline will 
be descriptively presented.
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The baseline results of the physical examination will be presented. Clinically significant, abnormal 
findings from the physical examination are to be reported as AEs. Separate summaries of the 
physical examination during and after treatment will not be provided.
The ECOG PS will be summarized descriptively by visit.
Further details on safety analyses will be specified in the SAP.
Statistical Analyses for the Dose Escalation Decision
Within each dose level and upon completion of Cycle 1 (i.e., the first 21 days) of treatment by the 
last subject, data from analyses will be presented to the SMC for a decision on dose escalation. 
These analyses will include safety data from Cycle 1, including listings of AEs graded according 
to NCI-CTCAE and DLT, listings of laboratory data, vital signs, 12-lead ECG, as well as each 
subject’s demographics, disease history, and treatment compliance in Cycle 1. Additionally, data 
from all other cycles for subjects dosed in previous dose levels have to be provided for each SMC 
meeting. Any protocol violation that could affect DLT will be monitored and reported at each 
SMC. The full data to be presented will be documented in detail in the SMC charter.
Any subject who is replaced with another subject in Cycle 1 will be included in the listings, but 
the information that the subject is not included in the DLT analysis population will be contained 
in the listings.
9.5.3.6
Pharmacokinetics
All PK parameters will be determined for each subject as described in Section 8.5.2. PK data of 
subjects enrolled up to 15 August 2017 will be considered for the analysis. The following analyses 
will be performed for each dose group of Phase Ib.
For PK, individual serum and mean (± standard deviation) concentration time plots will be 
provided for each treatment group using a linear and semi-logarithmic scale. Scatter-plots may 
also be prepared for exploratory purposes.
The plasma concentration data for MSC2156119J will be summarized descriptively per dose 
cohort and per time point. Descriptive statistics will include number of subjects (N), arithmetic 
mean, geometric mean, median, standard deviation, minimum and maximum values, and CV in %. 
Mean plasma concentration-time profiles will be generated on both linear and semi-logarithmic 
scales using time values as scheduled.
The derived PK parameters will be summarized descriptively per dose cohort. Descriptive statistics 
will include number of subjects (N), the arithmetic mean, geometric mean, standard deviation, 
SEM, median, minimum and maximum values, and CV in %.
The potential drug accumulation will be evaluated according to an appropriate manner. 
Additionally, the PK/Pd relationship may be explored. Pharmacodynamic variables might be 
chosen based on the trial outcome; efficacy, as well as safety variables, might be considered.
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The PK population includes all subjects who have received MSC2156119J and who have had at 
least 1 blood sample drawn that provide drug concentration data for PK evaluation. 
 
 Further details regarding 
PK analyses will be provided in the SAP.
 
 
 
 
 
 
 
 
 
 
 
 
9.5.4
Safety Analyses
See Section 9.5.3.5.
9.6
Interim Analysis
An IDMC will be formed from a group of 3 experts and will consist of at least a statistician and 1
oncologist who will not be either participant in the trial or an employee of the sponsor of this study 
as well as the independent statistician who is not a voting member of the IDMC. An IDMC charter 
and IDMC Analysis Plan will provide the details about the conduct of the IDMC meeting, 
frequency, and decision making rules.
The IDMC will be responsible for periodic (as defined by the IDMC charter) evaluations of the 
clinical trial to ensure continued subject safety as well as the validity and scientific merit of the 
study. 
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The designated independent statistician will provide the IDMC with the safety summaries 
periodically for review. No individuals involved with the direct monitoring of this study will have 
access to the treatment identities. 
In addition to periodic evaluations and a final analysis, a formal primary analysis based on key 
statistical endpoints will occur after observation of 40 TTP events (assessed by an IRC) in the 
primary analysis population or 15 August 2017, whichever occurs first.
10
Ethical and Regulatory Aspects
10.1
Responsibilities of the Investigator
The investigator is responsible for the conduct of the trial at his/her site. He/she will ensure that 
the trial is performed in accordance with the clinical trial protocol and with the ethical principles 
that have their origin in the Declaration of Helsinki, as well as with the ICH Note for Guidance on 
Good Clinical Practice (ICH Topic E6, 1996) and applicable regulatory requirements. In particular, 
the investigator must ensure that only subjects who have given their informed consent(s) are 
included into the trial.
In 1998, the US Food and Drug Administration (FDA) introduced a regulation (Code of Federal 
Regulations Title 21 Part 54) entitled “Financial Disclosure by Clinical Investigators”. For trials 
conducted in any country that could result in a product submission to the FDA for marketing 
approval and could contribute significantly to the demonstration of efficacy and safety of the 
investigational medicinal product (named “covered trials” by the FDA), the investigator and all 
sub-investigators are obliged to disclose any financial interest which they, their spouses or their 
dependent children may have in the sponsor or the sponsor’s product under study. This information 
is required during the trial and for 12 months following completion of the trial.
10.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the trial is his/her written informed 
consent(s). The subject’s written informed consent(s) to participate in the trial must be given before 
any trial-related activities are carried out.
Adequate information must therefore be given to the subject by the investigator before informed 
consent is obtained (a person designated by the investigator may give the information, if permitted 
by local regulations). A subject information sheet in the local language and prepared in accordance 
with the Note for Guidance on Good Clinical Practice (ICH Topic E6, 1996) will be provided by 
the sponsor for the purpose of obtaining informed consent. In addition to providing this written 
information to a potential subject, the investigator or his/her designate will inform the subject
verbally of all pertinent aspects of the trial. The language used in doing so must be chosen so that 
the information can be fully and readily understood by lay persons. 
Depending on national regulations, a person other than the investigator may inform the subject and 
sign the ICF(s), as above.
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Where the information is provided by the investigator, the ICF must be signed and personally dated 
by the subject and the investigator. 
The signed and dated declaration of informed consent(s) will remain at the investigator’s site, and 
must be safely archived by the investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information and ICF
should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written subject information sheet and any other written information provided to 
subjects will be revised by the sponsor and be submitted again to the IEC/IRB for review and 
favorable opinion. The agreed, revised information will be provided to each subject in the trial for 
signing and dating. The investigator will explain the changes to the previous version.
Absorption, distribution, metabolism, and elimination
 will be 
conducted for subjects who have consented specifically to them. The objectives and description of 
the 
 and the biopsy should be included in the subject information sheet for 
, and subjects are to give consent by checking the consent on 
and tumor biopsy in the ICF for 
.
10.3
Subject Identification and Privacy
A unique subject number will be assigned to each subject at inclusion, immediately after the main 
informed consent has been obtained. This number will serve as the subject’s identifier in the trial 
as well as in the clinical trial database.
The subject’s data collected in the trial will be stored under this number. Only the investigator will 
be able to link the subject’s trial data to the subject via an identification list kept at the site. The 
subject’s original medical data that are reviewed at the site during source data verification by the 
Monitor, audits and Health Authority inspections will be kept strictly confidential.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
After the additional research for 
is done, all remaining de-identified 
biological material (
) will be kept for a maximum of 12 years. 
During this time, samples will be stored at the sponsor’s biobank or a third party’s biobank. It is 
possible that the samples will be re-analyzed with newer, more exact technologies during that time.
 
 
 
 
 
