Clinical trial NCT03546608
Conditions: Hepatic Impairment
Keywords: Hepatic Impairment Tepotinib Pharmacokinetics
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2018-06-13; Completion date: 2019-02-05
Enrollment: 18 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study investigated the effect of various degrees of hepatic impairment on the pharmacokinetics (PK), safety and tolerability of tepotinib.

Detailed description:

Arms: arm 1: Participants with normal hepatic function matched to moderate hepatic impairment received single oral dose of 500 milligrams (mg) of tepotinib film-coated tablet on Day 1 after a standard breakfast. arm 2: Participants with mild hepatic impairment (Child-Pugh Class A, score 5 to 6) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast. arm 3: Participants with moderate hepatic impairment (Child-Pugh Class B, score 7 to 9) received single oral dose of 500 mg tepotinib film-coated tablet on Day 1 after a standard breakfast.
Interventions: intervention 1: Tepotinib
Intervention descriptions: intervention 1: Participants received a single oral dose of tepotinib in Part 1.

Protocol documents:
Prot_000.pdf: 
Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Te p oti ni b He p atic I m p air me nt Tri al
M S 2 0 0 0 9 5- 0 0 2 8
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 7 5
Cli nic al St u d y Pr ot oc ol
Cli nic al St u d y Pr ot oc ol N u m ber
M S 2 0 0 0 9 5- 0 0 2 8
Title
O pe n- La bel,  Parallel- Gr o u p  P hase  1  St u d y  t o  
I n vesti gate t he Effect of Vari o us De grees of He patic 
I m pair me nt  o n  t he  P har mac o ki netics,  Safet y  a n d  
T olera bilit y of t he c- Met Ki nase I n hi bit or Te p oti ni b
P h ase
I
I N D N u m ber
1 0 6 1 0 3
E u dr a C T N u m ber
N ot a p plica ble
Pri nci p al I n vesti g at ors
Orla n d o Cli nical Researc h Ce nter
5 0 5 5 S. Ora n ge A ve
Orla n d o, F L 3 2 8 0 9, U S A
P h o ne: 
E mail: 
Q P S M R A, L L C
6 2 8 0 S u nset Dri ve, S uite 6 0 0
Mia mi, F L., 3 3 1 4 3, U S A
P h o ne: 
E mail: 
S p o ns or
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I nc, 
4 5 A  Mi d dlese x  T ur n pi ke,  Billerica,  M A 0 1 8 2 1,  
U S A.
Me dical Res p o nsi ble:
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 
Dar msta dt, Ger ma n y
P h o ne: 
M o bile: 
E mail: 
S p o ns or Le g al  Re prese nt ati ve i n 
t he E ur o pe a n U ni o n
Merc k K G a A
Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
Cli nic al St u d y Pr ot oc ol Versi o n
2 4  A pril 2 0 1 8 / Versi o n 2. 0
Re pl aces Versi o n
1 5  Marc h 2 0 1 7 / Versi o n 1. 0
D o c u me nt N o. 
O bject N o. 
PI
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Tepotinib (MSC215619J)
Tepotinib Hepatic Impairment Trial
MS2095-028
C O N F I D E N T I A L
I N F O R M A T I O N
2/75
- Confidential -
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 ful or part – be pased on, reproduced, 
published or used without expres permision of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2018 by Merck KGaA, Darms
tadt, Germany, or its subsidiary. Al rights 
reserved.
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
3/75
Protocol Table of Contents
Protocol Table of Contents ..................................................................................................3
Table of In-Text Tables .......................................................................................................7
Table of In-Text Figures......................................................................................................7
List of Abbreviations ...........................................................................................................8
1
Synopsis..............................................................................................10
2
Sponsor, Investigators and Study Administrative Structure...............18
3
Background Information.....................................................................19
3.1
General Information............................................................................19
3.2
Study Rationale...................................................................................21
4
Study Objectives.................................................................................22
4.1
Primary Objective...............................................................................22
4.2
Secondary Objectives .........................................................................23
4.3
Other Objectives .................................................................................23
5
Investigational Plan ............................................................................23
5.1
Overall Study Design and Plan...........................................................23
5.2
Discussion of Study Design................................................................25
5.2.1
Scientific Rationale for Study Design ................................................27
5.2.2
Justification for Dose..........................................................................27
5.2.3
Rationale for Endpoints......................................................................27
5.2.4
Risks ...................................................................................................28
5.2.5
Inclusion of Special Populations ........................................................28
5.3
Selection of Study Population ............................................................28
5.3.1
Inclusion Criteria ................................................................................28
5.3.2
Exclusion Criteria...............................................................................30
5.4
Criteria for Initiation of Study Treatment...........................................31
5.5
Criteria for Subject Withdrawal..........................................................32
5.5.1
Withdrawal from Investigational Medicinal Product 
Administration....................................................................................32
5.5.2
Withdrawal from the Study ................................................................32
5.6
Premature Termination of the Study...................................................32
5.7
Definition of End of Study .................................................................33
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
4/75
6
Investigational Medicinal Product and Other Drugs Used in the 
Study...................................................................................................33
6.1
Description of the Investigational Medicinal Product........................33
6.2
Dosage and Administration ................................................................33
6.3
Assignment to Treatment Groups.......................................................33
6.4
Noninvestigational Medicinal Products to be Used............................33
6.5
Concomitant Medications and Nondrug Therapies/Interventions......34
6.5.1
Permitted Medicines...........................................................................34
6.5.2
Prohibited Medicines..........................................................................34
6.5.3
Other Interventions.............................................................................35
6.5.4
Special Precautions.............................................................................35
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................35
6.6
Packaging and Labeling of the Investigational Medicinal Product....35
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................36
6.8
Investigational Medicinal Product Accountability.............................36
6.9
Assessment of Investigational Medicinal Product Compliance .........37
6.10
Blinding ..............................................................................................37
6.11
Emergency Unblinding.......................................................................37
6.12
Treatment of Overdose .......................................................................37
6.13
Medical Care of Subjects after End of Study .....................................37
7
Study Procedures and Assessments....................................................37
7.1
Schedule of Assessments....................................................................38
7.1.1
Screening Visit....................................................................................38
7.1.2
Treatment Period ................................................................................38
7.1.3
End of Study Visit/Early Termination Visit.......................................39
7.2
Demographic and Other Baseline Characteristics ..............................39
7.2.1
Demographics.....................................................................................39
7.2.2
Medical History ..................................................................................39
7.2.3
Medication History.............................................................................39
7.2.4
Other Baseline Assessments...............................................................39
7.3
Efficacy Assessments .........................................................................40
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
5/75
7.4
Assessment of Safety..........................................................................40
7.4.1
Adverse Events ...................................................................................40
7.4.2
Pregnancy and In Utero Drug Exposure.............................................44
7.4.3
Clinical Laboratory Assessments .......................................................45
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............47
7.5
Pharmacokinetics................................................................................47
7.5.1
Body Fluids.........................................................................................47
7.5.2
Pharmacokinetic Calculations ............................................................48
7.6
Biomarkers..........................................................................................49
7.7
Other Assessments..............................................................................49
8
Statistics..............................................................................................49
8.1
Sample Size ........................................................................................49
8.2
Randomization....................................................................................50
8.3
Endpoints............................................................................................50
8.3.1
Primary Endpoints ..............................................................................50
8.3.2
Secondary Endpoints ..........................................................................50
8.3.3
Other Endpoints..................................................................................50
8.4
Analysis Sets.......................................................................................50
8.5
Description of Statistical Analyses.....................................................51
8.5.1
General Considerations.......................................................................51
8.5.2
Analysis of Primary Endpoints...........................................................51
8.5.3
Analysis of Secondary Endpoints.......................................................52
8.5.4
Analysis of Safety and Other Endpoints.............................................52
8.6
Interim and Additional Planned Analyses ..........................................52
9
Ethical and Regulatory Aspects..........................................................52
9.1
Responsibilities of the Investigator ....................................................52
9.2
Subject Information and Informed Consent .......................................53
9.3
Subject Identification and Privacy......................................................54
9.4
Emergency Medical Support and Subject Card..................................54
9.5
Clinical Study Insurance and Compensation to Subjects ...................54
9.6
Institutional Review Board.................................................................54
9.7
Health Authorities...............................................................................55
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Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
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10
Study Management .............................................................................55
10.1
Case Report Form Handling...............................................................55
10.2
Source Data and Subject Files ............................................................55
10.3
Investigator Site File and Archiving...................................................56
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................56
10.5
Changes to the Clinical Study Protocol..............................................57
10.6
Clinical Study Report and Publication Policy ....................................57
10.6.1
Clinical Study Report .........................................................................57
10.6.2
Publication..........................................................................................57
11
References Cited in the Text...............................................................57
12
Appendices .........................................................................................60
Appendix I:
Contraceptive Guidance and Woman of Childbearing Potential........61
Appendix II:
Signature Pages and Responsible Persons for the Study....................63
Signature Page – Protocol Lead.........................................................................................64
Signature Page – Principal Investigators ...........................................................................65
Signature Page – Principal Investigators ...........................................................................66
Sponsor Responsible Persons not Named on the Cover Page ...........................................67
Appendix III:
Protocol Amendments and List of Changes .......................................68
Amendment #1
............................................................................................................69
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
7/75
Table of In-Text Tables
Table 1
Schedule of Assessments: Part 1 and Part 2.......................................15
Table 2
Child-Pugh Grades/Class of Hepatic Impairment ..............................25
Table 3
Child-Pugh Criteria.............................................................................26
Table 4
Clinical Laboratory Evaluationsa........................................................46
Table 5
Definition of Pharmacokinetic Parameters.........................................49
Table of In-Text Figures
Figure 1
Design Diagram..................................................................................24
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
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List of Abbreviations
AE
Adverse event
ALBI
Albumin-Bilirubin
ANOVA
Analysis of variance
AUC
Area under the plasma concentration-time curve
AUCextra%
Area under the plasma concentration-time curve extrapolated from time t 
to infinity as a percentage of AUC0-∞
AUC0-240h
Area under the plasma concentration-time curve from time zero to 
240 hours postdose
AUC0-t
Area under the plasma concentration-time curve (AUC) from time zero to 
the last sampling time at which the concentration is at or above LLOQ
AUC0-∞
Area under the plasma concentration-time curve from time zero to infinity
β-hCG
Beta-human chorionic gonadotropin
BLQ
Below the lower limit of quantitation
CI
Confidence interval
CL/f
Apparent total body clearance of drug from plasma following oral 
administration
Cmax
Maximum plasma concentration observed
c-Met
Mesenchymal-epithelial transition factor gene
CRO
Contract research organization
CSR 
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
EMA
European Medicines Agency
FDA
Food and Drug Administration 
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
HCC
Hepatocellular carcinoma
HGF
Hepatocyte growth factor
ICH
International Council for Harmonization
IMP
Investigational medicinal product
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
9/75
IRB
Institutional Review Board
λZ
Apparent terminal rate constant
LLOQ
Lower limit of quantitation
MRAUC0-∞
Metabolite (MSC2571109 or MSC2571107) AUC0-∞ to tepotinib AUC0-∞ 
ratio
MRCmax
Metabolite (MSC2571109 or MSC2571107) Cmax to tepotinib Cmax ratio
NCI
National Cancer Institute
NSCLC
Non-small cell lung carcinoma
ODWG
Organ Dysfunction Working Group
PD
Pharmacodynamics
P-gp
P-glycoprotein
PK
Pharmacokinetics
QTcF
Corrected QT intervals using Fridericia’s formula
SAE
Serious adverse event
SMC
Safety Monitoring Committee
SUSAR
Suspected unexpected serious adverse reaction
t1/2
Apparent terminal half-life
TEAE
Treatment-emergent adverse event
TKI
Tyrosine kinase inhibitor
TPR
Translocated promoter region
tmax
Time to reach the maximum plasma concentration
VZ/f
Apparent volume of distribution during the terminal phase following 
extravascular administration
WOCBP
Woman of childbearing potential
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Te p oti ni b He p atic I m p air me nt Tri al
M S 2 0 0 0 9 5- 0 0 2 8
C O N F I D E N T I A L
I N F O R M A T I O N
1 0/ 7 5
1
S y n o psis
Cli nic al St u d y Pr ot oc ol N u m ber
M S 2 0 0 0 9 5- 0 0 2 8
Title
O pe n- La bel,  Parallel- Gr o u p  P hase  1  St u d y  t o  
I n vesti gate  t he  Effect  of  Vari o us  De grees  of  
He patic  I m pair me nt  o n  t he  P har mac o ki netics,  
Safet y  a n d  T olera bilit y  of  t he  c- Met  Ki nase  
I n hi bit or Te p oti ni b
St u d y P h ase
I
I N D N u m ber
1 0 6 1 0 3
F D A c o vere d st u d y
Yes
E u dr a C T N u m ber
N ot a p plica ble
Pri nci p al I n vesti g at ors
Orla n d o Cli nical Researc h Ce nter
5 0 5 5 S. Ora n ge A ve
Orla n d o, F L 3 2 8 0 9, U S A
P h o ne: 
 
E mail: 
 
Q P S M R A, L L C
6 2 8 0 S u nset Dri ve, S uite 6 0 0
Mia mi, F L., 3 3 1 4 3, U S A
P h o ne: 
E mail: 
S p o ns or
E M D Ser o n o Researc h & De vel o p me nt I nstit ute, 
I n c,
 4 5 A
 Mi d dlese x
 T ur n pi ke,
 Billerica,
 
M A 0 1 8 2 1, U S A.
Me dical Res p o nsi ble:
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 
Dar msta dt, Ger ma n y
P h o ne: 
M o bile: 
E mail: 
S p o ns or Le g al Re prese nt ati ve i n t he 
E ur o pe a n U ni o n
Merc k K Ga A
Fra n kf urter Strasse 2 5 0
6 4 2 9 3 Dar msta dt, Ger ma n y
D o c u me nt N o. 
 
O bject N o. 
 
PI
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Te p oti ni b He p atic I m p air me nt Tri al
M S 2 0 0 0 9 5- 0 0 2 8
C O N F I D E N T I A L
I N F O R M A T I O N
1 1/ 7 5
St u d y ce nters/c o u ntries
2  st u d y  ce nters  i n  t he  U S A:
 
a n d 
.
Pl a n ne d st u d y peri o d
(first s u bject i n-l ast s u bject o ut)
Ma y 2 0 1 8 (first s u bject scree ne d) t o 
Se pte m ber 2 0 1 8 (last s u bject last visit)
Tri al  Re gistr y
N ot a p plica ble
O bjecti ves: 
Pri m ar y o bjecti ve
!
T o assess t he p har mac o ki netics ( P K) of te p oti ni b ( M S C 2 1 5 6 1 1 9J) i n s u bjects wit h vari o us 
de grees of i m paire d he patic f u ncti o n (i n c o m paris o n t o healt h y s u bjects).
Sec o n d ar y o bjecti ves
!
T o  f urt her  i n vesti gate  t he  P K of  te p oti ni b  a n d  its  meta b olites  M S C 2 5 7 1 1 0 9  a n d  
M S C 2 5 7 1 1 0 7 i n s u bjects wit h vari o us de grees of i m paire d he patic f u ncti o n (i n c o m paris o n 
t o healt h y s u bjects)
!
T o assess safet y a n d t olera bilit y of te p oti ni b i n s u bjects wit h vari o us de grees of i m paire d 
he patic f u ncti o n (i n c o m paris o n t o healt h y s u bjects).
Met h o d ol o g y: 
T his is a P hase 1, t w o-sta ge d, o pe n-la bel st u d y t o i n vesti gate t he effect of 
vari o us  de grees  of  he patic  i m pair me nt  o n  t he  P K,  safet y  a n d  t olera bilit y  of  t he  
mese nc h y mal- e pit helial tra nsiti o n fact or ge ne (c- Met) ki nase i n hi bit or, te p oti ni b.
Part 1 will i ncl u de s u bjects  wit h he patic i m pair me nt ( C hil d- P u g h class A [ 6 s u bjects] a n d 
C hil d- P u g h class B [ 6 s u bjects]) a n d a c o ntr o l gr o u p ( 6 healt h y s u bjects  matc he d 1: 1 t o 6 
s u bjects wit h C hil d- P u g h class B  wit h re gar d t o a ge ± 1 0 years, wei g ht ± 1 0 k g, a n d sa me 
ge n der). All s u bjects will recei ve a si n gle d ose of 5 0 0 m g te p oti ni b.
Part 2 of t he st u d y is o pti o nal a n d, if c o n d ucte d,  will e val uate d oses a b o ve 5 0 0 m g u p t o 
1 0 0 0  m g i n 6 s u bjects wit h he patic i m pair me nt of eit her C hil d- P u g h class A or B. 
A Safet y M o nit ori n g C o m mittee ( S M C) ma y b e esta blis he d t o e val uate t he safet y a n d P K
res ults of Part 1 if t he o verall de vel o p me nt pr o gra m of te p oti ni b deci des t o use hi g her d oses 
t ha n 5 0 0 m g ( u p t o 1 0 0 0 m g) i n t he P hase 2 or P hase 3 st u dies. T he S M C will t he n ma ke a 
rec o m me n dati o n o n t he te p oti ni b d ose a n d w hic h p o p ulati o n ( C hil d- P u g h class A or B) t o be 
e nr olle d i n Part 2 base d o n t he safet y a n d P K res ults of Part 1.
S u bjects will be scree ne d fr o m D a y - 2 8 t o Da y - 2. S u bjects will be a d mitte d t o t he st u d y ce nter
o n  Da y - 1  a n d  will  re mai n  i n patie nt  at  t he  st u d y ce nter u n der  me dical  s u per visi o n  u ntil  
disc har ge o n t he m or ni n g of Da y 4. 
T he treat me nt c o nsists of a si n gle- d ose a d mi nistrati o n of 5 0 0 m g te p oti ni b o n Da y 1 i n Part 1. 
T he d ose t o be i n vesti gate d i n Part 2 will be deter mi ne d b y t he S M C after e val uati o n of t he 
safet y a n d P K res ults of Part 1.
D o c u me nt N o. 
 