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10.4
Emergency Medical Support and Subject Card
Subjects enrolled in this clinical trial will be provided with Emergency Medical Support cards 
during their trial participation, which will be furnished by the sponsor. The Emergency Medical 
Support card is based on the need to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial, and subsequently to give health care providers access 
to the information about this participation that may be needed to determine the course of the 
subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical trial; and this may include the possibility of emergency unblinding if needed, in case of 
blinded trials.
Clinical trial investigators, who are already aware of the clinical trial protocol and treatment, have 
other means of accessing the necessary medical information for the management of emergencies 
occurring in their subjects.
The first point of contact for all emergencies will be the clinical trial investigator caring for the 
affected subject. The investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the investigator is available when an event occurs, she/he will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard processes 
established for the investigators.
In cases where the investigator is not available, Merck Serono/EMD Serono provides the 
appropriate means to contact a sponsor physician. This includes the provision of a 24 hour contact 
number at a call center, whereby the health care providers will be given access to the appropriate 
sponsor physician to assist with the medical emergency and to provide support for the potential 
unblinding of the subject concerned.
10.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage shall be provided for each country participating to the trial. Insurance 
conditions shall meet local standards, as applicable.
10.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, the clinical trial protocol will be submitted 
together with its associated documents to the responsible IEC/IRB for its favorable 
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opinion/approval. The written favorable opinion/approval of the IEC/IRB will be filed in the 
Investigator Site File, and a copy will be filed in the Trial Master File at the sponsor.
The trial must not start at a site before the sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the trial, the clinical trial protocol version and the Subject
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained.
Amendments to the clinical trial will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes (see Section 11.5). Relevant safety information will 
be submitted to the IEC/IRB during the course of the trial in accordance with national regulations 
and requirements.
10.7
Health Authorities
The clinical trial protocol and any applicable documentation (e.g., Investigational Medicinal 
Product Dossier, Subject Information and ICF) will be submitted or notified to the Health 
Authorities in accordance with the regulations of the countries involved in the trial.
11
Trial Management
11.1
Case Report Form Handling
The investigator or designee will be responsible for entering trial data in the eCRF provided by the 
designated CRO, 
. It is the investigator’s responsibility to ensure the accuracy of the data 
entered in the eCRFs.
The data will be entered into a validated database. The data management department of the 
designated CRO, 
, will be responsible for data processing, in accordance with the defined 
data management procedures, under the supervision of the sponsor. Database lock will occur once 
quality control procedure, and quality assurance procedures (if applicable) have been completed. 
Portable document format files of the eCRFs will be provided to the investigators at the completion 
of the trial.
11.2
Source Data and Subject Files
The investigator must keep a subject file (medical file, original medical records) on paper or 
electronically for every subject included in the trial. This file will contain the available 
demographic and medical information for the subject, and should be as complete as possible. In 
particular, the following data should be available in this file:
!
Subject’s full name
!
Date of birth
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!
Sex
!
Height
!
Weight
!
Medical history and concomitant diseases
!
Prior and concomitant therapies (including changes during the trial)
!
Trial identification (Trial EMR200095-004)
!
Date of subject’s inclusion into the trial (i.e., date of giving the main informed consent)
!
Subject number in the trial
!
Dates of the subject’s visits to the site
!
Any medical examinations and clinical findings predefined in the clinical trial protocol
!
All AEs observed in the subject
!
Date of subject’s end of the trial
!
Date of and reason for early withdrawal of the subject from the trial or from IMP, if applicable
It must be possible to identify each subject by using this subject file.
Additionally, any other documents containing source data must be filed. This includes original 
printouts of data recorded or generated by automated instruments, photographic negatives, X-rays, 
CT or MRI, 12-lead ECG recordings, laboratory value listings, a subject diary for the compliance 
to IMP administration, etc. Such documents must bear at least the subject number and the date 
when the procedure was performed. Information should be printed by the instrument used to 
perform the assessment or measurement, if possible. Information that cannot be printed by an 
automated instrument will be entered manually. Medical evaluation of such records should be 
documented as necessary and the documentation signed and dated by the investigator.
The following information described in the eCRF is regarded as the source data.
! Any investigator’s comments
! Subject number
11.3
Investigator Site File and Archiving
The investigator will be provided with an Investigator Site File upon initiation of the trial. This 
file will contain all documents necessary for the conduct of the trial and will be updated and 
completed throughout the trial. It must be available for review by the Monitor, and must be ready 
for sponsor audit, as well as for inspection by Health Authorities during and after the trial, and 
must be safely archived for at least 15 years (or per local requirements or as otherwise notified by 
the sponsor) after the end of the trial. The documents to be archived include the Subject
Identification List and the signed subject ICF(s). If archiving of the Investigator Site File is no 
longer possible at the site, the investigator must notify the sponsor.
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All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines, whichever is longer. In any case, the investigator should ensure that no destruction 
of medical records is performed without the written approval of the sponsor.
11.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH Note for Guidance on GCP (ICH Topic 
E6, 1996). The site Monitor will perform visits to the trial site at regular intervals.
In line with ICH GCP guidelines, monitoring will include verification of data entered in the eCRF 
against original subject records. This verification will be performed by direct access to the original 
subject records, and the sponsor guarantees that subject confidentiality will be respected at all 
times. Participation in this trial will be taken as agreement to permit direct source data verification.
Representatives of the sponsor’s Quality Assurance unit or a designated organization, as well as 
Health Authorities, must be permitted to inspect all trial-related documents and other materials at 
the site, including the Investigator Site File, the completed eCRFs, the IMP, and the subjects’ 
original medical records/files.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data.
11.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in written protocol amendments. Major 
(substantial, significant) amendments will usually require submission to the Health Authorities and 
to the relevant IEC/IRB for approval or favorable opinion. In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained.
Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations.
Any amendment that could have an impact on the subject’s agreement to participate in the trial 
requires the subject’s informed consent prior to implementation (see Section 10.2).
11.6
Clinical Trial Report and Publication Policy
11.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report according to ICH Topic E3 will be written by 
the sponsor in consultation with the coordinating investigator.
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11.6.2
Publication
The first publication will be a publication of the results of the analysis of the primary endpoints
that will include data from all trial sites.
The investigator will inform the sponsor in advance about any plans to publish or present data from 
the trial. Any publications and presentations of the results (abstracts in journals or newspapers, 
oral presentations, etc.), either in whole or in part, by investigators or their representatives will 
require presubmission review by the sponsor.
The sponsor will not suppress or veto publications, but maintains the right to delay publication in 
order to protect intellectual property rights.
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12
References
1. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Semin Liver Dis 2010;30:52-60.
2. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and 
prevalence across five continents: Defining priorities to reduce cancer disparities in different 
geographic regions of the world. J Clin Oncol 2006;24:2137-2150.
3. International Agency for Cancer Research. GLOBCAN 2002: http://www-dep.iarc.fr 
(accessed March 18, 2009).
4. Parkin D, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin 
2005;55:74-108.
5. Bruix J, Sherman M. American Association for the Study of Liver Diseases. Management of 
hepatocellular carcinoma: an update. Hepatology 2011;53:1020-1022.
6. Poon D, Anderson BO, Chen L-T, et al. Management of hepatocellular carcinoma in Asia: 
Consensus statement from the Asian Oncology Summit 2009. 
Lancet Oncol 
2009;10:1111-1118.
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N 
Engl J Med 2008;359:378-390.
8. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-
Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, 
placebo-controlled trial. Lancet Oncol 2009;10:25-34.
9. Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more. Nat Rev 
Mol Cell Biol 2003;4(12):915-25.
10. Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: Targeting 
oncogene addiction and expedience. Nat Rev Drug Discov 2008;7(6):504-516.
11. Gherardi E, Birchmeier W, Birchmeier C, et al. Targeting MET in cancer: rationale and 
progress. Nat Rev Cancer 2012;12(2):89-103. 
12. Liu X, Yao W, Newton RC, et al. Targeting the c-MET signaling pathway for cancer therapy. 
Expert Opin Investig Drugs 2008;17:997-1011.
13. Benvenuti S, Comoglio PM. The MET receptor tyrosine kinase in invasion and metastasis. J 
Cell Physiol 2007;213:316-325.
14. Gentile A, Trusolino L, Comoglio PM. The Met tyrosine kinase receptor in development and 
cancer. Cancer Metastasis Rev 2008;27:85-94. 
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15. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase 
domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 1997;16:68-73.
16. Kim DW, Soo RA, Yang JCH, et al. Antitumor activity of tepotinib plus gefitinib in Asian 
patients with Met-positive NSCLC. 16th World Congress on Lung Cancer. 2015 September, 
Abstract No. 763.
17. Rimassa L. Tivantinib (ARQ 197) versus placebo in subjects (Pts) with hepatocellular 
carcinoma (HCC) who failed one systemic therapy: Results of a randomized controlled 
phase II trial (RCT). 2012 ASCO Annual Meeting.
18. Llovet JM, Peña CE, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients 
with advanced hepatocellular carcinoma. Clin Cancer Res 2012;18(8):2290-2300.
19. Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in 
hepatocellular carcinoma. J Natl Cancer Inst 2008;100:698-711.
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13
Appendices
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Appendix A: Scoring System for Met Immunohistochemistry 
Diagnostic
Clinical Score
Scoring Criteria
Positive
3+
U 50% tumor cells with membrane and/or cytoplasmic 
staining with strong intensity
2+
U 50% tumor cells with membrane and/or cytoplasmic 
staining with moderate intensity
Negative
1+
U 50% tumor cells with membrane and/or cytoplasmic 
staining with weak intensity but < 50% tumor cells with 
moderate or high intensity
0
Samples with no staining, or with < 50% tumor cells with 
membrane and/or cytoplasmic staining (could be 
combination of any staining intensities)
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Appendix B: Child-Pugh System 
The text below was obtained from the University of Washington Medical Center’s Criteria for 
Child-Pugh classification, which cites the following references:
Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for 
placement of adults on the liver transplant waiting list. Liver Transl Surg 1997;3(6):628-637.
Pugh RNH, Murray-Lyon IN, Dawson DL,  Pietroni MC, and Williams R. Transection of the 
esophagus for bleeding esophageal varices. Brit J Surgery 1973;60:646-645.
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood 
transfusion. N Engl J Med. 1996;274(9):473-481. 
Child-Pugh classification is defined as Grade A (mild; 5 to 6 points), Grade B (moderate; 
7 to 9 points), or Grade C (severe; 10 to 15 points). The clinical and biochemical measurements to 
determine Child-Pugh classification are presented in Table 8.
Table 8:
Clinical and Biochemical Measurements for Child-Pugh Classification
Clinical and Biochemical 
Measurements
Points Scored for Increasing Abnormality
1
2
3
Hepatic encephalopathy (grade)a
0b
1c or 2d
3e or 4f
Ascites
Absent
Mild
Moderate
Total bilirubin (mg/dL)
< 2.0
2.0 to 3.0
> 3.0
Serum albumin (g/dL)
> 3.5
2.8 to 3.5
< 2.8
Prothrombin time (sec prolonged)
or
Prothrombin time INRg
< 4
or
< 1.7
4 to 6
or
1.7 to 2.3
> 6
or
> 2.3
Abbreviations: INR, international normalized ratio.
a
Trey C, Burns DG, and Saunders SJ. Treatment of hepatic coma cornia by exchange blood transfusion. N Engl J Med. 
1996;274(9):473-481.
b
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram.
c
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves.
d
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
e
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves.
f
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
g
Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, et al. Minimal criteria for placement of adults on the liver 
transplant waiting list. Liver Transl Surg 1997;3(6):628-637.
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Appendix C: Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 
The text below was obtained from the following reference:  Eisenhauer EA, Therasse P, Bogaerts 
J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-247.
Definitions
Response and progression will be evaluated in this trial using the international criteria proposed 
by the RECIST Committee (version 1.1).  Changes in only the largest diameter (uni-dimensional 
measurement) of the tumor lesions are used in the RECIST criteria. Note:  Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy.
Measurable Disease
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
! 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm) 
! 10 mm caliper measurement by clinical exam (when superficial) 
! 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be U 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed.
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter U 10 to < 15 mm 
with conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques are all non-
measurable.
Bone lesions:
! Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance 
of bone lesions.
! Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross-sectional imaging techniques such as CT or MRI can be considered 
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as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
! Blastic bone lesions are non-measurable.
Cystic lesions:
! Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts.
! Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same subject, these are preferred for selection as target lesions.
Lesions with prior local treatment:
! Tumor lesions situated in a previously irradiated area, or in an area subjected to other local 
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Trial protocols should detail the conditions under which such lesions 
would be considered measurable.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 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), be representative of all 
involved organ, but in addition should be those that lend themselves to reproducible repeated 
measurements.
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis 
of U 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as 2 dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, saggital, or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis U 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered non-
pathological and should not be recorded or followed.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.  
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Non-target Lesions
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (e.g., ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and P10 mm diameter as assessed using calipers (e.g., skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the trial.
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 5 mm or less. As is described in Appendix II of the 
original source article cited above, when CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable 
in certain situations (e.g., for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from 1 assessment to the next. 
If new lesions are identified by ultrasound in the course of the trial, confirmation by CT or MRI is 
advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in 
selected instances.
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Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in trials where recurrence following complete response or 
surgical resection is an endpoint.
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a subject to 
be considered in complete response. Because tumor markers are disease specific, instructions for 
their measurement should be incorporated into protocols on a disease specific basis. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and prostate-specific antigen 
response (in recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer 
Intergroup has developed CA-125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line trials in ovarian cancer.
Cytology, histology: These techniques can be used to differentiate between partial response (PR)
and complete response (CR) in rare cases if required by protocol (for example, residual lesions in 
tumor types such as germ cell tumors, where known residual benign tumors can remain). When 
effusions are known to be a potential adverse event (AE) of treatment (e.g., with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of 
any effusion that appears or worsens during treatment can be considered if the measurable tumor 
has met criteria for response or stable disease (SD) in order to differentiate between response (or 
SD) and progressive disease (PD).
RESPONSE CRITERIA
Evaluation of Target Lesions
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-
target) must have reduction in short axis to < 10 mm.
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on trial (this includes the baseline sum if that is the smallest on trial). In addition to 
the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
(Note: the appearance of 1 or more new lesions is also considered progression). 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest sum diameters while on trial. 
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even 
if the nodes regress to below 10 mm on trial. This means that when lymph nodes are included as 
target lesions, the ‘sum’ of lesions may not be zero even if complete response criteria are met, 
since a normal lymph node is defined as having a short axis of < 10 mm. Electronic case report 
forms or other data collection methods may therefore be designed to have target nodal lesions 
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recorded in a separate section where, in order to qualify for CR, each node must achieve a short 
axis < 10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to be 
included in the sum of target lesions.
Target lesions that become ‘too small to measure’. While on trial, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes which 
are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not 
feel comfortable assigning an exact measure and may report them as being ‘too small to measure’. 
When this occurs it is important that a value be recorded on the CRF. If it is the opinion of the 
radiologist that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If 
the lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat, such as in 
the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible; therefore, 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
Lesions that split or coalesce on treatment. When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the ‘coalesced lesion’.
Evaluation of Non-target Lesions
While some non-target lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the time points specified in the protocol. 
CR: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.
PD: Unequivocal progression (see comments below) of existing non-target lesions. (Note: the 
appearance of 1 or more new lesions is also considered progression). 
When the subject also has measurable disease. In this setting, to achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target disease such that, even in the presence of SD or PR in target disease, the overall tumor 
burden has increased sufficiently to merit discontinuation of therapy. A modest ‘increase’ in the 
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size of 1 or more non-target lesions is usually not sufficient to quality for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target disease 
in the face of SD or PR of target disease will therefore be extremely rare.
When the subject has only non-measurable disease. This circumstance arises in some Phase III 
trials when it is not a criterion of trial entry to have measurable disease. The same general concept 
apply here as noted above, however, in this instance there is no measurable disease assessment to 
factor into the interpretation of an increase in non-measurable disease burden. Because worsening 
in non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable), a useful test that can be applied when assessing subjects for unequivocal progression 
is to consider if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e., an increase in tumor burden representing an additional 73% increase in 
‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic disease 
from localized to widespread, or may be described in protocols as ‘sufficient to require a change 
in therapy’. If ‘unequivocal progression’ is seen, the subject should be considered to have had 
overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial.
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e., not 
attributable to differences in scanning technique, change in imaging modality, or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the subject’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate PD. An example of this is the subject who has visceral 
disease at baseline and while on trial has a brain CT or MRI ordered which reveals metastases. 
The subject’s brain metastases are considered to be evidence of PD even if he/she did not have 
brain imaging at baseline.
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 initial scan.
While fludeoxyglucose positron emission tomography (FDG-PET) response assessments need 
additional trial, it is sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible ‘new’ disease). New 
lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
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a.
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans 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 FDG-PET 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.
Evaluation of Best Overall Response
The best OR is the best response recorded from the start of the trial treatment until the end of 
treatment taking into account any requirement for confirmation. On occasion, a response may not 
be documented until after the end of therapy, so protocols should be clear if post-treatment 
assessments are to be considered in determination of best OR. Protocols must specify how any 
new therapy introduced before progression will affect best response designation. The subject’s 
best OR assignment will depend on the findings of both target and non-target disease and will also 
take into consideration the appearance of new lesions. Furthermore, depending on the nature of 
the trial and the protocol requirements, it may also require confirmatory measurement. 
Specifically, in non-randomized trials where response is the primary endpoint, confirmation of PR 
or CR is needed to deem either one the ‘best OR’. 
The best OR is determined once all the data for the subject is known. Best response determination 
in trials where confirmation of complete or PR IS NOT required: Best response in these trials is 
defined as the best response across all time points (for example, a subject who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a best OR of PR). When SD 
is believed to be best response, it must also meet the protocol specified minimum time from 
baseline. If the minimum time is not met when SD is otherwise the best time point response, the 
subject’s best response depends on the subsequent assessments. For example, a subject who has 
SD at first assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD. The same subject lost to follow-up after the first SD assessment would be 
considered inevaluable.
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Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR*
CR
No
CR
CR
CR
Non-CR/non-PD
Not Evaluated
No
No
PR
PR
PR
Non-PD or not all evaluated
No
PR
SD
Not all evaluated
Non-PD or not all evaluated
Non-PD
No
No
SD
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
* CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease.
See text for more details.
Note:
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that subjects with CR may not 
have a total sum of ‘zero’ on the CRF. 
In trials where confirmation of response is required, repeated ‘NE’ time point assessments may 
complicate best response determination. The analysis plan for the trial must address how missing 
data/assessments will be addressed in determination of response and progression. For example, in 
most trials, it is reasonable to consider a subject with time point responses of PR-NE-PR as a 
confirmed response.
Subjects with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of PD at that time should be reported as ‘symptomatic deterioration’. Every 
effort should be made to document objective progression even after discontinuation of treatment. 
Symptomatic deterioration is not a descriptor of an objective response; it is a reason for stopping 
trial therapy. 
Conditions that define ‘early progression, early death and inevaluability’ are trial specific and 
should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of CR depends upon this determination, it is recommended that the residual lesion 
be investigated (fine needle aspirate/biopsy) before assigning a status of CR. The use of FDG-PET 
may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual 
radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and supported by disease specific 
medical literature for the indication. However, it must be acknowledged that both approaches may 
lead to false positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity.
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For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected.
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE
Confirmation
In non-randomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure the responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such trials. However, in all other circumstances, i.e., in 
randomized trials (Phase II or III) or studies where SD or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of the trial 
results.  However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not blinded.
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 to 8 weeks) that is defined in the trial protocol.
Duration of Overall Response
The duration of OR is measured from the time measurement criteria are first met for CR/PR 
(whichever is first recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded on 
trial).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Duration of Stable Disease
Stable disease is measured from the start of the treatment (in randomized trials, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
trial (if the baseline sum is the smallest, this is the reference for calculation of PD).
The clinical relevance of the duration of SD varies in different studies and diseases. If the 
proportion of subjects achieving SD for a minimum period of time is an endpoint of importance in 
a particular trial, the protocol should specify the minimal time interval required between 
2 measurements for determination of SD.
Note: The duration of response and SD as well as the progression-free survival are influenced by 
the frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define 
a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity, and standard practice. However, these 
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limitations of the precision of the measured endpoint should be taken into account if comparisons 
between trials are to be made.
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Appendix D: Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS)
Grade 
Description
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light housework, office work.
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair.
5
Dead.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol. 1982 Dec;5(6):649-55.
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Appendix E: New York Heart Association (NYHA) Criteria
Class
Description
I
No limitation: Ordinary physical activity does not cause undue fatigue, 
dyspnea, or palpitation.
II
Slight limitation of physical activity: Such subjects are comfortable at rest. 
Ordinary physical activity results in fatigue, palpitations, dyspnea, or 
angina.
III
Marked limitation of physical activity: Although subjects are comfortable 
at rest, less than ordinary physical activity will lead to symptoms.
IV
Inability to carry on physical activity without discomfort: Symptoms of 
congestive heart failure are present even at rest. With any physical activity, 
increased discomfort is experienced.
Source: Criteria Committee, New York Heart Association, Inc. Diseases of the heart and blood vessels. Nomenclature and 
criteria for diagnosis. 6th ed. Boston, Little, Brown and Co, 1964:114.
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Appendix F: FACT Hepatobiliary Symptom Index 8
The sponsor will provide training for relevant personnel (e.g., key investigators, clinical research 
associates) in the administration of the questionnaires so that subjects fill in the questionnaires as 
completely and accurately as possible. It is important that the significance and relevance of the 
data are explained carefully to participating subjects so that they are motivated to comply with 
data collection. The measures are self-reported and the subject must complete the questionnaires 
in private and should not be given help from relatives or clinic staff; help in interpreting the 
questions is not allowed. All subjects are required to take part in all PRO assessments. If feasible, 
ePRO software may be used for direct data entry by the subject.
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark 1 number per line to indicate your response as it applies to the past 7 days.
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GP1
I have a lack of energy
0
1
2
3
4
GP2
I have nausea
0
1
2
3
4
GP4
I have pain
0
1
2
3
4
C2
I am losing weight
0
1
2
3
4
CNS7
I have pain in my back
0
1
2
3
4
HI7
I feel fatigued
0
1
2
3
4
Hep2
I am bothered by jaundice or yellow color 
to my skin
0
1
2
3
4
Hep8
I have discomfort or pain in my stomach 
area
0
1
2
3
4
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Appendix G: Functional Assessment of Cancer Therapy – Hepatobiliary
The sponsor will provide training for relevant personnel (e.g., key investigators, clinical research 
associates) in the administration of the questionnaires so that subjects fill in the questionnaires as 
completely and accurately as possible. It is important that the significance and relevance of the 
data are explained carefully to participating subjects so that they are motivated to comply with 
data collection. The measures are self-reported and the subject must complete the questionnaires 
in private and should not be given help from relatives or clinic staff; help in interpreting the 
questions is not allowed. All subjects are required to take part in all PRO assessments. If feasible, 
ePRO software may be used for direct data entry by the subject.
Below is a list of statements that other people with your illness have said are important. Please 
circle or mark 1 number per line to indicate your response as it applies to the past 7 days.
PHYSICAL WELL-BEING
Not at 
all
A little 
bit
Some-
what
Quite 
a bit
Very 
much
GP1
I have a lack of energy
0
1
2
3
4
GP2
I have nausea
0
1
2
3
4
GP3
Because of my physical condition, I have 
trouble meeting the needs of my family
0
1
2
3
4
GP4
I have pain
0
1
2
3
4
GP5
I am bothered by side effects of treatment
0
1
2
3
4
GP6
I feel ill
0
1
2
3
4
GP7
I am forced to spend time in bed
0
1
2
3
4
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Please circle or mark 1 number per line to indicate your response as it applies to the 
past 7 days.
SOCIAL/FAMILY WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GS1
I feel close to my friends
0
1
2
3
4
GS2
I get emotional support from my family
0
1
2
3
4
GS3
I get support from my friends
0
1
2
3
4
GS4
My family has accepted my illness
0
1
2
3
4
GS5
I am satisfied with family communication 
about my illness
0
1
2
3
4
GS6
I feel close to my partner (or the person 
who is my main support)
0
1
2
3
4
Q1
Regardless of your current level of sexual 
activity, please answer the following question. 
If you prefer not to answer it, please mark this 
box and go to the next section.
GS7
I am satisfied with my sex life
0
1
2
3
4
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Please circle or mark 1 number per line to indicate your response as it applies to the 
past 7 days.
EMOTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GE1
I feel sad
0
1
2
3
4
GE2
I am satisfied with how I am coping with 
my illness
0
1
2
3
4
GE3
I am losing hope in the fight against my 
illness
0
1
2
3
4
GE4
I feel nervous
0
1
2
3
4
GE5
I worry about dying
0
1
2
3
4
GE6
I worry that my condition will get worse
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-
what
Quite
a bit
Very 
much
GF1
I am able to work (include work at home)
0
1
2
3
4
GF2
My work (include work at home) is 
fulfilling
0
1
2
3
4
GF3
I am able to enjoy life
0
1
2
3
4
GF4
I have accepted my illness
0
1
2
3
4
GF5
I am sleeping well
0
1
2
3
4
GF6
I am enjoying the things I usually do for 
fun
0
1
2
3
4
GF7
I am content with the quality of my life 
right now
0
1
2
3
4
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Please circle or mark 1 number per line to indicate your response as it applies to the 
past 7 days.
ADDITIONAL CONCERNS
Not at 
all
A little 
bit
Some-
what
Quite
a bit
Very 
much
C1
I have swelling or cramps in my stomach 
area
0
1
2
3
4
C2
I am losing weight
0
1
2
3
4
C3
I have control of my bowels
0
1
2
3
4
C4
I can digest my food well
0
1
2
3
4
C5
I have diarrhea (diarrhoea)
0
1
2
3
4
C6
I have a good appetite
0
1
2
3
4
Hep1
I am unhappy about a change in my 
appearance
0
1
2
3
4
CNS7
I have pain in my back
0
1
2
3
4
Cx6
I am bothered by constipation
0
1
2
3
4
H17
I feel fatigued
0
1
2
3
4
An7
I am able to do my usual activities 
0
1
2
3
4
Hep2
I am bothered by jaundice or yellow color 
to my skin
0
1
2
3
4
Hep 3
I have had fevers (episodes of high body 
temperature)
0
1
2
3
4
Hep 4
I have had itching
0
1
2
3
4
Hep 5
I have had a change in the way food tastes
0
1
2
3
4
Hep 6
I have had chills
0
1
2
3
4
HN 2
My mouth is dry
0
1
2
3
4
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Hep 8
I have discomfort or pain in my stomach 
area
0
1
2
3
4
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Appendix H: Phase Ib Schedule of Dosing and Assessments
Screening
Cycle 1
Day
Cycle 2
Daya
Cycle ; 3
Day
EoT 
Visitb
Post-
Treatment 
F/U Visitc
Survival 
F/Ud
DAY
-14 to 0
1
2
8
15
1
8
15
1
MSC2156119J
QD
Written informed consent
X
Dispensing of study drug 
X
X
X
Demography, height 
X
Medical history
X
Smoking status and alcohol use
X
Tumor biopsy
Xe
Xe
Xf
Physical examination/weight
X
Xg
X
X
X
X
X
X
X
X
X
ECOG PS
X
Xg
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
ECGi
X
Xj
Xj
Xk
Xk
Xl
X
Hematology and coagulationm
X
Xg
X
X
X
X
X
X
X
Xl
X
Chemistryn
X
Xg
X
X
X
X
X
X
X
Xl
X
Urinalysiso
X
Xg
X
X
Xl
X
HBV viral serology panelp
Xq
Xr
Xl,r
HBV DNA (viral load)r
Xq
Xr
Xl,r
HCV RNA-PCR (viral load)s
Xq
Xs
Xl,s
Serum pregnancy test (if applicable)t
X
Tumor assessment (RECIST v 1.1)u
X
Xv
Xw
Serum AFP
X
Xg
X
X
X
PK blood samples
Xx
Xx
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Screening
Cycle 1
Day
Cycle 2
Daya
Cycle ; 3
Day
EoT 
Visitb
Post-
Treatment 
F/U Visitc
Survival 
F/Ud
DAY
-14 to 0
1
2
8
15
1
8
15
1
Subject survival and anticancer therapies
X
Adverse events assessment
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication/procedure
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: AFP, alpha-fetoprotein; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; 
CNS, central nervous system; CT, computed tomography; ECG, electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; EoT, 
end of treatment; F/U, follow-up; GGT, gamma-glutamyl transpeptidase; HBc, hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface 
antigen; HBV, hepatitis B virus; HCC; hepatocellular carcinoma; HCV, hepatitis C virus; INR, international normalized ratio; RECIST, response evaluation 
criteria in solid tumors; MRI, magnetic resonance imaging; 
; PK, pharmacokinetic; PT, prothrombin time; RNA, ribonucleic acid.
a
All visits and assessments from Cycle 2 onwards may be performed +/- 5 days to accommodate unforeseen delays, holidays, or vacations.
b
End of treatment visit, performed on the last day of treatment, whether at the end of a cycle or not. The last day of treatment is defined as the day on which it is determined 
that the subject will no longer receive the study drug.
c
Post-treatment follow-up visit, performed within 30 ± 3 days after the last treatment for all subjects who discontinue trial treatment permanently, including subjects who 
have completed an end of treatment visit.
d
Survival data will be collected every 3 months after end of treatment until death or the end of the trial.
e
Undergoing paired tumor biopsy is not mandatory but highly recommended for subjects with accessible tumors: the paired tumor biopsy will be performed before the first 
trial treatment (i.e., during Screening or on Cycle 1, Day 1, prior to the first dose of trial treatment) and anytime between Cycle 1, Day 15, and the beginning of Cycle 3
(optional, will be collected after subjects have signed a separate Informed Consent Form). A predose PK is recommended to be taken on the day of the second biopsy.
f
Optional tumor biopsy, to be taken at the time of progression on the day of the last treatment.
g
Only if last assessments were performed > 7 days prior to Cycle 1, Day 1.
h
Heart rate, diastolic and systolic blood pressure in a seated position of 5 minutes. On days when ECGs are taken, vital signs should be taken within 30 minutes prior to the
ECG recording. Where ECGs are performed in triplicate, vital signs only need to be recorded once prior to the first ECG.
i
All ECGs to be taken as single 12-lead resting ECGs, except at time points where PK samples are also obtained, in which case triplicate ECGs should be obtained at 
2-minute intervals (± 1 minute). Vital signs (heart rate, systolic, and diastolic blood pressure, in a seated position) should be taken within 30 minutes prior to each ECG 
recording after sitting for 5 minutes.
j
ECGs are recorded after at least 5 minutes rest in supine position at predose (within 60 minutes prior to dosing on Cycle 1 Day 1 and within 40 minutes prior to dosing on 
Cycle 1 Day 15) and at 4 hours (± 12 minutes) postdose. ECG recordings should be performed within 10 minutes before PK sampling time-points on days where both 
assessments are performed.
k
Predose only.
l
Not required for subjects with a previous assessment within 7 days of the EoT visit.
m
Hemoglobin, hematocrit, red blood cell count, white blood cell count, differential, platelet count, and coagulation (PT, aPTT, and INR). For the subject eligibility check at 
screening, these samples must be reported by a local laboratory.
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n
BUN, creatinine, AST, ALT, GGT, total bilirubin (including direct fraction if total bilirubin is abnormal), lipase, amylase, total protein, albumin, alkaline phosphatase, 
sodium, potassium, calcium, magnesium, and glucose. For the subject eligibility check at screening, these samples must be reported by a local laboratory.
o
Urinalysis: dipstick followed by microscopic examination if abnormal results.
p
HBV serology panel: HBc antibodies, HBs antibodies, HBs antigen, HBe antigen, HBe antibodies.
q
The purpose of these samples is to establish baseline values. Alternatively, samples may be taken predosing on Day 1 of Cycle 1.
r
HBV DNA will be evaluated in all subjects at baseline. Thereafter, HBV DNA and serology will be monitored every 3 cycles and at EoT for all subjects with known HBV 
history, or who were positive for HBV DNA at baseline, or are positive for HBV serology. See Section 7.5.3.1.
s
HCV RNA-PCR will be evaluated in all subjects at baseline. Thereafter, HCV RNA-PCR will be monitored every 3 cycles and at EoT for all subjects with known HCV 
history or who were positive for HCV RNA-PCR at baseline. See Section 7.5.3.1.
t
Only for women of childbearing potential, including those who have had a tubal ligation.
u
Complete tumor assessment of all lesions by radiographic or other modality (using RECIST v 1.1). CT or MRI of the chest, abdomen, and pelvis to evaluate disease in 
these locations. CT/MRI of the head at baseline for subjects who are suspected to have CNS metastases. Tumor assessments to be performed at baseline and after every 
2 cycles (6 weeks) (i.e., before start of next odd-numbered cycle) until Cycle 13 and after every 4 cycles (12 weeks) after Cycle 13. The scheduled 6-week (or 12-week) 
interval between tumor response evaluations should be maintained through the trial regardless of any delay or interruption to trial treatment. Subjects who are discontinued 
from the trial due to unacceptable toxicity should perform the tumor assessment at 6 week intervals until Cycle 13 and 12 week interval (4 cycles) after Cycle 13 until 
disease progression, starting a new therapy, or death. Clinical progression, at any time, requires a physical examination and prompt radiological confirmation rather than 
waiting for the next scheduled imaging assessment. If unscheduled imaging does not meet progressive disease by RECIST v1.1, the next scheduled imaging assessment 
should still be performed on time unless the next scheduled imaging assessment is within 14 days following the unscheduled imaging. See Section 8.3.
v
To be performed predose on, or within 5 days prior to, Day 1 of Cycles 3, 5, 7, 9, 11, 13, i.e., at 6-week intervals, and every 4 cycles thereafter, i.e., at 12-week intervals,
until disease progression, starting a new anti-tumor therapy, or death. The scheduled 6-week (or 12-week) interval between tumor response assessments should be 
maintained through the trial regardless of any delay or interruption to trial treatment.
w
If a subject discontinues trial treatment for a reason other than disease progression or death, tumor assessment will be performed at EoT if it has not been done within the 
past 6 weeks, and will be repeated every 6 weeks (± 1 week) until radiological progression per RECIST v 1.1, death or start of new anticancer therapy, whichever occurs 
first.
x
Samples will be taken predose, and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours postdose. Note: The 24-hour postdose samples from Day 1 and Day 15 are the predose samples 
from Day 2 and Day 16, respectively. The predose sample on Cycle 1 Day 1 should be taken within 60 minutes prior to dose. The predose sample on Cycle 1 Day 15 
(trough value) should be taken within 30 minutes predose. Postdose PK samples should be taken within ± 5% of the scheduled assessment time, e.g., the 4-hour postdose 
sample should be obtained at 4 hours ± 12 minutes.
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Appendix I:
Phase II Schedule of Dosing and Assessments
Screening
Cycle 1
Day
Cycle 2
Daya
Cycle ; 3
Day
EoT 
Visitb
Post-
Treatment 
F/U Visitc
Survival 
F/Ud
Molecular 
Prescreening
Clinical 
Screening
DAY
N -14 to 0
1
8
15
1
8
1
MSC2156119J
QD
Sorafenib
BID
Written informed consent
(Prescreening)e
X
Written informed consent (main study)e
X
Eligibility
Xe
Randomization by IVRS
X
Dispensing of study drug 
X
X
X
Demography, heighte
X
Medical historye
X
Smoking status and alcohol use
X
Tumor biopsy
Xf
Xf
Xg
MET status determinatione
X
Physical examination/weighth
X
Xi
X
X
X
X
X
X
X
ECOG PSh
X
Xi
X
X
X
X
Vital signsh,j
X
X
X
X
X
X
X
X
ECGh,k
X
Xl
Xm
Xl
Xm
Xn
X
Hematology and coagulationh,o
X
Xi
X
X
X
X
X
Xn
X
Chemistryh,p
X
Xi
X
X
X
X
X
Xn
X
Urinalysish,q
X
Xi
X
X
Xn
X
HBV viral serology panelh,r
Xs
Xt
Xn,t
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Screening
Cycle 1
Day
Cycle 2
Daya
Cycle ; 3
Day
EoT 
Visitb
Post-
Treatment 
F/U Visitc
Survival 
F/Ud
Molecular 
Prescreening
Clinical 
Screening
DAY
N -14 to 0
1
8
15
1
8
1
HBV DNA (viral load)h,t
Xs
Xt
Xn,t
HCV RNA-PCR (viral load)h,u
Xs
Xu
Xn,u
Serum pregnancy test (if applicable)h,v
X
Tumor assessment (RECIST v 1.1)w
X
Xx
Xy
Serum AFP
X
Xi
X
X
X
Subject survival and anticancer therapies
X
Adverse events assessment
X
X
X
X
X
X
X
X
X
Concomitant medication/procedure
X
X
X
X
X
X
X
X
X
FHSI-8
X
X
X
X
X
X
PRO (FACT-HP)
X
X
Xdd
Xdd
Abbreviations: AFP, alpha-fetoprotein; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; 
CNS, central nervous system; CT, computed tomography; ECG, electrocardiogram; ECOG PS, Eastern Cooperative Oncology Group performance status; EoT, 
end of treatment; 
; FHSI-8, FACT Hepatobiliary Symptom Index 8; F/U, follow-up; GGT, 
gamma-glutamyl transpeptidase; HBc, hepatitis B core antigen; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC; 
hepatocellular carcinoma; HCV, hepatitis C virus; ICF, Informed Consent Form; INR, international normalized ratio; IVRS; interactive voice response system; 
RECIST, response evaluation criteria in solid tumors; MRI, magnetic resonance imaging; 
; 
; PRO, subject reported 
outcomes; PT, prothrombin time; RNA, ribonucleic acid.
a
All visits and assessments from Cycle 2 onwards may be performed +/- 5 days to accommodate unforeseen delays, holidays, or vacations.
b
End of treatment visit, performed on the last day of treatment, whether at the end of a cycle or not. The last day of treatment is defined as the day on which it is determined 
that the subject will no longer receive the study drug.
c
Post-treatment follow-up visit, performed within 30 ± 3 days after the last treatment for all subjects who discontinue trial treatment permanently, including subjects who 
have completed an end of treatment visit.
d
Survival data will be collected every 3 months after end of treatment until death or the end of the trial.
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e
MET status will be confirmed during Molecular Prescreening after the subject has signed the prescreening ICF. Demographic data and disease history will also be collected 
during Molecular Prescreening once the subject has signed the main ICF. Clinical Screening will include laboratory parameters, medical history and all other assessments 
needed to confirm subject eligibility, plus demographic data and disease history if not already collected. Clinical Screening assessments must be completed within 14 days 
prior to the initiation of study treatment. MET status rescoring will be performed as a quality control measure; subjects with a MET status of 1+ or ‘not assessable’ on 
rescoring will be excluded from the modified intent-to-treat population.
f
Undergoing paired tumor biopsy is not mandatory, but highly recommended for subjects with accessible tumors: the paired tumor biopsy will be performed before the first 
treatment (i.e., during screening or on Cycle 1, Day 1, prior to the first dose of trial treatment) and anytime between Cycle 1, Day 15 and the beginning of Cycle 3 (optional, 
will be collected after subjects have signed a separate ICF).
g
Optional tumor biopsy, to be taken at the time of progression on the day of the last treatment.
i.
Only if screening/last assessments were performed & 7 days prior to Cycle 1, Day 1.
j
Heart rate, diastolic and systolic blood pressure in a seated position of 5 minutes. On days when ECGs are taken, vital signs should be taken within 30 minutes prior to the 
ECG recording. Where ECGs are performed in triplicate, vital signs only need to be recorded once prior to the first ECG.
k
All ECGs to be taken as single 12-lead resting ECGs, except at time points where PK samples are also obtained, in which case triplicate ECGs should be obtained at 
2-minute intervals (± 1 minute). Vital signs (heart rate, systolic, and diastolic blood pressure, in a seated position) should be taken within 30 minutes prior to each ECG 
recording after sitting for 5 minutes.
l
ECGs are recorded after at least 5 minutes rest in supine position at predose (within 60 minutes prior to dosing on Cycle 1 Day 1 and within 40 minutes prior to dosing on 
Cycle 2 Day 1) (MSC2156119J and sorafenib arms) and at 4 hours (± 12 minutes) postdose (MSC2156119J arm only). ECG recordings should be performed within 
10 minutes before PK sampling time-points on days where both assessments are performed.
m
Predose only.
n
Not required for subjects with a previous assessment within 7 days of the EoT visit.
o
Hemoglobin, hematocrit, red blood cell count, white blood cell count, differential, platelet count, and coagulation (PT, aPTT, and INR). For the subject eligibility check at 
Clinical Screening, these samples must be reported by a local laboratory.
p
BUN, creatinine, AST, ALT, GGT, total bilirubin (including direct fraction if total bilirubin abnormal), lipase, amylase, total protein, albumin, alkaline phosphatase, 
sodium, potassium, calcium, magnesium and glucose. For the subject eligibility check at Clinical Screening, these samples must be reported by a local laboratory.
q
Urinalysis: dipstick followed by microscopic examination if abnormal results.
r
HBV serology panel: HBc antibodies, HBs antibodies, HBs antigen, HBe antigen, HBe antibodies.
s
The purpose of these samples is to establish baseline values. They may be taken during Clinical Screening or predose on Day 1 of Cycle 1.
t
HBV DNA will be evaluated in all subjects at baseline. Thereafter, HBV DNA and serology will be monitored every 3 cycles and at EoT for all subjects with known HBV 
history, or who were positive for HBV DNA at baseline, or are positive for HBV serology. See Section 7.5.3.1.
u
HCV RNA-PCR will be evaluated in all subjects at baseline. Thereafter, HCV RNA-PCR will be monitored every 3 cycles and at EoT for all subjects with known HCV 
history or who were positive for HCV RNA-PCR at baseline. See Section 7.5.3.1.
v
Only for women of childbearing potential, including those who have had a tubal ligation. 
w
Complete tumor assessment of all lesions by radiographic or other modality (using RECIST v 1.1). CT or MRI of the chest, abdomen, and pelvis to evaluate disease in 
these locations. CT/MRI of the head at baseline for subjects who is suspected to have CNS metastases. Tumor assessments to be performed at baseline and after every 2
cycles (6 weeks) (i.e., before start of next odd-numbered cycle) until Cycle 13 and after every 4 cycles (12 weeks) after Cycle 13. The scheduled 6-week (or 12-week) 
interval between tumor response evaluations should be maintained through the trial regardless of any delay or interruption to trial treatment. Subjects who are discontinued 
from the trial due to unacceptable toxicity should perform the tumor assessment at 6-week intervals until Cycle 13 and 12-week interval (4 cycles) after Cycle 13 until 
disease progression, starting a new therapy, or death. Clinical progression, at any time, requires a physical examination and prompt radiological confirmation rather than 
waiting for the next scheduled imaging assessment. If unscheduled imaging does not meet progressive disease by RECIST v1.1, the next scheduled imaging assessment 
should still be performed on time unless the next scheduled imaging assessment is within 14 days following the unscheduled imaging. See Section 8.3.
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x
To be performed predose on, or within 5 days prior to, Day 1 of Cycles 3, 5, 7, 9, 11, 13, i.e., at 6-week intervals, and every 4 cycles thereafter, i.e., at 12-week intervals,
until disease progression, starting a new anti-tumor therapy, or death. The scheduled 6-week (or 12 week) interval between tumor response assessments should be 
maintained through the trial regardless of any delay or interruption to trial treatment.
y
If a subject discontinues trial treatment for a reason other than disease progression or death, tumor assessment will be performed at EoT if it has not been done within the 
past 6 weeks, and will be repeated every 6 weeks (± 1 week) until radiological progression per RECIST v 1.1, death or start of new anticancer therapy, whichever occurs 
first.
 
 
 
dd
On Cycle 5, Day 1 and the end of treatment visit (only if the subject discontinued before Cycle 5, Day 1).
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Appendix J: Blood Sampling Schedule and Blood Volumes for PK, 
, and 
Phase Ib
Day
Time points
H = hours after dosing
PK
Cycle
2 mL
Cycle 1
Day 1
Predosing
X
H 0.25
X
H 0.5
X
H 1
X
H 2
X
H 4
X
H 8
X
H 10
X
H 24b
X
Day 15
Predosing
X
H 0.25
X
H 0.5
X
H 1
X
H 2
X
H 4
X
H 8
X
H 10
X
H 24c
X
Cycle 2
Day 1
Predosing
-
Cycle 3
Day 1
Predosing
-
EoT
-
Abbreviation: EoT, end of treatment; H, hour; Pd, pharmacodynamic; 
; PK, pharmacokinetic.
a  Optional. Will be collected after subjects have signed a separate Informed Consent Form.
b  The 24-hour postdose sample is the predose samples from Day 2.
c  The 24-hour postdose sample is the predose samples from Day 16.
The predose PK sample on Cycle 1 Day 1 should be taken within 60 minutes prior to dose. The predose PK sample on Cycle 1 
Day 15 (trough value) should be taken within 30 minutes prior to dose. Postdose PK samples should be taken within ± 5% of the 
scheduled assessment time, e.g., the 4-hour postdose sample should be obtained at 4 hours ± 12 minutes.
All other predosing samples should be taken within 60 minutes before each treatment administration.
An anticipated total blood sample volume of approximately 122 mL will be taken in Phase Ib.
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Appendix K: Barcelona Clinic Liver Cancer Staging Classification
The BCLC staging classification is used to stage HCC at baseline according to the number and 
size of tumors, and the subject’s ECOG performance status and hepatic function (using the 
Child-Pugh score) (Table 9). 
Table 9:
Barcelona Clinical Liver Cancer Staging Classification
Barcelona Clinic Liver Cancer Staging Classificationa
Stage
ECOG PS
Tumor characteristics
Hepatic Function
A1
0
Solitary < 5 cm
No portal hypertension; 
normal bilirubin
A2
0
Solitary < 5 cm
Portal hypertension; 
normal bilirubin
A3
0
Solitary < 5 cm
Portal hypertension; 
abnormal bilirubin
A4
0
Multifocal Z 3 and < 3 cm
Child Pugh A-B
B
0
Multifocal > 3 or U 3 cm
Child Pugh A-B
C
1-2
Vascular invasion or extrahepatic spread
Child Pugh A-B
D
3-4
Any
Child Pugh C
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status.
a
Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 
1999;19(3):329-38.
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SAP_001.pdf: 
MSC2156119J
Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with HCC
EMR200095-004
Appendix 16.1.9
Documentation of Statistical Methods
x
Statistical Analysis Plan for Phase Ib, Version 1.0, Amend 1.0; 08 May 2017
x
Statistical Analysis Plan for Phase II, Version 1.1; 12 February 2018
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 Statistical Analysis Plan for Phase Ib 
Clinical Trial Protocol 
Identification No. 
EMR 200095-004 
Title: 
A Multicenter, Treated, Phase Ib/II Trial to Evaluate the 
Efficacy, Safety, and Pharmacokinetics of MSC2156119J as 
Monotherapy Versus Sorafenib in Asian Subjects with MET+ 
Advanced Hepatocellular Carcinoma and Child-Pugh Class A 
Liver Function 
Trial Phase 
Phase Ib/II 
Investigational Medicinal 
Product(s) 
MSC2156119J (Tepotinib)  
Clinical Trial Protocol 
Version 
24 Mar 2017/Version 4.0 
 
Statistical Analysis Plan 
Author 
 
Statistical Analysis Plan 
Date and Version 
30 Dec 2016/ Version 1.0 
08 May 2017/ Final Amend 1.0 
 
Statistical Analysis Plan 
Reviewers 
, Senior Statistical Reviewer, 
  
, Trial Biostatistician, Merck Serono 
, 
, Merck Serono 
, 
, Merck Serono 
, 
, Merck Serono 
 
 
 
 
 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies. 
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany or its affiliate.  
Copyright © 2016 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved. 
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Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with HCC 
EMR 200095-004  
Version 1.0, Amend 1.0 
 
 
 
 
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2 
   Table of Contents 
1 
Signature Page .................................................................................. 2 
2 
Table of Contents .............................................................................. 3 
3 
List of Abbreviations and Definition of Terms .................................. 5 
4 
Modification History ......................................................................... 9 
5 
Purpose of the Statistical Analysis Plan ............................................. 9 
6 
Summary of Clinical Trial Features ................................................... 9 
7 
Sample Size .................................................................................... 12 
8 
Overview of Planned Analyses for Phase Ib .................................... 13 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol ....... 13 
10 
Protocol Deviations and Analysis Sets............................................. 13 
10.1 
Definition of Protocol Deviations .................................................... 13 
10.2 
Definition of Analysis Sets and Subgroups ...................................... 13 
11 
General Specifications for Statistical Analyses ................................ 14 
12 
Trial Subjects .................................................................................. 18 
12.1 
Disposition of Subjects and Discontinuations .................................. 18 
12.2 
Protocol Deviations ......................................................................... 18 
12.2.1 
Important Protocol Deviations ......................................................... 18 
13 
Demographics and Other Baseline Characteristics ........................... 19 
13.1 
Demographics ................................................................................. 19 
13.2 
Medical History .............................................................................. 19 
13.3 
Other Baseline Characteristics, Anti-Cancer Therapy and Surgery .. 19 
13.3.1 
Disease History ............................................................................... 19 
13.3.2 
Other Baseline Characteristics ......................................................... 20 
13.3.3 
Prior Anti-Cancer Therapy and Surgery .......................................... 20 
 
 
 
 
 
 
14 
Previous and Concomitant Medications/Procedures......................... 23 
14.1 
Previous and concomitant medications: ........................................... 24 
14.2 
Concurrent procedures .................................................................... 24 
14.3 
Anti-Cancer Treatment after Treatment Termination ....................... 24 
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15 
Treatment Exposure ........................................................................ 25 
16 
Endpoint Evaluation ........................................................................ 26 
16.1 
Primary Endpoint Analyses ............................................................. 26 
16.2 
Secondary Endpoint Analyses ......................................................... 26 
16.2.1 
Progression-free Survival (PFS) Assessed by Investigator ............... 26 
16.2.2 
Time-to-Progression (TTP) Assessed by Investigator ...................... 28 
16.2.3 
Overall Survival (OS) ..................................................................... 28 
16.2.4 
Antitumor Activity Assessed by Investigator ................................... 29 
16.2.5 
Pharmacokinetics ............................................................................ 30 
16.3 
Other Endpoint Analyses ................................................................. 33 
16.3.1 
Tumor Shrinkage ............................................................................ 33 
 
 
17 
Safety Evaluation ............................................................................ 34 
17.1 
Adverse Events ............................................................................... 34 
17.1.1 
All Adverse Events ......................................................................... 35 
17.1.2 
Adverse Events Leading to Treatment Discontinuation ................... 36 
17.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ............................................................................... 36 
17.2.1 
Deaths ............................................................................................. 36 
17.2.2 
Serious Adverse Events ................................................................... 37 
17.2.3 
Adverse Event of Special Interest .................................................... 37 
17.3 
Clinical Laboratory Evaluation ........................................................ 37 
17.4 
Vital Signs ...................................................................................... 38 
17.5 
ECG ................................................................................................ 39 
17.6 
Other Safety Evaluations ................................................................. 40 
18 
Reporting Conventions .................................................................... 40 
19 
References ...................................................................................... 40 
20 
Appendix ........................................................................................ 40 
 
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3 
List of Abbreviations and Definition of Terms 
 
Abbreviation 
Definition 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
AST 
Aspartate Aminotransferase 
ATP 
Adenosine Triphosphate 
AUC 
Area Under the Curve 
AUC0-t 
Area Under the Concentration-time Curve from Time Zero to the 
Last Quantifiable Concentration 
Cav 
Average Plasma Concentration 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CL/F 
Apparent Systemic Clearance 
Cmax 
Maximum Plasma Concentration 
c-Met 
Mesenchymal-Epithelial Transition Factor Gene 
Cmin 
Minimum Plasma Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
CV 
Coefficient of Variation (%) 
DBP 
Diastolic Blood Pressure 
DLT 
Dose-Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DS 
Drug Substance 
ECG  
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
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GCP 
Good Clinical Practice 
GeoCV 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
GGT 
Gamma-Glutamyl Transpeptidase  
GMP 
Good Manufacturing Practice 
HBeAg 
Hepatitis B extracellular antigen 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular carcinoma 
HR 
Hazard ratio 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDMC  
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISH 
In Situ Hybridization 
ITT 
Intent-to-Treat 
IVRS 
Interactive Voice Response System 
LCSS 
Lung Cancer Symptom Scale 
LLOQ 
Lower Level of Quantification 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary For Regulatory Activities 
MR(AUC0-t) 
Metabolite to Parent Ratio based on AUC0-t 
MR(Cmax) 
Metabolite to Parent Ratio based on Cmax 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MW 
Molecular Weight 
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NCI 
National Cancer Institute 
OR 
Objective Response 
OS  
Overall Survival 
PD  
Progressive Disease 
Pd 
Pharmacodynamics 
PET 
Positron Emission Tomography 
PFS  
Progression Free Survival 
P-gp 
P-Glycoprotein 
PGx 
Pharmacogenomics 
PK 
Pharmacokinetics 
PoC 
Proof of Concept 
PP 
Per Protocol 
PR 
Partial Response 
PT 
Prothrombin Time 
PTF 
Peak Trough Fluctuation Ratio (in %) 
Racc(AUC) 
Accumulation Factor for AUCĲ 
Racc(Cmax) 
Accumulation Factor for Cmax 
RBC 
Red Blood Cells 
RECIST  
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Stable Disease 
SEM 
Standard Error of the Mean 
SMC  
Safety Monitoring Committee 
StD  
Standard Deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
Ĳ 
Dosing Interval 
t1/2 
Half-Life 
TEAE 
Treatment-Emergent Adverse Event 
TKI 
Tyrosine Kinase Inhibitor 
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tlag 
Time Prior to the First Quantifiable Concentration 
tmax 
Time to Maximum Concentration 
TNM 
Tumor, Lymph Nodes, Metastasis 
TTSP 
Time to Symptom Progression 
UDP 
Uridine 5’-Diphospho 
ULN 
Upper Limit of Normal 
V/f 
Volume of Distribution  
Vss/f 
Volume of Distribution at Steady State 
Vz/f 
Apparent Volume of Distribution Associated to the Terminal 
Phase 
WBC 
White Blood Cells 
Ȝz 
Terminal Phase Rate Constant  
 
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Efficacy, Safety, and PK of MSC2156119J in Asian Subjects with HCC 
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4 
Modification History 
Unique Identifier for SAP 
Version 
Date of SAP 
Version 
Author 
Changes from the Previous Version 
Final V1.0 
02Dec2016 
 
Not Applicable – First Version 
Amend v1.0 
26Mar2017 
 
Add 
 sections and update per dry run 
comments 
Final Amend V1.0 
08May2017 
 
Update review comment 
 
5 
Purpose of the Statistical Analysis Plan 
The purpose of this SAP is to document technical and detailed specifications for the phase Ib 
final analysis of data collected for protocol EMR 200095-004 Version 4.0 dated 24Mar2017 and 
Version 4.1 dated 27Mar2017 for Korea only. Results of the analyses described in this SAP will 
be included in the Clinical Study Report (CSR). Additionally, the planned analyses identified in 
this SAP will be included in regulatory submissions or future manuscripts. Any post-hoc, or 
unplanned analyses performed to provide results for inclusion in the CSR but not identified in 
this prospective SAP will be clearly identified in the CSR.  
The SAP is based upon section 8 (Statistics) of the trial protocol and is prepared in compliance 
with ICH E9.  
6 
Summary of Clinical Trial Features 
 
Trial Objectives 
Primary Objectives 
• To confirm the recommended Phase II dose (RP2D) of 
MSC2156119J administered orally once daily at a 21-day cycle 
in subjects with advanced hepatocellular carcinoma (HCC) and 
Child-Pugh class A liver function. The target RP2D in HCC 
subjects is the RP2D as determined in the global first-in-man 
(FIM) trial, i.e., 500 mg once daily 
Secondary Objectives 
• To characterize the single and multiple dose pharmacokinetics 
(PK), preliminary antitumor activity, and biochemical response 
of MSC2156119J in Asian subjects with HCC and Child-Pugh 
class A liver function 
Exploratory Objectives 
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• 
 
 
Trial design and 
plan 
Phase Ib will be an open label, single arm trial at selected sites in 
mainland China, South Korea, and Taiwan. 
The classical “3+3” design will be applied for sites in South Korea and 
Taiwan, with a dose escalation phase and a dose confirmation phase. In 
addition and separate from the “3+3” trial cohorts, the SMC may 
recommend to add up to an additional 12 subjects in 1 or more dose 
cohorts at dose levels at or above the RP2D, and up to 3 subjects will be 
enrolled in a separate cohort at selected sites in mainland China. 
Planned number of 
subjects 
Up to 21 subjects, including 18 subjects from South Korea and Taiwan 
following a “3+3” dose escalation method. The SMC may recommend 
to enroll up to an additional 12 subjects in one or more dose cohorts at 
dose levels at or above the RP2D. Up to an additional 3 subjects from 
the mainland China sites. 
Schedule of visits 
and assessments 
Subjects will be screened for up to 14 days prior to study treatment. 
Informed consent will be obtained prior to performing any trial 
assessment. 
MSC2156119J (Phase Ib) will be administered once daily over a 21-day 
cycle, which may repeat until disease progression (as determined by the 
investigator), intolerable toxicity, or withdrawal from the trial. 
For Phase Ib, scheduled visits during the treatment period will occur on 
Days 1, 2, 8, and 15 of Cycle 1; Days 1, 8, and 15 of Cycle 2; and Day 
1 of Cycles  3.  
At each scheduled visit during the treatment period, physical 
examination/weight, vital signs (except as noted below), hematology, 
coagulation, chemistry, adverse events (AEs), and concomitant 
medication assessments will be performed.  
Subjects will also be assessed at the discontinuation of the trial
medication. Study drug post-treatment follow-up visit will be 
performed within 30 ± 3 days after the last dose for subjects who 
discontinue the trial medication. Survival data (subject survival and 
anticancer therapies) in Phase Ib will be collected every 3 months (± 2 
weeks) after the dose of study drug. Subjects will be contacted by 
telephone. 
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Primary endpoints 
• Incidence of subjects experiencing at least 1 dose limiting 
toxicity (DLT) within the first administration cycle (i.e., 21 days 
after the first dose) 
• Incidence and type of other AEs 
Secondary 
endpoint(s) 
Secondary efficacy endpoints are:  
• Progression-free survival (PFS) assessed by investigator. 
PFS time is defined as the time (in months) 
from first 
administration to either first observation of disease 
progression or occurrence of death due to any cause within 
84 days of either first administration or the last tumor 
assessment. 
• Overall survival (OS) time. OS time is defined as the time 
(in months) from first administration to the date of death. 
• TTP assessed by investigator. TTP is defined as the time (in 
months) from first administration to date of the observation 
of radiological PD assessed by the investigator. 
• Objective response (OR). OR is defined as complete 
response (CR) or partial response (PR) as the best overall 
response according to local radiological assessments from 
first administration to first occurrence of PD. Responses do 
not require confirmation according to RECIST v 1.1. 
• Disease control. Disease control is defined as CR, PR, or 
stable disease (SD) as the best overall response according 
to local radiological assessments from the date of first 
administration to the first occurrence of PD. In the case of 
SD, measurements must have met the SD criteria at least 
once after study entry at a minimum interval of 42 days after 
first administration. 
Secondary safety endpoints are:  
• Drug exposure. 
• Incidence and type of AEs (all grades as per the National 
Cancer Institute’s (NCI)-CTCAE version 4.0): all treatment 
emergent adverse events (TEAEs), related TEAEs, 
treatment emergent serious adverse events (SAEs), related 
treatment emergent SAEs, TEAEs of NCI-CTCAE (version 
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4.0) with Grade  3, related TEAEs  Grade 3, and TEAEs 
leading to permanent/temporary treatment discontinuation. 
• Incidence and reasons for deaths, including deaths within 
33 days after the last dose of study drug. 
• Safety laboratory tests graded by NCI-CTCAE (version 
4.0). 
• Vital signs; 12-lead ECG changes; physical examinations, 
including change in body weight; and ECOG PS. 
Pharmacokinetics 
• PK endpoint : area under the curve from time zero to time t 
(AUC0-t), area under the plasma concentration versus time 
curve within 1 dosing interval (AUC0-tau), maximum 
concentration (Cmax), average plasma concentration within 
1 dosing interval (Cav), observed minimum plasma 
concentration (Cmin), time to maximum concentration 
(tmax), area under the curve from time zero to infinity 
following 
last 
administration 
(AUC0-), 
apparent 
clearance (CL/f), apparent volume distribution associated 
to the terminal phase (Vz/f), volume of distribution at 
steady state (Vss/f), area under the curve terminal phase 
rate constant (Ȝz), and half-life (t1/2) when appropriate  
Exploratory 
endpoints 
• 
 
 
 
 
 
7 
Sample Size 
For Phase Ib, the total number of subjects in this trial is up to 21. Of these subjects, up to 18 will 
be enrolled based on the “3+3” dose-escalation method with 2 dose cohorts: 3 to 6 subjects in the 
first dose cohort and 3 to 12 subjects in the second dose cohort (if dose de-escalation does not 
occur). In addition, separate from the “3+3” dose escalation cohorts, the SMC may recommend to 
enroll up to an additional 12 subjects in 1 or more dose cohorts at or above the RP2D, and up to 3 
subjects will be enrolled in the mainland China sites. The final sample size will depend on the 
number of subjects who experience DLTs observed at each dose level, the number of dose levels 
explored, the safety data, and the decision from the SMC meeting. 
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8 
Overview of Planned Analyses for Phase Ib 
The methods described in this document will be applied to the preparation of tables, figures and 
listings (TLFs) for the Phase Ib CSR. Statistical analyses will be performed using cleaned 
electronic clinical report form (eCRF) data collected.  
This SAP will cover the final analysis only. 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol 
The dosing and sampling scheme in this study does not allow the reliable estimation of Ȝz, 
considering the apparent terminal half-life of tepotinib and its metabolites. Therefore, all PK 
parameters dependent on Ȝz will not be determined, i.e. AUC0-, %AUCextra, CL/F (single dose); 
t1/2, Vz/F, and Vss/F. 
 
 
 
10 
Protocol Deviations and Analysis Sets  
10.1 
Definition of Protocol Deviations 
Protocol deviations describe how close the study has been conducted according to the protocol as 
expected per GCP.  Some of these deviations may be significant contributors to analysis bias. 
Important protocol deviations are a subset of protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being. 
The following, but not limited to, are defined as important protocol deviations: 
• Subjects that are dosed on the study despite not satisfying the inclusion criteria; 
• Subjects that develop withdrawal criteria whilst on the study but are not withdrawn; 
• Subjects that receive an excluded concomitant medication; 
• Deviation from GCP. 
A data review will be held to discuss and update the definition of important protocol deviations so 
as to determine the evaluability of the subjects prior to database lock. 
10.2 
Definition of Analysis Sets and Subgroups 
Screening Analysis Set  
The Screening Analysis Set includes all subjects who have signed the main informed consent (i.e., 
screening failures plus subjects enrolled). 
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DLT Analysis Set: 
The DLT Analysis Set includes all subjects who experienced a DLT during Cycle 1, or did not 
experience a DLT, and completed at least 80% of planned treatment during the DLT observation 
period (21 days after the first dose administered). Subjects who have been replaced during the 
Cycle 1 or whom belong to the Chinese (Mainland) subject cohort or expansion cohort will be 
excluded from the DLT Analysis set. The primary analysis will use the DLT analysis set. 
Safety Analysis Set (SAF) 
The Safety Analysis Set includes all subjects who have received at least 1 dose of the trial 
treatment. Subjects who were replaced for evaluation of the dose limited toxicity (DLT) will still 
be included in the Safety Analysis Set, if they are treated at least once (i.e., if the above criterion 
is met).  
The SAF will be used for summaries of demographic and baseline characteristics, as well as for 
summary of safety and efficacy data per dose and in total. And analyses performed on the SAF 
will consider subjects as treated. 
PK Analysis Set 
The PK Analysis Set includes all subjects who have received at least one dose of tepotinib and 
who had at least one post dose blood sample drawn that provides drug concentration data for PK 
evaluation and was not impacted by a protocol deviation or other event (eg, vomiting within the 
time frame of 2 * tepotinib median tmax, etc.) affecting PK. This analysis set will be used for 
summaries of the PK data for tepotinib and its metabolites. If a subject undergoes a tepotinib dose 
change after Cycle 1 Day 1, their PK data will no longer be included in the PK Analysis Set from 
the time of the change.  
All PK data will be included in listings regardless of whether or not they are included in the PK 
analysis set. 
 