O bject N o. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
12/75
Serial blood samples (PK and clinical laboratory assessments) and urine samples (clinical 
laboratory assessments) will be collected at specified timepoints. There is a PK sampling period 
of 2 weeks for healthy subjects and 3 weeks for hepatic impaired subjects.
The End of Study visit is planned on Day 15 for healthy subjects and on Day 22 for hepatic 
impaired subjects. An Early Termination visit will be conducted for subjects who withdraw 
prematurely. The same assessments as for the End of Study visit will be conducted at the Early 
Termination visit.
Planned number of subjects: Eighteen subjects in Part 1 and 6 subjects in Part 2.
Primary endpoints: 
! PK profile of tepotinib (plasma) in terms of AUC0-t, AUC0-∞, and Cmax at Day 1 to Day 15 
(healthy subjects) or Day 22 (hepatic impaired subjects) calculated by noncompartmental 
analyses.
Secondary endpoints: 
! PK profile of tepotinib (plasma) in terms of tmax, t1/2, CL/f, VZ/f, AUCextra% at Day 1 to 
Day 15 (healthy subjects) or Day 22 (hepatic impaired subjects) calculated by 
noncompartmental analyses
PK profile of the major tepotinib metabolites MSC2571109 and MSC2571107 (plasma) in 
terms of AUC0-t, AUC0-∞, Cmax, tmax, t1/2, AUCextra% at Day 1 to Day 15 (healthy subjects) or 
Day 22 (hepatic impaired subjects) calculated by noncompartmental analyses, and
MRAUC0-∞and MRCmax
! Occurrence of treatment-emergent adverse events, changes from baseline in laboratory 
safety tests, 12-lead electrocardiograms (ECG) morphology and time intervals (PR, QRS, 
RR, QT and corrected QT intervals using Fridericia’s formula [QTcF]), and vital signs.
Pharmacokinetics: Blood samples for PK analysis will be collected on Day 1 predose and 
0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 16.0 hours postdose, Day 2 at 24, 
30, and 36 hours postdose, Day 3 at 48, 54, and 60 hours postdose, Day 4 (72 hours), Day 5 
(96 hours), Day 6 (120 hours), Day 7 (144 hours), Day 8 (168 hours), Day 10 (216 hours), 
Day 13 (288 hours), Day 15 (336 hours), and Day 22 (504 hours postdose; hepatic impaired 
subjects only).
Other assessments: Throughout the study at specified timepoints treatment-emergent adverse 
events, changes from baseline in laboratory safety tests, 12-lead ECG morphology and time 
intervals (PR, QRS, RR, QT and QTcF), and vital signs will be assessed.
Document No. 
 
Object No. 
 
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Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
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Diagnosis and key inclusion and exclusion criteria: Men and women (of nonchildbearing 
potential), 18 to 75 years (inclusive) of age, with a body mass index of 18 to 36 kg/m2
(inclusive) and a body weight ≥50 kg at Screening, with the absence of acute hepatitis or 
HIV 1 and 2, who have given informed consent and are willing and able to comply with study 
procedures will be eligible for enrollment. Subjects with impaired hepatic function (Child-Pugh 
class A or Child-Pugh class B) and subjects with normal hepatic function will be eligible to 
enroll in the study. Healthy subjects will be excluded if they have hepatitis B or C or had a 
previous infection with hepatitis C treated with Sofosbuvir or other antiviral compounds, or 
any other clinically relevant disease, as considered by the Investigator. Subjects with impaired 
hepatic function will be excluded if they have primary biliary liver cirrhosis, nonstabilized 
chronic heart failure, hepatocarcinoma, hepatic encephalopathy (Grade III or IV), sepsis or 
gastrointestinal bleeding, or any other clinically relevant disease, as considered by the 
Investigator.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule: One 
single oral dose of 500 mg tepotinib tablets (Tablet Formulation 2) will be administered in 
Part 1 and up to 1000 mg in Part 2 after the subject has completed a standard breakfast.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable
Planned study and treatment duration per subject: Each subject will receive a single
administration of the investigational medicinal product (IMP) on Day 1.
In both Part 1 and Part 2, the planned study duration per subject from Screening until the End 
of Study visit is approximately 6 weeks for healthy subjects and approximately 7 weeks for 
hepatic impaired subjects. 
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
14/75
Statistical methods:
Sample size:
Pharmacokinetic studies, including subjects with impaired liver function, are usually 
exploratory by nature. Considering the CVs for the primary endpoints AUC0-t and Cmax of 
tepotinib, 20.4% and 22.8% respectively, 6 evaluable subjects per group will provide 80% 
power at alpha level of 0.05 for detecting a group difference of 44% (AUC0-t) and 50% (Cmax), 
which is considered sufficient to meet the study objectives. Therefore, 18 subjects (3 groups x 
6 subjects) should be included in Part 1 and 6 subjects in Part 2. 
Analysis of primary endpoints:
As the primary analysis, an analysis of variance (ANOVA) model including hepatic function 
group as a fixed effect will be applied to log-transformed tepotinib PK parameters AUC0-t, 
AUC0-∞, and Cmax. Differences between the hepatic impairment groups and matched control 
will be estimated together with their 90% CIs then back-transformed to the original scale for 
presentation. 
Additionally, a generalized linear model including hepatic function group and sex (gender) as 
fixed effects, age and weight as covariates, will be applied to the same primary PK parameters. 
A further covariate log(dose) will be introduced when Part 2 data is included.
All endpoints will be descriptively analyzed using summary statistics by hepatic function
group. Graphical displays will be given, where appropriate.
Analysis of secondary endpoints:
For the secondary PK parameters AUC0-t, AUC0-∞, and Cmax of the tepotinib metabolites, the 
same analyses as defined for the primary endpoints will be performed.
Analysis of safety:
Safety data will be listed and descriptively summarized as appropriate.
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
15/75
Table 1
Schedule of Assessments: Part 1 and Part 2
Activity/Asesment
Screning
On Treatment
Study Wek
-4 to -1
1
Study Day
-28 to -2
-1
1
2
Visit Number
0
1
2
3
Time (h:m)
Pre-
dose
0:0 0:15 0:30 0:45 1:0 1:30 2:0 3:0 4:0 6:0 8:0 10:0 12:0 16:0 24:0 30:0 36:0
Informed consent
X
Inclusion and exclusion 
criteria
X
X
Demographics and 
medical history
X
X
j
Ultrasound and 
asesment of 
encephalopathy
a
X
Administration of IMP
b
X
PK blod sampling
c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tepotinib fre fraction
d
X
X
X
X
Physical examination
X
X
Vital signs
c , height
e and 
weight
e
X
X
X
X
X
X
12-lead ECG
c
X
X
X
X
X
Clinical laboratory tests
f
X
X
X
Pregnancy test, FSH
g
X
X
Urine drugs of abuse
h , 
alcohol breathalyzer test, 
cotinine test
X
X
Subject confinement
i
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Previous/concomitant 
medication and nondrug 
therapy/intervention 
monitoring
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
16/75
Activity/Assessment
On Treatment
End of Study for 
Healthy Subjects
/ Treatment visit 
for Hepatic 
Impaired 
Subjects
End of Study
for Hepatic 
Impaired 
Subjects
Study Week
1
2
3
4
Study Day
3
4
5
6
7
8
10
13
15
22
Visit Number
4
5
6
7
8
9
10
11
12
13
Time (hh:mm)
48:00
54:00
60:00
72:00
96:00
120:00
144:00
168:00
216:00
288:00
336:00
504:00
PK blood sampling c
X
X
X
X
X
X
X
X
X
X
X k
X l
Vital signs c, height e and 
weight e
X
X
X
X k
X l
12-lead ECG c
X
X
X
X k
X l
Clinical laboratory tests f
X
X
X k
X l
Physical examination
X
X k
X l
Subject confinement i
X
X
X
X
AE monitoring
X
X
X
X
X
X
X
X
X
X
X k
X l
Previous/concomitant 
medication and nondrug 
therapy/intervention 
monitoring
X
X
X
X
X
X
X
X
X
X
X k
X l
AE = adverse event; β-hCG = Beta-human chorionic gonadotropin; ECG = electrocardiogram; FSH = follicle-stimulating hormone; IMP = investigational medicinal 
product; PK = pharmacokinetic.
a
For hepatic insufficiency assessment in subjects with hepatic impairment only.
b
Drug administration will occur 30 minutes after start of the intake of a standard breakfast with 240 mL of water. Subjects should eat this meal within 
25 minutes or less. The subject will remain fasting for 4 hours after the breakfast, after which a standardized lunch will be served.
The standard breakfast will contain approximately 500 calories and will be balanced in macronutrients (approximately 50% carbohydrates, 25% protein, and 
25% fat). The menu must be approved by the Sponsor. The subject will be expected to eat the entire meal. The percentage consumed will be recorded for 
all subjects. A deviation will be recorded if the subject eats less than 90% of the meal. Subjects will not be excluded from dosing if they are unable to 
complete the meal in full.
c
When several procedures are scheduled at the same theoretical time, the following sequence should be followed: 12-lead ECG followed by vital signs 
before the specified timepoint, preceding the PK sampling which will be performed at the specified timepoint. 
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
17/75
d
The Tepotinib Free Fraction (TFF) sample will not be drawn separately; TFF will be analyzed from the PK back up sample.
e
Height will be measured at Screening only. Body weight will be measured at Screening and at Day -1 only.
f
Clinical laboratory tests comprise of clinical chemistry, hematological parameters, coagulation (at Screening and Day 1 only), urinalysis, and other tests (at 
Screening and Day 1 only) as specified in Table 4. Subjects should fast for 8 hours prior to clinical laboratory blood sample collection.
g
A β-hCG test will be done at Screening and on the day of admission to exclude pregnancy. If necessary to confirm postmenopausal status, FSH samples 
will be drawn at Screening.
h
For all subjects, a negative cannabinoid (THC) result on drugs of abuse screening  is required to participate in the study. If the result is positive, the 
Principal Investigator may request to repeat the test. For subjects with hepatic impairment, a positive cannabinoid (THC) result on drugs of abuse screening 
will not be exclusionary (at Screening or Day -1) if the subject uses cannabinoids on medical recommendation. In subjects with hepatic impairment, positive 
test for drugs used on medical recommendation will be not exclusionary.
i
Subjects will be admitted in the morning of Day -1 as indicated. Subjects will leave the study center in the morning of Day 4, after all assessments have 
been performed.
j
An update of medical history will be performed at admission to the study center on Day -1.
k
Day 15 is considered End of Study visit for healthy subjects only. Subjects with hepatic impairment are expected to have a follow-up visit on Day 15, with 
the following assessments: PK sampling, monitoring of AEs and previous/concomitant medication and nondrug therapy/intervention.
l
Hepatic impaired subjects only.
Document No. 
 
Object No. 
 
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Te p oti ni b He p atic I m p air me nt Tri al
M S 2 0 0 0 9 5- 0 0 2 8
C O N F I D E N T I A L
I N F O R M A T I O N
1 8/ 7 5
2
S p o ns or, I n vesti g at ors a n d St u d y  A d mi nistr ati ve Str uct ure
T his cli nical st u d y  will be s p o ns ore d b y: E M D Ser o n o Researc h & De vel o p me nt I nstit ute, I n c, 
4 5 A Mi d dlese x T ur n pi ke, Billerica, M A 0 1 8 2 1, U S A. T he S p o ns or’s le gal re prese ntati ve i n t he 
E U/ E E A is  Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y.
T he st u d y  will be c o n d ucte d at 2 st u d y ce nters ( h o s pital- base d, i n patie nt, P hase 1 researc h ce nters) 
i n t he U S A: 
!
, U S A
!
, U S A
T he  Pri nci pal I n vesti gat ors,  
 ( Orla n d o  Cli nical  Researc h  Ce nter),  a n d  
 ( Q P S M R A, L L C)  will pr o vi de e x pert me dical i n p ut a n d a d vice relati n g t o 
st u d y desi g n a n d e xec uti o n a n d are res p o nsi ble f or t he re vie w a n d si g n off of t he cli nical st u d y
re p ort ( C S R). 
Si g nat ure pa ges f or t he Pr ot oc ol Lea d a n d t he Pri nci pal I n vesti gat ors as well as a list of S p o ns or 
res p o nsi ble pers o ns are i n A p pe n di x II.
A Safet y M o nit ori n g C o m mittee ( S M C) ma y be esta blis he d. If a n S M C is esta blis he d it will c o nsist 
of, b ut ma y n ot be li mite d t o, t he f oll o wi n g me m bers: t he Cli nical P har mac ol o gist, Pri nci pal 
I n vesti gat ors, S p o ns or’s Me dical Res p o nsi ble, a n d t he S p o ns or’s Gl o bal Dr u g Safet y Pr o d uct 
Lea d. A d h oc me m bers will be c o ns ulte d as nee de d a n d ma y i ncl u de, b ut is n ot restricte d t o, t he 
Bi ostatisticia n.  Details re gar di n g t he S M C res p o nsi bilities are pr o vi de d i n Secti o n  5. 1.
T he S p o ns or's Gl o bal Dr u g Safet y de part me nt or its desi g nate d re prese ntati ve will s u per vise dr u g 
safet y a n d t he ti meli ne f or re p orti n g of a d verse e ve nts ( A Es) a n d seri o us a d verse e ve nts ( S A Es) t o 
all c o ncer ne d parties i n acc or da nce wit h t he a p plica ble g ui deli nes, la ws, a n d re g ulati o ns.
T he S p o ns or will part ner wit h a c o ntract researc h or ga nizati o n ( C R O), t o c o n d uct t he cli nical part 
of t he st u d y i ncl u di n g st u d y set- u p, c o or di nati o n, m o nit ori n g, data ca pt ure, data ma na ge me nt, 
statistical a nal ysis, a n d C S R pre parati o n. A ce ntral la b orat or y will be use d f or cli nical la b orat or y 
a nal ysis. A testi n g la b orat or y will be res p o nsi ble f or a nal ysis of t he p har mac o ki netic ( P K) sa m ples. 
T he S p o ns or will s u per vise all o uts o urce d acti vities.
T he S p o ns or will arra n ge deli ver y of t he i n vesti gati o nal me dici nal pr o d uct (I M P) t o t he st u d y 
ce nters. 
La b orat or y sa m ple pr ocessi n g, ha n dli n g, a n d st ora ge i nstr ucti o ns as well as d ose pre parati o n a n d 
dis pe nsi n g details will be prese nte d i n se parate ma n uals w hic h will be pre pare d b y t he C R O i n 
c o or di nati o n wit h t he S p o ns or.
D o c u me nt N o. 
 
O bject N o. 
 