 
 
 
 
11 
General Specifications for Statistical Analyses 
All statistical analyses will be performed using SAS® version 9.2. 
Unless otherwise indicated baseline characteristic data will be presented separately for the 
treatment cohorts and for overall, safety data and efficacy data will be presented separately for the 
treatment cohorts and overall. 
Data handling after cut-off date: 
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In general, if a cut-off date is set, data obtained after the cut-off will not be displayed in any listings 
or used for summary statistics, e.g. laboratory values of samples taken after data cut-off, AE with 
onset date after data cut-off, death, etc. will not be included in any analysis or listing. The only 
exceptions are the date of death and the date last known to be alive from the “Subject Follow-up” 
eCRF.  
In particular, the following steps will be taken to derive and report some eCRF data that might be 
potentially affected by the cutoff date:  
• If the last known alive date is after the cutoff date, the date will be updated to the cutoff date. 
• If the death date is after the cutoff date, the death date will be set to missing, and the last 
known alive date will be updated to the cutoff date. 
Stop dates are not affected by this rule, e.g. a stop date of AEs, which starts prior to the cut-off, 
but stops after date of cut-off, will not be changed 
Pooling of centers: 
Because of the high number of participating centers and the anticipated small number of subjects 
treated in each center data will be pooled across centers.  
Significance level: 
All statistical analysis mentioned in this SAP are in a descriptive manner, no formal tests are to be 
performed. If confidence intervals (CIs) are to be calculated, these will be two-sided with a 
confidence probability of 90%, unless otherwise in this SAP specified.  
Presentation of continuous and qualitative variables: 
Continuous variables will be summarized using the following descriptive statistics unless 
otherwise specified (see Section Error! Reference source not found.), i.e.  
• number of subjects (N), number of subjects with non-missing values  
• mean, standard deviation 
• median, 25th Percentile - 75th Percentile (Q1-Q3),  
• minimum, and maximum, 
Categorical variables will be summarized by counts and percentages. 
Unless otherwise stated the calculation of proportions will be based on the number of subjects of 
the sample size of the population of interest. Therefore counts of missing observations will be 
included in the denominator and presented as a separate category. 
Trial day and treatment day:  
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Trial day/ Treatment day are defined relative to the date of first administration of trial drug. Day 
1 is defined as the day of the first administration, the day before is defined as Trial day –1 (no Trial 
day 0 is defined).  
• Trial day or treatment day =  
o date of event – the date of first administration, if date of event < the date of first 
administration 
o or date of event – the date of first administration + 1 , if date of event  the date of 
first administration 
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings, and Trial Day or Treatment Day, and any corresponding durations will be presented 
as missing. Rules of handling missing dates relevant to efficacy will specified in the subsequent 
sections.  
Definition of baseline:  
In general the last non-missing measurement prior to or on the day of first administration will serve 
as the baseline measurement.  
Definition of on-treatment value:  
On-treatment data refers to assessment values collected after the first study drug administration of 
any trial drug and within 33 days (inclusive) after the last study drug administration.  
Unscheduled visits and end of treatment data: 
Unscheduled measurements and end of treatment data will contribute to worst case value.  
Listings will include all scheduled, unscheduled and end of treatment data.  
End of treatment data will be presented separately by its nominal visit name in the by-visit 
summaries.  
Visit Windowing conventions:  
No visit windowing will be performed for this study. The by-visit summaries are based on subjects 
who have available data or who are expected to have available data only. Subjects who are 
expected to have available data are subjects who are still in the trial at the visit, that is, the planned 
visit date is <= the discontinuation date of the “Study Procedure Termination” eCRF form.  
Definition of duration: 
Duration will be calculated by the difference of start and stop date + 1 if not otherwise specified. 
For example, survival time (days) = date of death - the date of first administration + 1. 
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Common calculations:  
For quantitative measurements, change from baseline will be calculated as: 
 
• Test Value at Visit X – Baseline Value 
Conversion factors: 
Unless specified, Conversion of days to months /years will be defined as:  
• 1 month= 30.4375 days 
• 1 year = 365.25 days 
Handling of missing data: 
Unless otherwise specified, missing data will not be replaced.  
In all subject data listings imputed values will be presented and the respective imputed information 
will be flagged. 
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd”. For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “nd”. 
For the derivation of new date variables the following rules will apply: 
• Partial birth dates will be handled this way: day will be imputed as 15 if it is missing, and 
month imputed as June if missing. If both of day and month are missing, they will be 
imputed as July 1st. If year is missing then the date will not be imputed. 
• For imputing missing parts of dates for the efficacy analyses the missing day in a date will 
be imputed as the 15th of the month, if month and year is documented. This includes also 
dates of start of follow-up therapy.  
• In case the last administration date is incomplete the date of last administration will be 
taken from the Treatment Termination eCRF page. 
• Incomplete AE-related dates will be handled as follows: 
o In case the onset date is missing completely or missing partially but the onset month 
and year, or the onset year are equal to the start of trial treatment then the onset date 
will be replaced by the minimum of start of trial treatment and AE resolution date.  
o In all other cases the missing onset day or missing onset month will be replaced by 
1. 
o Incomplete stop dates will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of subject's death. In the latter 
case the date of death will be used to impute the incomplete stop date.  
o In all other cases the incomplete stop date will not be imputed. If stop date of AE 
is after date of cut-off outcome of AE is ongoing at cut-off.  
• In all other cases missing or incomplete dates will not be imputed if not indicated otherwise. 
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12 
Trial Subjects 
This section includes specifications for reporting subject disposition and treatment/trial 
discontinuations.  
12.1 
Disposition of Subjects and Discontinuations 
Population: Screening Analysis Set 
All subjects who provide informed consent will be accounted for in this study. Subject disposition 
and withdrawals will be presented for the screening analysis set. 
The following summaries will be provided for overall and each dose level when applicable: 
• Total number of subjects screened (i.e. subjects who gave informed consent) 
• Number of subjects who completed the screening phase, but discontinued from the trial 
prior to the date of first administration 
• Number of subjects who did not complete the screening phase grouped by the main reasons, 
that is, screening failures 
• Number of subjects treated  
• Number of subjects who completed the treatment. A subject who completed treatment is 
defined as the subject died or the subject has been assessed as having progressive disease 
• Number of subjects who discontinued the study treatment after the first administration, 
grouped by the main reason 
• Number of subjects in survival follow up 
12.2 
Protocol Deviations 
12.2.1 
Important Protocol Deviations 
Population: Safety Analysis Set 
Important protocol deviations will be based upon the Clinical Trial Management System (CTMS) 
data and determined for all subjects by medical review processes. All the important protocol 
deviations will be included in Study Data Tabulation Model (SDTM) datasets, if identified by 
means of medical review. The Analysis Data Model (ADaM) datasets will be derived from SDTM 
and include all important protocol deviations. 
A data review will be held to discuss and update the definition of important protocol deviations so 
as to determine the evaluability of the subjects prior to database lock. 
The following outputs will be provided: 
• Summary of important protocol deviations 
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13 
Demographics and Other Baseline Characteristics 
Population: Safety Analysis Set  
Demographic data and other baseline characteristics will be presented using summary statistics for 
continuous variables and frequency tables for categorical variables. 
13.1 
Demographics 
Demographic characteristics will be summarized using the following information from the 
Screening/Baseline visit CRF pages. 
Demographic characteristics: 
• Age (years): summary statistics, age will be presented to 1 decimal place.  
• Age in categories: <65 years, >=65 years (65 -< 75, 75 -< 85, >= 85 years) 
• Gender: male, female 
• Race: Asian, other 
• Region: Taiwan, South Korea, Mainland China 
• Pooled region of site: Greater China (i.e. mainland China and Taiwan), outside of Greater 
China 
Specifications for computation of age (years):  
(date of given informed consent - date of birth + 1) / 365.25 
13.2 
Medical History 
The medical history will be summarized from the “Medical History” eCRF page, using Medical 
Dictionary for Regulatory Activities (MedDRA), current version, preferred term (PT) as event 
category and MedDRA system organ class (SOC) body term as Body System category. 
Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetical order.  
13.3 
Other Baseline Characteristics, Anti-Cancer Therapy and 
Surgery 
13.3.1 
Disease History 
Information on disease history collected on the “Disease History” eCRF form at the pre-treatment 
evaluation visit will be presented. Summaries and listings will be presented for  
• Site of Primary Tumor  
• Time since initial diagnosis (months)  
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Time since initial diagnosis (months) = (date of informed consent – date of initial 
diagnosis+1) / 30.4375. 
• Time since first occurrence of metastatic or locally advanced disease(months) 
Time since first occurrence of metastatic or locally advanced disease (months) = (date of 
informed consent – date of the first occurrence of metastatic or locally advanced disease 
+1) / 30.4375. 
• BCLC Stage at Initial Diagnosis: 0, A, B, C, D  
• BCLC Stage at Study Entry:  0, A, B, C, D 
• Tumor histology 
o Macroscopic 
o Microscopic 
o Vascular invasion 
o Grading  
• Metastatic sites at the first diagnosis 
• Metastatic sites at the study entry 
13.3.2 
Other Baseline Characteristics 
The following baseline characteristics will be summarized for this study: 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2): BMI (kg/m2) is derived as weight (kg) / height (m)2 
• Nicotine and alcohol consumption 
• ECOG at baseline 
• Alpha-fetoprotein (AFP) elevation at the baseline: >=200 IU/ml, <200 IU/ml 
Elevated AFP refers to a state where AFP is above the reference range. 
• Viral serology at baseline 
o HBsAg: negative vs. positive 
o Anti-HBc: negative vs. positive 
o HBeAg: negative vs. positive 
o Anti-HCV: negative vs. positive 
o HBV carrier: HBeAg is positive but HBsAg, anti-HBc and anti-HCV are all 
negative. 
Baseline characteristics with respect to hematology/biochemistry, vital signs, ECG will be part of 
Section 17. 
13.3.3 
Prior Anti-Cancer Therapy and Surgery 
Prior anti-cancer therapy and surgery information, including drug therapies, radiotherapy, local-
regional therapies and surgeries will be summarized.  
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• Prior anti-cancer drug therapy 
o Any prior anti-cancer drug therapy (yes/ no) 
o Type of systemic therapy  
o Intent of therapy  
o Prior anti-cancer therapy drugs, preferred terms will be presented alphabetically 
o Number of prior anti-cancer therapy lines 
o Number of prior anti-cancer therapy lines for locally advanced/metastatic/palliative 
disease 
o Sequence number of previous TKI therapy lines 
Lines of previous TKI anti-cancer therapies are those lines collected on the “Prior 
Anti-Cancer Drug Therapies Details” eCRF and containing one or more TKI 
therapies. The TKI therapies will those whose type of systemic therapy=“Kinase 
inhibitors”. 
o The sequence number of the immediate TKI therapy line 
An immediate prior TKI therapy is the one which meets: 1) the corresponding line 
is the last one reported on the “Prior Anti-Cancer Drug Therapies Details” eCRF, 
2) the therapy is a TKI therapy. 
o Best response 
• Prior anti-cancer radiotherapy 
o Any prior anti-cancer radiotherapy 
o Intent of therapy 
o Number of prior anti-cancer radiotherapies 
o Best response 
• Prior anti-cancer local-regional therapy 
o Any prior anti-cancer local-regional therapy 
o Type of therapy 
o Intent of therapy 
o Number of prior anti-cancer local-regional therapy 
o Outcome of therapy 
• Prior anti-cancer surgery  
o Any prior anti-cancer surgery 
o Prior anti-cancer surgeries, preferred terms will be presented alphabetically 
o Number of prior anti-cancer surgeries 
o The surgery was curative in intent (yes/ no) 
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o Outcome of surgery 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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14 
Previous and Concomitant Medications/Procedures 
Population: Safety Analysis Set  
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14.1 
Previous and concomitant medications: 
The medications recorded on the “Concomitant Medication Details” eCRF form will be used as 
data source. 
All terms will be coded using the most current World Health Organization Drug Dictionary (WHO 
Drug) version at the time of database lock. Medications will be presented using the Anatomical 
Therapeutic Chemical (ATC) classification system. Numbers of subjects with concomitant 
medications/ treatment procedures will be presented overall and by ATC 2nd level, preferred terms. 
Missing or partial dates for medications will not be imputed. In the case where it is not possible to 
define a medication as prior or concomitant, the event will be classified by the worst case; i.e. prior 
and concomitant.  
• Previous medications are medications other than trial drugs, which are taken before first 
administration of trial drug.  
• Concomitant treatments are medications other than trial drugs, which are taken by subjects 
any time on-treatment (on or after the first day of any trial drug treatment for each subject) 
or within 33 days after last dose of trial drug.  
14.2 
Concurrent procedures 
Procedures collected from the “Concomitant Procedures” eCRF will be used as the data source. 
Number of subject with concurrent procedures, i.e, those on-treatment procedures (prior, on or 
after the first day of trial treatment or within 33 days after last dose of trial treatment) will be 
summarized overall and by reason and preferred name. 
All medication/ treatment procedures will be listed. 
14.3 
Anti-Cancer Treatment after Treatment Termination 
New anticancer therapy will be recorded for subjects who discontinue from the treatment for 
reasons other than PD at the additional follow-up visits. The following summaries will be 
presented for anti-cancer treatment after discontinuation:  
• Any anti-cancer treatment after discontinuation (yes/ no) 
• Type of systemic therapy 
• Anti-cancer therapy drugs after treatment termination: preferred terms will be presented 
alphabetically 
• Time to start of new anti-cancer treatment after discontinuation (weeks): derived as the 
duration in weeks from first administration to the earliest start date of anti-cancer drugs 
after discontinuation 
• Best response 
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15 
Treatment Exposure 
Population: Safety Analysis Set 
The extent of exposure to MSC2156119J will be presented by the following summaries: 
• Duration of therapy (weeks):  
Duration of therapy (weeks)= ൬date of last dose-date of first dose+1
7
൰ 
Interruptions, compliance, and dose changes are not taken into account for the calculation 
of duration of therapy.  
• Cumulative dose (mg):  
The cumulative dose per subject in a time period is the sum of the total dosage that the 
subject received.  
• Dose intensity (mg/day):  
Dose intensity (mg/day) = ൬
ሺሻ
ሺሻ൰ 
• Relative dose intensity (%): 
(%)= ൬
Dose intensity (mg/day)
ሺȀሻ൰כ ͳͲͲ 
It will be summarized as continuous variables and also categorized into groups as the 
following:  
o < 60%  
o 60% - <80%  
o 80% - <90%  
o 90% - 110%  
o >110% 
• Dose reductions: Dose reduction is defined as a change to a non-zero dose level lower than 
that planned in the protocol. A change from a less-than-planned non-zero dose level to 
another less-than-planned non-zero dose level will be considered as a new dose reduction.   
o Number and percentage of subjects with at least one dose reduction as well as a 
breakdown of dose reductions (1 / 2 / 3 / ı4) will be summarized by treatment 
group. 
o Cumulative duration of dose reductions (days) will be summarized. 
• Dose temporary discontinuation: Dose temporary discontinuation is defined as a change to 
dose interrupted, i.e. “0” dose level.  
o Number and percentage of subjects with interrupted study drug administration and 
maximum length of temporary discontinuation (1-2 days, 3-7 days, ı8 days) i.e. 
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the worst case will be summarized by treatment group if subjects have multiple 
dose temporary discontinuations. 
o Cumulative duration of dose temporary discontinuation (days) will be summarized. 
 
16 
Endpoint Evaluation 
16.1 
Primary Endpoint Analyses 
Population: DLT Analysis Set. 
Number of subjects  experiencing  at  least  1 DLT  within  the  first  treatment  cycle  
DLTs are those AEs collected in the “Adverse Events Details” eCRF and with “Is this adverse 
event a dose limiting toxicity?” flagged as “Yes”.  
The following will be provided for DLTs during cycle 1 (i.e. first 21 days) for each dose level and 
overall: 
• Incidences of DLTs 
• Listing of DLTs 
Incidence and type of other AEs will be specified in Section 17.1. 
16.2 
Secondary Endpoint Analyses 
Population: Safety Analysis Set 
16.2.1 
Progression-free Survival (PFS) Assessed by Investigator 
Progression Free Survival is defined as the time from first administration date to the date of the 
first documentation of objective progression of disease (PD) or death due to any cause, whichever 
occurs first. PFS data will be censored on the date of the last adequate tumor assessment for 
subjects who do not have an event (PD or death), for subjects with an event after two or more 
missing tumor assessments (i.e. 84 days). Subjects who do not have a baseline tumor assessment 
or who do not have any post-baseline tumor assessments will be censored on the start date unless 
death occurred on or before the time of the second planned tumor assessment in which case the 
death will be considered an event.  
PFS (months) = [date of event or censoring– first administration date +1]/30.4375 
The censoring and event date options to be considered for the PFS are presented in table 1. 
Table 1: PFS Events/censoring rules  
Scenario 
Date of event/censoring 
Outcome 
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Radiological PD observed within 12 
weeks of the last valid tumor assessment 
or first treatment administration 
Date of PD 
Event 
Death without previously confirmed PD is 
observed within 12 weeks of the first 
administration or the last valid tumor 
assessment 
Date of death 
Event 
No baseline or post-baseline assessment 
Date of first 
administration 
Censored 
Event after 2 or more missing assessments, 
including death which is not within 12 
weeks of the first administration or the last 
tumor assessment, whatever occurs later 
Date of last known tumor 
assessment or date of first 
administration, whatever 
occurs later 
Censored 
Lost to follow-up / withdraw consent 
without PD/death observed, including 
subjects with a last tumor assessment date 
>12 weeks prior to the analysis cut-off date
Date of last known tumor 
assessment or date of first 
administration, whatever 
occurs later 
Censored 
Ongoing in the study without an event, that 
is, no PD/death event observed within 84 of 
the cut-off date from the last adequate 
tumor assessment for this still-in-trial 
subject (administrative censoring) 
Date of last known tumor 
assessment or date of first 
administration, whatever 
occurs later 
Censored 
     * Note: Not evaluable (NE) or Missing is not considered as a valid tumor assessment.  
Kaplan-Meier survival curves (product-limit estimates) will be presented by treatment cohort 
together with a summary of associated statistics (25th quintile, median and 75th quintile survival 
time, 2-months, 4-months KM estimates and estimates for every 2 months thereafter as applicable) 
including the corresponding two-sided 90% CIs. The CIs for the median will be calculated 
according to Brookmeyer and Crowley (1982), and CIs for the survival function estimates at above 
defined 
time 
points 
will 
be 
derived 
directly 
from 
the 
Kaplan-Meier 
estimates 
(CONFTYPE=LOGLOG in proc LIFETEST). The estimate of the standard error will be computed 
using Greenwood's formula. SAS procedure LIFETEST will be used to obtain Kaplan-Meier 
estimates and plots. 
Frequency (number and percentage) of subjects with each event type (PD or death) and 
censoring reasons will be presented. Censoring reasons are as follows:  
• Event after 2 or more missing assessments  
• No baseline assessment  
• No post baseline assessments  
• Withdrawal of consent / Lost to follow-up  
• Ongoing in the study without an event due to the cutoff 
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The PFS time or censoring time and the reasons for censoring will also be presented in a subject 
listing. 
16.2.2 
Time-to-Progression (TTP) Assessed by Investigator  
TTP is defined as the time (in months) from the date of first administration to the first observation 
of PD (as assessed by investigator): 
PFS (months) = (date of 1st PD – the date of first administration+ 1) / 30.4375. 
Similar event/censoring rules will be applied except that the death will not be considered as a 
TTP event and instead will be censored at the last available tumor assessment. Analysis methods 
analogous to the ones for PFS will employed.  
16.2.3 
Overall Survival (OS) 
Overall survival is defined as the time from start date to the date of death due to any cause. Subjects 
last known to be alive will be censored at date of last contact. 
OS (months) = [date of death or censoring– first administration date +1]/30.4375 
Censoring reasons are as follows: 
• Alive  
• Withdrawal of consent  
• Lost to follow-up 
Censoring rules: 
• Alive subjects will be censored at the last date known to be alive. 
• If the subject is still in the trial at the cutoff of the analysis and found alive within 90 days 
of the cutoff date, it is considered administrative censoring, otherwise non-administrative 
censoring. 
• Non-administrative censoring will be included in the “lost to follow-up” category if no 
other detailed reason specified. 
The last known alive date will be the latest date of the alive dates (refers to Table 2) 
Table 2: Data source of alive dates  
eCRF or Dataset 
CRF Items or Variables 
Subject Status / Survival Follow-Up 
Last known alive date, follow-up date 
SDTM.SV 
the latest dates of SVSTDTC, SVENDTC 
Adverse Events 
Start date, end date 
Concomitant Medications 
Start date, end date 
Drug Administration 
Start date, end date 
End of Assessment Visit 
Completion/discontinuation date 
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Additional Follow-Up / Progression Disease 
Progression date 
Anti-Cancer Treatment After Discontinuation Start date, end date 
Analyses analogous to the ones for FPS will be performed, expect that the survival rate will be 
estimated at 3-month, 6-month and for every 3 months thereafter as applicable. 
16.2.4 
Antitumor Activity Assessed by Investigator 
Best Overall Response 
Best overall response (BOR) is defined as the best result obtained among all tumor assessment 
visits from baseline until end of treatment or determination of PD, excluding assessments after 
tumor surgery.  
Not Evaluable (NE) is not considered a valid measurement. Overall response of NE will be 
changed to PD if subsequent scan is a PD. As a consequence, a BOR of NE will only be assigned 
if NE is the only one treatment assessment (for instance, a subject having assessments of NE and 
PD will be assigned BOR of PD).  
Subjects with BOR of non-CR/non-PD (possible only for subjects without measurable disease at 
baseline) are not considered as having achieved objective response, nor clinical benefit. 
The following will be provided: 
• The number and percentage of subjects with a best overall response (BOR) of CR, PR, SD, 
PD, non-CR/non-PD, and NE will be tabulated. 
• The number and percentage of subjects will be tabulated over time grouped by the overall 
response. 
• The number and percentage of subjects will be tabulated by cMet status (Positive (2+ or 
3+) /Negative (0 or 1+) /Indeterminate/Missing) for best overall response. 
• Bar chart with time to response and duration of study treatment 
Objective Response Rate (ORR) 
The objective response rate is defined as the proportion of subjects having achieved complete 
response (CR) or partial response (PR) as the BOR according to radiological assessments from the 
date of first administration to end of treatment. Responses do not require confirmation according 
to RECIST v1.1. 
The ORR  will be presented for each dose level including the corresponding 90% Newcombe-
Wilson CIs.  
Disease Control Rate (DCR) 
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The disease control rate is defined as the proportion of subjects having achieved CR, PR, or stable 
disease (SD) as the BOR according to radiological assessments from first administration until end 
of study treatment the first occurrence of PD. In the case of SD, measurements must have met the 
SD criteria at least once after study entry at a minimum interval of 42 days after first 
administration.  
The DCR and its 90% Newcombe-Wilson CI will be calculated.  
Other secondary endpoints are provided in other sections: 
• Exposure refers to Section 15. 
• Other safety secondary endpoints refers to Section 16.1. 
16.2.5 
Pharmacokinetics 
Analysis Set: PK 
Tepotinib and metabolite (MSC2571109A and MSC2571107A ) concentrations in plasma will be 
listed and presented in tables and descriptively summarized by dose level, day and scheduled time 
point. Descriptive statistics will include N, arithmetic mean, standard deviation, standard error of 
the mean (SEM), median, minimum, maximum, and  coefficient of variation (CV) (%). For 
descriptive statistics of concentration data, values below the lower limit of quantification (LLOQ) 
will be assigned values as defined in Section Error! Reference source not found.. Descriptive 
statistics of PK parameters will additionally show the geometric mean (GeoMean), the geometric 
CV percentage (GeoCV%), and the 95% confidence interval (CI) for the geometric mean.  
Individual plasma concentration-time profiles (linear and semi-logarithmic scales) of tepotinib and 
its metabolites will be plotted by dose level and day; these profiles (i.e. all three analytes) will be 
overlaid in one plot per subject. Spaghetti plots overlaying all subjects’ concentration-time profiles 
(linear and semi-logarithmic scales) will be plotted by dose level and day for each of the 3 analytes 
separately (i.e., tepotinib, MSC2571109A and MSC2571107A ). Mean plasma concentrations of 
tepotinib and metabolites (MSC2571109A and MSC2571107A) overlaid will also be plotted by 
dose level and day on linear (±standard deviation) and semi-logarithmic scales using scheduled 
time points. Mean concentration time profiles, separately by analyte and dose level, will also be 
displayed for each of the 3 analytes (i.e., tepotinib, MSC2571109A and MSC2571107A), 
overlaying both Day 1 and Day 15 in one plot. 
At the dose level which includes the mainland Chinese subgroup, data will be summarized for 
Chinese subjects alone, non-Chinese subjects alone, and Chinese and non-Chinese subjects 
combined, in all descriptive summary tables and plots described above.  
A listing of PK blood sample collection times by individual as well as derived sampling deviations 
will be provided. 
PK profiles of tepotinib and its active metabolites (MSC2571109A, MSC2571107A) from study 
EMR200095-004 phase Ib part will be analyzed jointly with data from studies EMR200095-001, -002, 
-003, -005, -006, and -007 by a non-linear mixed effect approach.  The plasma concentration time 
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patients will be evaluated with compartment models. Covariates of demographics, lab values, disease 
status and co-medication will be tested in order to identify any intrinsic and extrinsic factors that are 
predictive of PK inter-individual variability. More details are given in a separate Data Analysis Plan 
for Pooled Population Pharmacokinetic Analysis. The results will be reported separately. 
16.2.5.1 
Pharmacokinetic Endpoints 
The following pharmacokinetic endpoints will be analyzed:  
• Plasma PK parameters of tepotinib and metabolites MSC2571109A and MSC2571107A : 
the definition of the parameters and the planned analysis is described in the subsequent 
sections 
16.2.5.2 
Estimation of Individual Pharmacokinetic Parameters 
Pharmacokinetic parameters will be calculated by the 
 PK group using standard 
non-compartmental methods, actual elapsed sampling times, and the actual administered dose. The 
PK parameters listed below will be calculated for tepotinib and metabolites (MSC2571109A and 
MSC2571107A) in plasma, when applicable, based on frequent PK sampling as applied in phase 
Ib. PK parameters will be summarized by PK analyte, dose level, and day. At the dose level 
received by the Chinese subgroup, data will be summarized for Chinese subjects alone, non-
Chinese subjects alone, and Chinese and non-Chinese subjects combined. 
 