PI
PI
PI
PI


Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
19/75
3
Background Information
3.1
General Information
The mesenchymal-epithelial transition factor (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 (1). 
Under physiological conditions, c-Met regulates invasive growth and morphogenesis in multiple 
embryonic tissues, such as muscles, the nervous system, bones, and vascular system and is 
essential for development. c-Met/HGF have been implicated in carcinogenesis and metastatic 
tumor progression by enhancing angiogenesis, cancer cell proliferation, migration, invasion, and 
conferring resistance to apoptosis. Activating c-Met point mutations and amplification as well as 
c-Met/HGF co-expression have been observed in a number of human tumors. Pharmacological 
interference with the HGF/c-Met axis is considered with increasing interest as a promising strategy 
to inhibit primary tumor growth and metastasis.
The resistance of advanced epithelial tumors to conventional standard chemotherapies have been 
linked to their genetic complexity; however recent findings indicate that many solid tumors are 
“addicted” to particular activated kinases. 
Targeting such kinases with selective inhibitors represents a promising anticancer approach. The 
role of c-Met in tumor progression and metastatic dissemination makes it a privileged candidate 
for therapeutic intervention.
Given the important role of aberrant HGF/c-Met signaling in cancer, several different therapeutic 
strategies, aimed at inhibiting HGF/c-Met signaling, have been developed and are currently being 
evaluated in clinical studies. These include agents that directly inhibit HGF and/or its binding to 
c-Met, antibodies targeted at c-Met, and small-molecule c-Met tyrosine kinase inhibitors (1 - 6).
Proof of concept has been shown in Phase 2 studies with onartuzumab (a monoclonal antibody 
against the c-Met receptor) in combination with erlotinib in subjects with stage IIIB/IV non-small 
cell lung carcinoma (NSCLC) with c-Met overexpressing tumors (7), and with rilotumumab (a 
monoclonal antibody against HGF) in combination with chemotherapy in advanced/metastatic 
gastro-esophageal cancer with c-Met overexpressing tumors (8).
The free base form of tepotinib (EMD 1160879) has an identical structure to tepotinib
(MSC2156119J). Both compounds have been used in a number of pharmacological studies, 
yielding comparable results. Competition experiments and crystallographic studies indicate that 
tepotinib is a reversible adenosine triphosphate-competitive kinase inhibitor. The biochemical 
activity of tepotinib, measured with the recombinant human c-Met kinase domain and a peptide 
substrate, resulted in an average half maximal inhibitory concentration of 1.7 nM. Tepotinib (free 
base form) displayed high selectivity towards c-Met using in vitro kinase reactions. Using a panel 
of more than 100 different kinases, high doses of the free base form of tepotinib (10 micromolar 
[μM]) inhibited only the oncogenic kinases ALK, Axl, Blk, Ron, and TrkB by > 50%, and blockade 
of these kinases is suggested to further support the antitumor activity of the free base form of 
tepotinib through c-Met kinase.
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
20/75
In vivo, the activity of both tepotinib and the free base form of tepotinib was demonstrated in 
tumor models with ligand independent c-Met activation (Gastric Hs746T, gastric MKN-45, 
NSCLC NCI-H441, NSCLC EBC-1) and in tumor models co-expressing HGF and c-Met
(Glioblastoma U87MG, pancreatic carcinoma KP-4, liver cancer MHCC97H) as well as in 
translocated promoter region (TPR)-Met transformed murine fibroblasts. Tepotinib and the free 
base form of tepotinib significantly inhibited tumor growth and induced partial or complete 
regression of established EBC-1, Hs746T, MKN-45, NCI-H441, U87MG, KP-4, MHCC97H, and 
TPR-Met NIH3T3 tumors. The antitumor efficacy of the combination of tepotinib with cetuximab, 
erlotinib, sorafenib, and temozolomide was demonstrated in mouse xenograft models of NSCLC, 
glioblastoma, and hepatocellular carcinoma (HCC).The mechanism of action of tepotinib was 
investigated in vivo in a PK/pharmacodynamic (PD) study, conducted on Hs746T gastric cancer 
xenografts and the finding indicate that treatment with tepotinib induces cell cycle arrest and 
inhibition of tumor cell proliferation.
In primary PD studies, tepotinib potently inhibited c-Met kinase activity in a dose-dependent 
manner. This inhibitory effect was confirmed both in tumor cells expressing full-length c-Met 
upon stimulation with HGF, and in tumor cells in which c-Met was activated in a ligand 
independent manner, ie, in cells harboring c-Met gene amplification or expressing the oncogenic 
fusion protein, TPR-Met. Serum proteins only moderately interfered with the inhibitory activity of 
tepotinib, which persisted over a prolonged period of time. Tepotinib treatment of susceptible 
tumor cells inhibited cell survival and HGF-dependent cell migration in a dose-dependent manner. 
Both effects were associated with inhibition of c-Met activation. 
As of 30 September 2017, about 452 subjects had been exposed to tepotinib in 5 completed studies,
in healthy volunteers (EMR200095-002, EMR200095-007, and MS200095-0012; n=79 subjects), 
and in subjects with different solid tumors (EMR200095-001 and EMR200095-003; n=161), and 
4 ongoing studies in subjects with HCC, or epidermal growth factor receptor mutated or c-Met 
mutated NSCLC (EMR200095-004, EMR200095-005, EMR200095-006, and MS200095-0022). 
In the ongoing studies, subjects with HCC have received tepotinib as monotherapy and subjects 
with NSCLC received either tepotinib monotherapy or a combination with gefitinib in Phase 1 or 
Phase 1b/2 studies thus far. Doses of tepotinib up to 1400 mg daily and 1000 mg daily have been 
explored in patients with solid tumors in Study EMR200095-001 and in patients with HCC in 
Study EMR200095-004, respectively.
Investigations in clinical pharmacology studies are often done in healthy volunteers. Based on the 
currently available nonclinical as well as clinical safety data there is no objection against 
administration of single doses of tepotinib to healthy volunteers. Accordingly, healthy volunteer 
studies have already been performed administering single tepotinib doses of up to 500 mg. It is 
recognized that healthy volunteers will not benefit by participating in this study. However, this 
study will generate mandatory human data about the administration of tepotinib to subjects with 
hepatic impairment. This is basic information to safeguard the further clinical development of 
tepotinib in patients suffering from malignancies such as HCC. During the development of 
tepotinib 3 healthy volunteer studies have been performed in 79 healthy volunteers. Healthy 
volunteers tolerated a single or 3 doses of tepotinib (different dose levels) well. All 
treatment-emergent adverse events (TEAEs) were mild to moderate, except for one Grade 3 
asymptomatic lipase elevation in 1 subject. Across all 3 studies, the TEAEs did not show a pattern. 
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
21/75
No SAEs were reported and no subject died. No clinically significant findings with regard to 
laboratory parameters, vital signs, and electrocardiograms (ECGs) including corrected QT 
intervals using Fridericia’s formula (QTcF) values were noted.
Volunteers enrolled in this study might be exposed to a potential risk, including pancreatic enzyme 
elevation. However, inclusion of healthy volunteers is justified when the administration of 
tepotinib is limited to a single dose or short term multiple administrations that will be given under 
close monitoring conditions to reduce the risk for untoward effects.
Asymptomatic elevations in serum lipase and amylase are considered as important potential risk 
for subjects administered tepotinib. These elevations were observed in 5 out of 78 healthy 
volunteers exposed to tepotinib and were mild to moderate in severity (exception: one Grade 3 
lipase elevation). The asymptomatic increase of serum amylase/lipase was not associated with a 
pancreatitis.
Knowing that the inhibition of c-Met shows teratogenic effects in knockout mice, stringent criteria 
are applied to ensure exclusion of women of childbearing potential in this study. Only healthy 
women that are known to be postmenopausal or surgically sterile (ie, hysterectomy and 
oophorectomy) will be enrolled in this study (for details see Appendix I).
In order to further mitigate any risk, a close monitoring of the clinical laboratory parameters, ECG, 
and vital signs will be performed in all healthy volunteer studies. Volunteers will be admitted to 
the study site and remain resident there for at least 72 hours after administration of a single dose 
in each treatment period, to allow continuous safety monitoring. In addition, frequent monitoring 
of volunteers is ensured by subsequent ambulant visits and by choosing a CRO experienced in the 
conduct of clinical pharmacology studies.
Based on previous studies, the 500 mg once daily dose achieves c-Met inhibition ≥ 90% and results 
in sufficiently high steady state (trough) exposure levels in ≥90% of subjects to induce activity in 
tumors with varying degrees of sensitivity to c-Met inhibition. The 500 mg once daily dose is, 
therefore, considered to be safe and in the biologically active range.
Refer to the Investigator’s Brochure for further information about the nonclinical and clinical 
programs and Guidance for the Investigator.
3.2
Study Rationale
In a mass balance trial, 14C-MSC2156119 was moderately metabolized in human subjects and a 
total of 10 different Phase 1 and Phase 2 metabolites were found. Total radioactivity was also 
mainly eliminated via feces (~78%) while only about 14% was recovered in urine. In feces, roughly 
45% of the administered dose could be related to parent drug. This indicates a high extent of active 
secretion (likely via bile), but unabsorbed drug as well as reduction of N-oxides and hydrolysis of 
the glucuronide to parent drug may have also contributed to this high recovery. Based on AUCall
(which corresponds to the AUC0-240h within the observation period), the M506 could be identified 
as major metabolite both with respect to European Medicines Agency (EMA) Guidance ICH 
M3(2) EMA/CPMP/ICH/286/1995 (4) and the draft Food and Drug Administration (FDA) 
Guidance for Industry – Drug Interaction Studies (5). Ratios of geometric mean values of AUCall
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
22/75
of M506 to total radioactivity and to parent MSC2156119J compound were about 40.4% and 
74.9%, respectively. M506 is formed from MSC2156119J with a median tmax of 24 hours ranging 
from 24 to 60 hours and showed an apparent geometric mean half-life of 93 hours ranging from 
66 to 145 hours estimated on concentration data from 4 subjects. Urinary excretion was identified 
as minor route of excretion with an average recovery in urine of only 13.6% (range 8.8% to 17.7%).
According to the hepatic impairment guidances (FDA Guidance for Industry 2003 (9), EMA
Guideline CPMP/EWP/2339/02 2005) it should be determined if alterations of excretory and 
metabolic activities by hepatic impairment can lead to drug accumulation.
Currently, enrolment of subjects into tepotinib HCC studies is restricted to subjects with mild 
hepatic impairment, ie, Child-Pugh class A.
This study will evaluate the PK and safety of tepotinib in subjects with mild (Child-Pugh class A) 
and moderate (Child-Pugh class B) hepatic impairment.
In most cases, HCC develops within an established background of chronic liver disease (70 to 90% 
of all patients) (10) and patients with cirrhosis have the highest risk of developing HCC (90 to 
95% of subjects who develop HCC have underlying cirrhosis) (11). It is therefore assumed that 
the results of this study in subjects with hepatic impairment are also applicable to patients with 
HCC, especially patients with Child-Pugh class B.
In Part 1 of the study, PK and safety of a single dose of 500 mg tepotinib will be assessed in 
subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic impairment in 
comparison to healthy subjects. A higher dose than 500 mg may be evaluated in Part 2 of the study
in subjects with hepatic impairment if deemed necessary by the project team. In this case, the SMC 
will assess the results of Part 1 and make a recommendation on the tepotinib dose and which 
population (Child-Pugh class A or B) to be enrolled in Part 2. Healthy subjects will not be enrolled 
in Part 2 of the study.
This clinical study will be conducted in compliance with the clinical study protocol, ICH GCP, the 
Declaration of Helsinki, and any additional applicable regulatory requirements.
Based on the available nonclinical and clinical data to date, the conduct of the study specified in 
this protocol is considered justifiable. 
4
Study Objectives
4.1
Primary Objective
! To assess the PK of tepotinib in subjects with various degrees of impaired hepatic function (in
comparison to healthy subjects).
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
23/75
4.2
Secondary Objectives
! To further investigate the pharmacokinetics of tepotinib and its metabolites MSC2571109 and 
MSC2571107 in subjects with various degrees of impaired hepatic function (in comparison to 
healthy subjects)
! To assess safety and tolerability of tepotinib in subjects with various degrees of impaired 
hepatic function (in comparison to healthy subjects).
4.3
Other Objectives
Not applicable
5
Investigational Plan
5.1
Overall Study Design and Plan
This is a Phase 1, two-staged, open-label study to investigate the effect of various degrees of 
hepatic impairment on the PK, safety and tolerability of the c-Met kinase inhibitor, tepotinib.
Part 1 will include subjects with hepatic impairment (Child-Pugh class A [6 subjects] and 
Child-Pugh class B [6 subjects]) and a control group (6 healthy subjects matched 1:1 to 6 subjects 
with Child-Pugh class B with regard to age ± 10 years, weight ± 10 kg, and same gender). All
subjects will receive a single dose of 500 mg tepotinib.
Part 2 of the study is optional and, if conducted, will evaluate doses above 500 mg up to 1000 mg
in 6 subjects with hepatic impairment of either Child-Pugh class A or B. 
An SMC may be established to evaluate the safety- and PK results of Part 1 if the overall 
development program of tepotinib decides to use higher doses than 500 mg (up to 1000 mg) in the 
Phase 2 or Phase 3 studies. The SMC will then make a recommendation on the tepotinib dose and 
which population (Child-Pugh class A or B) to be enrolled in Part 2 based on the safety- and PK 
results of Part 1. See Figure 1 for a diagram of the study design.
Subjects will be screened from Day -28 to Day -2. Subjects will be admitted to the study center on 
Day -1 and will remain inpatient at the study center under medical supervision until discharge on 
the morning of Day 4. 
The treatment consists of a single-dose administration of 500 mg tepotinib on Day 1 in Part 1. The 
dose to be investigated in Part 2 will be determined by the SMC after evaluation of the safety- and 
PK results of Part 1.
Serial blood samples (PK and clinical laboratory assessments) and urine samples (clinical 
laboratory assessments) will be collected at the timepoints provided in Table 1. There is a PK 
sampling period of 2 weeks for healthy subjects and 3 weeks for hepatic impaired subjects.
The End of Study visit is planned on Day 15 for healthy subjects and on Day 22 for hepatic 
impaired subjects. An Early Termination visit will be conducted for subjects who withdraw 
Document No. 
 
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prematurely. The same assessments as for the End of Study visit will be conducted at the Early 
Termination visit.
Figure 1
Design Diagram
Part 2 of the study is optional.
CSR = Clinical study report; HCC = Hepatocellular carcinoma; PK = Pharmacokinetic, SMC = Safety Monitoring 
Committee.
Document No. 
 
Object No. 
 
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Child-Pugh A, n=6 
Child-Pugh B, n=6 
dose: 500mg 
Hea"hy Subjects, n=6 
matching to subjects with 
Child-Pugh B - dose: 500mg 
final CSR 
Project Team Decision if dose in HCC > 500mg is required 
Child-Pugh A or B 
n=6 
dose: up to 1000 mg 
Final Analysis 
of 
dataMt 
as Addendum to CSR 
Safety and PK 
not acceptable 


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5.2
Discussion of Study Design
A parallel design with a small number of hepatic impaired subjects and controls with normal 
hepatic function is the standard design for hepatic impairment studies, in line with the FDA and 
EMA guidances/guidelines. According to the hepatic impairment guidances (FDA Guidance for 
Industry 2003, EMA Guideline CPMP/EWP/2339/02 2005), 6 evaluable subjects should be 
enrolled per group. The control group will consist of 6 healthy subjects with normal hepatic 
function, matched 1:1 to the subjects with moderate (Child-Pugh class B) impaired hepatic
function with regard to age ± 10 years, weight ± 10 kg, and same gender. 
Subjects with hepatic impairment will be assigned to a group of mild (Child-Pugh class A) or 
moderate (Child-Pugh class B) hepatic impairment at Screening by use of the Child-Pugh system. 
See Table 2 and Table 3.
Table 2
Child-Pugh Grades/Class of Hepatic Impairment
Child-Pugh Score
Child-Pugh Grade/Class
Severity of Hepatic Impairment
5-6
A
Mild
7-9
B
Moderate
10-15
C
Severea
a
Subjects with severe hepatic impairment will not be included in this study
Grading of hepatic impairment by use of the Child-Pugh system, including ultrasound examination 
for detection and classification of ascites as well as assessment of hepatic encephalopathy, will 
only be performed in subjects with hepatic impairment.
Document No. 
 
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Table 3
Child-Pugh Criteria
Points Scored for Observed Findings (14, 15, 16)
1
2
3
Encephalopathy gradea
none
1 or 2 or medically 
controlled c
3 or 4 or medically
controlled c
Ascitesb
absent
slight or medically 
controlled c
Moderate or medically 
controlled c
Serum bilirubin (mg/dL)
< 2
2 to 3
> 3
Serum albumin (g/dL)
> 3.5
2.8 to 3.5
< 2.8
International Normalized Ratio (INR)
< 1.70
1.70 to 2.20
> 2.20
a
Encephalopathy will be assessed by an experienced physician at Screening using the following criteria: 
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second waves
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2 to 3 cycles per second delta activity.
b
Ascites will be assessed by an experienced physician by physical examination as well as ultrasound 
examination at Screening using the following criteria: 
Absent: No ascites is detectable by manual and also not by ultrasound investigation.
Slight: Ascites palpitation doubtful, but ascites measurable by ultrasound investigation.
Moderate: Ascites detectable by palpitation and by ultrasound investigation.
c
Diagnosis and treatment of medically controlled subjects must be confirmed by the subject’s medical records.
The majority of healthy volunteers are not expected to have measurable concentrations after Day 
15; therefore sampling until Day 15 is sufficient. Sampling for one additional week for the subjects 
with hepatic impairment to cover a possibly longer half-life appears appropriate. This was 
confirmed with a compound model developed in Simcyp, which allowed to simulate the impact of 
change in active liver size in subjects with hepatic impairment. Simulations using the population 
representatives indicate that the concentration reached after 21 days decline is attained in subjects 
with hepatic impairment about 1 to 2 days later, ie, the predicted difference between the healthy 
and subjects with moderate hepatic impairment.
Model limitations include non-consideration of possibly reduced metabolic enzyme expression. 
Of the number of physiological changes known to occur in subjects with hepatic impairment (size 
of active liver, plasma protein binding, blood flow, metabolizing enzymes), only the reduction of 
active hepatocytes could be implemented in the model. Thus the effect of hepatic impairment could 
be stronger than predicted. 
Document No. 
 
Object No. 
 
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5.2.1
Scientific Rationale for Study Design
The study design includes matched pairs of patients with hepatic impairment and healthy 
volunteers and is the recommended design to characterize the effects of impaired hepatic function 
on the PK of a drug. Part 2 is required if within the total tepotinib program, a higher therapeutic 
dose than 500 mg once daily will be used.
5.2.2
Justification for Dose
In clinical studies in healthy subjects, good safety and tolerability was observed after 
administration of single doses of 30 mg to 500 mg.
From patients with solid tumors, safety data is available for a dose regimen of 1400 mg tepotinib 
once daily. Even in case of a significant delay in elimination in patients with hepatic impairment, 
exposure in this study with single dose administration is expected to be less. 
For Part 1 of this study, the recommended Phase 2 dose of 500 mg has been selected. 
Tepotinib will be administered in the fed state, which is also the recommended mode of 
administration in clinical studies with tepotinib performed thus far.
Part 2 of the study is optional and will be conducted if the overall development program of 
tepotinib decides to use higher doses than the 500 mg in Phase 2 and Phase 3 studies. An SMC 
will make a recommendation on the tepotinib dose and which population to be enrolled in Part 2. 
Further details are provided in Section 5.1.
5.2.3
Rationale for Endpoints
The primary and secondary endpoints are relevant exposure parameters that are required to assess 
the impact of hepatic impairment on the exposure of tepotinib.
The rationale for including metabolites as secondary endpoints are as follows:
M506 was identified as the only major circulating metabolite and contributes with a low extent to 
the overall activity. Its contribution to safety and tolerability is not evaluated by nonclinical safety, 
as tepotinib is developed under the ICH S9 guidance. 
M506 is formed from MSC2156119J with a median tmax of 24 hours, ranging from 24 to 60 hours, 
and showed an apparent geometric mean half-life of 93 hours, ranging from 66 to 145 hours, 
estimated on concentration data from 4 subjects. M506 consists of 2 enantiomers, the 
S-enantiomer, MSC2571107, and the R-enantiomer, MSC2571109, which have been included as 
secondary endpoints. MSC2571109 represents the major human plasma metabolite of tepotinib 
(64.6% of parent AUC0-240h), while MSC2571107 is a metabolite of less significance (4.54% of 
parent AUC0-240h). A bioanalytical assay is available, which analyzes tepotinib and the 
enantiomers.
Document No. 
 
Object No. 
 
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5.2.4
Risks
On the basis of available clinical data, asymptomatic increase of lipase and amylase are considered 
as an identified risk of tepotinib. Such elevations have been reported for a number of other tyrosine 
kinase inhibitors with molecular targets other than c-Met (eg, sunitinib, imatinib, sorafenib) and 
can therefore be regarded as a class effect. The underlying mechanism that causes the enzyme 
elevation is unknown. The pancreas was not identified as a potential target organ in animal 
toxicology studies. No pancreatitis has been reported so far.
Tepotinib was identified as a P-glycoprotein (P-gp) substrate, as well as an inhibitor of P-gp, 
BCRP, OCT1, OCT2, MATE1, and MATE2. Intestinal and systemic drug-drug interactions on the 
transporter level with relevance cannot be ruled out. In vitro drug transporter interaction studies 
revealed a pronounced inhibition of OCT1, OCT2, and MATE2 by the major metabolite 
MSC257119A with the potential for clinically relevant drug-drug interactions considering its 
current mean exposure at steady state in clinical studies.
5.2.5
Inclusion of Special Populations
Standard inclusion and exclusion criteria have been selected for the inclusion of healthy subjects 
and subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) impaired hepatic 
function. Women of childbearing potential are excluded from participation in the study.
5.3
Selection of Study Population
Only volunteers meeting all of the inclusion criteria and none of the exclusion criteria may be 
enrolled into the study. Prior to performing any study 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 consent following the procedure described in Section 9.2.
5.3.1
Inclusion Criteria
All subjects:
1. Men and women (of nonchildbearing potential), 18 to 75 years (inclusive) of age at Screening
2. Body mass index of 18 to 36 kg/m2 (inclusive) with a body weight ≥ 50 kg at Screening 
3. Women must be postmenopausal for at least 1 year, as confirmed by follicle stimulating 
hormone (FSH) assessments performed at Screening, or surgically sterile (ie, documented 
hysterectomy, documented bilateral salpingectomy, or documented bilateral oophorectomy). 
Pregnancy assessments will also be performed on female subjects at Screening and at 
admission to the study center
4. A male participant must agree to use a barrier method, and to have their female partners use
highly effective, medically acceptable methods of contraception (ie, methods with a failure 
rate of less than 1 % per year) as detailed in Appendix I of this protocol during participation in 
Document No. 
 
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the study and for at least 90 days after the last dose of IMP. Men must refrain from donating 
sperm during the same period
5. Heart rate in the range of 50 to 99 beats per minute after 10 minutes rest in the semi-supine 
position at Screening
6. Negative drug-screening results and a negative alcohol breathalyzer test at Screening and 
Day -1. For all subjects, a negative cannabinoid (THC) result on drugs of abuse screening is 
required to participate in the study. If the result is positive, the Principal Investigator may 
request to repeat the test. For subjects with hepatic impairment, a positive cannabinoid (THC) 
result on drugs of abuse screening will not be exclusionary (at Screening or Day -1) if the 
subject uses cannabinoids on medical recommendation. In subjects with hepatic impairment, 
positive test for drugs used on medical recommendation will be not exclusionary.
7. Negative human immunodeficiency virus 1 and 2 antibodies at Screening 
8. Subject must have given written informed consent before any study-related activities are 
carried out and must be able to understand the full nature and purpose of the study, including 
possible risks and adverse effects
9. Absence of acute hepatitis.
Subjects with normal hepatic function:
10. Healthy volunteers, as judged by the Investigator
11. Medical history without any ongoing clinically relevant findings as judged by the Investigator
12. Physical examinations without any clinically relevant findings as judged by the Investigator.
Subjects with impaired hepatic function:
13. Subjects with mild (Child-Pugh class A) and moderate (Child-Pugh class B) impaired hepatic 
function at Screening
14. Subjects with confirmed cirrhosis (excluding primary biliary liver cirrhosis)
15. Systolic blood pressure in the range of 80 to 180 mmHg and diastolic blood pressure in the
range of 45 to 95 mmHg at the Screening visit after 10 minutes rest in the semi-supine position
16. A 12-lead ECG recording that is normal, or with abnormalities which are not hazardous to the 
subject in the opinion of the Investigator at Screening.
Document No. 
 
Object No. 
 
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5.3.2
Exclusion Criteria
All subjects:
1. Subject has taken an investigative medication within 30 days prior to administration of IMP
2. Subject has donated blood within 60 days or plasma within 14 days prior to Screening
3. Subject is lactating
4. Diseases or surgeries of the gastrointestinal tract, which could influence the gastrointestinal 
absorption or motility
5. A history of epilepsy
6. A history of malignant diseases other than basalioma
7. Clinically relevant allergies that require medical treatment, as judged by the Investigator
8. Inability to refrain from alcohol intake during confinement. Subjects should not consume more 
than 14 (women) or 21 (men) units of alcohol a week (unit = 1 glass of wine (125 mL) = 
1 measure of spirits = ½ pint of beer)
9. Any other clinically relevant disease, which in the Investigator’s opinion would exclude the 
subject from the study
10. Inability to communicate or cooperate with the Investigator (eg, language problem, illiterate, 
poor mental status) or to comply with the requirements of the entire study, including dietary 
restrictions
11. Smoking > 10 cigarettes per day, or equivalent use of other forms of nicotine (ie, patches, gum, 
chewing tobacco, vaping) for the duration of the study
12. Antacid drugs, H2-blocker and proton pump inhibitors might affect the absorption of tepotinib. 
H2-blocker or proton pump inhibitors should be stopped 5 days prior to Day 1 until Day 2. 
Antacids should not be taken 1 hour before the IMP administration until 2 hours after the IMP 
administration.
13. Renal dysfunction (defined as creatinine clearance < 60 mL/minute, calculated by use of the 
Cockcroft-Gault formula)
Healthy Subjects:
14. Presence of hepatitis B or hepatitis C or previous infection with hepatitis C, treated with 
Sofosbuvir or other antiviral compounds
15. Use of any medication, including multivitamin preparations, received within 10 days prior 
Day 1 or 6 times the elimination half-life, whichever is the longest, until the End of Study visit,
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except the occasional use of paracetamol/acetaminophen or ibuprofen (not > 500 mg per day) 
within 7 days before Day 1 until the End of Study visit.
Subjects with impaired hepatic function:
16. Primary biliary liver cirrhosis
17. Nonstabilized chronic heart failure (New York Heart Association Class III and IV)
18. Hepatocarcinoma
19. Hepatic encephalopathy Grade III and IV
20. Sepsis or spontaneous bacterial peritonitis within the last 2 years prior to Screening
21. Gastrointestinal bleeding within 30 days prior to or during Screening
22. Esophageal varices > Grade II at Screening
23. Acute hepatic failure of any etiology (including viral, toxic, or drug induced)
24. Portosystemic shunt
25. Current 
intake 
of 
any 
drug 
with 
dose 
dependent 
hepatotoxicity, 
such 
as 
paracetamol/acetaminophen (> 500 mg per day)
26. Change in used medication (prescribed by a physician or over-the-counter medication) other 
than for hepatic insufficiency within 7 days prior to Day 1
27. Co-medication inducing or inhibiting P-gp, BCRP, OCT1, OCT2, MATE1, or MATE2 should 
be stopped from 5 days prior to Day 1 until the End of Study visit
28. Clinical evidence of severe ascites
29. Ascites requiring paracentesis within 21 days prior to Day 1.
5.4
Criteria for Initiation of Study Treatment
Inclusion and exclusion criteria will be checked within the Screening period and at Day -1.
Subjects meeting all of the inclusion and none of the exclusion criteria will be enrolled to Part 1
or Part 2 of the study, as appropriate, and admitted to the study center on Day -1 for IMP
administration on Day 1.
Document No. 
 
Object No. 
 
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5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal 
from 
Investigational 
Medicinal 
Product
Administration
Not applicable since the IMP is administered only once in the study.
5.5.2
Withdrawal from the Study
Subjects may withdraw from the study at any time without giving a reason.
A subject must be withdrawn from the study if any of the following occur during the study:
! Subject withdrew consent
! Participation in another clinical study during the duration of this study
! Use of nonpermitted concomitant medications, as defined in Section 6.5. However, any 
medications that are considered necessary for the subject’s wellbeing may be given at the 
discretion of the Investigator
! Protocol noncompliance judged as significant by the Investigator, including noncompliance to 
the required study considerations (eg, food/diet requirements)
! Subject lost to PK sampling
! Any event that unacceptably endangers the safety of the subject.
If there is a medical reason for the withdrawal, the subject will remain under the supervision of the 
Investigator until satisfactory health has returned or care has been transferred to the subject’s 
general practitioner or to a hospital consultant.
In case of premature withdrawal from the study, the assessments scheduled for the End of Study 
visit should be performed, if possible, with the focus on the most relevant assessments (see 
Table 1). Regardless, the appropriate electronic case report form (eCRF) section should be 
completed.
Subjects who are withdrawn after IMP administration and are not evaluable will be replaced, as 
discussed by the Investigator and Medical Responsible of the Sponsor.
5.6
Premature Termination of the Study
The clinical study may be terminated prematurely or suspended at the request of the Health 
Authorities or if new safety or efficacy information leads to an unfavorable risk benefit judgment 
for the IMP. The Sponsor may discontinue the study if it becomes unjustifiable for medical or 
ethical reasons, for poor enrollment, or because of discontinuation of clinical development of the
IMP or withdrawal of the IMP or comparator from the market for safety reasons.
The Health Authorities and Institutional Review Boards (IRBs) will be informed about the 
discontinuation of the study in accordance with applicable regulations.
Document No. 
 
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5.7
Definition of End of Study
The end of the study is defined as the completion of the last visit of the last subject.
6
Investigational Medicinal Product and Other Drugs Used in 
the Study
The term “Investigational Medicinal Product” refers to an active substance or a placebo being 
tested or used as a reference therapy in a clinical study, including products that have a marketing 
authorization but are formulated, packaged, or administered differently from the authorized form, 
used for an unauthorized indication, or used to gain further information about the authorized form.
6.1
Description of the Investigational Medicinal Product
Tablet Formulation 2 (film-coated tablet formulation) of tepotinib will be used in this study. For 
Part 1, 500 mg tablets of Tablet Formulation 2 will be used. For Part 2, 100 mg tablets of Tablet 
Formulation 2 or a bioequivalent formulation may also be used for doses other than 500 mg or 
1000 mg.
Tepotinib 100 mg and 500 mg film-coated tablets for Phase 1, 2 and 3 clinical studies contain the 
excipients D-mannitol, silica colloidal anhydrous, crospovidone, magnesium stearate, and 
Opadry® II pink (for 100 mg) or Opadry II yellow (for 500 mg). The film-coated tablets are 
intended for oral administration.
6.2
Dosage and Administration
All subjects will receive the IMP once only in the course of the study. A single oral dose of 500 mg 
in Part 1 and up to 1000 mg in Part 2 tepotinib tablets will be administered to subjects after they
have completed a standard breakfast. The IMP administration will occur 30 minutes after the start 
of the intake of a standard meal. Subjects should eat this meal within 25 minutes or less. The IMP 
will be administered with 240 mL of water. The subject will remain fasting for 4 hours after the 
breakfast, after which a standardized lunch will be served. Further details on the standard breakfast 
are provided in Section 6.5.3.
6.3
Assignment to Treatment Groups
Part 1 will have 1 treatment group and 1 control group receiving a single dose of 500 mg tepotinib. 
Part 2 is optional, and if conducted, will have 1 treatment group receiving a single dose of between 
500 mg up to 1000 mg, as per SMC decision.
6.4
Noninvestigational Medicinal Products to be Used
Not applicable
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6.5
Concomitant 
Medications 
and 
Nondrug 
Therapies/Interventions
All concomitant medications taken by the subject during the study, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
duration and indication of each drug. Nondrug interventions and any changes to a concomitant 
medication or other intervention should also be recorded in the eCRF.
6.5.1
Permitted Medicines
Any medications that are considered necessary to protect subject welfare and will not interfere 
with the study medication may be given at the Investigator’s discretion.
Healthy Subjects
Occasional use of paracetamol/acetaminophen or ibuprofen (not > 500 mg per day) within 7 days 
before IMP administration is allowed.
Hepatic Impaired Subjects
A stable regimen of other prescribed drugs and vitamins is allowed.
6.5.2
Prohibited Medicines
All Subjects
Antacids, H2-blockers, and proton pump inhibitors might affect the absorption of tepotinib. 
H2-blockers or proton pump inhibitors should be stopped 5 days prior Day 1, until Day 2. Antacids 
should not be taken 1 hour before IMP administration until 2 hours after IMP administration. 
Healthy Subjects
Use of any medication, including multi-vitamin preparations, received within 10 days prior to 
Day 1, or within 6 times the elimination half-life, whichever is the longest, except the occasional 
use of paracetamol/acetaminophen or ibuprofen (> 500 mg per day is prohibited) within 7 days 
before Day 1 until the End of Study visit.
Hepatic Impaired Subjects:
Concomitant medication inducing or inhibiting P-gp, BCRP, OCT1, OCT2, MATE1, or MATE2
should be stopped from 5 days prior to Day 1 until the End of Study visit.
Current intake of any drug with dose dependent hepatotoxicity, such as paracetamol/
acetaminophen > 500 mg per day is not allowed. 
A change in the medication (prescribed by a physician or over-the-counter) used other than for 
hepatic insufficiency within 7 days prior to Day 1 is not allowed.
Document No. 
 
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The use of nonpermitted concomitant medications for any reason during the study must result in 
withdrawal of the subject from the study. However, any medications that are considered necessary 
for the subject’s wellbeing may be given at the discretion of the Investigator.
6.5.3
Other Interventions
All Subjects
Subjects are not allowed to smoke > 10 cigarettes per day, or equivalent use of other forms of 
nicotine (ie, patches, gum, chewing tobacco, vaping) for the duration of the study. 
Subjects are required to refrain from alcohol intake during confinement. Subjects should not 
consume more than 14 (women) or 21 (men) units of alcohol a week (unit = 1 glass of wine 
(125 mL) = 1 measure of spirits = ½ pint of beer).
Subjects will receive the IMP after they have completed a standard breakfast. Drug administration 
is 30 minutes after start of the intake of a standard breakfast with 240 mL of water. Subjects should 
eat this meal within 25 minutes or less. The subject will remain fasting for 4 hours after the 
breakfast, after which a standardized lunch will be served. The standard breakfast will contain
approximately 500 calories and will be balanced in macronutrients (approximately 
50% carbohydrates, 25% protein, and 25% fat). The menu must be approved by the Sponsor. The 
subject will be expected to eat the entire meal. The percentage consumed will be recorded for all 
subjects. A deviation will be recorded if the subject eats less than 90% of the meal. Subjects will 
not be excluded from dosing if they are unable to complete the meal in full.
6.5.4
Special Precautions
This study will be performed at 2 hospital-based, inpatient, Phase 1 research centers with personnel 
trained in basic or immediate life support. Equipment and other agents (ie, epinephrine and 
prednisolone equivalents, etc.) will be available at the study center in case of allergic reactions.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
No specific measures for management of specific AEs or adverse drug reactions are proposed at 
this stage. Adverse drug reactions should be treated symptomatically. Standard medical care will
be provided at the study center for all AEs encountered during the study.
For details on the management of AEs and adverse drug reactions, see Section 7.4.1.6.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
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 Guidelines.
Document No. 
 
Object No. 
 
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Tepotinib tablets will be supplied in aluminum-aluminum blisters. The blisters will be packed in a 
suitable carton box labeled with (but not limited to) the following required information: study 
number, number of tablets per box, storage conditions, the words “Caution: New Drug – Limited 
by Federal (or United States) law to investigational use”, batch number, and the Sponsor’s name.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
The pharmacy or designee will receive tepotinib labeled and packaged according to the local 
regulatory requirements and the storage requirements. Tepotinib is formulated as tablets, and is 
ready for use. The responsible pharmacist or designee will dispense a single dose of tepotinib for 
administration to the subject during the IMP administration visit. Detailed guidance will be 
provided in the pharmacy manual.
The IMP supplies will be recorded in a drug inventory and stored in a locked cabinet, protected 
from environmental extremes until used in the study. Tepotinib should be stored at or below 25°C. 
Any deviations from the recommended storage conditions should immediately be reported to the 
Sponsor specified in the pharmacy manual, and the medication should not be used until 
authorization has been received from the Sponsor.
6.8
Investigational Medicinal Product Accountability
The Investigator (or designee) is responsible for ensuring tepotinib (IMP) accountability, including 
reconciliation of drugs and maintenance of records.
! Upon receipt of the IMP, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File
! The dispensing of the IMP will be recorded on the appropriate drug accountability forms so that 
accurate records will be available for verification at each monitoring visit
! Study center IMP accountability records will include the following:
! Confirmation of IMP receipt, in good condition and in the defined temperature range
! The inventory of IMP provided for the clinical study and prepared at the center
! The use of each dose by each subject
! The disposition (including return, if applicable) of any unused IMP
! Dates, quantities, batch numbers, kit numbers, expiry dates, and the individual subject study 
numbers.
The study center should maintain records, which adequately document that subjects were provided 
the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present study. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
Document No. 
 
Object No. 
 
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A Study Monitor will periodically collect the IMP accountability forms.
At the conclusion or termination of this trial, all used and unused IMP kits will be destroyed at the 
trial site according to local regulations and institutional guidelines. All used and unused 
medications will be carefully recorded and documented before destruction.
6.9
Assessment of Investigational Medicinal Product Compliance
The IMP will be administered by the study center staff within the confines of the study center. A 
mouth and hand check will be performed after administration of the IMP to ensure that the dose 
has been swallowed.
6.10
Blinding
Blinding is not applicable. (Note: the bioanalytical assay will be performed without knowledge of 
hepatic function group information. Access to hepatic function group information will be restricted 
and defined in a Data Access Plan).
6.11
Emergency Unblinding
Not applicable
6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical study
protocol or planned for an individual subject enrolled in the study. Even if it does not meet other 
criteria for an SAE, any overdose must be recorded in the study medication section of the eCRF
and reported to Drug Safety in an expedited manner using the SAE Report Form, and following 
the procedure in Section 7.4.
The effects of an overdose are unknown, and therefore no standard treatment is currently 
established. In the event of an overdose, the Investigator or treating physician should use 
appropriate clinical judgement for the management of any clinical symptoms or evaluation results.
6.13
Medical Care of Subjects after End of Study
Since this is not an interventional study, medical care of subjects after the End of Study visit is not 
applicable. After a subject has completed the study or has withdrawn early, follow up treatment 
will only be administered if required due to an ongoing TEAE.
7
Study Procedures and Assessments
Prior to performing any study assessments, the Investigator will ensure that the subject has 
provided written informed consent according to the procedure described in Section 9.2.
A subject identifier (see Section 9.3) will be assigned for each subject for who provided written 
informed consent. 
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Subjects are not allowed to have participated in a clinical study within the 30 days prior to 
administration of IMP.
All efforts should be made to perform assessments as close as possible to the scheduled timepoints.
Subjects will be admitted to the study center on Day -1 and remain resident at the study center 
until the morning of Day 4, after completion of the Day 4 assessments.
When several procedures are scheduled at the same theoretical time, the following sequence should 
be followed: 12-lead ECG followed by vital signs before the specified timepoint, preceding the 
PK sampling which will be performed at the specified timepoint. Therefore, assessments not 
performed at the exact timepoint are not to be considered protocol deviations as long as the actual 
collection date and time is recorded. Every effort should be made to perform assessments at the 
appropriate timepoint.
7.1
Schedule of Assessments
The detailed Schedule of Assessments for Part 1 and Part 2 are provided in Table 1.
7.1.1
Screening Visit
Screening of the subjects will take place within 2 to 28 days prior to Day 1. At the start of 
Screening, candidates for the study will be fully informed about the nature of the study and the 
possible risks, and will receive a copy of the subject information and informed consent form for 
review. 
After written informed consent is obtained for all procedures in the study, subjects will be 
evaluated for entry into the study according to the inclusion and exclusion criteria (Section 5.3). 
Screening procedures specified in the Schedule of Assessments for Part 1 and Part 2 (Table 1)
must be performed and evaluated during Days -28 to -2.
If the subject meets all of the protocol inclusion criteria and none of the exclusion criteria, he/she 
will be considered as eligible and will be enrolled into the clinical study.
Subjects who fail to meet the protocol specified criteria for dosing, who withdraw from the study
or who withdraw their consent in the Screening period are considered screening failures. The 
following data, as a minimum, should be recorded for these subjects: date of informed consent, 
inclusion/exclusion criteria, demographics (including age, sex (gender), weight, and height), AEs 
(if any) from the date of informed consent until the subject is considered a screen failure by the 
Investigator, reason for screening failure, and the Investigator’s signature. Rescreening for 
eligibility of subjects who failed the initial screening will be allowed once per subject within the 
28 day Screening period.
7.1.2
Treatment Period
A review and update of the subject’s medical history, possible AEs, concomitant medication use
and inclusion/exclusion criteria, to ensure the subject remains eligible for participation in the study, 
Document No. 
 
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should be performed prior to admission to the study center, on Day -1. Eligible subjects will 
participate in Part 1 of the study. Subjects will receive their respective IMP dose on Day 1. Subjects 
will be discharged from the study center on the morning of Day 4, after completion of the Day 4 
assessments.
Part 2 of the study is optional. Details are provided in Section 5.1.
Specific assessments to be performed during the treatment periods are presented in the Schedule 
of Assessments (Table 1).
7.1.3
End of Study Visit/Early Termination Visit
Healthy subjects will partake in the End of Study visit on Day 15 and hepatic impaired subjects 
will partake in the End of Study visit on Day 22. Assessments at the End of Study visit are specified 
in the Schedule of Assessments for Part 1 and Part 2 (Table 1). Subjects who discontinue from the 
study for any reason prior to the End of Study visit must undergo an Early Termination visit 
immediately upon discontinuation. Assessments at the Early Termination visit are the same as for 
the End of Study visit.
7.2
Demographic and Other Baseline Characteristics
7.2.1
Demographics
At Screening, the following demographic data will be collected: date of birth, sex (gender), weight, 
height, race, and ethnicity.
Demographic data collected at Screening will be recorded in the eCRF. 
7.2.2
Medical History
A complete review of the subject’s medical history (including the hepatic insufficiency) should be 
performed at Screening to determine the subject’s eligibility. An update of medical history will be 
performed at admission to the study center on Day -1. At Screening, subjects with hepatic 
impairment will be allocated to the mild (Child-Pugh class A) and moderate (Child-Pugh class B) 
hepatic impairment group according to the Child-Pugh classification as specified in Table 2 and 
Table 3.
7.2.3
Medication History
The medication history of subjects must be collected at Screening and updated at admission to the 
study center. See Section 6.5 for details regarding permitted and prohibited medications.
7.2.4
Other Baseline Assessments
All other baseline measurements, such as vital signs, height and weight, a complete physical 
examination, clinical laboratory parameters, alcohol breathalyzer test, cotinine test, drugs of abuse 
screen, pregnancy test in women, FSH levels in postmenopausal women, and 12-lead ECGs will 
Document No. 
 