Cmax  
Maximum observed concentration  
tmax 
Time of Cmax 
AUC0-t 
Area under the concentration-time curve from time zero to 
the last quantifiable concentration 
tlag 
tlag is the time prior to the first quantifiable (non-zero) 
concentration (for Cycle 1 Day 1 only) 
Cav 
The average concentration at steady state, calculated on 
Cycle 1 Day 15 only. Cav = AUCĲ /Ĳ (AUC0-t if necessary).  
Cmin 
The minimum observed concentration during a complete 
dosing interval, calculated on Cycle 1 Day 15 only   
AUCĲ 
The area under the concentration-time curve over the dosing 
interval from T1=0 h (predose) to T2=Ĳ h. Calculated using 
the mixed log linear trapezoidal rule (linear up, log down). 
For Cycle 1 Day 1, AUCĲ will be calculated as a partial area 
within the defined time range. For Cycle 1 Day 15, AUCτ 
will be calculated at steady state from the pre-dose time point 
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to the dosing interval time. AUCτ will be calculated based on 
the observed concentration at the actual observation time, as 
long as actual time deviation is less than +/-10% at τ. If actual 
time deviation is equal to or greater than 10%, AUCτ will be 
reported as missing. 
CL/F 
Apparent systemic clearance (calculated for tepotinib only), 
as Dose/AUCĲ, where Dose is the tepotinib free base dose 
(i.e., adjusted for salt form). Calculated on Cycle 1 Day 15 
only. The tepotinib free base dose is calculated as: Actual 
dose * MW(free base)/MW(salt), where MW(free base) is the 
molecular weight (MW) of free base (i.e., 492.57), and 
MW(salt) is the MW of the hydrochloride hydrate salt (i.e., 
547.05) 
AUC0-t/Dose 
Dose-Normalized AUC0-t (calculated for tepotinib only). 
Normalized using actual dose (i.e., unadjusted for salt form).
AUCĲ/Dose 
Dose-Normalized AUCĲ (calculated for tepotinib only). 
Normalized using actual dose (i.e., unadjusted for salt form).
Cmax/Dose 
Dose-Normalized Cmax (calculated for tepotinib only), 
Normalized using actual dose (i.e., unadjusted for salt form).
PTF 
The peak trough fluctuation ratio within a complete dosing 
interval at steady state in %, calculated on Cycle 1 Day 15 
only. PTF = 100*(Cmax-Cmin)/Cav 
Vss/F 
For Cycle 1 Day 15 
 
Potential drug accumulation for tepotinib and its metabolites will be evaluated by means of 
individual accumulation ratios for AUCĲ and Cmax [Racc(AUC) and Racc(Cmax) respectively], that will 
be calculated by dividing the values obtained after multiple dose (i.e. on Cycle 1 Day 15) by the 
values obtained after single dose (i.e. Cycle 1 Day1) and summarized descriptively for each dose 
level. 
 
Individual metabolite to parent ratios for AUC0-t and Cmax [MR(AUC0-t) and MR(Cmax) respectively], 
will be calculated for tepotinib and its metabolites by dividing the value obtained for each 
metabolite by the value obtained for the parent (i.e. MSC2571107A/tepotinib and 
MSC2571109A/tepotinib) after correction for MW differences between parent and metabolite 
(MW of tepotinib free base is 492.57, MW of MSC2571107A is 506.56, and MW of 
MSC2571109A is 506.56), separately for single dose (i.e. Cycle 1 Day1) and multiple dose (i.e. 
Cycle 1 Day 15), and summarized descriptively for each dose level and day. 
The dosing and sampling scheme in this study does not allow the reliable estimation of Ȝz, 
considering the apparent terminal half-life of tepotinib and its metabolites. Therefore, all PK 
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parameters dependent on Ȝz will not be determined, i.e. AUC0-ɱ, %AUCextra, CL/F (single dose); 
t1/2, Vz/F, and Vss/F. 
Other parameters may be added as appropriate. 
The calculation of the AUCs will be performed using the mixed log-linear trapezoidal method 
(linear up, log down). The actual (unrounded) time of blood sampling will be used for PK 
evaluation. In cases where the actual sampling time is missing, calculations will be performed 
using the scheduled time. Otherwise, there will be no further imputation of missing data. The 
pre-dose samples will be considered as if they had been taken simultaneously with the 
administration. Plasma concentrations below LLOQ before the last quantifiable data point will be 
taken as zero for calculating the AUC (ie, embedded BLQ values will be set to zero). Plasma 
concentrations below LLOQ after the last quantifiable data point will be set to ‘zero’. 
PK parameters will be evaluated and listed for all subjects who provide sufficient 
concentration-time data. Formal statistical hypotheses have not been planned for PK parameters. 
Any statistical tests that might be performed will be considered exploratory.  
For tepotinib and its metabolites, dose proportionality will be presented graphically by day as 
follows:  
• 
Boxplots for dose-normalized PK parameters (AUCĲ /Dose and Cmax/Dose) by dose level 
• 
Scatter plots on individual AUCĲ and Cmax versus Dose on a linear scale. 
PK Parameters are to be rounded for reporting as appropriate. In export datasets, PK parameters 
will be provided with full precision, and will not be rounded. 
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing. 
16.3 
Other Endpoint Analyses 
 
 
 
 
 
 

 
 
 
 
 
 
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17 
Safety Evaluation 
Population: Safety Analysis Set 
17.1 
Adverse Events 
Population: Safety Analysis Set 
Treatment emergent adverse events: those events with onset dates occurring within the treatment 
periods, i.e, starts on or after the earliest dosing date of any study treatment and prior to the latest 
dosing date of any trial treatment + 33 days (inclusive). AE occurring after the first administration 
will always be considered as TEAE regardless of whether its onset date beyond the 33 days if it is 
assessed as trial-drug related by investigator. 
“Timing related to study treatment” from the AE eCRF will be used to judge whether the AE is a 
TEAE when the AE onset date is the same day as the day of first administration. 
In the case where it is not possible to define an AE as being treatment emergent or not, the AE will 
be classified as treatment emergent as the most conservative approach.  
Summaries for the number of subjects in total and within each dose level will be presented, for 
each of the categories described in the sub-sections below.  
Listings will include all TEAEs and Non-TEAEs. Summary tables described in Section 17.1, 
17.2.2 and 17.2.3 will be based on TEAEs if not otherwise specified. 
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No formal statistical comparisons are planned. 
17.1.1 
All Adverse Events 
AEs will be coded using the most current version of MedDRA dictionary. The investigator will be 
responsible for assigning the Common Toxicity Criteria (CTC) grades for AEs, using the most 
current version of NCI-CTCAE.  
Incidence rates (frequencies and percentages) of individual AEs, that is, the number of subjects 
experiencing events AEs in each PT or SOC, and the proportion relative to the number of subjects 
in the SAF analysis set, will be presented. 
Unless otherwise stated adverse events will be displayed in terms of frequency tables: PT and 
primary SOC in alphabetical order.  
The relationship to a trial treatment, as indicated by the investigator, is classified as “not related” 
or “related”. TEAEs with a related or missing relationship to the trial treatment will be regarded 
as “related” to the trial treatment. If a subject reports the same AE more than once within that 
SOC/PT, the AE will be categorized as “unrelated” only when all relationship records are 
“unrelated”, otherwise it will be classed as “related” in the corresponding relationship summaries. 
Severity is classified as grade 1, 2, 3, 4, 5 (increasing severity) by referencing the most current 
NCI-CTCAE 4.0 (publication date: 28May2009). If a subject reports a TEAE more than once 
within that SOC/PT, the AE with the worst case severity will be used in the corresponding severity 
summaries. In case a subject had events with missing and non-missing severities, the maximum of 
the non-missing severities will be displayed. In case all the TEAEs of a subject are all with missing 
severities then grade 3 (severe) will be used unless there is any evidence that it should be grade 4 
or 5. 
An overview summary of TEAEs will be provided by dose level for cycle 1 (i.e. first 21 days from 
drug administration) and all cycles: 
• TEAEs  
• Related TEAEs 
• Serious TEAEs 
• Serious related TEAEs 
• TEAEs of grade  3 by NCI-CTCAE 
• Related TEAEs of grade  3 by NCI-CTCAE 
• TEAEs of special interest (refer to Section 17.2.3) 
• Related TEAEs of special interest 
• TEAEs leading to death (AEs with grade 5 or outcome “fatal” if grade 5 not applicable) 
• Related TEAEs leading to death (AEs with grade 5 or outcome “fatal” if grade 5 not 
applicable) 
• TEAEs leading to temporary discontinuation of study treatment 
• TEAEs leading to permanent discontinuation of study treatment 
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• TEAEs leading to study discontinuation 
Also the following tables will be presented by SOC, PT in alphabetical order for TEAEs for cycle 
1 and all cycles: 
• Incidence of TEAEs  
• Incidence of related TEAEs  
• Incidence of TEAEs by worst severity (CTCAE grade) 
• Incidence of related TEAEs by worst severity (CTCAE grade) 
• Incidence of TEAEs with CTCAE grade >= 3  
• Incidence of treatment related TEAEs with CTCAE grade >= 3  
17.1.2 
Adverse Events Leading to Treatment Discontinuation 
Population: Safety Analysis Set 
AEs leading to permanent or temporary discontinuation of study treatment are those AEs whose 
actions taken with study treatment is reported as “drug withdrawn” or “drug interrupted” in the 
“Adverse Events Details” eCRF. The following will be presented by SOC and PT in alphabetical 
order: 
• Incidence of TEAEs leading to permanent discontinuation of study treatment  
• Incidence of TEAEs leading to temporary discontinuation of study treatment  
 
17.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events 
Population: Safety Analysis Set 
17.2.1 
Deaths 
All deaths, deaths within 33 days after last dose of trial treatment as well as reason for death, will 
be tabulated based on information from the “Death” eCRF.  
Summaries will be presented for:  
• Number of deaths  
• Number of deaths within 33 days after last dose of treatment (i.e. Death date – date of last 
dose <=33 days) 
• Primary reason of death  
o Disease progressions 
o Adverse event related to study treatment 
o Adverse event not related to study treatment 
o Other  
o Unknown 
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All deaths for screening analysis set will be listed:  
• In addition, date and cause of death will be provided in individual subject data listing 
together with selected dosing information (date of first / last administration, dose intensity, 
etc). 
• Including columns for:  
o AEs with fatal outcome (list preferred terms of AEs with outcome=fatal) 
o flag for death within 33 days of last study treatment administration 
17.2.2 
Serious Adverse Events 
SAEs are those events with a response of “Yes” for the item “Serious Adverse Event” on the 
“Adverse Events Details” eCRF. Serious TEAE, serious related TEAEs and a full list of all SAEs 
will be presented: 
• Incidence of Serious TEAEs by SOC and PT 
• Incidence of Serious Related TEAEs by SOC and PT  
• Incidence of Serious TEAEs leading to death by SOC and PT 
• Listing of all SAEs. 
17.2.3 
Adverse Event of Special Interest 
AE of Special Interest (AESI) is defined as AEs of asymptomatic lipase and/or amylase elevations 
of Grade  3. The following are collected and will be presented: 
• Incidence of treatment emergent AESIs by SOC and PT 
• Incidence of  related treatment emergent AESIs by SOC and PT 
• Any lipase or amylase increase will be listed with a column flagging the ones meeting 
AESI definition, as noted in Section 17.2.3. 
17.3 
Clinical Laboratory Evaluation 
Population: Safety Analysis Set 
Laboratory values (including corresponding normal ranges) from Central Lab will be used for 
summary statistics and shift tables.  
Qualitative data based on reference ranges will be described according to the categories (i.e. 
Low, Normal, High). The number of subjects with clinical laboratory values below, within, or 
above normal ranges at baseline compared to worst on-treatment endpoint will be tabulated for 
each test by dose level. Shift tables of baseline versus worst on-treatment endpoint will be 
presented.  
Thus the following tabulations will be provided for each dose level: 
• Actual and changes from baseline to each scheduled visit over time 
• Number of subjects with shifts from normal baseline to worst on-treatment result 
above/below normal limit. Please refer to the AdaM template 2.0 to find parameters to be 
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split into high and low. For example, glucose will be presented by “glucose high” and 
“glucose low” separately.  
• Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values that are identified by the 
investigator as being clinically significant will be shown in a data listing.  
• Listing of any lipase or amylase increase. 
Laboratory results will also be classified according to the most current version of NCI-CTC 
Version as provided by the central laboratory. Parameters with available NCI-CTC grades will 
be summarized as the following: 
• Shifts in toxicity grading baseline to highest on-treatment: The worst on-treatment grade 
will be summarized by NCI-CTC grade (0, 1, 2, 3, 4, any). Please refer to the AdaM 
template 2.0 to find parameters to be split into high and low. For example, glucose will be 
presented by “glucose high” and “glucose low” separately.  
17.4 
Vital Signs 
Population: Safety Analysis Set 
Weight will be classified according to the NCI-CTCAE (version 4.0) criteria.  Please find the 
CTCAE grading rules from the appendix. 
The maximum changes of vital sign measurements screening/baseline to maximum on-treatment 
changes after start of 1st treatment will be grouped as follows:  
Vital Sign Parameter 
Increase/  
decrease 
Baseline category 
Change from baseline category  
Temperature  
Increase 
<37 °C,  
37 - <38 °C 
38 - <39 °C 
39 - <40 °C 
>=40 °C 
< 1°C ,  
1-<2°C ,  
2-<3°C,  
≥ 3 °C 
Heart rate  
Increase 
<100 bpm ; 
 ൒ 100 bpm 
≤20 bpm,  
>20 – 40 bpm,  
>40 bpm 
  
Decrease 
<100 bpm ;  
൒ 100 bpm 
≤20 bpm,  
>20 – 40 bpm,  
>40 bpm 
SBP  
Increase 
<140 mmHg;  
൒ 140 mmHg  
≤20 mmHg, 
 >20 – 40 mmHg, 
 >40 mmHg 
  
Decrease 
<140 mmHg;  
൒ 140 mmHg, 
≤20 mmHg, 
 >20 – 40 mmHg, 
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 >40 mmHg 
DBP  
Increase 
<90 mmHg;  
൒ 90 mmHg  
≤20 mmHg, 
 >20 – 40 mmHg, 
 >40 mmHg 
  
Decrease 
<90 mmHg;  
൒ 90 mmHg 
≤20 mmHg, 
 >20 – 40 mmHg, 
 >40 mmHg 
Respiration rate  
Increase 
<20 bpm ;  
൒ 20 bpm 
≤5 bpm,  
>5 – 10 bpm,  
>10 bpm 
  
Decrease 
<20 bpm ;  
൒ 20 bpm 
≤5 bpm,  
>5 – 10 bpm,  
>10 bpm 
The following summaries will be prepared for vital sign parameters as grouped above considering 
only subjects with post baseline values: 
• Change from baseline to worst on-treatment CTCAE toxicity grade for weight 
• Maximal Shifts (changes in categories) 
 
17.5 
ECG 
Population: Safety Analysis Set 
All ECG readings will be recorded as 12-lead resting ECGs in triplicates. The average of these 3 
results will be used for inclusion in the reporting of this study for numeric parameters. If some of 
the 3 results are missing, the average of available results will be used. For categorical data, the 
worst result among the 3 results will be used.  
The Fridericia’s Correction (QTcF) is derived as follows:  
• 
Fridericia's Correction (ms):  ܳܶܿܨሺሻൌ
ொ்ሺ௠௦ሻ
ටோோሺ௠௦ሻȀଵ଴଴଴
య
  
In case RR is not available ܴܴሺ݉ݏሻൌͳͲͲͲ כ
଺଴
ுோሺ௕௣௠ሻ will be used. 
The following summaries will be provided for ECG data: 
• Summary over time for numeric parameters: only subjects at the visit will be summarized.  
• Categorical shift from baseline to worst on-treatment value for the QTcB and QTcF: the 
baseline and the worst on-treatment value will be grouped as follows: 
Parameter 
Baseline category 
Worst on treatment value  
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QTcB, QTcF 
<=450ms 
>450 - <=480ms 
>480 - <=500ms 
>500ms 
<=450ms 
>450 - <=480ms 
>480 - <=500ms 
>500ms 
• Categorical change from baseline to worst on-treatment value for the QTcB and QTcF: the 
baseline and the worst change from baseline value will be grouped as follows: 
Parameter 
Baseline category 
Worst change from baseline  
QTcB, QTcF 
Normal (i.e.<=450ms) 
Abnormal (i.e.>450ms) 
 
<=0 ms 
>0 - <=30ms 
>30 - <=60ms 
>60ms  
17.6 
Other Safety Evaluations 
Population: Safety Analysis Set 
The following will be provided for the ECOG performance status:  
• Summary of ECOG over time: ECOG will be classified as 0, 1, 2, 3, 4, 5. Only subjects at 
the visit will be summarized.  
18 
Reporting Conventions 
The mock shells will be provided in a separate document EMR200095-004 Phase Ib CSR Mock 
Shells. 
 
19 
References 
• Eisenhauer EA, Therasse P, Bogaerts J,Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 
45: 228-247.  
20 
Appendix 
• Non-CRF Data are listed as:  
 
Data to be Analyzed 
Collected by  
Protocol deviations 
Clinical Trial Management System (CTMS). 
Laboratory data 
Central Lab 
• Laboratory parameters with CTCAE grading are:  
Lab Test Name 
  
Grade 1 
Grade 2 
Grade 3 
Grade 4 
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Chemistry 
 
 
 
 
 
Total Bilirubin (umol/L) 
Increase 
>ULN 
>1.5ULN 
>3ULN 
>10ULN 
Aspartate Aminotransferase 
(U/L), SGOT 
Increase 
>1xULN 
>3xULN 
>5xULN 
>20xULN
Alanine Aminotransferase 
(U/L), SGPT 
Increase 
>1xULN 
>3xULN 
>5xULN 
>20xULN
Sodium (mmol/L) Low 
Decrease <LLN 
NA 
<130 
<120 
Sodium (mmol/L) High 
Increase 
>ULN 
>150 
>155 
>160 
Calcium (mmol/L) Low  
(Albumin corrected), (Not 
total calcium) 
Decrease <LLN 
<2 
<1.75 
<1.5 
Calcium (mmol/L) High 
(Albumin corrected), (Not 
total calcium) 
Increase 
>ULN 
>2.88 
>3.12 
>3.38 
Magnesium (mmol/L) Low 
Decrease <LLN 
<0.5 
<0.35 
<0.3 
Magnesium (mmol/L) High 
Increase 
>ULN 
NA 
>1.25 
>3.3 
Creatinine (umol/L) 
Increase 
>BL or 
ULN 
>1.5BL or 
1.5ULN 
>3BL or 
3ULN 
>6ULN 
Albumin (g/L)      
Decrease <LLN 
<30 
<20 
NA 
Alkaline phosphatase (U/L)   Increase 
>1xULN 
>2.5xULN 
>5xULN 
>20xULN
Amylase (U/L) 
Increase 
>1xULN 
>1.5xULN 
>2xULN 
>5xULN 
Lipase (U/L) 
Increase 
>ULN 
>1.5xULN 
>2xULN 
>5xULN 
Glucose (mmol/L) Low 
Decrease <LLN 
<3.1 
<2.2 
<1.7 
Glucose (mmol/L) High 
Increase 
>ULN 
>8.9 
>13.9 
>27.8 
Gamma Glutamyl 
Transferase (U/L) 
Increase 
>1ULN 
>2.5xULN 
>5xULN 
>20xULN
Potassium (mmol/L) Low 
Decrease NA 
<LLN 
<3 
<2.5 
Potassium (mmol/L) High 
Increase 
>ULN 
>5.5 
>6 
>7 
Creatinine Clearance, C&G 
(mL/min) 
Decrease NA 
<60 
<30 
<15 
Hematology 
 
 
 
 
 
Hemoglobin (g/L) Low 
Decrease <LLN 
<100 
<80 
NA 
Hemoglobin (g/L) High 
Increase 
>ULN 
>ULN+20 
>ULN+40 
NA 
Platelet (10E9/L), PLT 
Decrease <LLN 
<75 
<50 
<25 
Leukocytes (10E9/L) Low 
Decrease <LLN 
<3 
<2 
<1 
Leukocytes (10E9/L) High 
Increase 
NA 
NA 
>100 
NA 
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Neutrophils (10E9/L), 
Absolute Neutrophils Count 
, ANC 
Decrease <LLN 
<1.5 
<1 
<0.5 
Lymphocytes (10E9/L) 
Low 
Decrease <LLN 
<0.8 
<0.5 
<0.2 
Lymphocytes (10E9/L) 
High 
Increase 
NA 
>4 
>20 
NA 
Coagulation 
 
 
 
 
 
 
 
 
 
 
 
Activated Partial 
Thromboplastin Time (sec) 
Increase 
>1ULN 
>1.5ULN 
>2.5ULN 
NA 
Prothrombin Intl. 
Normalized Ratio 
Increase 
>BL or 
ULN 
>1.5BL or 
1.5ULN 
>2.5BL or 
2.5ULN 
NA 
* BL=Baseline, ULN=Upper limit of normal range. 
• Vital sign parameters with CTCAE grading are:  
Vital Sign 
Parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 
4 
Weight Loss (kg) 
Decrease 5 - <10% from 
BL 
10 - <20% from 
BL 
>=20% from 
BL 
NA 
Weight Gain (kg) 
Increase 5 - <10% from 
BL 
10 - <20% from 
BL 
>=20% from 
BL 
NA 
* BL=Baseline. 
 
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Statistical Analysis Plan
Clinical Trial Protocol 
Identification No.
EMR 200095-004
Title:
A Multicenter, Randomized, Phase Ib/II Trial to Evaluate the
Efficacy, Safety, and Pharmacokinetics of MSC2156119J as 
Monotherapy Versus Sorafenib in Asian Patients with MET+ 
Advanced Hepatocellular Carcinoma and Child-Pugh Class A 
Liver Function
Trial Phase
Phase Ib/II
Investigational Medicinal 
Product(s)
MSC2156119J (Tepotinib)
Clinical Trial Protocol 
Version
19 May 2017/Version 4.0
Statistical Analysis Plan 
Author
Statistical Analysis Plan
Date and Version
12 Feb 2018/Final Version 1.1
Statistical Analysis Plan 
Reviewers
, Senior Statistical Reviewer, 
, Trial Biostatistician, Merck Serono
, 
, Merck SeronoCharles 
, 
, Merck Serono
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
It is intended for restricted use only and may not - in full or part - be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany or its affiliate. 
Copyright © 2015 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.

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Document Approval Signature(s)
This document has been signed electronically in compliance with 
 electronic
signature policies and procedures. This page is a manifestation of the electronic signatures, 
which may be confirmed within the 
 source system in accordance with 
 
records retention policies.
Note: the Title field in the signature block has been intentionally left blank.
 