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be assessed at timepoints as specified in the Schedule of Assessments for Part 1 and Part 2
(Table 1).
7.3
Efficacy Assessments
Not applicable
7.4
Assessment of Safety
Subjects will be admitted to the study center on Day -1 and closely monitored for AEs after 
administration of the IMP. The safety profile of tepotinib will be assessed through the recording, 
reporting and analysis of baseline medical conditions, AEs, physical examination findings 
including vital signs, 12-lead ECG recordings, and laboratory tests. Pre-existing conditions that 
are present before the IMP administration will be recorded as baseline conditions.
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the study. The Investigator will report 
any AEs, whether observed by the Investigator or reported by the subject (see Section 7.4.1.2). 
The reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigators are required to grade the severity or toxicity of each AE.
Investigators will reference the most recent version of the National Cancer Institute (NCI) -
Common Terminology Criteria for Adverse Events (CTCAE), a descriptive terminology that can 
be used for AE reporting when describing AEs.
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.
Document No. 
 
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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 an 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 then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to the IMP using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to the 
IMP include, but may not be limited to, temporal relationship between the AE and the IMP, known 
side effects of the IMP, medical history, concomitant medication, course of the underlying disease, 
study procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
study protocol. A reasonable alternative explanation must be available.
Related:
Reasonably 
related 
to 
the 
IMP. 
The 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the IMP under study in this clinical 
study protocol.
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, 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 Investigators. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, or increased alanine aminotransferase) must be reported as the AE rather 
than the abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death
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! 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 prolongs an existing hospitalization
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
! Is otherwise considered to be 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 an IMP is also 
considered an SAE, as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study treatment or study procedures (for 
example, 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 (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the Screening visit that do not worsen in severity or frequency during 
the study are defined as Baseline Medical Conditions, and are not to be considered AEs.
Adverse Events of Special Interest 
No AEs of special interest have been defined.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each study visit, the subject will be queried on changes in his or 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. 
Subjects will be educated to inform the study staff of any AE they may be experiencing, as they 
occur. While the subjects are confined to the study center, study staff will solicit responses from 
subjects daily for any AEs or any changes to their health in general. Furthermore, any changes in 
safety monitoring (eg, vital signs, laboratory results, etc), notable as AEs through review by the 
Investigator/designee, will be recorded accordingly.
Document No. 
 
Object No. 
 
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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 must be additionally documented and reported using the appropriate Report Form as 
described in Section 7.4.1.4.
It is important that each AE report include 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 IMP, any other 
potential causal factors, any treatment given or other action taken, including discontinuation of the 
IMP, and its outcome. In addition, serious cases should be identified and the appropriate 
seriousness criteria documented. 
Specific guidance can be found in the eCRF Completion Guidelines provided by the CRO.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
study (date of first signature of informed consent/) and continues until the End of Study visit. 
Any SAE assessed as related to the IMP must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of the IMP. 
7.4.1.4
Procedure for Reporting Serious Adverse Events
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee using the SAE Report Form following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report Form must be provided immediately thereafter.
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). 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 (for example, 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.
Document No. 
 
Object No. 
 
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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.
7.4.1.5
Safety Reporting to Health Authorities, Institutional Review 
Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigators must comply with any applicable study center-specific requirements related to 
the reporting of SAEs (particularly deaths) involving study subjects to the IRB that approved the
study.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the study or alter the IRB’s 
approval/favorable opinion to continue the study.” 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”). The Investigators 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 the 
appropriate Safety Reports directly to the concerned lead IRB and will maintain records of these 
notifications. When direct reporting is not clearly defined by national or study center-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IRB of any 
Safety Reports provided by the Sponsor/designee and of filing copies of all related correspondence 
in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/suspected unexpected serious adverse reactions/Safety Issues will 
be carried out in accordance with that Directive and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
AEs are recorded and assessed continuously throughout the study (see Section 7.4.1.3) and are 
assessed for final outcome at the End of Study visit. All SAEs ongoing at the End of Study visit
must be monitored and followed up by the Investigators 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. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to the IMP (for example, resulting 
from a drug interaction with a contraceptive medication) are considered to be AEs. However, all 
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pregnancies with an estimated conception date during the period defined in Section 7.4.1.3 must 
be recorded by convention in the AE page/section of the eCRF. 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 7.4.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the study.
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 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a female subject occurring during the course of the study, the subject 
must be discontinued from study medication immediately.  
In the unlikely event of a pregnancy in a female partner of a male subject occurring during the 
course of the study, The Sponsor/designee must be notified without delay. The Investigator will 
attempt to collect pregnancy information on any female partner who becomes pregnant while her 
male partner is participating in the study. The Investigator will request the necessary signed 
informed consent from the female partner and if the consent is provided, the Investigator will 
record pregnancy information on the appropriate form for submission to the Sponsor. If consent is 
provided, follow up on the pregnancy will continue through the delivery date or termination of the 
pregnancy, and information regarding the pregnancy outcome and fetal/infant status at outcome 
(presence or absence of anomalies) will be documented.
7.4.3
Clinical Laboratory Assessments
Blood and urine samples will be collected for the following clinical laboratory tests, following the 
timing noted in the Schedule of Assessments for Part 1 and Part 2 (Table 1). All samples should 
be clearly identified.  
The Sponsor should receive a list of laboratory normal ranges before shipment of the IMP. Any 
change in laboratory normal ranges during the study should be forwarded to the Sponsor or its 
designee.
The laboratory variables to be assessed for safety evaluations are provided in Table 4. Unscheduled 
retest of laboratory safety tests at the discretion of the investigator are permitted during screening 
and throughout the study.
Document No. 
 
Object No. 
 
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Table 4
Clinical Laboratory Evaluationsa
Biochemistry
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyltransferase
Lactate dehydrogenase
Creatine phosphokinase
Bilirubin (total)
Protein (total)
Albumin
α-1-acid glycoprotein
Cholesterol
Triglycerides
Amylase
Lipase
Uric acid
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Magnesium
Phosphate
Creatinine
Urea
Glucose
Hematology
Hematocrit
Hemoglobin
Red blood cell count
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin
concentration
Platelet count
White blood cell 
count
White blood cell differentials 
and absolute counts:
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils
Coagulation
International Normalized Ratio 
(INR)
Other Tests
Hepatitis B surface antigen
Hepatitis B core antibody
Hepatitis C antibody
Human immunodeficiency virus I 
and II antibodies
Cotinine
Alcohol (breathalyzer)
Follicle-stimulating hormone
(for postmenopausal women)
Urinalysis
pH
Nitrite
Protein
Glucose
Ketone bodies
Urobilinogen
Bilirubin
Leukocyte esterase
Blood
Urine Microscopyb
Urine Drug Screenc
Cocaine
Amphetamines
Methamphetamines
Opiates
Barbiturates
Ecstasy
Benzodiazepine
Methadone
Cannabinoids (THC)
Phencyclidine
Oxycodone
Tricyclic antidepressants
a
Subjects should fast for 8 hours prior to clinical laboratory blood sample collection.
b
Only if blood, protein, nitrite, or white blood cell count is positive on the dipstick.
c
For all subjects, a negative cannabinoid (THC) result on drugs of abuse screening is required to participate in 
the study. If the result is positive, the Principal Investigator may request to repeat the test. For subjects with 
hepatic impairment, a positive cannabinoid (THC) result on drugs of abuse screening will not be exclusionary 
(at Screening or Day -1) if the hepatic-impaired subject uses cannabinoids on medical recommendation. In 
subjects with hepatic impairment, positive test for drugs used on medical recommendation will be not 
exclusionary.
The total blood volume to be drawn from each subject for planned assessments during the study 
will not exceed the volume of a standard donation (approximately 450 mL) and will be specified 
in the laboratory manual.
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7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Vital signs, including oral temperature, systolic and diastolic blood pressure, and pulse rate will 
be assessed as per the timepoints specified in the Schedule of Assessments for Part 1 and Part 2
(Table 1).
A semi-automated pulse rate and blood pressure recording device with an appropriate cuff size
will be utilized. The pulse rate and blood pressure will be measured after 10 minutes rest in the 
semi-supine position (supine at timepoints where the assessment coincides with 12-lead ECG 
assessment) with the subject’s arm unconstrained by clothing or other material. The blood pressure 
should be assessed on the same arm for each subject throughout the study.
7.4.4.2
Physical Examination
Complete physical examinations will be performed at the timepoints specified in the Schedule of 
Assessments for Part 1 and Part 2 (Table 1) and will include an assessment of: general appearance, 
skin, head and neck, lymph nodes, thyroid, abdomen, and musculoskeletal, cardiovascular, 
respiratory, and neurological systems.
Body weight will be measured at Screening and at Day -1. Height will be measured at Screening 
only.
All clinically significant abnormalities occurring before signature of informed consent should be 
recorded in the medical history and/or disease history section of the eCRF; all abnormalities
occurring or worsening after the subject signed the Informed Consent Form should be recorded in 
the AE section of the eCRF.
7.4.4.3
Electrocardiograms
Standard 12-lead ECGs will be performed at the timepoints specified in the Schedule of 
Assessments for Part 1 and Part 2 (Table 1) after 10 minutes rest in the supine position. Only the 
overall evaluation (normal/abnormal) will be recorded in the eCRF, and if abnormal, the specific 
abnormality will be recorded. Abnormal evaluations will be judged as clinically significant or not 
clinically significant by the Investigator. The ECG recordings must be performed before PK 
sampling timepoints on days where both assessments are performed.
7.5
Pharmacokinetics
7.5.1
Body Fluids
Blood samples for the PK evaluation of tepotinib and its metabolites (MSC2571109 and 
MSC2571107) in plasma will be collected at the timepoints specified in the Schedule of 
Assessments for Part 1 and Part 2 (Table 1). The exact date and time of sample collection will be 
recorded in the eCRF. Samples not collected at the exact timepoint are not to be considered 
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protocol deviations as long as the actual collection date and time is recorded. Every effort should 
be made to collect samples at the appropriate timepoint.
Details of the sample collection, blood volume, labeling, storage and shipment requirements will 
be provided in a separate manual of operations or laboratory manual.
The PK sampling is planned differently for healthy subjects than for hepatic impaired subjects as 
a different half-life is expected. As the majority of healthy subjects do not have measureable 
concentrations after Day 15, PK sampling until Day 15 is considered sufficient. As the optimal 
sampling schemes of the hepatic impairment group is difficult to predict, an additional sampling 
time of 1 week (up to Day 22) is considered to be sufficient. The SMC may decide on a different 
sampling scheme for Part 2.
All sample analyses will be performed using a validated method measuring parent drug and 
metabolites.
The free fraction of tepotinib will be determined to assess a potential effect of low serum albumin 
concentration which might result in an increased free fraction of tepotinib in subjects with hepatic 
impairment. 
7.5.2
Pharmacokinetic Calculations
The PK parameters (see Table 5) of tepotinib and its metabolites MSC2571109 and MSC2571107, 
if applicable, will be evaluated. Noncompartmental computation of PK parameters will be 
performed using the software Phoenix® WinNonlin® 6.4 or higher (Certara, L.P., Princeton, NJ, 
USA, SAS® System (Version 9.4 or later; SAS Institute, Cary, NC, USA) or equivalent software.
Individual PK parameters will be calculated using actual sample collection times. The predose 
sample time will be considered as if it had been taken simultaneously with the IMP administration.
Pharmacokinetic variables will be evaluated and listed for all subjects who provide sufficient 
concentration-time data.
If AUCextra% is greater than 20%, λz and all derived parameters should be flagged as invalid.
Plasma concentrations BLQ before the last quantifiable data point will be taken as zero for 
calculating the AUC (ie, embedded BLQ values set to zero). Plasma concentrations BLQ after the 
last quantifiable data point will not be considered for the determination of λZ.
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Table 5
Definition of Pharmacokinetic Parameters
Tepotinib and its Metabolites
Symbol
Definition
AUC0-t
Area under the plasma concentration-time curve (AUC) from time zero to the 
last sampling time at which the concentration is at or above LLOQ, calculated 
according to the mixed log linear trapezoidal rule (ie, linear up/log down)
AUC0-∞
Area under the plasma concentration-time curve from time zero to infinity, 
calculated as AUC0-t + AUCextra%, according to the mixed log linear 
trapezoidal rule (ie, linear up/log down). AUCextra% represents the extrapolated 
part of AUC0-∞ calculated by Clastcalc/λZ, where Clastcalc is the calculated plasma 
concentration at the last sampling timepoint at which the measured plasma 
concentration is at or above LLOQ
Cmax
Maximum plasma concentration observed
tmax
Time to reach the maximum plasma concentration
t1/2
Apparent terminal half-life, calculated as ln2/λZ
λZ
Apparent terminal rate constant determined from the terminal slope of the 
log∀transformed plasma concentration curve using linear regression on 
terminal data points of the curve
CL/f
Total body clearance of drug from plasma following oral administration, 
calculated as Dose/AUC0-∞(for tepotinib only)
VZ/f
Apparent volume of distribution during the terminal phase following 
extravascular administration, calculated as Dose/(AUC0-∞*λz)
AUCextra%
Area under the plasma concentration-time curve extrapolated from time t to 
infinity as a percentage of AUC0-∞
MRAUC0-∞
Metabolite (MSC2571109 or MSC2571107) AUC0-∞to tepotinib AUC0-∞ ratio
MRCmax
Metabolite (MSC2571109 or MSC2571107) Cmax to tepotinib Cmax ratio
7.6
Biomarkers
No biomarker assessments are planned.
7.7
Other Assessments
No other assessments are planned.
8
Statistics
Details of the statistical analyses will be described in a separate statistical analysis plan.
8.1
Sample Size
Pharmacokinetic studies including subjects with impaired hepatic function are usually exploratory 
by nature. Considering the CVs for the primary endpoints AUC0-t and Cmax of tepotinib, 20.4% 
and 22.8% respectively (Study EMR200095-007), 6 evaluable subjects per group will provide 80% 
power for detecting a group difference of 44% (AUC0-t) and 50% (Cmax), which is considered 
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sufficient to meet the study objectives having the therapeutic window of tepotinib in mind. The 
significance level was set to 0.05 two-sided.
Therefore, 18 subjects (3 groups x 6 subjects) should be included in Part 1 and 6 subjects in Part 2. 
Drop-outs will be replaced only if they cannot provide an evaluable PK profile.
8.2
Randomization
Not applicable.
8.3
Endpoints
8.3.1
Primary Endpoints
! PK profile of tepotinib (plasma) in terms of AUC0-t, AUC0-∞, and Cmax at Day 1 to Day 15 
(healthy subjects) or Day 22 (hepatic impaired subjects) calculated by noncompartmental 
analyses.
8.3.2
Secondary Endpoints
! PK profile of tepotinib (plasma) in terms of tmax, t1/2, CL/f, VZ/f, AUCextra% at Day 1 to Day 15 
(healthy subjects) or Day 22 (hepatic impaired subjects) calculated by noncompartmental 
analyses
PK profile of the major tepotinib metabolites MSC2571109 and MSC2571107 (plasma) in 
terms of AUC0-t, AUC0-∞, Cmax, tmax, t1/2, AUCextra% at Day 1 to Day 15 (healthy subjects) or 
Day 22 (hepatic impaired subjects) calculated by noncompartmental analyses, and MRAUC0-∞
and MRCmax
! Occurrence of TEAEs, changes from baseline in laboratory safety tests, 12-lead ECG
morphology and time intervals (PR, QRS, RR, QT and QTcF), and vital signs.
8.3.3
Other Endpoints
Not applicable.
8.4
Analysis Sets
Screening Analysis Set
The Screening Analysis Set will include all subjects who provide signed informed consent,
regardless of treatment status in the trial. This analysis set will be used for subject disposition.
Safety Analysis Set
The Safety Analysis Set will include all subjects who receive study treatment. All safety analyses 
will be based on this analysis set.
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Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set will include all subjects who receive a single dose of the study
treatment and have at least 1 postdose PK measurement without important protocol 
deviations/violations or events (such as vomiting within 2 times the median tmax, after dosing) that 
may affect the PK. All PK analyses will be based on this analysis set.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
Section 10.6.1 describes the process for performing analyses and reporting of results.
Statistical analysis will be performed using the computer program package SAS System 
(Version 9.4 or later; SAS Institute, Cary North Carolina, US). 
Details on the statistical analysis will be presented in the statistical analysis plan that will be 
finalized prior to database lock.
The statistical analyses will not be started until all data for Part 1 have been corrected and checked 
for plausibility and until all necessary coding and assessments have been completed. Part 2 of the 
study is optional, and if conducted, the results will be provided in an addendum to the CSR.
All data recorded during the study will be presented in individual data listings performed on the 
Safety Analysis Set, as appropriate.
All data will be evaluated as observed; no imputation method for missing values will be used.
Plasma concentration data will be summarized descriptively for all PK analytes (tepotinib and its 
metabolites) by hepatic function group and scheduled timepoint using appropriate summary 
statistics. Any values BLQ will be taken as zero for descriptive statistics.
8.5.2
Analysis of Primary Endpoints
As the primary analysis, an analysis of variance (ANOVA) model including hepatic function group 
as a fixed effect will be applied to log-transformed tepotinib PK parameters AUC0-t, AUC0-∞, and 
Cmax of the hepatic impairment groups (Child-Pugh class A and Child-Pugh class B) and matched 
control group (healthy subjects). Differences between the hepatic impairment groups and matched 
control will be estimated together with their 90% CIs on the log scale. Point estimates and CIs will 
be back-transformed to the original scale for presentation. 
Additionally, a generalized linear model including hepatic function group and sex (gender) as fixed 
effects, age and weight as covariates, will be applied to the same primary PK parameters. A further 
covariate log(dose) will be introduced, when/if Part 2 data is included. The model may be reduced 
for the final estimates, if appropriate. 
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All endpoints will be descriptively analyzed using summary statistics by hepatic function group. 
Graphical displays will be presented, where appropriate.
8.5.3
Analysis of Secondary Endpoints
For the secondary PK parameters AUC0-t, AUC0-∞,and Cmax of the tepotinib metabolites, the same 
analyses as defined for the primary endpoints will be performed.
In a further analysis, the subjects with liver impairment will be evaluated according to the 
Albumin-Bilirubin (ALBI) score and the Organ Dysfunction Working Group (ODWG) 
classification (12,13). Further details of the statistical analyses will be described in a statistical 
analysis plan. 
8.5.4
Analysis of Safety and Other Endpoints
Safety data analysis will be conducted on the Safety Analysis Set. The number and percentage of 
subjects experiencing at least one or more AEs will be summarized by group, relationship to IMP, 
and severity. Adverse events will be coded using the latest version of the Medical Dictionary for 
Regulator Activities terminology. Severity of AEs will be graded using the most up-to-date version 
of the NCI-CTCAE toxicity grades. 
Observed and change-from-baseline laboratory values will be summarized by hepatic function 
group using descriptive statistics, by postdose shifts relative to baseline and data listings of 
clinically significant abnormalities/outliers, as appropriate. 
Clinically significant, abnormal findings from the physical examination are to be reported as AEs. 
Separate summaries of the physical examination will not be provided. Vital signs and 12-lead ECG 
data will be summarized for observed and change-from-baseline values by hepatic function group 
and timepoint using descriptive statistics. Clinically noteworthy 12-lead ECG findings for 
individual subjects will be listed and summarized as appropriate.
8.6
Interim and Additional Planned Analyses
An SMC may be established to evaluate the safety and PK results of Part 1 and provide 
recommendations on the tepotinib dose and population to be enrolled in Part 2 if the overall 
development program of tepotinib decides to use higher doses than 500 mg (up to 1000 mg) in the 
Phase 2 or Phase 3 studies. Details regarding the SMC responsibilities are provided in Section 5.1.
No additional planned analyses are scheduled.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigators are responsible for the conduct of the study at the study centers and will ensure 
that the study is performed in accordance with this protocol, the ethical principles outlined in the 
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Declaration of Helsinki, ICH GCP, and any other applicable regulations. The Investigators must 
ensure that only subjects who have given informed consent are included in the study.
According to United States Code of Federal Regulations Part 54.2 (e), for studies conducted in any 
country that could result in a product submission to the United States FDA for marketing approval 
and could contribute significantly to the demonstration of efficacy and safety of an IMP (which 
are considered “covered clinical trials” by the FDA), the Investigator and all subinvestigators 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 
study and for 12 months following completion of the study.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the study is written informed 
consent, which must be given before any study-related activities are carried out. Adequate 
information must therefore be given to the subject by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained. 
A subject information sheet must be prepared in the local language in accordance with ICH GCP
and 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 a designate will inform 
the subject verbally of all pertinent aspects of the study, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given sufficient 
time to read the information and the opportunity to ask questions and to request additional 
information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the study and sign the Informed Consent Form, as above.
After the information is provided by the Investigator, the Informed Consent Form must be signed 
and dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s study 
center, and must be safely archived 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 Informed 
Consent Form should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be
provided to the subjects and submit them to the IRB for review and opinion. Using the approved 
revised subject information sheet and other written information, The Investigator will explain the 
changes to the previous version to each study subject and obtain new written consent for continued 
participation in the study. The subject will be given sufficient time to read the information and the 
opportunity to ask questions and to request additional information and clarification about the 
changes.
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9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the study as well as in the clinical 
study database. All subject data collected in the study will be stored under the appropriate subject
number. Only the Investigator will be able to link study data to an individual subject via an 
identification list kept at the study center. For each subject, original medical data will be accessible 
for the purposes of source data verification by the Monitor, audits and regulatory inspections, but 
patient confidentiality will be strictly maintained.
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.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the CRO for use
during study participation in order to provide clinical study subjects with a way of identifying 
themselves as participating in a clinical study and to give health care providers access to any
information about this participation that may be needed to determine the course of medical 
treatment for the subject.
The first point of contact for emergencies will be an emergency room, who should contact the 
clinical study Investigator caring for the affected subject for relevant information. 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, they will answer any questions. Any subsequent 
action will follow the standard process established for Investigators.
In cases where the Investigator is not available, the study centers will provide the appropriate 
means to contact a physician. This includes the provision of a 24-hour contact number at the 
facility, whereby the health care providers will be given access to an appropriate physician to assist 
with the medical emergency.
9.5
Clinical Study Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable.
9.6
Institutional Review Board
Prior to commencement of the study at a given center, this clinical study protocol will be submitted 
together with its associated documents (Subject Information, Informed Consent Form, 
Investigator’s Brochure, subject card) to the responsible IRB for its favorable opinion or approval, 
which will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial Master 
File at the CRO.
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The IRB will be asked to document the date of the meeting at which the favorable opinion or 
approval was given and the members and voting members present. Written evidence of favorable 
opinion or approval that clearly identifies the study, the clinical study protocol version and the 
Subject Information and Informed Consent Form version reviewed should be provided. Where 
possible, copies of the meeting minutes should be obtained.
Amendments to this clinical study protocol will also be submitted to the concerned IRB, before 
implementation of substantial changes (see Section 10.5). Relevant safety information will be 
submitted to the IRB during the course of the study in accordance with national regulations and 
requirements.
9.7
Health Authorities
The clinical study protocol and any applicable documentation (ie, Investigational Medicinal 
Product Dossier, Subject Information and Informed Consent Form) will be submitted or notified 
to the Health Authorities in accordance with all local and national regulations for each study center.
10
Study Management
10.1
Case Report Form Handling
Refer to the manual of operations for eCRF handling guidelines.  
The main purpose of the eCRF is to obtain data required by the clinical study protocol in a 
complete, accurate, legible and timely manner. The data in the eCRF should be consistent with the 
relevant source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
study is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to the Sponsor or its designated organization contain no mention of any subject names.
The data will be entered into a validated database. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s data management procedures. Database lock 
will occur once quality control and quality assurance procedures have been completed. PDF files 
of the eCRFs will be provided to the Investigators at the completion of the study.
The eCRFs are essential study documents and must be suitable for regulatory inspections and 
submissions.
10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the study. It must be possible to identify each subject by using this subject file. 
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible:
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! Subject’s full name, date of birth, sex (gender), height, weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the study)
! Study identification, that is, the Sponsor study number for this clinical study, and subject 
number
! Dates for entry into the study (informed consent) and visits to the study center
! Any medical examinations and clinical findings predefined in this clinical study protocol
! All AEs
! Date that the subject left the study including any reason for early study discontinuation or 
withdrawal from IMP (if applicable).
All documents containing source data must be filed, including, but not limited to computed 
tomography or magnetic resonance imaging scan images, ECG recordings, and laboratory results.
Such documents must bear the subject number and the date of the procedure. If possible, this
information should be printed by the instrument used to perform the assessment or measurement. 
As necessary, medical evaluation of such records should be performed; all evaluations should be 
documented, signed, and dated by the Investigator.
The Monitor will be trained to use the electronic database / eCRF and will have read-only access 
to the study data in the eCRF for source data verification. Data reviewed can be signed off and 
queries issued directly in the eCRF.
10.3
Investigator Site File and Archiving
Upon initiation of the study, the Investigator will be provided with an Investigator Site File 
containing all necessary study documents, which will be completed throughout the study and 
updated as necessary. The file must be available for review by the Monitor, during Sponsor audits
and for inspection by Health Authorities during and after the study, and must be safely archived 
for at least 15 years (or longer, per local requirements or as otherwise notified by the Sponsor) 
after the end of the study. The documents to be archived include the Subject Identification List and 
the signed subject Informed Consent Forms. If archiving of the Investigator Site File is no longer 
possible at the study center, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the study center 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.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This study will be monitored in accordance with the ICH GCP, and any other applicable 
regulations. The study center Monitor will perform visits to the study center at regular intervals.
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The clinical study protocol, each step of the data capture procedure, and the handling of the data, 
including the final CSR, will be subject to independent Quality Assurance activities. Audits may 
be conducted at any time during or after the study to ensure the validity and integrity of the study
data. Representatives of the Quality Assurance unit from the Sponsor or a designated organization, 
as well as Health Authorities, must be permitted to access all study documents and other materials 
at the study center, including the Investigator Site File, the completed eCRFs, all IMP and IMP 
accountability records, and the original medical records or files for each subject.
10.5
Changes to the Clinical Study Protocol
Changes to the clinical study protocol will be documented in writing. Substantive amendments 
will usually require submission to the Health Authorities and to the relevant 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 study center. They will be submitted to the relevant IRB or to Health 
Authorities only where requested by pertinent regulations. Any amendment that could affect the 
subject’s agreement to participate in the study requires additional informed consent prior to 
implementation following the process as described in Section 9.2.
10.6
Clinical Study Report and Publication Policy
10.6.1
Clinical Study Report
After completion of Part 1 of the study, the final CSR will be written by the CRO in consultation 
with the Sponsor and the Principal Investigators following the guidance in ICH Topic E3. Part 2 
of the study is optional, and if conducted, the results will be provided in an addendum to the CSR.
10.6.2
Publication
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study. 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 review by the Sponsor before submission. The Sponsor will not 
suppress publication, but maintains the right to delay publication in order to protect intellectual 
property rights.
11
References Cited in the Text
1. Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more. Nat Rev 
Mol Cel Biol
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2. Comoglio PM, Giordano S, Trusolino L. Drug development of MET inhibitors: targeting 
oncogene addiction and expedience. Nat Rev Drug Discov
. 2008;7(6):504-16.
Document No. 
 