 
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Tepotinib
Efficacy, Safety, and PK of Tepotinib in Asian Patients with HCC
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Final Version 1.1
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2
Table of Contents
1 
Signature Page ......................................................................................2 
2 
Table of Contents..................................................................................3 
3 
List of Abbreviations and Definition of Terms ....................................6 
4 
Modification History ............................................................................9 
5 
Purpose of the Statistical Analysis Plan ...............................................9 
6 
Summary of Clinical Trial Features .....................................................9 
7 
Sample Size/Randomization...............................................................13 
8 
Overview of Planned Analyses...........................................................14 
8.1 
Primary Analysis ................................................................................14 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol........14 
10 
Protocol Deviations and Analysis Sets...............................................15 
10.1 
Definition of Protocol Deviations.......................................................15 
10.2 
Definition of Analysis Sets and Subgroups........................................15 
11 
General Specifications for Statistical Analyses..................................19 
12 
Trial Subjects......................................................................................23 
12.1 
Disposition of Subjects and Discontinuations....................................23 
12.2 
Protocol Deviations ............................................................................23 
12.2.1 
Important Protocol Deviations............................................................23 
12.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................24 
13 
Demographics and Other Baseline Characteristics.............................24 
13.1 
Demographic.......................................................................................24 
13.2 
Medical History ..................................................................................24 
13.3 
Other Baseline Characteristics, Anti-Cancer Therapy and Surgery...25 
13.3.1 
Disease History...................................................................................25 
13.3.2 
Other Baseline Characteristics............................................................25 
13.3.3 
Prior Anti-Cancer Therapy and Surgery.............................................26 
 
 
 
 
 
 
 
 
 
 
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14 
Previous and Concomitant Medications/Procedures ..........................30 
14.1 
Previous and concomitant medications ..............................................30 
14.2 
Concurrent procedures........................................................................30 
14.3 
Anti-Cancer Treatment after Discontinuation ....................................30 
15 
Treatment Compliance and Exposure.................................................31 
16 
Endpoint Evaluation ...........................................................................32 
16.1 
Primary Endpoint Analyses ................................................................32 
16.2 
Secondary Endpoint Analyses ............................................................35 
16.2.1 
Progression-free Survival (PFS) on tumor assessment by IRC..........35 
16.2.2 
PFS based on tumor assessment by Investigator ................................37 
16.2.3 
Overall Survival (OS).........................................................................37 
16.2.4 
TTP Assessed by Investigator ............................................................38 
16.2.5 
Time-to-Symptomatic Progression (TTSP)........................................38 
16.2.6 
Antitumor Activity Assessed by IRC .................................................39 
16.2.7 
Antitumor Activity Assessed by Investigator.....................................41 
16.3 
Other Endpoint Analyses....................................................................41 
 
 
16.3.2 
Patient Reported Outcome..................................................................42 
 
 
 
 
16.3.5 
Tumor Shrinkage by IRC....................................................................46 
16.3.6 
Tumor Shrinkage by Investigator .......................................................46 
17 
Safety Evaluation................................................................................46 
17.1 
Adverse Events ...................................................................................47 
17.1.1 
All Adverse Events.............................................................................47 
17.1.2 
Adverse Events Leading to Treatment Discontinuation.....................48 
17.2 
Deaths, Other SAEs, and AEs of Special Interest ..............................49 
17.2.1 
Deaths .................................................................................................49 
17.2.2 
Serious Adverse Events ......................................................................49 
17.2.3 
Adverse Event of Special Interest.......................................................49 
17.3 
Clinical Laboratory Evaluation...........................................................50 
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17.4 
Vital Signs ..........................................................................................51 
17.5 
ECG ....................................................................................................52 
17.6 
Other Safety Evaluations ....................................................................53 
18 
Reporting Conventions .......................................................................53 
19 
References...........................................................................................53 
20 
Appendix.............................................................................................54 
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3
List of Abbreviations and Definition of Terms
Abbreviation
Definition
AE
Adverse Event
AESI
Adverse Events of Special Interest
AST
Aspartate Aminotransferase
ATP
Adenosine Triphosphate
CHF
Congestive Heart Failure
CI
Confidence Interval
c-Met
Mesenchymal-Epithelial Transition Factor Gene
CNS
Central Nervous System
CR
Complete Response
CRO
Contract Research Organization
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation (%)
DBP
Diastolic Blood Pressure
DLT
Dose-Limiting Toxicity
DNA
Deoxyribonucleic Acid
DS
Drug Substance
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase 
GMP
Good Manufacturing Practice
HBeAg
Hepatitis B extracellular antigen
HBsAg
Hepatitis B surface antigen
HBc
Hepatitis B core antigen
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HR
Hazard Ratio
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HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDMC 
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IRB
Institutional Review Board
ISH
In Situ Hybridization
IVRS
Interactive Voice Response System
LCSS
Lung Cancer Symptom Scale
LLQ
Lower Level of Quantification
LVEF
Left Ventricular Ejection Fraction
MedDRA
Medical Dictionary For Regulatory Activities
mITT
Modified Intent-to-Treat
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
OR
Objective Response
OS
Overall Survival
PD
Progressive Disease
PET
Positron Emission Tomography
PFS 
Progression Free Survival
P-gp
P-Glycoprotein
PGx
Pharmacogenomics
PK
Pharmacokinetics
PoC
Proof of Concept
PP
Per Protocol
PR
Partial Response
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PT
Prothrombin Time
RBC
Red Blood Cells
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
Stable Disease
SEM
Standard Error of the Mean
SMC
Safety Monitoring Committee
StD 
Standard Deviation
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment-Emergent Adverse Event
TKI
Tyrosine Kinase Inhibitor
TNM
Tumor, Lymph Nodes, Metastasis
TTSP
Time to Symptomatic Progression
UDP
Uridine 5’-Diphospho
ULN
Upper Limit of Normal
WBC
White Blood Cells
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4
Modification History
Unique Identifier 
for SAP Version
Date of SAP 
Version
Author
Changes from the Previous Version
Final V1.0
13 Jul 2017
Not Applicable – First Version
Final V1.1
12 Feb2018
x
Update one criteria of the definition of Per-Protocol 
Analysis Set from ‘Completed at least 80% of the planned 
dose for at least one cycle, except for patients discontinue 
due to early death or progression’ to ‘Dosed for at least 
80% of the planned dosing days for at least one cycle,
except for patients discontinue due to early death or 
progression’
x
Clarify long term follow-up analysis which will be 
included in CSR addendum in section 11‘Safety data 
collected after the cut-off date for final analysis from the 
subjects who will still be on trial treatment will be reported 
through patient profile in an addendum to the clinical study 
report.’ 
x
Add subgroup “Baseline HBV or HCV status” to the part 
of ‘Subgroup of interest’
x
Add section 16.3.5 of Tumor Shrinkage by IRC
x
Add section 16.3.6 of Tumor Shrinkage by Investigator
x
Modify subgroup analysis of TTP and PFS from only for 
‘predefined biomarker’ subgroups to all predefined 
subgroups section 16.2.1 and 16.2.3
5
Purpose of the Statistical Analysis Plan
The purpose of this SAP is to document technical and detailed specifications for the primary and 
final analysis of data collected for the phase II of the protocol EMR 200095-004 version 4.0
dated 19May2017. Results of the analyses described in this SAP will be included in the Clinical 
Trial Report (CTR). Additionally, the planned analyses identified in this SAP will be included in 
regulatory submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to 
provide results for inclusion in the CTR but not identified in this prospective SAP will be clearly 
identified in the CTR. 
The SAP is based upon section 8 (Statistics) of the trial protocol and is prepared in compliance 
with ICH E9.
6
Summary of Clinical Trial Features
Trial 
Objectives
Primary Objectives
z To evaluate efficacy as measured by time to progression (TTP) of 
Tepotinib as monotherapy in the first-line treatment compared with
sorafenib in patients with MET+ advanced HCC and Child-Pugh 
class A liver function.
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Secondary Objectives
z To evaluate the safety and tolerability of Tepotinib versus sorafenib
z To evaluate antitumor activity of Tepotinib versus sorafenib
Exploratory Objectives
z To evaluate patient reported outcomes (PROs) of Tepotinib 
compared with sorafenib. PROs will be assessed using FACT-HP 
questionnaire.
z
 
 
 
 
Trial design 
and plan
Phase II will be a randomized, open label, active controlled trial to evaluate 
the efficacy, safety, and PK of Tepotinib as first-line treatment versus
sorafenib in patients with MET+, Barcelona Clinic Liver Cancer (BCLC)
Stage B or C, systemic treatment naive advanced HCC and Child-Pugh class
A liver function. Phase II is planned to be conducted at 45 to 55 sites in
mainland China, South Korea, Taiwan, and other Asian countries.
Patients will receive either Tepotinib once daily (at the recommended 
Phase II dose (RP2D) determined from Phase Ib) or 400 mg sorafenib twice
daily until disease progression, intolerable toxicity or consent withdrawal 
from the trial.
Planned 
number of 
patients
Approximately 140 patients were planned to be randomized on a 1:1 basis to 
receive Tepotinib or sorafenib. The sponsor subsequently decided to stop 
prescreening after 40 TTP events (confirmed by the IRC) or on
15 August 2017, whichever occurs first.
Schedule of 
visits and 
assessments
Patients will be screened for up to 14 days prior to trial treatment. Informed 
consent will be obtained prior to performing any trial assessment.
Tepotinib (Phase II) will be administered once daily over a 21-day cycle and 
sorafenib (Phase II) will be administered twice daily over a 21-day cycle,
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which may repeat until disease progression (as determined by the
investigator), intolerable toxicity, or withdrawal from the trial.
For Phase II, scheduled visits during the treatment period will occur on Days
1, 8, and 15 of Cycle 1; Days 1 and 8 of Cycle 2; and Day 1 of Cycles  3.
At
each scheduled visit
during the treatment
period, physical
examination/weight, vital signs, hematology, coagulation, chemistry,
adverse events (AEs), and concomitant medication assessments will be
performed.
Patients will also be assessed at the discontinuation of the trial medication.
Trial drug post-treatment follow-up visit will be performed within 30 ± 3
days after the last dose for patients who discontinue the trial medication. 
Survival data (patient survival and anticancer therapies) will be collected
every 3 months (± 2 weeks) after the dose of trial drug. Patients will be 
contacted by telephone.
Subjects undergoing prescreening at the prescreening stop date may still be 
enrolled into the trial, if eligible. Subjects receiving study treatment may 
continue treatment after discussion with their Investigator. Subjects who 
decide to continue treatment will continue on their originally randomized 
treatment, at their most recent dose according to the protocol. Safety 
monitoring and data collection will continue without modification through to 
the end of treatment assessment.
Primary 
endpoints
x TTP assessed by an Independent Review Committee (IRC). TTP is
defined as the time (in months) from randomization to date of the
observation of radiological progressive disease (PD) assessed by an 
IRC.
Secondary 
endpoint(s)
x Secondary efficacy endpoints are: 
x Progression-free survival (PFS) based on tumor assessed by the IRC.
PFS time is defined as the time (in months) from randomization to
either first observation of disease progression or occurrence of death
due to any cause within 84 days of either randomization or the last 
tumor assessment.
x PFS based on tumor assessment by investigator. PFS time is defined 
as the time (in months) from randomization to either first observation 
of radiologically confirmed PD by the investigator or occurrence of 
death due to any cause within 84 days of either randomization or the 
last tumor assessment.
x Overall survival (OS) time. OS time is defined as the time (in months) 
from randomization to the date of death.
x TTP assessed by investigator. TTP is defined as the time (in months) 
from randomization to date of the observation of radiological PD 
assessed by the investigator. 
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x Time-to-symptomatic progression (TTSP). TTSP is defined as the time 
(in months) from the date of randomization to the date of deterioration 
of symptoms assessed by FHSI-8, defined as the total score increase 
by at least 4 points compared with the baseline value, or deterioration 
to ECOG PS of 4.
x Objective response (OR) based on tumor assessment by IRC. OR is 
defined as complete response (CR) or partial response (PR) as the best
overall response according to radiological assessments as adjudicated 
by the IRC from randomization to first occurrence of PD. Responses 
do not require confirmation according to RECIST v 1.1.
x OR based on tumor assessment by the investigator. OR is defined as 
CR or PR as the best overall response according to radiological 
assessments as adjudicated by the investigator from randomization to 
first occurrence of PD. Responses do not require confirmation 
according to RECIST v 1.1.
x BOR (Best Overall Response) based on tumor assessment by the IRC. 
BOR is defined as the best result obtained among all tumor 
assessments adjudicated by the IRC from baseline until end of 
treatment or determination of PD, excluding assessments after tumor 
surgery.
x BOR (Best Overall Response) based on tumor assessment by the 
investigator.  BOR is defined as the best result obtained among all 
tumor assessments adjudicated by the investigator from baseline until 
end of treatment or determination of PD, excluding assessments after 
tumor surgery
x Disease control based on tumor assessment by the IRC. Disease control 
is defined as CR, PR, or stable disease (SD) as the best overall response 
according to radiological assessments as adjudicated by the IRC from 
the date of randomization to the first occurrence of PD. In the case of 
SD, measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 42 days after randomization.
x Disease control based on tumour assessment by the investigator. 
Disease control is defined as CR, PR, or SD as the best overall response 
according to radiological assessments as adjudicated by the 
investigator from the date of randomization to the first occurrence of 
PD. In the case of SD, measurements must have met the SD criteria at 
least once after study entry at a minimum interval of 42 days after 
randomization.
Safety 
Endpoints
x Drug exposure
x Incidence and type of AEs (all grades as per NCI-CTCAE version 4.0): 
all treatment emergent adverse events (TEAEs), related TEAEs, 
treatment emergent SAEs, related treatment emergent SAEs, TEAEs 
of NCI-CTCAE (version 4.0) with Grade  3, related TEAEs  Grade 
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3, 
and 
TEAEs 
leading 
to 
temporary/permanent 
treatment 
discontinuation
x Incidence and reasons for deaths, including deaths within 33 days after 
the last dose of study Drug
x Safety laboratory tests graded by NCI-CTCAE (version 4.0)
x Vital signs; 12-lead ECG changes; physical examinations, including 
change in body weight; and ECOG PS.
Exploratory
endpoints
x PRO assessments of Tepotinib compared with sorafenib will be
assessed using the FACT-HP questionnaire.
x
 
b
x
 
 
x
 
x
 
 
7
Sample Size/Randomization
The initial sample size planning required 100 TTP events (assessed by an IRC) to ensure 80%
power with a two-sided significance level of 10% for rejecting the null hypothesis of equal
treatment effect between treatment arms, assuming a true hazard ratio (HR) of 0.6. Assuming
a median TTP in Asian patients for the sorafenib arm of 2.8 months, an HR of 0.6 represents a 
1.87 month increase, resulting in a median TTP of 4.67 months for the Tepotinib arm. One
formal interim futility analysis with O’Brien-Flemming method as futility boundary calculation 
was planned to be performed after observation of 50% of TTP events. With the additional 
assumption of accrual period of 12 months and follow up period of 6 month, and an overall drop-
out rate of 17.4%, a total number of 140 patients with MET+ HCC will be randomized (1:1
basis) to receive Tepotinib or sorafenib.
However, due to business-related considerations not related to any safety issues, the sponsor 
decided to stop prescreening/enrollment when 40 TTP events are observed (assessed by an IRC) 
or 15 August 2017, whichever occurs first. It is expected that approximately 90 subjects will be 
randomized by 15 August 2017. 
Randomization will be performed centrally by using an IVRS. A stratified permuted block 
randomization procedure will be employed using the following strata:
x
BCLC Stage: Stage B versus Stage C
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The purpose of stratification is to ensure an even distribution of the 2 treatment arms within the 
stratum.
8
Overview of Planned Analyses
Cut-off date
This SAP covers the analyses for efficacy and safety based on the data cut-off. 
x The cut-off date for the primary analysis will be determined by the date after 40 reported 
TTP events (confirmed byIRC) for the modified Intent-To-Treat (mITT) Population or 
15th August 2017, whichever occurs first. 
x The final analysis will be conducted approximately 6 months after the last subject is first 
dosed.
Due to cleaning activities final number of events might deviate from the planned number. The data 
applied with the cut-off date will not be adjusted retrospectively in this case.
This SAP will cover the primary and final analysis. Separate SAPs will be provided covering the 
following analyses:
x Safety analyses for IDMCs
8.1
Primary Analysis
The primary analysis will be conducted when 40 TTP events (confirmed byIRC) reported for mITT 
population or 15 August 2017, whichever occurs first. Final Analysis
The final statistical analysis is planned to be conducted approximately 6 months after the last 
subject is first dosed.
Data review meetings will be held prior to database lock for both primary and final analysis.
9
Changes to the Planned Analyses in the Clinical Trial Protocol
The following change was made in the planned analysis between the study protocol and the SAP 
prior to database lock:
x
The following additional criteria added to the definition of PP analysis set: 
¾ The absence of any clinical important protocol deviations with respect to factors 
likely to affect the efficacy of treatment. 
¾ Data review will be held to determine the evaluability of the subjects prior to the 
database lock.
¾ Change the criteria of ‘complete at least 1 cycle of treatment’ to ‘completed at least 
80% of the planned dose for at least one cycle, except for patients discontinue due 
to early death or progression’.
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x
Kaplan-Meier estimates for TTP will be presented by 2 months, 4 months and every 2 
months instead of 6 month, 12 month and every 6 month.
 
 
10
Protocol Deviations and Analysis Sets
10.1
Definition of Protocol Deviations 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being. 
Important protocol deviations include:
x Subjects that receive study medication despite not satisfying the inclusion criteria or
violating exclusion criteria;
x Subjects that develop withdrawal criteria whilst on the study but are not withdrawn;
x Subjects that receive the wrong treatment or an incorrect dose;
x Subjects that receive an excluded concomitant medication.
x Deviation from GCP
The following deviations will be identified and confirmed prior to or at the Data Review Meeting 
at the latest. 
x Important protocol deviations include
o
Deviations from the inclusion and exclusion criteria
o
Deviations post inclusion
x Subset of these important protocol deviations are clinically important if leading to the 
exclusion of the subject from the PP set (see section 10.2).
All important protocol deviations should be documented in CDISC datasets whether identified 
through sites monitoring or medical review. Please refer to Protocol Deviation Guide for more 
details. 
10.2
Definition of Analysis Sets and Subgroups
Screening Analysis Set (SCR)
The screening (SCR) analysis set includes all patients who have signed the main informed consent
(i.e., screening failures plus patients enrolled).
Intent-to-treat Analysis Set (ITT)
The intention-to-treat (ITT) analysis set in Phase II part of this trial consists of all subjects who 
were randomized to study treatment. Subjects will be allocated as randomized.
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Modified Intent-to-Treat Analysis Set (mITT)
The modified intention-to-treat (mITT) analysis set will include all patients with MET+ HCC who 
were randomized to trial treatment. Subjects with IHC c-Met status 1+ or ‘not assessable’ on re-
scoring will be excluded from the primary analysis set. The mITT Analysis Set will be used to 
assess the tumor activity and the efficacy of the compound. Analyses performed on the mITT set 
will take into account patients’ allocation to treatment groups as randomized.
Per-Protocol Analysis Set (PP)
The per-protocol (PP) analysis set is defined as all mITT patients who meet the following criteria:
x
Histologically or cytologically confirmed hepatocellular carcinoma
x
Correct treatment allocation according to randomization or dose selection
x
Measurable or evaluable disease at baseline
x
Dosed for at least 80% of the planned dosing days for at least one cycle, except for patients 
discontinue due to early death or progression
x
Received only permitted medications or procedures according to this protocol
x
The absence of any clinical important protocol deviations (see Section 12.2). The 
exclusion from PP set will be determined in case-by-case scenario, and will be confirmed 
by a blind data review meeting prior to the database lock.
PP analysis set data will be presented according to as-randomized principle.
If the PP analysis set includes at least 90% of patients in the mITT analysis set, additional efficacy 
analyses on the PP analysis set will be omitted as the differences in the results based upon these 
two analysis sets are expected to be negligible.
 
 
Safety Analysis Set (SAF)
The safety (SAF) analysis set includes all patients who have received at least 1 dose of Tepotinib
or sorafenib. The SAF analysis set will be used for all summaries of safety data. Analyses 
performed on the safety analysis set will consider patients as treated. As an example, if a patient
was randomized to control arm, but received active treatment throughout the trial rather than 
control treatment, the patient’s safety data should be reported under active treatment. 
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An overview of analysis sets and analyses is given in Table 1:
Table 1: Analysis Sets
Analyses
Modified Intent-to-Treat 
Analysis Set
Per Protocol 
Analysis Set
Safety 
Analysis Set
Baseline Assessments
9
9
Past, Concomitant and 
Post Therapies
9
Medical History
9
9
Compliance and Exposure
9
Efficacy: Primary 
9
9
Efficacy: Secondary 
9
9
Safety Analysis
9
Subgroup of interest
Subgroup analyses will be performed on subgroups as defined below. 
For the purpose of including baseline variables into Cox's proportional hazards model the 
following subgroup variables are to be used. For variables with more than two categories, an 
indicator variable will be defined for each category except for the first category, which defines the 
reference always. The following subgroups will be defined:
x Type of MET+ (please refer to Section 13.3.2)
o
moderate [2+] (reference level)
o
strong [3+]
x Gene amplification status
o
mean gene copy number <5 (reference level)
o
mean gene copy number  5
x Age 
o
age < 65 years  (reference level)
o
age  65 years
x Gender
o
male (reference level)
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o
female
x Geographic region  (please refer to Section 13.1)
o
Greater China 
o
outside of Greater China (reference level)
x BCLC stage
o
Stage B (reference level)
o
Stage C
x Vascular invasion and/or extrahepatic spread
o
presence
o
absence (reference level)
x The underlying disease or medical condition related to etiology (please refer to Section 
13.3.2): 
o
HBV 
o
Other (reference level)
x Baseline  HBV or HCV status 
o
Either HBV or HCV positive
o
Both HBV and HCV negative
x AFP elevation at the baseline (please refer to Section 13.3.2)
o
yes 
o
no (reference level)
x Prior local-regional therapy: 
o
yes 
o
no (reference level)
x Baseline tumor HGF group
o
0 (reference level)
o
Other
x Baseline plasma shedded cMet group
o
above the median
o
below/at the median (reference level)
x Baseline plasma IL-8 group
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o
below/at the median (reference level)
x Baseline plasma HGF Group
o
above the median
o
below/at the median (reference level)
x Baseline plasma HGF Group
o
above upper quartile (25% quantile)
o
below/at the upper quartile (25% quantile) (reference level)
x Type of IHC c-Met status (based on ITT population):
o
1+ (reference level)
o
2+
o
3+
The analysis of individual subgroups will be done in a case there are enough observations in each 
subgroup (i.e. more than 10 subjects in any treatment group). A summary for a number of patients 
in each subgroup will be produced.
11
General Specifications for Statistical Analyses
Unless otherwise indicated all analyses will be presented separately for the treatment groups.
Data handling after cut-off date:
In general, if a cut-off date is set, data obtained after the cut-off will not be displayed in any listings 
or used for summary statistics, e.g. laboratory values of samples taken after data cut-off, AE with 
onset date after data cut-off, death, etc. will not be included in any analysis or listing. In particular, 
the following steps will be taken to derive and report some eCRF data that might be potentially 
affected by the cutoff date: 
x If the start date of a visit, or a prior, concomitant and post medication/procedure/treatment, 
or an adverse event is before or on the cutoff date, and the stop date is after the cutoff date, 
the stop date will be set to the cutoff date, and
o
For the medication/procedure/treatment, it will be considered in the status of 
ongoing. 
o
For the adverse event, its outcome will be considered as ongoing. 
x If the last known alive date is after the cutoff date, the date will be updated to the cutoff date.
x If the death date is after the cutoff date, the death date will be set to missing, and the last 
known alive date will be updated to the cutoff date.
Pooling of centers:
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Because of the high number of participating centers and the anticipated small number of patients
treated in each center data will be pooled across centers, and the factor center will not be considered 
in statistical models or for subgroup analyses. 
Significance level:
If confidence intervals (CIs) are to be calculated, these will be two-sided with a confidence 
probability of 90%, unless otherwise in this SAP specified. 
Presentation of continuous and qualitative variables:
Continuous variables other than PK will be summarized using the following descriptive statistics, 
i.e.
x
number of patients (N), number of patients with non-missing values 
x
mean, standard deviation
x
median, 25th Percentile - 75th Percentile (Q1-Q3), 
x
minimum, and maximum,
 