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3. Eder JP, Vande Woude GF, Boerner SA, et al. Novel therapeutic inhibitors of the c-Met 
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6. Liu X, Newton RC, Scherle PA. Development of c-MET pathway inhibitors. Expert Opin 
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7. Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacy results from OAM4558g, a randomized 
phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced 
NSCLC. J Clin Oncol. 2011;29(suppl; abstr 7505).
8. Oliner KS, Tang R, Abraham A, et al. Evaluation of MET pathway biomarkers in a Phase II 
study of rilotumumab (R, AMG 102) or placebo (P) in combination with epirubicin, cisplatin, 
and capecitabine (ECX) in patients (pts) with locally advanced or metastatic gastric (G) or 
esophagogastric junction (EGJ) cancer. J Clin Oncol. 2012;30(suppl; abstr 4005).
9. U.S. Food and Drug Administration. Guidance for Industry Pharmacokinetics in Patients with 
Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and Labeling, 
U.S. Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research 
(CBER), May 2003.
10. Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin 
Liver Dis. 2010;30:3-16.
11. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245-55.
12. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with 
hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 
2015; 33(6): 550-558.
13. LoRusso PM, Venkatakrishnan K, Ramanathan RK, et al. Pharmacokinetics and safety of 
bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: 
Phase 1 NCI Organ Dysfunction Working Group study NCI-6432. Clin Cancer Res. 2012;
18(10), doi:10.1158/1078-0432.CCR-11-2873.
14. Pugh RN, Murray-Lyon IM, Dawson JL, et. al. Transection of the oesophagus for bleeding 
oesophageal varices. Br J Surg. 1973; 60:646-649. 
15. Child CG, Turcotte JG. The Liver and Portal Hypertension. Philadelphia, WB Saunders Co. 
1964. NLMN: 46218  
Document No. 
 
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16. Trey C, Burns DG, Saunders SJ. Treatment of hepatic coma by exchange blood transfusion. 
NEJM. 1966; 274:473-481.  
Document No. 
 
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12
Appendices
Document No. 
 
Object No. 
 
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Appendix I:
Contraceptive Guidance and Woman of Childbearing Potential
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
1. Premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Note:  Documentation can come from the study center personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
2. Premenarchal 
3. Postmenopausal female
! Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at Screening.
! Females on HRT and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment.
Document No. 
 
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Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya. 
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb
!
oral 
!
intravaginal 
!
transdermal 
!
Progestogen-only hormonal contraception associated with inhibition of ovulationb
!
oral 
!
injectable
Highly Effective Methods That Are User Independent 
!
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion
!
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. 
!
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse 
during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case two highly effective methods of contraception should be utilized during the 
treatment period and for at least 90 days after the last dose of study treatment
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Appendix II: Signature Pages and Responsible Persons for the Study
Document No. 
 
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T e p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
T e p oti ni b H e p ati c I m p ai r m e nt T ri al 
M S 2 0 0 0 9 5- 0 0 2 8 
Si g n at u r e P a g e - P r ot o c ol L e a d 
St u d y Title: 
O p e n- L a b el , P ar all el- Gr o u p 
P h as e 
St u d y 
t o 
I n v esti g at e t h e Eff e ct of V ari o us D e gr e es of H e p ati c 
I m p air m e nt o n t h e P h ar m a c o ki n eti cs , S af et y a n d 
T ol er a bilit y of t h e c- M et Ki n as e I n hi bit or T e p oti ni b 
I N D N u m b e r: 
1 0 6 1 0 3 
Cli ni c al 
St u d y 
P r ot o c ol  D at e 
I 2 4 A pril 2 0 1 8 I V ersi o n 2. 0 
V e rsi o n: 
P r ot o c ol L e a d: 
I a p pr o v e t h e d esi g n of t h e cli ni c al st u d y: 
Si g n at ur e 
D at e of Si g n at ur e 
N a m e , a c a d e mi c d e gr e e: 
 
F u n cti o n I Titl e: 
 
I nstit uti o n: 
M er c k K G a A 
A d dr ess: 
Fr a n kf urt er Str ass e 2 5 0 , 6 4 2 9 3 D ar mst a dt , G er m a n y 
T el e p h o n e n u m b er : 
 
F a x n u m b er: 
 
E- m ail a d dr ess: 
 
D o c u m e nt N o. 0 9 0 0 b a be 8 0 f3 7 4 5 2 vl. O 
O bject N o. 0 9 0 0 ba b e 8 0f 6 5 5e 0 
C O N FI D E N TI A L 
I  N F  O  R M A
TI O N 
6 4 / 7 5 
PI
PI
PI
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T e p oti ni b ( M S C 2l 5 6 1 1 9 J) 
T e p oti ni b H e p ati c I m p ai r m e nt T ri al 
M S 2 0 0 0 9 5- 0 0 2 8 
Si g n at u r e P a g e- Pri nci p al I n v esti g at o rs 
St u d y Titl e 
O p e n- L a b el, 
P ar all el- Gr o u p 
P h as e 
St u d y 
t o 
I n v esti g at e t he Eff e ct of V ari o us D e gr e es of He patic 
I m p air m e nt o n t h e P h ar m a c o ki n eti cs, S af et y a n d 
T ol er a bilit y of t he c- M et Ki n as e I n hi bit or T e p oti ni b 
I N D N u m b e r 
Cli ni c al St u d y P r ot o c ol D at e I 
V e rsi o n 
C e nt e r N u m b e r 
P ri n ci p al I n v esti g at o r 
1 0 6 1 0 3 
2 4 A pril 2 0 1 8 I V ersi o n 2. 0 
I, t h e u n d ersi g n e d, a m r es p o nsi bl e f or t he c o n d u ct of t he st u d y at t his st u d y c e nt er a n d affir m t h at 
I u n d erst a n d a n d will c o n d u ct t he st u d y a c c or di n g t o t h e cli ni c al st u d y pr ot o c ol, a n y a p pr o ve d 
pr ot o c ol a m e n d m e nts, I nt er n ati o n al C o u n cil f or H ar m o ni z ati o n G o o d Cli ni c al Pr a cti c e ( T o pic E 6) 
a n d all a p pli c a bl e H e alt h A ut h orit y r e q uir e m e nts a n d n ati o n al la ws. 
I als o affir m t h at I u n d erst a n d t h at H e alt h A ut h oriti es m a y r e q uir e t he S p o ns ors of cli ni c al st u di es 
t o o bt ai n a n d s u p pl y details a b o ut o w n ers hi p i nt er ests i n t h e S p o ns or or I n v esti g ati o n al Me dici nal 
Pr o d u ct a n d a n y ot h er fi n a n ci al ti es wit h t he S p o ns or. T h e S p o ns or will use a n y s u c h i nf or mati o n 
s ol el y f or t h e p ur p os e of c o m pl yi n g wit h t h e r e g ul at or y r e q uir e m e nts. I t h er ef or e a gr e e t o s u p pl y 
t h e S p o ns or wit h a n y n e c ess ar y i nf or m ati o n r e g ar di n g o w n ers hi p i nt er est a n d fi na ncial ti es 
i n cl u di n g t h os e of m y s p o use a n d d e p e n d e nt c hil dr e n, a n d t o pr o vi d e u p d at es as n e c ess ar y t o m e et 
H e alt h A ut h orit y r e q uir e m e nts. 
 