 
Categorical variables will be summarized by counts and percentages.
Unless otherwise stated the calculation of proportions will be based on the number of patients of 
the sample size of the population of interest. Therefore counts of missing observations will be 
included in the denominator and presented as a separate category.
Trial day and treatment day:
Trial day is defined relative to the date of randomization. Day 1 is defined as the day of the 
randomization, the day before is defined as Trial day –1 (no Trial day 0 is defined). 
x
Trial day =
o
date of event – the date of randomization, if date of event < the date of 
randomization
o
or date of event – the date of randomization + 1 , if date of event  the date of
randomization
Treatment day will be calculated relative to the date of the first administration of trial treatment,
treatment day 1 is defined as the first administration day.
x
Treatment day = date of event – first administration day + 1
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In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings, and Trial Day or Treatment Day, and any corresponding durations will be presented 
as missing. Rules of handling missing dates relevant to efficacy will be specified in the subsequent 
sections. 
Definition of baseline: 
In general the last non-missing measurement prior to or on the day of randomization will serve as 
the baseline measurement. If such a value is not available, the last measurement prior to or on the 
day of the first trial treatment administration will serve as the baseline measurement. 
If an assessment is planned to be performed prior to the first dose of study treatment in the protocol 
and the assessment is performed on the same day as the first dose of study treatment, it will be 
assumed that it was performed prior to study treatment administration, if assessment time point is 
not collected or is missing. If assessment time points are collected, the observed time point will be 
used to determine pre-dose on study day 1 for baseline calculation. Unscheduled assessments will 
be used in the determination of baseline. However, if time is missing, an unscheduled assessment 
on study day 1 will be considered to have been obtained after study treatment administration.
Definition of on-treatment value: 
On-treatment data refer to assessment values collected after the first trial drug administration of 
any trial treatment and within 33 days (inclusive) after the last trial drug administration. 
End of treatment (EOT) data
Data reported at the EOT visit are not eligible for the baseline selection. EOT data will be presented 
in a separate visit in the by-visit summaries.
Unscheduled visits:
Generally, data collected at unscheduled visits will be included and analyzed for both safety and 
efficacy analyses in the same fashion as the data collected at scheduled visits except where 
otherwise noted in the sections that follow. Descriptive statistics (mean, SD, median, minimum, 
maximum, quartiles) by nominal visit or time point for safety endpoints such as laboratory 
measurements, ECGs and vital signs will include only data from scheduled visits.
Definition of duration:
Duration will be calculated by the difference between start and stop date + 1 if not otherwise 
specified. For example, survival time (days) = date of death - the date of randomization + 1.
Common calculations: 
For quantitative measurements, change from baseline will be calculated as:
x
Test Value at Visit X – Baseline Value
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Conversion factors:
Unless specified, Conversion of days to months /years will be defined as: 
x
1 month= 30.4375 days
x
1 year = 365.25 days
Handling of missing data:
For the derivation of new date variables the following rules will apply:
x
Partial birth dates will be handled this way: day will be imputed as 15 if it is missing, and 
month imputed as June if missing. If both of day and month are missing, they will be 
imputed as July 1st. If year is missing then the date will not be imputed.
x
For imputing missing parts of dates for the efficacy analyses the missing day in a date will 
be imputed as the 15th of the month, if month and year is documented. This includes also 
dates of start of follow-up therapy. 
x
In case the last administration date is incomplete the date of last administration will be 
taken from the Treatment Termination eCRF page.
x
Incomplete AE-related dates will be handled as follows:
o
In case the onset date is missing completely or missing partially but the onset month 
and year, or the onset year are equal to the start of trial treatment then the onset date 
will be replaced by the minimum of start of trial treatment and AE resolution date. 
o
In all other cases the missing onset day or missing onset month will be replaced by 
1.
o
Incomplete stop dates will be replaced by the last day of the month (if day is missing 
only), if not resulting in a date later than the date of patient's death. In the latter case 
the date of death will be used to impute the incomplete stop date. 
o
In all other cases the incomplete stop date will not be imputed. If stop date of AE 
is after date of cut-off outcome of AE is ongoing at cut-off. 
x
In all other cases missing or incomplete dates will not be imputed if not indicated otherwise.
Unless otherwise specified, missing data will not be replaced. 
In individual patient data listings (to be included in section 16.4 of the Clinical Trial Report) the 
documented date as given in the eCRF will be reported (e.g. __May2009 in case of day missing, 
but month and year available). In all other patient data listings imputed values (of dates captured 
on the eCRF) will be presented and the respective dates will be flagged as imputed.
Missing statistics, e.g. when they cannot be calculated, should be presented as “nd”. For example, 
if n=1, the measure of variability (SD) cannot be computed and should be presented as “nd”.
All statistical analyses will be performed using SAS® version 9.3 or higher version.
Safety data collected after the cut-off date for final analysis from the subjects who will still be on 
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report.
12
Trial Subjects
The subsections in this section include specifications for reporting subject disposition and 
treatment/trial discontinuations. Additionally procedures for reporting protocol deviations are 
provided.
12.1
Disposition of Subjects and Discontinuations
Population: Screening Analysis Set
All patients who provide informed consent will be accounted for in this study. Patient disposition 
and withdrawals will be presented for the screening analysis set.
The following summaries will be provided for overall and each treatment group when applicable:
x
Number of patients prescreened, and screened among them
x
Total number of patients screened (i.e. patients who gave informed consent)
x
Number of patients who completed the screening phase, but discontinued from the trial 
prior to the date of randomization
x
Number of patients who did not complete the screening phase grouped by the main reasons, 
that is, screening failures
x
Number of randomized patients
x
Number of patients randomized but not treated
x
Number of patients who completed the treatment. A patient who completed treatment is 
defined as the patient died or the patient has been assessed as having progressive disease
x
Number of randomized patients who discontinued the trial treatment after randomization, 
grouped by treatment and main reason
x
Number of patients in survival follow up
Treatment randomized to, treatment treated, the first/last dosing date, completion/termination 
status, and analysis set allocated in will be presented to listing for the mITT analysis set. 
12.2
Protocol Deviations
12.2.1
Important Protocol Deviations
The following summary tables and listings of important protocol deviations will be provided 
(separately for pre-/post inclusion deviations):
x
Frequency table per reason of important protocol deviations
x
Listing of important protocol deviations
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12.2.2
Reasons Leading to the Exclusion from an Analysis Set
Subjects who meet one of the criteria described in section 10.2 will be excluded from the PP. For 
these subjects, the reasons for exclusion will be summarized and listed;
x
Frequency table per reason of exclusion from the PP population
x
Listing of reasons of exclusion from the PP population
13
Demographics and Other Baseline Characteristics
Population: mITT Analysis Set 
Demographic data and other baseline characteristics will be presented using summary statistics for 
continuous variables and frequency tables for categorical variables. Demographic characteristics 
will be based on mITT and SAF analysis sets.
13.1
Demographic
Demographic characteristics will be summarized using the following information from the
Screening/Baseline visit eCRF pages.
Demographic characteristics:
x
Age (years): summary statistics
ሺሻൌሺȂ  ൅ͳሻȀ͵͸ͷǤʹͷ
Age will be presented to 1 decimal place. 
x
Age in categories:
¾ <65 years
¾ >=65 years (65 -< 75, 75 -< 85, >= 85 years)
x
Gender: male, female
x
Race: Asian
x
Ethnicity: Japanese, not Japanese
x
Pooled region of site: 
¾ Greater China (i.e. mainland China and Taiwan),
¾ Outside of Greater China
x
Region:
¾ Mainland China
¾ Taiwan
¾ South Korea
13.2
Medical History
The medical history will be summarized from the “Medical History” eCRF page, using MedDRA, 
current version, preferred term (PT) as Event category and MedDRA system organ class (SOC) 
body term as Body System category.
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Medical history will be displayed in terms of frequency tables: ordered by primary SOC and PT 
in alphabetical order.
Ongoing medical histories are the ones recorded as “ongoing” in the “Medical History Details” 
eCRF form, otherwise will be classified as previous medical conditions. The following will be 
summarized:
x
Ongoing medical conditions
13.3
Other Baseline Characteristics, Anti-Cancer Therapy and 
Surgery
13.3.1
Disease History
Information on disease history collected on the “Disease History” eCRF page at the pre-treatment 
evaluation visit will be presented. Summaries and listings will be presented for the followings: 
x
Site of Primary Tumor
x
Time since initial diagnosis (years) 
Time since initial diagnosis (years) = (date of informed consent – date of initial 
diagnosis+1) / 365.25.
x
Time since first occurrence of metastatic or locally advanced disease (years)
Time since first occurrence of metastatic or locally advanced disease (years) = (date of 
informed consent – date of the first occurrence of metastatic or locally advanced disease 
+1) / 365.25.
x
BCLC Stage at Initial Diagnosis: 0, A, B, C or D
x
BCLC Stage at Study Entry: 0, A, B, C or D
x
Tumor histology: Macroscopic Tumors, Microscopic Tumors, Vascular invasion, Tumor
histology Grading
x
Metastatic sites at the first diagnosis of advanced disease
x
Metastatic sites at study entry
13.3.2
Other Baseline Characteristics
The following baseline characteristics will be summarized for this study:
x
Height (cm)
x
Weight (kg)
x
BMI (kg/m2): BMI (kg/m2) is derived as weight (kg) / height (m)2
x
Nicotine and alcohol consumption
x
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x
MET+ Status
x
Alpha-fetoprotein (AFP) elevation at the baseline: yes vs. no
Elevated AFP refers to a state where AFP is above the reference range.
x
The underlying disease or medical condition related to etiology - Hepatitis B Virus (HBV 
or HCV): positive vs. negative.
HBV or HCV could be missing because the virus load at baseline was not collected.
¾ HBV+ is defined as: The HBV DNA Virus load (IU/ml) is detectable /any 
numerical value (including HBV Virus load < 116 copy/ml);
¾ HBV- is defined as: The HBV DNA Virus load (IU/ml) is target not detected;
¾ HCV+ is defined as: The HCV RNA Virus load (IU/ml) is detectable /any 
numerical value;
¾ HCV- is defined as: The HCV RNA Virus load (IU/ml) target not detected;
x
Viral serology at baseline:
HBsAg: negative vs. positive
Anti-HBc: negative vs. positive
HBeAg: negative vs. positive
Anti-HCV: negative vs. positive
HBV carrier: HBs Ag (+), HBeAg (-), anti-HBe (+), normal ALT (Within 40IU/ml), HBV 
DNA undetectable or < 2000IU/ml, anti-HCV should be negative
Baseline characteristics with respect to hematology/biochemistry, vital signs, ECG will be part of 
Section 17.
13.3.3
Prior Anti-Cancer Therapy and Surgery
Prior anti-cancer therapy and surgery information, including drug therapies, radiotherapy, 
local-regional therapies and surgeries will be summarized. 
x
The following will be summarized for prior anti-cancer drug therapy:
¾ Any prior anti-cancer drug therapy (yes/ no)
¾ Type of therapy
¾ Intent of therapy 
¾ Prior anti-cancer therapy drugs, presented by preferred terms alphabetically
¾ Number of prior anti-cancer therapy lines
¾ Best response
x
The following will be summarized for prior anti-cancer radiotherapy
¾ Any prior anti-cancer radiotherapy (yes/ no)
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¾ Intent of therapy
¾ Number of prior anti-cancer radiotherapies
¾ Best response
x
The following will be summarized for prior anti-cancer local-regional therapy
¾ Any prior anti-cancer local-regional therapy (yes/ no)
¾ Type of therapy
¾ Intent of therapy
¾ Number of prior anti-cancer radiotherapies
¾ Prior anti-cancer local-reginal therapy drugs, presented by preferred terms
alphabetically
¾ Best response
x
The following will be summarized for prior anti-cancer surgery
¾ Any prior anti-cancer surgery (yes/ no)
¾ Number of prior anti-cancer surgeries
¾ Prior anti-cancer surgeries, preferred terms will be presented alphabetically
¾ The surgery was curative in intent (yes/ no)
¾ Outcome of surgery
 
 
 
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14
Previous and Concomitant Medications/Procedures
Population: mITT Analysis Set
14.1
Previous and concomitant medications
The medications recorded on the “Concomitant Medication Details” eCRF form will be used as 
data source.
All terms will be coded using the most current World Health Organization Drug Dictionary (WHO 
Drug) version at the time of database lock. Medications will be presented using the Anatomical 
Therapeutic Chemical (ATC) classification system. Numbers of patients with concomitant 
medications/ treatment procedures will be presented overall and by ATC 2nd level, preferred terms.
Missing or partial dates for medications will not be imputed. In the case where it is not possible to 
define a medication as prior or concomitant, the medication will be classified by the worst case; 
i.e. considered as both previous and concomitant.
x
Previous medications are medications, other than trial treatments and pre-medications for 
trial treatment, which are taken before first administration of trial treatment.
x
Concomitant treatments are medications, other than trial treatments, which are taken by 
patients any time on-treatment (on or after the first day of any trial treatment for each 
patient) or within 33 days after last dose of trial treatment.
14.2
Concurrent procedures
All concurrent procedures, which were undertaken any time on trial, will be summarized according 
to the CRF page “Concurrent Procedures”. Concurrent procedures will be classified by medical 
review.
Number of patient with concurrent procedures, i.e, those on-treatment procedures will be 
summarized per treatment arm and overall and by reason and preferred name.
All medication/ treatment procedures will be listed.
14.3
Anti-Cancer Treatment after Discontinuation
New anticancer therapy will be recorded for patients who discontinue from the treatment for 
reasons other than PD at the additional follow-up visits. The following summaries will be 
presented for anti-cancer treatment after discontinuation: 
x
Any anti-cancer treatment after discontinuation (yes/ no)
x
Type of systemic therapy
x
Anti-cancer treatment drugs after discontinuation, presented by preferred terms
alphabetically
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x
Time to start of new anti-cancer treatment after discontinuation (months): derived as the 
duration from randomization to the earliest start date of anti-cancer drugs after 
discontinuation
x
Best response
15
Treatment Compliance and Exposure
Population: Safety Analysis Set
The date of first drug administration will be taken from the “Tepotinib Administration Details” 
and “Sorafenib Administration Details” eCRF forms respectively. The date of last drug 
administration will be taken from the “Treatment Termination for Tepotinib” and “Treatment 
Termination for Sorafenib” eCRF forms respectively. 
The extent of exposure to Tepotinib or sorafenib will be presented by the following summaries:
x
Duration of therapy (weeks):
Duration of therapy (weeks)= date of last dose-date of first dose+1
7
Interruptions, compliance, and dose changes are not taken into account for the calculation 
of duration of therapy.
x
Cumulative dose (mg):
The cumulative dose per patient in a time period is the sum of the total dosage that the
patient received.
x
Dose intensity (mg/day):
Dose intensity (mg/day) =
ሺሻ
ሺሻ
x
Relative dose intensity (%):
Relative dose intensity (%) =
Dose intensity (mg/day)
ሺȀሻכ ͳͲͲ
It will be summarized as continuous variables and also categorized into groups as the 
following: 
o
< 60% 
o
60% - <80% 
o
80% - <90% 
o
90% - 110% 
o
>110%
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16
Endpoint Evaluation
16.1
Primary Endpoint Analyses
Population: mITT Analysis Set; PP Analysis Set as sensitivity analysis if less than 90% of mITT.
Definition of primary endpoint
The primary endpoint is Time-to-Progression (TTP) as assessed by IRC according to RECIST 1.1 
(Eisenhauer EA et al, 2009).
TTP is defined as the time (in months) from randomization to the first observation of PD (as 
assessed by IRC). The earliest scan date of target/non-target/new lesions will be used as the date 
of an overall response. 
TTP (months) = (date of 1st PD – date of randomization+ 1) / 30.4375.
Start date of TTP:
x
The date of randomization
Event date is the earliest date of the following events:  
x
Observed PD before the patient drops out. Overall response of “not evaluable” will be 
changed to PD if subsequent scan is a PD. PD data from “Overall response” in Assessment 
of Disease Based on Imaging eCRF will be used.
x
PD assessed by imaging after the patient drops out. Imaging PDs collected in the “Survival 
Follow-Up / Progression Disease” eCRF will be used.
Censoring rules: 
x
Censored on the date of randomization if no baseline or post-baseline assessment.
x
Censored at the date of death, if the patient died without documented PD.
x
Censored on the date of last tumor assessment or the date of randomization, whatever 
occurs later, if:
¾ Lost to follow-up / withdraw consent without PD observed (includes also patients
whose last available radiological assessment is at least 42 days before data cut-off), 
or
¾ No PD observed up to the cut-off date (administrative censoring)
An overview of event/censoring rules is given in table 2: 
Table 2: General events/censoring rules 
Date of event/censoring
Censored
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Radiological PD observed before the patient
drops out.
Date of PD
No
Radiological PD assessed after the patient drops 
out.
Date of PD
No
Censoring: 
No baseline or post-baseline assessment
Date of randomization
Yes
Lost to follow-up / withdraw consent without PD 
observed 
(includes 
also 
patients 
with 
a 
radiological assessment that is at least 42 days 
before data cut-off)
Date of last known tumor 
assessment or date of 
randomization, whatever 
occurs later
Yes
No PD observed up to the cut-off date 
(administrative censoring)
Date of last known tumor 
assessment or date of 
randomization, whatever 
occurs later
Yes
Died without documented PD
Date of death
Yes
Primary analysis
The primary analysis will test the equality of TTP between treatment arms in the randomized part
of Phase II, based on the mITT population, applying a two-sided stratified log-rank test at a 
significance level of Į = 10%, taking into account the strata used for randomization, i.e., baseline 
BCLC stage. IVRS strata other than the eCRF strata will be used.
The following null-hypothesis is tested by the Cox's proportional hazards model stratified
according to strata used for randomization: 
H0: Oexperimental (t) = Ocontrol (t) 
H1: Oexperimental (t) = TOcontrol (t), Tz 1,
where O(t) represents the hazard at time t and T the unknown constant of proportionality of hazards 
in the allocated treatment groups in the randomized part. Ties will be handled by replacing the 
proportional hazards model by the discrete logistic model. With this ties option the Score-test in 
the Cox's proportional hazards model is identical to the log-rank test:
SURFSKUHJdata=xxx; 
strata BCLC;
model TTE*TTE_censor(1) = treatment / ties = discrete rl; 
ods output globaltests=logRank_TTE (where=(test='Score')) 
parameterestimates = HR_TTE ; 
UXQ;
Where:
TTE_censor = 1 if censored, 0 otherwise 
Treatment  = 1 if in experimental arm, =0 if in control arm 
TTE    
= Time to event variable, for primary analysis it is TTP by IRC.
The hazard ratio T and 90% CIs of Tepotinib compared to sorafenib will be calculated by Cox's 
proportional hazards model stratified by baseline BCLC (stage B vs stage C).
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Kaplan-Meier curves (product-limit estimates) will be presented by treatment arm together with a 
summary of associated statistics (25th quintile, median and 75th quintile survival time, 2-months, 
4-months KM estimates and estimates for every 2 months thereafter as applicable) including the 
corresponding two-sided 90% CIs. The CIs for the median will be calculated according to 
Brookmeyer and Crowley (1982), and CIs for the survival function estimates at above defined time 
points will be derived from the Kaplan-Meier estimates using the log-log transformation 
(CONFTYPE=LOGLOG in SAS PROC LIFETEST). The estimate of the standard error will be 
computed using Greenwood's formula. Comparisons of survival rates will be performed from a Z-
test using estimates and standard errors derived from the Kaplan-Meier method and Greenwood’s 
formula. SAS procedure LIFETEST will be used to obtain Kaplan-Meier estimates and plots.
Sensitivity analysis
An un-stratified Cox model will be fitted, by which the hazard ratio T, the 90% CIs and p- value 
will be calculated. 
Multivariate analysis will be performed with a stepwise selection to assess the effect of predefined 
baseline covariates, which are the subgroup variables in Section 10.2 (except for baseline tumor 
HGF and baseline biomarker variables measured in plasma).
The model selection is performed without fitting the treatment group in the proportional hazards 
model. The values 0.15 and 0.40 will be used as the p-value for entry into the model inclusion and 
p-value for staying in the model, respectively exclusion criteria. 
SURFSKUHJ data=Eff_mITT ;
class all-subgroup variables;
strata BCLC;
model TTE*censor(1)= all-subgroup variables /ties=discrete rl selection=stepwise 
slentry=0.15 slstay=0.40 details;
ods output globaltests=logRank(where=(test='Score')) parameterestimates=HR;
UXQ
Where:
slentry= boundary for p-value of Score test for inclusion, other values than 0.15 can be 
considered
slstay= boundary for p-value of Wald test for exclusion, other values than 0.40 can be considered
Once the selection procedure is finalized the model will be refitted with the strata and the treatment 
group, plus the selected covariates.
SURFSKUHJdata=xxx; 
strata BCLC;
class all-selected-covariates;
model TTE*TTE_censor(1) = treatment all-selected-covariates / ties = discrete rl; 
ods output globaltests=logRank_TTE (where=(test='Score')) 
parameterestimates = HR_TTE ; 
UXQ;
Where:
TTE_censor = 1 if censored, 0 otherwise 
Treatment = 1 if in experimental arm, =0 if in control arm 
TTE
= Time to event variables, for primary analysis it is TTP by IRC..
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Subgroup analyses will be performed separately for each of the predefined subgroup variables
without stratification due to the potential low number of patients per subgroup category. Cox 
regression models will be fitted for TTP by IRC as the dependent variable and with a subgroup 
type, the treatment group assignment and with and without the treatment by subgroup type 
interaction as explanatory variables. Hazard ratio (including 90% confidence interval) of Tepotinib 
compared to sorafenib is computed per subgroup level. P-value for the interaction test (Likelihood 
Ratio test) will be provided together with the hazard ratios and confidence intervals of the 
interaction model parameter. Forest plots will be presented with hazard ratios and 90% CIs of
treatment for the overall treatment effect and for each subgroup level.
Kaplan-Meier curves will be presented by treatment arm for each predefined biomarkers 
subgroups.
A cross table of TTP assessed by IRC vs TTP assessed by investigator will be summarized to 
check the consistency of two definitions. If the TTP assessed by IRC and the TTP assessed by 
investigator are at most 30 days apart, the two TTPs will be considered consistent.
TTP assessed by IRC assessed will be further explored considering the PP population if the number 
of patients in the PP population is less than 90% of the number of patients in the mITT population.
16.2
Secondary Endpoint Analyses
Population: mITT Analysis Set; PP Analysis Set if less than 90% of mITT.
16.2.1
Progression-free Survival (PFS) on tumor assessment by IRC
PFS time is defined as the time (in months) from randomization to either first observation of 
disease progression or occurrence of death due to any cause within 84 days of either randomization
or the last tumor assessment. The 84-day time window represents the time span between scheduled 
tumor assessments. The earliest scan date of target/non-target/new lesions will be used as the date 
of an overall response.
PFS (months) = (date of 1st PD or death –date of randomization+ 1) / 30.4375.
Start date of PFS:
x
The date of randomization
Event date is the earliest date of the following events:
x
Observed PD before the patient drops out. Overall response of “not evaluable” will be 
changed to PD if subsequent scan is a PD. PD data from “Overall response” in Assessment 
of Disease Based on Imaging eCRF will be used.
x
PD assessed by imaging after the patient drops out. Imaging PDs collected in the “Survival 
Follow-Up / Progression Disease” eCRF will be used.
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x
Death without previously documented PD is observed within 84 days of the date of 
randomization or last tumor assessment. The Death date is collected on the “Death” eCRF 
form.
Censoring rules: 
x
Censored on the date of randomization if no baseline or post-baseline assessment.
x
Censored on the date of last tumor assessment or the date of randomization, whatever 
occurs later, if:
¾ Death without previously documented PD is observed not within 84 days of the
randomization or last tumor assessment, or 
¾ Lost to follow-up / withdraw consent without PD/death observed (including also 
patients whose last available radiological assessment is at least 84 days before data 
cut-off), or
¾ No PD/death observed yet up to the cut-off date (administrative censoring)
An overview of PFS event/censoring rules is given in table 3:
Table 3: PFS Events/censoring rules 
Date of event/censoring
Censored
Events: 
Radiological PD observed before the patient
drops out.
Date of PD
No
Radiological PD assessed after the patient drops 
out.
Date of PD
No
Death without previously documented PD is 
observed within 84 days of the randomization or
the last tumor assessment
Date of death
No
Censoring: 
No baseline or post-baseline assessment
Date of randomization
Yes
Death without previously documented PD is 
observed not within 84 days of the randomization
or the last tumor assessment
Date of last known tumor 
assessment or date of 
randomization, whatever 
occurs later
Yes
Lost to follow-up / withdraw consent without 
PD/death observed (includes also patients with a 
radiological assessment that is at least 84 days 
before data cut-off)
Date of last known tumor 
assessment or date of 
randomization, whatever 
occurs later
Yes
No PD/death observed up to the cut-off date
(administrative censoring)
Date of last known tumor 
assessment or date of 
randomization, whatever 
occurs later
Yes
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Analysis methods analogous to the ones of the primary endpoint will employed. Subgroup analyses 
will be performed for each of the subgroup variables. Kaplan-Meier curves will be presented by 
treatment arm for each predefined biomarker subgroup.
16.2.2
PFS based on tumor assessment by Investigator 
PFS time is defined as the time (in months) from randomization to either first observation of 
radiologically confirmed PD by the investigator or occurrence of death due to any cause within 84 
days of either randomization or the last tumor assessment.
16.2.3
Overall Survival (OS)
A preliminary analysis on OS may be performed when the primary analysis on TTP is analyzed. 
Final OS analysis will be carried out after the database lock. 
Overall survival (OS) time is defined as the time (in months) from randomization to the date of 
death. For patients who do not have a date of death, the last date known to be alive will be used:
OS (months) = (date of death or last date known to be alive – the date of randomization+
1) / 30.4375.
Event date:
x
Date of death if the death is before the cut-off date
For patients who do not have a date of death, the patient will be censored at the last known alive 
date, and will be categorized as:
x
Administrative censoring: For patients whose last date known to be alive is within 90 days 
of cutoff date. 
x
Non-administrative censoring: For patients whose last date known to be alive is outside of 
90 days before cutoff date.
The last known alive date will be the latest date of alive dates (refers to Table 4)
Table 4: Data source of alive dates
eCRF or Dataset
CRF Items or Variables
Patient Status / Survival Follow-Up
Last known alive date, follow-up date
SDTM.SV
SVSTDTC, SVENDTC
Adverse Events
Start date, end date
Concomitant Medications
Start date, end date
End of Assessment Visit
Completion/discontinuation date
Additional Follow-Up / Progression Disease
Progression date
Anti-Cancer Treatment After Discontinuation
Start date, end date
Analyses analogous to the ones for TTP will be performed, expect that the survival rate will be 
estimated at 3-month, 6-month and for every 3 months thereafter as applicable. Subgroup analyses 
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will be performed for each of the subgroup variables. Kaplan-Meier curves will be presented by 
treatment arm for each predefined biomarker subgroup.
16.2.4
TTP Assessed by Investigator 
TTP assessed by investigator is defined as the time (in months) from randomization to the date of 
the observation of radiological PD assessed by investigator:
TTP (months) = (date of 1st PD –date of randomization+ 1) / 30.4375.
Analysis methods analogous to the ones of TTP assessed by IRC will employed. 
16.2.5
Time-to-Symptomatic Progression (TTSP)
Time-to-symptomatic progression (TTSP) is defined as the time (in months) from the date of
randomization to the date of deterioration of symptoms assessed by FHSI-8, defined as the total 
score increase by at least 4 points compared with the baseline value, or deterioration to ECOG
PS of 4.
Start date of TTSP:
x
The date of randomization
Event date is the date of the earliest deterioration.
Censoring rules: 
x
Censored on the date of randomization if no baseline or post-baseline assessment.
x
Censored at the date of death, if the patient died without deterioration.
x
Censored on the date of last FHSI-8 / ECOG assessment or the date of randomization, 
whatever occurs later, if:
¾ Lost to follow-up / withdraw consent without deterioration observed (includes also 
patients whose last available FHSI-8 / ECOG assessment is at least 42 days before 
data cut-off), or
¾ No deterioration observed up to the cut-off date (administrative censoring)
The FHSI-8 will be scored by the following scoring guideline (version 4):
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Analyses analogous to the ones of TTP will be performed.
16.2.6
Antitumor Activity Assessed by IRC
Best Overall Response
Best overall response (BOR) is defined as the best result obtained among all tumor assessment 
visits from baseline until end of treatment or determination of PD, excluding assessments after 
tumor surgery.
Not Evaluable (NE) is not considered a valid measurement. Overall response of NE will be 
changed to PD if subsequent scan is a PD. As a consequence, a BOR of NE will only be assigned 
if NE is the only one treatment assessment (for instance, a patient having assessments of NE and 
PD will be assigned BOR of PD). 
Patients with BOR of non-CR/non-PD (possible only for patients without measurable disease at 
baseline) are not considered as having achieved objective response, nor clinical benefit.
The following will be provided:
x
The number and percentage of patients with a best overall response (BOR) of CR, PR, SD, 
PD, non-CR/non-PD, and NE will be tabulated.
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x
The number and percentage of patients will be tabulated over time grouped by the overall 
response.
x
Bar chart with time to response and duration of trial treatment
x
The number and percentage of patients will be tabulated by predefined biomarker subgroup 
and treatment group over time grouped by the best overall response.
Objective Response Rate (ORR) based on tumor assessment by IRC
The objective response rate is defined as complete response (CR) or partial response (PR) as the 
best overall response (BOR) according to radiological assessments as adjudicated by the IRC from 
randomization to first occurrence of PD.Responses do not require confirmation according to
RECIST v1.1.
The Cochran-Mantel-Haenszel test will be performed for analysis using the randomization strata, 
i.e., type of Met+. The Cochran-Mantel-Haenszel will test the following two-sided hypothesis:
H0: Ȍ = 1
H1: Ȍ  1
where Ȍ defines the common odds ratio across all strata.
The common Mantel-Haenszel odds ratio (OR) adjusted by strata and the corresponding 90% CIs
using the variance formula for the log of the common odds ratio estimate will be presented. The 
odds ratio is defined as the odds of showing response with the investigational drug, divided by the 
odds of showing response with the control treatment, i.e. an odds ratio greater than one corresponds 
to a benefit of the investigational arm. The homogeneity of the odds ratio across strata will be 
checked by the Breslow-Day test, The null hypothesis of no association in any of the strata is tested 
against the alternative, which says that at least in one stratum there is an association between 
treatment effect and tumor response. Additional to the Mantel-Haenszel estimate, odds ratios per 
stratum are indicated with the corresponding exact confidence interval. The common odds ratio 
with no adjustment by strata and its 90% CI will be provided as well.
The ORR rate will be presented for each treatment group including the corresponding 90%
Newcombe-Wilson CIs.
The best percent change (%) from baseline for the sum of longest diameters will be displayed in a 
waterfall plot.
Disease Control Rate (DCR) by IRC
The disease control rate is defined as the proportion of patients having achieved CR, PR, or stable 
disease (SD) as the BOR according to radiological assessments from randomization until end of 
trial treatment the first occurrence of PD. In the case of SD, measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 42 days after randomization.
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The DCR rate and its 90% Newcombe-Wilson CI will be calculated. 
16.2.7
Antitumor Activity Assessed by Investigator
Best overall response
BOR is defined as the best result obtained among all tumor assessment visits by investigator from 
baseline until end of treatment or determination of PD, excluding assessments after tumor surgery.
ORR based on tumor assessment by Investigator
OR based on tumor assessment by the investigator. OR is defined as CR or PR as the best overall 
response according to radiological assessments as adjudicated by the investigator from
randomization to first occurrence of PD. Responses do not require confirmation according to
RECIST v 1.1 (see Appendix C).
DCR based on tumor assessment by the investigator
Disease control is defined as CR, PR, or SD as the best overall response according to radiological 
assessments as adjudicated by the investigator from the date of randomization to the first 
occurrence of PD. In the case of SD, measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 42 days after randomization.
16.3
Other Endpoint Analyses
 
 
 
 
 
 
 
 
 
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16.3.2
Patient Reported Outcome
Population: mITT Analysis Set
Functional assessment of cancer therapy-hepatobiliary (FACT-HP)
The FACT-HP questionnaire will be scored by the FACT-Hep Scoring Guideline (version 4): 
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The absolute value and change from baseline of FACT-Hep Total score, Trial Outcome Index 
(TOI) score and FACT-G score will be summarized over time descriptively for each treatment 
group.
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16.3.5
Tumor Shrinkage by IRC
Population: Safety Analysis Set
The percent change from baseline in target lesions assessed by IRC (sum of longest diameter for 
non-nodal lesions and short axis for nodal lesions, SOD) per time point will be derived for subjects 
with post baseline target lesion assessments as:
 ൌͳͲͲ כ ሺܺ
 െͳሻ
The earliest scan date of target lesions will be used as the date of SOD.
The best relative change in target lesions from baseline will be derived across all post-baseline 
assessments by IRC until documented disease progression as:
 ൌݐ݄݁݉݅݉݅݉ݑ݉ݒ݈ܽݑ݁݋݂݌݁ݎܿ݁݊ݐ݄ܿܽ݊݃݁݂ݎ݋݉ܾܽݏ݈݁݅݊݁
The following will be provided:
x
Waterfall plot for the best relative change of SOD
x
Waterfall plot for the best relative change of SOD by cMet status (Positive (2+ or 3+) 
/Negative (0 or 1+) /Indeterminate/Missing)
x
The percent change from baseline in target lesions per time point will be displayed in a line 
plot and presented in a data listing as well as other relevant information. 
16.3.6
Tumor Shrinkage by Investigator
The percent change from baseline in target lesions assessed by investigator (sum of longest 
diameter for non-nodal lesions and short axis for nodal lesions, SOD) per time point will be derived 
for subjects with post baseline target lesion assessments as:
 ൌͳͲͲ כ ሺܺ
 െͳሻ
The earliest scan date of target lesions will be used as the date of SOD.
The best relative change in target lesions from baseline will be derived across all post-baseline 
assessments by investigator until documented disease progression as:
 ൌݐ݄݁݉݅݉݅݉ݑ݉ݒ݈ܽݑ݁݋݂݌݁ݎܿ݁݊ݐ݄ܿܽ݊݃݁݂ݎ݋݉ܾܽݏ݈݁݅݊݁
Analysis methods analogous to the ones of tumor shrinkage assessed by IRC will employed. 
17
Safety Evaluation
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The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs. Analyses will 
be performed using the Safety Analysis set. 
Safety analyses will be done on the safety analysis set and according to the as-treated principle.
17.1
Adverse Events
Population: Safety Analysis Set
Treatment emergent adverse events: those events with onset dates occurring within the treatment 
periods, i.e, starts on or after the earliest dosing date of any trial treatment and prior to the latest
dosing date of any trial treatment + 33 days (inclusive). AE occurring after the first administration
will always be considered as TEAE regardless of whether its onset date beyond the 33 days if it is 
assessed as trial-drug related by investigator.
“Timing related to study treatment” from the AE eCRF will be used to judge whether the AE is a 
TEAE when the AE onset date is the same day as the day of first administration.
In the case where it is not possible to define an AE as being treatment emergent or not, the AE will 
be classified as treatment emergent as the most conservative approach. 
Summaries for the number of patients in total and within each treatment group will be presented, 
for each of the categories described in the sub-sections below. 
Listings will include all TEAEs and Non-TEAEs. Summary tables described in Section 17.1,
17.2.2 and 17.2.3 will be based on TEAEs if not otherwise specified.
No formal statistical comparisons are planned.
17.1.1
All Adverse Events
AEs will be coded using the most current version of MedDRA dictionary. The investigator will be 
responsible for assigning the Common Toxicity Criteria (CTC) grades for AEs, using the most 
current version of NCI-CTCAE. 
Incidence rates (frequencies and percentages) of individual AEs, that is, the number of patients
experiencing events AEs in each PT or SOC, and the proportion relative to the number of patients
in the SAF analysis set, will be presented.
Unless otherwise stated adverse events will be displayed in terms of frequency tables: PT and 
primary SOC in alphabetical order. 
The relationship to the trial treatment, as indicated by the investigator, is classed as “not related” 
or “related”. TEAEs with a related or missing relationship to the trial treatment will be regarded 
as “related”. If a patient reports the same AE more than once within that SOC/PT, the AE will be 
categorized as “unrelated” only when all relationship records are “unrelated”, otherwise it will be 
classed as “related” in the corresponding relationship summaries.
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Severity is classified as grade 1, 2, 3, 4, 5 (increasing severity) by referencing the most current 
NCI-CTCAE 4.0 (publication date: 28May2009). If a patient reports a TEAE more than once 
within that SOC/PT, the AE with the worst case severity will be used in the corresponding severity 
summaries. In case a patient had events with missing and non-missing severities, the maximum of 
the non-missing severities will be displayed. In case all the TEAEs of a patient are all with missing 
severities then grade 3 (severe) will be used unless there is any evidence that it should be grade 4 
or 5.
An overview summary of TEAEs will be provided by treatment group for cycle 1 and all cycles:
x
TEAEs 
x
Related TEAEs
x
Serious TEAEs
x
Serious related TEAEs
x
TEAEs of grade  3 by NCI-CTCAE
x
Related TEAEs of grade  3 by NCI-CTCAE
x
TEAEs of special interest (refer to Section 17.2.3)
x
Related TEAEs of special interest
x
TEAE leading to death (AEs with grade 5 or outcome “fatal” if grade 5 not applicable)
x
Related TEAE leading to death (AEs with grade 5 or outcome “fatal” if grade 5 not 
applicable)
x
TEAEs leading to dose reduction of trial treatment
x
TEAEs leading to temporary discontinuation of trial treatment
x
TEAEs leading to permanent discontinuation of trial treatment
x
TEAEs leading to study discontinuation
Also the following tables will be presented by SOC, PT in alphabetical order for TEAEs:
x
Incidence of TEAEs
x
Incidence of TEAEs by worst severity (CTCAE grade)
x
Incidence of related TEAEs 
x
Incidence of TEAEs with CTCAE grade >= 3 
x
Incidence of treatment related TEAEs with CTCAE grade >= 3 
17.1.2
Adverse Events Leading to Treatment Discontinuation
AEs leading to permanent or temporary discontinuation of trial treatment are those AEs whose 
actions taken with trial treatment is reported as “drug withdrawn” or “drug interrupted” in the 
“Adverse Events Details” eCRF. The following will be presented by SOC and PT in alphabetical 
order:
x
Incidence of TEAEs leading to dose reduction of trial treatment 
x
Incidence of TEAEs leading to permanent discontinuation of trial treatment
x
Incidence of TEAEs leading to temporary discontinuation of trial treatment
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17.2
Deaths, Other SAEs, and AEs of Special Interest
Population: Safety Analysis Set
17.2.1
Deaths
All deaths, deaths within 33 days after last dose of trial treatment, will be tabulated based on 
information from the “Death” eCRF.
Summaries will be presented for: 
x
Number of deaths 
x
Number of deaths within 33 days after last dose of treatment
x
Primary reason of death 
¾ Disease progressions
¾ Adverse event related to trial treatment
¾ Adverse event not related to trial treatment
¾ Other 
¾ Unknown
All deaths for screening analysis set will be listed: 
x
In addition, date and cause of death will be provided in individual patient data listing 
together with selected dosing information (date of first / last administration, dose intensity, 
etc).
x
Including columns for:
¾ AEs with fatal outcome (list preferred terms of AEs with outcome=fatal)
¾ flag for death within 33 days of last trial treatment administration
17.2.2
Serious Adverse Events
SAEs are those events with a response of “Yes” for the item “Serious Adverse Event” on the 
“Adverse Events Details” eCRF. Serious TEAE, serious related TEAEs and a full list of all SAEs 
will be presented:
x
Incidence of serious TEAEs by SOC and PT
x
Incidence of serious related TEAEs by SOC and PT 
x
Incidence of serious TEAEs leading to death by SOC and PT
x
Incidence of related serious TEAEs leading to death by SOC and PT
x
Listing of all SAEs
17.2.3
Adverse Event of Special Interest
AE of Special Interest (AESI) is defined as AEs of asymptomatic lipase and/or amylase elevations 
of Grade  3. The following are collected and will be presented:
x
Incidence of treatment emergent AESIs by SOC and PT
x
Incidence of  related treatment emergent AESIs by SOC and PT
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17.3
Clinical Laboratory Evaluation
Population: Safety Analysis Set
Laboratory values (including corresponding normal ranges) from Central Lab will be used for 
summary statistics and shift tables. Only patients with post baseline laboratory values will be
included in these analyses.
Qualitative data based on reference ranges will be described according to the categories (i.e. 
Low, Normal, High). The number of patients with clinical laboratory values below, within, or 
above normal ranges at baseline compared to worst on-treatment results will be tabulated for 
each test by treatment groups. Shift tables of baseline versus worst on-treatment endpoint will be 
presented. 
Thus the following tabulations will be provided for each treatment arm:
x
Actual and changes from baseline to each scheduled visit over time
x
Number of patients with shifts from baseline to worst on-treatment result above/below 
normal limit. Please refer to the AdaM template 2.0 to find parameters to be split into high 
and low. For example, glucose will be presented by “glucose high” and “glucose low” 
separately. 
x
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values that are identified by the 
investigator as being clinically significant will be shown in a data listing. 
x
Any lipase or amylase increase will be listed with a column flagging the ones meeting 
AESI definition, as noted in Section 17.2.3.
Laboratory results will also be classified according to the most current version of NCI-CTC 
Version as provided by the central laboratory. Parameters with available NCI-CTC grades will 
be summarized as the following:
x
Number and percentage of subjects with any, NCI-CTC grade 0, 1, 2, 3, or 4 laboratory 
abnormalities under treatment – (worst case)
x
/Shifts in toxicity grading from baseline to worst
on-treatment grade: The worst on-
treatment grade will be summarized by NCI-CTC grade (0, 1, 2, 3, 4, any). Please refer to 
the AdaM template 2.0 to find parameters to be split into high and low. For example, 
glucose will be presented by “glucose high” and “glucose low” separately. 
Parameter
Baseline category
Worst on trial value 
Lab parameters with 
NCI-CTCAE grade
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Any (Total)
Grade 0
Grade 1
Grade 2
Grade 3
Grade 4
Any (Total)
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17.4
Vital Signs
Population: Safety Analysis Set
Weight will be classified according to the NCI-CTCAE (version 4.0) criteria. Please find the 
CTCAE grading rules from the appendix.
Parameter
Baseline category
Worst on trial value 
Weight
Grade 0
Grade 1
Grade 2
Grade 3
Any (Total)
Grade 0
Grade 1
Grade 2
Grade 3
Any (Total)
The maximum changes of vital sign measurements screening/baseline to maximum on-treatment 
changes after start of 1st treatment will be grouped as follows: 
Vital Sign Parameter
Increase/ 
decrease
Baseline category
Change from baseline category 
Temperature 
Increase
<37 °C, 
37 - <38 °C
38 - <39 °C
39 - <40 °C
>=40 °C
< 1qC , 
1-<2qC , 
2-<3qC, 
t 3 qC
Heart rate 
Increase
<100 bpm ;
൒100 bpm
d20 bpm, 
>20 – 40 bpm, 
>40 bpm
Decrease
<100 bpm ; 
൒100 bpm
d20 bpm, 
>20 – 40 bpm, 
>40 bpm
SBP 
Increase
<140 mmHg; 
൒140 mmHg 
d20 mmHg,
>20 – 40 mmHg,
>40 mmHg
Decrease
<140 mmHg; 
൒140 mmHg,
d20 mmHg,
>20 – 40 mmHg,
>40 mmHg
DBP 
Increase
<90 mmHg; 
൒90 mmHg 
d20 mmHg,
>20 – 40 mmHg,
>40 mmHg
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Decrease
<90 mmHg; 
൒90 mmHg
d20 mmHg,
>20 – 40 mmHg,
>40 mmHg
Respiration rate 
Increase
<20 bpm ; 
൒20 bpm
d5 bpm, 
>5 – 10 bpm, 
>10 bpm
Decrease
<20 bpm ; 
൒20 bpm
d5 bpm, 
>5 – 10 bpm, 
>10 bpm
The following summaries will be prepared for vital sign parameters as grouped above considering 
only subjects with post baseline values:
x
Change from baseline to worst on-treatment CTCAE toxicity grade for weight
x
Maximal Shifts (changes in categories)
17.5
ECG
Population: Safety Analysis Set
All ECG readings will be recorded as 12-lead resting ECGs in triplicates. The average of these 3 
results will be used for inclusion in the reporting of this study for numeric parameters. If some of 
the 3 results are missing, the average of available results will be used. For categorical data, the 
worst result among the 3 results will be used. 
The following summaries will be provided for ECG data:
x
The ECG overall assessment as reported by the investigator on the “Electrocardiogram” 
eCRF page will be summarized by time point/visit (Number and percentage of subject with 
result of ECG reported as Normal/Abnormal/Abnormal NCS/Abnormal CS)
x
Summary over time for numeric parameters: only patients still stay at the visit will be 
summarized.
x
Categorical shift from baseline to worst on-treatment value for QTcF: the baseline and the 
worst on-treatment value will be grouped as follows:
Parameter
Baseline category
Worst on trial value 
QTcF
<=450ms
>450 - <=480ms
>480 - <=500ms
>500ms
<=450ms
>450 - <=480ms
>480 - <=500ms
>500ms
x Categorical change from baseline to worst on-treatment value for QTcF: the baseline and 
the worst change from baseline value will be grouped as follows:
Parameter
Baseline category
Worst change from baseline 
QTcF
Normal (i.e.<=450ms)
<=0 ms
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Abnormal (i.e.>450ms)
>0 - <=30ms
>30 - <=60ms
>60ms 
17.6
Other Safety Evaluations
Population: Safety Analysis Set
The following will be provided for the ECOG performance status: 
x Summary of ECOG over time: ECOG will be classified as 0, 1, 2, 3, 4, 5. Only patients still 
stay at the visit will be summarized. 
x Shifts in ECOG performance status from baseline to worst on-treatment performance status 
will be summarized by treatment group
18
Reporting Conventions
The mock shells will be provided in a separate document EMR200095-004 Phase II CTR Mock 
Shells.
19
References
x
Eisenhauer EA, Therasse P, Bogaerts J,Schwartz LH, Sargent D, Ford R, et al. New response
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 
45: 228-247.
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20
Appendix
x
Non-CRF Data are listed as:
Data to be Analyzed
Collected by 
Protocol deviations
Clinical Trial Management System (CTMS).
Laboratory data
Central Lab
x
Laboratory parameters with CTCAE grading are: 
Lab Test Name
Grade 1
Grade 2
Grade 3
Grade 4
Chemistry
Total Bilirubin 
(umol/L)
Increase
>ULN
>1.5ULN
>3ULN
>10ULN
Aspartate 
Aminotransferase 
(U/L), SGOT
Increase
>ULN
>3xULN
>5xULN
>20xULN
Alanine
Aminotransferase 
(U/L), AST
Increase
>ULN
>3xULN
>5xULN
>20xULN
Sodium (mmol/L) Low
Decrease
<LLN
NA
<130
<120
Sodium (mmol/L) High
Increase
>ULN
>150
>155
>160
Calcium (mmol/L) Low 
(Albumin corrected), 
(Not total calcium)
Decrease
<LLN
<2
<1.75
<1.5
Calcium (mmol/L) High
(Albumin corrected), 
(Not total calcium)
Increase
>ULN
>2.9
>3.1
>3.4
Magnesium (mmol/L) 
Low
Decrease
<LLN
<0.5
<0.4
<0.3
Magnesium (mmol/L) 
High
Increase
>ULN
NA
>1.23
>3.3
Creatinine (umol/L)
Increase
>BL or 
ULN
>1.5BL or 
1.5ULN
>3BL or 
3ULN
>6ULN
Albumin (g/L)     
Decrease
<LLN
<30
<20
NA
Alkaline phosphatase 
(U/L)  
Increase
>ULN
>2.5xULN
>5xULN
>20xULN
Amylase (U/L)
Increase
>ULN
>1.5xULN
>2xULN
>5xULN
Lipase (U/L)
Increase
>ULN
>1.5xULN
>2xULN
>5xULN
Glucose (mmol/L) Low
Decrease
<LLN
<3.0
<2.2
<1.7
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Glucose (mmol/L) High
Increase
>ULN
>8.9
>13.9
>27.8
Gamma Glutamyl 
Transferase (U/L)
Increase
>ULN
>2.5xULN
>5xULN
>20xULN
Potassium (mmol/L) 
Low
Decrease
<LLN
<LLN
<3
<2.5
Potassium (mmol/L) 
High
Increase
>ULN
>5.5
>6
>7
Creatinine Clearance, 
C&G (mL/min)
Decrease
NA
<60
<30
<15
Hematology
Hemoglobin (g/L) Low
Decrease
<LLN
<100
<80
NA
Hemoglobin (gm/dL)
High
Increase
>ULN or 
BL if 
BL>ULN
>ULN+2 or 
BL+2 if 
BL>ULN
>ULN+4 or 
BL+4 if 
BL>ULN
NA
Platelet (10E9/L), PLT
Decrease
<LLN
<75
<50
<25
Leukocytes (10E9/L) 
Low
Decrease
<LLN
<3
<2
<1
Leukocytes (10E9/L) 
High
Increase
NA
NA
>100
NA
Neutrophils (10E9/L), 
Absolute Neutrophils 
Count , ANC
Decrease
<LLN
<1.5
<1
<0.5
Lymphocytes (10E9/L) 
Low
Decrease
<LLN
<0.8
<0.5
<0.2
Lymphocytes (10E9/L) 
High
Increase
NA
>4
>20
NA
Coagulation
Activated Partial 
Thromboplastin Time 
(sec)
Increase
>1ULN
>1.5ULN
>2.5ULN
NA
Prothrombin Intl. 
Normalized Ratio
Increase
>BL or 
ULN
>1.5BL or 
1.5ULN
>2.5BL or 
2.5ULN
NA
* BL=Baseline, ULN=Upper limit of normal range.
x
Vital sign parameters with CTCAE grading are: 
Vital Sign 
Parameter
Grade 1
Grade 2
Grade 3
Grade 
4
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Weight Loss (kg)
Decrease 5 - <10% from 
BL
10 - <20% from 
BL
>=20% from 
BL
NA
Weight Gain (kg)
Increase
5 - <10% from 
BL
10 - <20% from 
BL
>=20% from 
BL
NA
* BL=Baseline.
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