Si g n at ur e 
N a m e, a c a d e mi c de gree: 
F u n cti o n I Titl e: 
I nstit uti o n: 
A d dr ess: 
T el e p h o n e n u m b er: 
F a x n u m b er: 
E- m ail a d dr ess: 
 
Pri n ci p al I n v esti g at or 
D at e of Si g n at ur e 
Orl a n d o Cli ni c al R es e ar c h C e nt er 
5 0 5 5 S. Or a n g e A v e 
Orl a n d o, F L 3 2 8 0 9, U S A 
 
 
D o c u m e nt N o. 0 9 0 0 b a b e 8 0f 3 7 4 5 2 v 1. 0 
O bj e ct N o. 0 9 0 0 b a b e 8 0f 6 5 5 e 0 
C O N FI D E N TI A L 
I N F O R M A TI O N 
6 5 1 7 5 
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T c p oti ni h ( M S C 2 1 5 6 1 1 9. 1) 
T c p oti ni b H e p ati c I m p air m e nt Tri al 
M S 2 0 0 0 9 5- 0 0 2 8 
Si g n at ur e P a g e- Pri n ci p al I n v esti g at ors 
St u d y Titl e 
I N D N u m b er 
Cli ni c al St u d y Pr ot o c ol D at e I 
V ersi o n 
C e nt er N u m b er 
Pri n ci p al I n v esti g at or 
O p e n- L a b el. 
P ar all el- G. u u p 
P h as e 
St u d y 
t o 
I n v esti g at e t h e Eff e ct of V ari o us D e gr e es of H e p ati c 
I m p air m e nt o n t he P h ar m a c o ki n eti cs, S al' et y a n d 
T ol er a bilit y of t h e c- M et Ki n as e I n hi bit or T e p oti ni b 
1 0 6 1 0 3 
2 4 A pril 2 0 1 8 / V ersi o n 2. 0 
I, t h e u n d ersi g n e d, a m r es p o nsi bl e t or t h e c o n d u ct of t h e st u d y at t his st u d y c e nt er a n d affir m t h at 
I u n d erst a n d a n d will c o n d u ct t h e st u d y a c c or di n g t o t h e cli ni c al st u d y pr ot o c ol. a n y a p pr o v e d 
pr ot o c ol a m e n d m e nts, I nt er n ati o n al C o u n cil t or H ar m o ni z ati o n G o o d Cli ni c al Pr a cti c e ( T o pi c E 6) 
all a p pli c a bl e H e alt h A ut h orit y r e q uir e m e nts a n d n ati o n al la ws. 
, .. 
I als o affir m t h at I u n d erst a n d t h at H e alt h A ut h oriti es ma y r e q uir e t he S p o ns ors of cli ni c al st u di es 
t o o bt ai n a n d s u p pl y d et ails a b o ut o w n ers hi p i nt er ests i n t h e S p o ns or or I n v esti g ati o n al M e di ci n al 
Pr o d u ct a n d a n y ot h er fi na ncial ti es wit h t h e S p o ns or. T h e S p o ns or will us e a n y s u c h i nf or m ati o n 
s ol el y f or t he p ur p os e of c o m pl yi n g wit h t h e r e g ul at or y r e q uir e m e nts. I t h er ef or e a gr e e t o s u p pl y 
t he S p o ns or wit h a n y n e c ess aiJ i nf or m ati o n r e g ar di n g o w n ers hi p i nt er est a n d fi n a n ci al ti es 
i n cl u di n g t h os e of m y s p o us e a n d d e p e n d e nt c hil dr e n. a n d t o pr o vi d e u p d at es as n e c ess ar y t o m e et 
Si g n at ur e 
D at e of Si g n at ur e 
N a m e. a c a d e mi c d e gr e e: 
 
F u n cti o n I Titl e: 
Pri n ci p al I n v esti g at or 
I nstit uti o n: 
Q P S M R A. L L C 
A d dr ess: 
6 2 8 0 S u ns et Dri v e, S uit e 6 0 0 
Mi a mi. F L., 3 3 1 4 3. U S A 
T el e p h o n e n u m b er: 
 
F a x n u m b er: 
 
E- mail a d dr ess: 
 
O oc u mc nl N o. 0 9 0 0 ba b d! O G 7 4 5 2 vi. O 
O hjccl N o. 0 9 0 0 ha bcl!fllr. 5 5cll 
C O NI · I D L N I 1/\ L 
I Nf O R M A TI O N 
..... 
PI
PI
PI
PI
PI
PI


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Te p oti ni b  He p atic I m p air me nt Tri al
M S 2 0 0 0 9 5- 0 0 2 8
C O N F I D E N T I A L
I N F O R M A T I O N
6 7/ 7 5
S p o ns or Res p o nsi ble Pers o ns n ot N a me d o n t he C o ver P a ge
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n: 
E M D Ser o n o, I nc.
A d dress: 
4 5 A Mi d dlese x T ur n pi ke, Billerica, M A 0 1 8 2 1, U S A
Tele p h o ne n u m ber:
Fa x n u m ber: 
-
E- mail a d dress:
Na me, aca de mic de gree:
, 
F u ncti o n / Title:
I nstit uti o n:
Merc k K Ga A
A d dress:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
Fa x n u m ber:
E- mail a d dress:
Na me, aca de mic de gree:
F u ncti o n / Title:
I nstit uti o n:
Merc k K Ga A
A d dress:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
Fa x n u m ber:
-
E- mail a d dress:
D o c u me nt N o. 
 
O bject N o. 
 
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Appendix III:Protocol Amendments and List of Changes
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or Country
Included in the 
current document
(Y/N)
1
N
24 April 2018
Global
Y
Document No. 
 
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Amendment #1
Effective date: 24 April 2018, applicable globally.
Rationale 
Change in clinical sites for the study and few administrative changes.
Major Scientific Changes
None.
Administrative and Editorial Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and amended 
text are shown in bold. If the original clinical trial protocol text was already bold, changes are 
shown in bold and underlined, deletions are marked using strike through.
Document No. 
 
Object No. 
 
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Te p oti ni b  He p atic I m p air me nt Tri al
M S 2 0 0 0 9 5- 0 0 2 8
C O N F I D E N T I A L
I N F O R M A T I O N
7 0/ 7 5
C o m p aris o n wit h Cli nic al Tri al Pr ot oc ol Versi o n 1. 0, 1 5  M arc h 2 0 1 7
C h a n g e 
S e cti o n 
P a g e 
Pr e vi o u s W or di n g
N e w W or di n g
C h a n g e i n 
cli ni c al sit e s
a n d S p o n s or 
M e di c al 
R e s p o n si bl e.
Titl e p a g e, 
s y n o p si s, 
S e cti o n 2,
A p p e n di x II
1, 1 8, 
6 4, 6 5
D a Vit a Cli ni c al R e s e ar c h –
Mi n n e a p oli s
8 2 5 S o ut h 8t h Str e et, S uit e 3 0 0
Mi n n e a p oli s, M N 5 5 4 0 4, U S A
P h o n e: 
E m ail: 
D a Vit a Cli ni c al R e s e ar c h –
D e n v er
St. A nt h o n y' s M e di c al Pl a z a 1
1 1 7 5 0 W e st 2 n d Pl a c e, S uit e 
3 0 0
L a k e w o o d, C O 8 0 2 2 8, U S A
P h o n e: 
E m ail:
M e di c al R e s p o n si bl e:
M er c k K G a A, Fr a n kf urt er 
Str a s s e 2 5 0, 6 4 2 9 3 D ar m st a dt, 
G er m a n y
P h o n e: 
M o bil e: 
E m ail: 
D a Vit a Cli ni c al R e s e ar c h –  Mi n n e a p oli s
8 2 5 S o ut h 8t h Str e et, S uit e 3 0 0
Mi n n e a p oli s, M N 5 5 4 0 4, U S A
P h o n e: 
E m ail: 
D a Vit a Cli ni c al R e s e ar c h –  D e n v er
St. A nt h o n y' s M e di c al Pl a z a 1
1 1 7 5 0 W e st 2 n d Pl a c e, S uit e 3 0 0
L a k e w o o d, C O 8 0 2 2 8, U S A
P h o n e: 
E m ail:
Orl a n d o Cli ni c al R e s e ar c h C e nt er
5 0 5 5 S. Or a n g e A v e
Orl a n d o, F L 3 2 8 0 9, U S A
P h o n e: 
 
E m ail: 
 
Q P S M R A, L L C
6 2 8 0 S u n s et Dri v e, S uit e 6 0 0
Mi a mi, F L., 3 3 1 4 3, U S A
P h o n e:
E m ail:
M e di c al R e s p o n si bl e:
 
 
M er c k K G a A, Fr a n kf urt er Str a s s e 2 5 0, 
6 4 2 9 3 D ar m st a dt, G er m a n y
P h o n e: 
 
M o bil e: 
 
E m ail: 
D o c u me nt N o. 
 
O bject N o. 
 
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Change
Section
Page
Previous Wording
New Wording
Matching 
criteria was 
changed so 
that matches 
can be 
identified 
before the 
last moderate 
hepatic 
impairment 
subject is 
identified.
Synopsis
11
Part 1 will include subjects with 
hepatic impairment (Child-Pugh 
class A [6 subjects] and Child-
Pugh class B [6 subjects]) and a 
control group (6 healthy 
subjects matched to 6 subjects 
with Child-Pugh class B). All 
subjects will receive a single 
dose of 500 mg tepotinib.
Part 1 will include subjects with hepatic 
impairment (Child-Pugh class A [6 
subjects] and Child-Pugh class B [6 
subjects]) and a control group (6 
healthy subjects matched 1:1 to 6 
subjects with Child-Pugh class B with 
regard to age ± 10 years, weight 
± 10 kg, and same gender). All 
subjects will receive a single dose of 
500 mg tepotinib.
Subject visits 
were clarified.
Table 1
15
-
Visit number was added.
Schedule of 
assessments 
clarified
Table 1
16
“x” was marked for "subject 
confinement" at EOS for healthy 
subjects
“x” marked for "subject confinement" at 
EOS for healthy subjects was
removed.
Row for Visit number was added.
Day 15 visit 
column was 
renamed.
Table 1 Day 15 
visit column
16
End of Study for Healthy 
Subjects
End of Study for Healthy Subjects /
Treatment visit for Hepatic Impaired 
Subjects
Drug 
screening 
instructions 
were clarified.
Table 1, 
footnote j
16
For healthy subjects, a positive 
cannabinoid (THC) result on 
drugs of abuse screening may 
be repeated and if negative on 
repeat, the subject will be 
allowed to participate in the 
study.  
For healthy all subjects, a positive
negative cannabinoid (THC) result on 
drugs of abuse screening may be 
repeated and if negative on repeat, the 
subject will be allowed is required to 
participate in the study. If the result is 
positive, the Principal Investigator 
may request to repeat the test. 
New footnote 
added to 
clarify TFF 
sampling in 
Schedule of 
assessments 
and following 
footnotes 
were 
renumbered.
Table 1, 
footnote f
17
The Tepotinib Free Fraction (TFF) 
sample will not be drawn separately; 
TFF will be analyzed from the PK 
back up sample.
CRO name 
was removed
2 Sponsor, 
Investigators 
and Study 
Administrative 
Structure
18
The Sponsor will partner with 
QuintilesIMS, a contract 
research organization (CRO), to 
conduct the clinical part of the 
study including study set-up, 
coordination, monitoring, data 
capture, data management, 
statistical analysis, and CSR 
preparation.
The Sponsor will partner with 
QuintilesIMS, a contract research 
organization (CRO), to conduct the 
clinical part of the study including study 
set-up, coordination, monitoring, data 
capture, data management, statistical 
analysis, and CSR preparation.
"LabCorp" 
and “Nuvisan” 
names were
removed 
2 Sponsor, 
Investigators 
and Study 
Administrative 
Structure
18
LabCorp will serve as the 
central laboratory for clinical 
laboratory analysis. Nuvisan will 
be responsible for analysis of 
the pharmacokinetic (PK) 
samples.
LabCorp will serve as the A central 
laboratory will be used for clinical 
laboratory analysis. A testing 
laboratory Nuvisan will be responsible 
for analysis of the pharmacokinetic (PK) 
samples.
Document No. 
 
Object No. 
 
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Change
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Page
Previous Wording
New Wording
Text was 
made more 
generic.
2 Sponsor, 
Investigators 
and Study 
Administrative 
Structure
18
The Sponsor’s Clinical Trial 
Supplies department will supply 
the investigational medicinal 
product (IMP) to the study 
centers.
The Sponsor’s Clinical Trial Supplies 
department will supply The Sponsor 
will arrange delivery of the 
investigational medicinal product (IMP) 
to the study centers.
Matching 
criteria was 
changed so 
that matches 
can be 
identified 
before the 
last moderate 
hepatic 
impairment 
subject is 
identified.
5.1 Overall 
Study Design 
and Plan
23
Part 1 will include subjects with 
hepatic impairment (Child-Pugh 
class A [6 subjects] and Child 
Pugh class B [6 subjects]) and a 
control group (6 healthy 
subjects matched to 6 subjects
with Child-Pugh class B).
Part 1 will include subjects with hepatic 
impairment (Child-Pugh class A [6 
subjects] and Child Pugh class B [6 
subjects]) and a control group (6 
healthy subjects matched 1:1 to 6 
subjects with Child-Pugh class B with 
regard to mean age ± 10 years, mean 
weight ± 10 kg, and same gender).
Figure 1 
Design 
Diagram was 
modified
Figure 1 Design 
Diagram
24
‘One Protocol – One Report’ box was 
deleted.
Matching 
criteria was 
changed so 
that matches 
can be 
identified 
before the 
last moderate 
hepatic 
impairment 
subject is 
identified.
5.2 Discussion 
of Study Design
25
The control group will consist of 
6 subjects with normal hepatic 
function, matched to the 
subjects with moderate (Child-
Pugh class B) impaired hepatic 
function with regard to mean 
age ± 10 years, mean weight ± 
10 kg, and same gender.
The control group will consist of 6 
healthy subjects with normal hepatic 
function, matched 1:1 to the subjects 
with moderate (Child-Pugh class B) 
impaired hepatic function with regard to 
mean age ± 10 years, mean weight ± 
10 kg, and same gender.
Text was 
made more 
generic for 
the 
bioanalytical 
assay.
5.2.3 Rationale 
for Endpoints
28
An enantiomer selective 
bioanalytical assay is available, 
which analyzes tepotinib and 
the enantiomers in 1 run.
An enantiomer selective A bioanalytical 
assay is available, which analyzes 
tepotinib and the enantiomers in 1 run.
Drug 
screening 
instructions
were clarified.
5.3.1 Inclusion 
Criterion 6
30
For healthy subjects, a positive 
cannabinoid (THC) result on 
drugs of abuse screening may 
be repeated and if negative on 
repeat, the subject will be 
allowed to participate in the 
study. For subjects with hepatic 
impairment, a positive 
cannabinoid (THC) result on 
drugs of abuse screening will 
not be exclusionary (at 
Screening or Day -1) if the 
subject uses cannabinoids on 
medical recommendation.
For healthy all subjects, a positive
negative cannabinoid (THC) result on 
drugs of abuse screening may be 
repeated and if negative on repeat, the 
subject will be allowed is required to 
participate in the study. If the result is 
positive, the Principal Investigator 
may request to repeat the test. For 
subjects with hepatic impairment, a 
positive cannabinoid (THC) result on 
drugs of abuse screening will not be 
exclusionary (at Screening or Day -1) if 
the subject uses cannabinoids on 
medical recommendation. In subjects 
with hepatic impairment, positive 
test for drugs used on medical 
recommendation will be not 
exclusionary.
Document No. 
 
Object No. 
 
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Page
Previous Wording
New Wording
Exclusion 
criterion 25 
was moved to 
“all subjects” 
to ensure that 
liver impaired 
participants 
have 
sufficient 
renal function 
5.3.2 Exclusion 
Criterion 13
30
Renal dysfunction (defined as 
creatinine clearance < 60 mL/minute, 
calculated by use of the Cockcroft-
Gault formula).
Text was 
amended to 
make the
study less 
restrictive for 
potential 
subjects.
5.3.2 Exclusion 
Criteria
31
Subject has taken an 
investigative medication within 
30 days prior to Screening.
Subject has taken an investigative 
medication within 30 days prior to 
Screening administration of IMP.
It was 
documented 
that used and 
unused IMP 
kits will be 
destroyed at 
the trial site.
6.8 
Investigational 
Medicinal 
Product 
Accountability
38
-
At the conclusion or termination of 
this trial, all used and unused IMP 
kits will be destroyed at the trial site 
according to local regulations and 
institutional guidelines. All used and 
unused medications will be carefully 
recorded and documented before 
destruction.
Blinding 
procedure 
was clarified 
for 
bioanalytical 
assay.
6.10 Blinding
37
Not Applicable.
Blinding is not applicable. (Note: the 
bioanalytical assay will be performed 
without knowledge of hepatic 
function group information. Access 
to hepatic function group 
information will be restricted and 
defined in a Data Access Plan).Not 
applicable.
Unscheduled 
safety 
laboratory 
retest at the 
discretion of 
the 
investigator 
during 
screening 
was added to 
the protocol
7.4.3 Clinical 
Laboratory 
Assessments
46
-
Unscheduled retest of laboratory 
safety tests at the discretion of the 
investigator are permitted during 
screening and throughout the study.
Document No. 
 
Object No. 
 
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Change
Section
Page
Previous Wording
New Wording
Drug 
screening 
instructions 
were clarified.
7.4.3 Clinical 
Laboratory 
Assessments, 
Table 4, 
footnote c
47
For healthy subjects, a positive 
cannabinoid (THC) result on 
drugs of abuse screening may 
be repeated and if negative on 
repeat, the subject will be 
allowed to participate in the 
study. For subjects with hepatic 
impairment, a positive 
cannabinoid (THC) result on 
drugs of abuse screening will 
not be exclusionary (at 
Screening or Day -1) if the 
subject uses cannabinoids on 
medical recommendation.
For healthy all subjects, a positive
negative cannabinoid (THC) result on 
drugs of abuse screening may be 
repeated and if negative on repeat, the 
subject will be allowed is required to 
participate in the study. If the result is 
positive, the Principal Investigator 
may request to repeat the test. For 
subjects with hepatic impairment, a 
positive cannabinoid (THC) result on 
drugs of abuse screening will not be 
exclusionary (at Screening or Day -1) if 
the hepatic-impaired subject uses 
cannabinoids on medical 
recommendation. In subjects with 
hepatic impairment, positive test for 
drugs used on medical 
recommendation will be not 
exclusionary.
Text was 
made more 
generic for 
the 
bioanalytical 
assay.
7.5.1 Body 
Fluids
49
All sample analyses will be 
performed using a validated 
enantioselective ultra-
performance liquid 
chromatography coupled to 
tandem high-definition mass 
spectrometry method measuring 
parent drug and metabolites in 1 
run.
All sample analyses will be performed 
using a validated enantioselective ultra-
performance liquid chromatography 
coupled to tandem high-definition mass 
spectrometry method measuring parent 
drug and metabolites in 1 run.
ODWG 
classification 
was added to 
the analysis.
8.5.3 Analysis of 
Secondary 
Endpoints
53
In a further analysis, the 
subjects with liver impairment 
will be evaluated according to 
the Albumin Bilirubin (ALBI) 
score (12).
In a further analysis, the subjects with 
liver impairment will be evaluated 
according to the Albumin Bilirubin 
(ALBI) score and the Organ 
Dysfunction Working Group (ODWG) 
classification (12,13).
eCRF entry 
time was
aligned within 
site CTA 
language
10.1 Case 
Report Form 
Handling
55
The main purpose of the eCRF 
is to obtain data required by the 
clinical study protocol in a 
complete, accurate, legible and 
timely.
The main purpose of the eCRF is to 
obtain data required by the clinical 
study protocol in a complete, accurate, 
legible and timely manner.
Text 
regarding 
withdrawal 
from the 
study or IMP 
was clarified
10.2 Source 
Data and 
Subject Files
57
Date that the subject left the 
study including any reason for 
early withdrawal from the study 
or IMP (if applicable).
•
Date that the subject left the 
study including any reason for early 
study discontinuation or withdrawal 
from IMPearly withdrawal from the 
study or IMP (if applicable).
Text was 
made more 
generic.
10.2 Source 
Data and 
Subject Files
57
The Monitor will be trained in 
INFORM (electronic database) 
and will have read-only access 
to the study data in INFORM for 
source data verification. Data 
reviewed can be signed off and 
queries issued directly in 
INFORM.
The Monitor will be trained in INFORM 
(electronic database) to use the 
electronic database / eCRF and will 
have read-only access to the study data 
in INFORM the eCRF for source data 
verification. Data reviewed can be 
signed off and queries issued directly in 
INFORM the eCRF.
Document No. 
 
Object No. 
 
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Change
Section
Page
Previous Wording
New Wording
Reference 
was added for 
ODWG 
classification
11 References 
Cited in the Text
59
-
LoRusso PM, Venkatakrishnan K, 
Ramanathan RK, et al. 
Pharmacokinetics and safety of 
bortezomib in patients with 
advanced malignancies and varying 
degrees of liver dysfunction: Phase 
1 NCI Organ Dysfunction Working 
Group study NCI-6432. Clin Cancer 
Res. 2012; 18(10), doi:10.1158/1078-
0432.CCR-11-2873.
Reference 
was added for 
Child-Pugh 
Criteria
Table 3 Child-
Pugh Criteria, 
11 References 
Cited in the Text
26, 58, 
59
-
Pugh RN, Murray-Lyon IM, Dawson 
JL, et. al. Transection of the 
oesophagus for bleeding 
oesophageal varices. Br J Surg. 
1973; 60:646. PMID: 4541913  
Child CG, Turcotte JG. The Liver and 
Portal Hypertension. Philadelphia, 
WB Saunders Co. 1964. NLMN: 
46218  
Trey C, Burns DG, Saunders SJ. 
Treatment of hepatic coma by 
exchange blood transfusion. NEJM. 
1966; 274:473. PMID: 5904286
Document No. 
 
Object No. 
 
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Tepotinib (MSC2156119J)
Tepotinib Hepatic Impairment Trial
MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
3/23
1
Table of Contents
Integrated Analysis Plan ......................................................................................................1
Signature Page
..............................................................................................................2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................5
3
Modification History ............................................................................8
4
Purpose of the Integrated Analysis Plan...............................................8
5
Objectives and Endpoints .....................................................................8
6
Overview of Planned Analyses.............................................................9
6.1
Interim Analysis....................................................................................9
6.2
Final Analysis .......................................................................................9
7
Changes to the Planned Analyses in the Clinical Study Protocol ........9
8
Protocol Deviations and Analysis Sets.................................................9
8.1
Definition of Protocol Deviations.........................................................9
8.2
Definition of Analysis Sets and Subgroups........................................10
9
General Specifications for Data Analyses ..........................................11
10
Study Subjects ....................................................................................12
10.1
Disposition of Subjects and Discontinuations....................................12
10.2
Protocol Deviations ............................................................................13
10.2.1
Important Protocol Deviations............................................................13
10.2.2
Reasons Leading to the Exclusion from an Analysis Set ...................13
11
Demographics and Other Baseline Characteristics.............................13
11.1
Demographics.....................................................................................13
11.2
Medical History ..................................................................................13
11.3
Other Baseline Characteristics............................................................14
12
Previous or Concomitant Medications/Procedures.............................14
13
Treatment Compliance and Exposure.................................................14
14
Efficacy Analyses ...............................................................................14
15
Safety Analyses ..................................................................................14
15.1
Adverse Events...................................................................................14
15.1.1
All Adverse Events.............................................................................15
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C O N F I D E N T I A L
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15.1.2
Adverse Events Leading to Study Discontinuation............................15
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events...................................................................................16
15.2.1
Deaths .................................................................................................16
15.2.2
Serious Adverse Events ......................................................................16
15.3
Clinical Laboratory Evaluation...........................................................16
15.4
Vital Signs ..........................................................................................16
15.5
Other Safety or Tolerability Evaluations............................................16
16
Analyses of Other Endpoints..............................................................17
16.1
Pharmacokinetics................................................................................17
16.1.1
Primary Endpoints ..............................................................................17
16.1.2
Secondary Endpoints ..........................................................................18
16.1.3
Concentration Data .............................................................................19
16.1.4
Estimation of Pharmacokinetic Parameters........................................20
16.2
Pharmacodynamics.............................................................................23
17
References...........................................................................................23
18
Appendices .........................................................................................23
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MS200095-0028
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2
List of Abbreviations and Definition of Terms
ADAM
Analysis Data Model
AE
Adverse event
ALBI
Albumin-Bilirubin
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-!
The AUC from time zero (dosing time) extrapolated to infinity
AUC0-!∀u
The AUC for unbound drug from time zero (dosing time) extrapolated to 
infinity
AUC0-t
The AUC from time zero (dosing time) to the last sampling time (tlast) at 
which the concentration is at or above the lower limit of quantification
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of 
AUC0-!
BLQ
Below the lower limit of quantification
BMI
Body mass index
CI
Confidence interval
CL/f
The apparent total body clearance of drug following extravascular 
administration.
CL/f,u
The apparent total body clearance of unbound drug following 
extravascular administration.
Cmax
Maximum observed plasma concentration
Cmax,u
Maximum observed unbound plasma concentration
CRF
Case report form
CSP
Clinical study protocol
CSR
Clinical study report
CV%
Coefficient of variation 
ECG
Electrocardiogram
FSH
Follicle-stimulating hormone
fu
Average free fraction of analyte, ie unbound
GCP
Good Clinical Practice
GeoCV%
Geometric coefficient of variation
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C O N F I D E N T I A L
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GeoMean
Geometric mean
IAP
Integrated analysis plan 
ICH
International Council for Harmonisation
IMP
Investigational medicinal product
LLOQ
Lower limit of quantification
Max
Maximum
Mean
Arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MRAUC0-∞
Metabolite to parent drug ratio for AUC0-∞
MRCmax
Metabolite to parent drug ratio for Cmax
MW
Molecular weight
N, n
Number of subjects or number of non-missing observations
NCI
National Cancer Institute
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
ODWG
Organ Dysfunction Working Group
PK
Pharmacokinetic/Pharmacokinetics
PT
Preferred Term
Q1
25th percentile
Q3
75th percentile
SAE
Serious adverse event
SD
Standard deviation
SDTM
Study Data Tabulation Model
SEM
Standard error of the mean
SI
Système International
SOC
System Organ Class
t1/2
Apparent terminal half-life
TEAE
Treatment-emergent adverse event
tlast
The last sampling time at which the concentration is at or above the 
lower limit of quantification
tmax
The time to reach the maximum observed concentration 
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MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
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ULN
Upper limit of normal
Vz/F
Apparent volume of distribution during the terminal phase following 
extravascular administration
WHO DDE
Enhanced World Health Organization Drug dictionary 
λz
Terminal elimination rate constant
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C O N F I D E N T I A L
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Objective
Endpoint
IAP 
Section
To assess safety and tolerability 
of tepotinib in subjects with 
various degrees of impaired 
hepatic function (in comparison 
to healthy subjects).
#
Occurrence of treatment-emergent adverse 
events (TEAEs), changes from baseline in 
laboratory safety tests, 12-lead 
electrocardiograms (ECG) morphology and time 
intervals (PR, QRS, RR, QT, and QTcF), and vital 
signs
15
The analyses of the endpoints will be described in the respective sections for PK and safety, 
regardless of whether the endpoint is a primary endpoint or not.
6
Overview of Planned Analyses
6.1
Interim Analysis
There is no formal interim analysis planned.
6.2
Final Analysis
All final, planned analyses identified in the CSP and this IAP will be performed only after the 
last subject has completed the End of Study visit with all study data in-house, all data queries 
resolved, and the database locked.
A data review meeting will be held prior to database lock. In addition, no database can be locked 
until this IAP has been approved.
7
Changes to the Planned Analyses in the Clinical Study
Protocol
There are no changes to the planned analyses.
8
Protocol Deviations and Analysis Sets
8.1
Definition of Protocol Deviations
Important protocol deviations or events are protocol deviations or events 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 important deviations or events will be identified and confirmed prior to or at the 
Data Review Meeting:
#
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 incorrect dose
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MS200095-0028
C O N F I D E N T I A L
I N F O R M A T I O N
10/23
#
Subjects that receive a prohibited concomitant medication
#
Deviation from Good Clinical Practice (GCP)
#
Other events/factors related to PK data include, but may not be limited to, the following:
o
Sample processing errors that may lead to incorrect bioanalytical results
o
Incomplete samples collected
o
Use of prohibited medication that could affect PK
o
Events that could affect PK (ie such as vomiting within 2 times the median tmax, 
after dosing), to be evaluated on a case-by-case basis.
Subset of these important protocol deviations are considered clinically important, if leading to 
the exclusion of a subject from an analysis set (see Section 8.2).
All protocol deviations are documented in Study Data Tabulation Model (SDTM) datasets
whether identified through site monitoring, medical review or programming.
8.2
Definition of Analysis Sets and Subgroups
Screening Analysis Set
The Screening Analysis Set will include all subjects who provide signed informed consent,
regardless of treatment status in the study. This analysis set will be used for subject disposition.
Safety Analysis Set
The Safety Analysis Set will include all subjects who receive the study treatment. All safety 
analyses will be based on this analysis set.
Pharmacokinetic Analysis Set
The PK Analysis Set will include all subjects who receive the study treatment and have at least 1 
postdose PK measurement without important protocol deviations/violations or events that may 
affect the PK. All PK analyses will be based on this analysis set.
The use of the analysis sets in the different analyses (no subgroup analyses are planned) is 
presented in the following table:
Analyses
Screening
Analysis Set
Safety 
Analysis Set
PK Analysis 
Set
Subject Disposition

Baseline Assessments

Previous or Concomitant 
Medications / Procedures

Treatment Compliance and 

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C O N F I D E N T I A L
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Analyses
Screening
Analysis Set
Safety 
Analysis Set
PK Analysis 
Set
Exposure
PK Analysis

Safety and Tolerability

9
General Specifications for Data Analyses
Listings
All listings will be sorted by hepatic function group (impairment and healthy control), subject,
and/or scheduled timepoint, as appropriate. Data from assessments which are only performed
before administration of the investigational medicinal product (IMP) will be sorted by subject 
and scheduled timepoint (if appropriate).
Tables
All data will be summarized by hepatic function group and/or scheduled timepoint, as 
appropriate. Repeated and unscheduled measurements included in the listings will not be used 
for statistical analyses or summaries, unless the repeated measurement was performed due to 
unreliable values/technical reasons, eg, clotted samples. 
Presentation of Continuous and Qualitative Variables for Safety 
Continuous variables will be summarized using descriptive statistics, ie, number of subjects (N), 
number of non-missing observations (n), arithmetic mean (Mean), standard deviation (SD), 
median, 25th Percentile - 75th Percentile (Q1 - Q3), minimum (Min) and maximum (Max).
Qualitative variables will be summarized by counts and percentages.
Unless otherwise stated, the calculation of proportions will be based on the number of subjects in 
the analysis set of interest. Therefore, counts of missing observations will be included in the 
denominator and presented as a separate category.
When the analysis refers only to certain visits, percentages will be based on the number of 
subjects still present in the study at that visit, unless otherwise specified.
Mean, Median, Q1, Q3, Min, and Max will have the same precision as the raw data included in 
the SDTM datasets for non-derived data. Standard deviation will be presented with one digit 
more than the mean. Derived data will be rounded to reasonable digits whereas maximal digits 
should be available in Analysis Data Model (ADaM) datasets then the similar precision 
definitions will be followed for descriptive statistics. Percentage will be reported using 1 decimal 
digit, if not otherwise specified. 
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Definition of Baseline
If not otherwise specified, “baseline” refers to the last non-missing scheduled measurement prior 
to dosing, as appropriate. It will in general correspond to Day 1 predose for laboratory
parameters, vital signs, and ECG data. However, if a subject is missing the baseline collection, 
the previous non-missing evaluation (as applicable) will become the baseline value. If no 
baseline or previous to baseline evaluations exist then the baseline value will be treated as 
missing. 
Common Calculations
For quantitative measurements:
# Change from baseline: Value at Visit X – Baseline Value
Definition of Duration
Duration will be calculated by the difference of start and stop/end date + 1 if not otherwise 
specified. 
Conversion Factors
The following conversion factors will be used to convert days into months or years: 1 month = 
30.4375 days, 1 year = 365.25 days.
Handling of Missing Data
Unless otherwise specified, missing data will not be replaced. Handling of missing data for PK 
parameter calculations are discussed under Section 16.1.
Software
Pharmacokinetic parameters will be derived using noncompartmental methods with the validated 
computer program Phoenix® WinNonlin® 6.4 or higher (Certara, L.P., Princeton, New Jersey, 
USA), and/or SAS® Windows Version 9.4 or higher (Statistical Analysis System, SAS-Institute, 
Cary, North Carolina, USA). Pharmacokinetic figures will be developed using SAS®. All 
statistical analyses will be performed using SAS®.
10
Study Subjects
The subsections in this section include specifications for reporting subject disposition and 
treatment/study discontinuations. Additionally, procedures for reporting protocol deviations are 
provided.
10.1
Disposition of Subjects and Discontinuations
A summary table describing the number and percentage of subjects (as applicable) in each of the 
following disposition categories will be produced by hepatic function group and overall:
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# Total number of subjects screened (ie, subjects who gave informed consent)
# Number of subjects treated (used as denominator for percentage calculation for the categories 
below)
# Number of subjects who completed the study
# Number of subjects who discontinued the study/treatment, with the reason of discontinuation.
Corresponding individual listings for study termination status and study entry (including 
screening failures) will be presented. Subjects discontinued the study/treatment will be listed 
with the corresponding reasons. 
Summary of the number and percentage (as applicable) of subjects included in each analysis set 
(as described in Section 8.2) will be presented. 
10.2
Protocol Deviations
10.2.1
Important Protocol Deviations
The listing of important protocol deviations will be provided.
10.2.2
Reasons Leading to the Exclusion from an Analysis Set
For subjects and/or individual concentration or parameter data excluded from the PK Analysis 
Set, the reasons for exclusion will be listed.
11
Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be presented for the Safety Analysis Set.
11.1
Demographics
Descriptive statistics will be presented for age, height, weight, and body mass index (BMI). 
Frequency counts and percentages will be presented for sex (gender), race, and ethnicity. The 
summary will be performed by hepatic function group and overall.
Subjects with hepatic impairment will be assigned to a group of mild (Child-Pugh class A) or 
moderate (Child-Pugh class B) hepatic impairment at Screening by use of the Child-Pugh 
system. A listing of points scored for observed findings based on Child-Pugh criteria will be 
presented.
11.2
Medical History
Medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), current version, and listed. Prior surgery, if any, will also be listed.
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11.3
Other Baseline Characteristics
Other baseline characteristics and assessments, including nicotine and alcohol consumption,
virus screen, alcohol breathalyzer test, cotinine test, drugs of abuse screen, pregnancy test in 
women, and follicle-stimulating hormone (FSH) in postmenopausal women, will be listed.
12
Previous or Concomitant Medications/Procedures
Medications will be presented for the Safety Analysis Set.
Previous medications are defined as any medication discontinued prior to the IMP
administration. Concomitant medications are defined as any medication taken during the course 
of the study, with a starting date greater than or equal to the IMP administration, or with a 
starting date prior to the IMP administration and ongoing at the time of the IMP administration.
The Enhanced World Health Organization Drug dictionary (WHO DDE), current version, will be 
used for coding of prior and concomitant medications.
Previous and concomitant medications, as well as concomitant procedures, if any, will be listed.
13
Treatment Compliance and Exposure
The IMP will be administered by the study center staff within the confines of the study center.
The administration of IMP, meal consumption and fasting details will be listed for the Safety 
Analysis Set.
14
Efficacy Analyses
There are no efficacy endpoints and analyses defined for this CSP.
15
Safety Analyses
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical studies such as adverse events (AEs), laboratory tests, and vital signs.
All analyses will be performed for the Safety Analysis Set.
15.1
Adverse Events
All AEs recorded during the course of the study will be coded according to the MedDRA, 
current version, and each AE will be assigned to a System Organ Class (SOC) and a Preferred
Term (PT). 
Treatment-emergent AEs are those events with onset dates occurring after the IMP 
administration on Day 1. Any AE occurring before the IMP administration on Day 1 and 
resolved before the administration will be included in the AE listings, but will not be included in 
the summary tables (unless otherwise stated). These will be referred to as “pre-treatment”.
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In case of (partly) incomplete AE-related dates, the available information will be used in a 
conservative approach to determine whether the AE is treatment-emergent.
All analyses described in this section will be based on TEAEs if not otherwise specified.
15.1.1
All Adverse Events
Treatment-emergent adverse events will be summarized by hepatic function group and overall in 
tables with:
# The number and percentage of subjects with any TEAE, any IMP related TEAE, any serious 
TEAE, any IMP related serious TEAE, any grade >=3 TEAE, any IMP related grade >=3
TEAE, any TEAE leading to death, any IMP related TEAE leading to death, any TEAE 
leading to study discontinuation
# The number and percentage of subjects with at least one TEAE by SOC and PT
# The number and percentage of subjects with at least one TEAE by SOC, PT, and worst grade
according to the National Cancer Institute – Common Terminology Criteria for Adverse 
Events (NCI-CTCAE), current version
# The number and percentage of subjects with at least one IMP related TEAE by SOC and PT
# The number and percentage of subjects with at least one TEAE by PT only, sorted in 
decreasing incidence overall
# The number and percentage of subjects with at least one non-serious TEAE by SOC and PT.
Unless otherwise stated, AEs will be displayed with SOC terms sorted alphabetically and PTs 
within each SOC term sorted in decreasing incidence overall. 
For determining incidence counts, if a subject experiences more than one occurrence of the same 
TEAE, the subject will only be counted once for that TEAE. 
If an AE is reported for a given subject more than once during treatment, the worst grade and the 
worst relationship to study treatment will be tabulated.
Adverse events related to IMP are those events with relationship missing or ‘related’.
In case a subject had events with missing and non-missing grade, the maximum of the non-
missing grade will be displayed.
15.1.2
Adverse Events Leading to Study Discontinuation
A listing of TEAEs leading to study discontinuation, if any, will be provided.
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15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.2.1
Deaths
All deaths as well as reason for death will be based on information from the “Report of Subject 
Death” case report forms (CRFs). Listing of deaths, if any, will be provided displaying date and 
cause of death (including TEAE leading to death and relatedness to trial treatment, when 
applicable), and date and time of treatment administration.
15.2.2
Serious Adverse Events
A listing of serious TEAEs, if any, will be provided.
15.3
Clinical Laboratory Evaluation
All clinical laboratory data will be stored in the database in the units in which they were reported 
with the laboratory reference ranges. Listings and summary statistics at each assessment time 
will be presented using the Système International (SI) units. Laboratory data not reported in SI 
units will be converted to SI units before processing.
Continuous clinical laboratory data (hematology and biochemistry) will be summarized by 
hepatic function group and timepoint using descriptive statistics for baseline (see definition in 
Section 9), each evaluation during the study, and change from baseline to each evaluation.
When applicable, laboratory results will be graded using the NCI-CTCAE, current version, and 
summarized by worst post-baseline toxicity grade and shift from baseline to highest grade.
Based upon laboratory normal ranges, these laboratory test results will be categorized according 
to the normal range as low (below the lower limit), normal (within the normal range), and high 
(above the upper limit). Listings of all clinical laboratory data for each subject will be provided 
with values outside the normal ranges indicated. Listings of abnormal test results (low and high) 
will be provided. 
15.4
Vital Signs
Vital signs data (including oral temperature, systolic and diastolic blood pressure, and pulse rate) 
will be summarized by hepatic function group and timepoint using descriptive statistics for 
baseline (see definition in Section 9), each evaluation during the study, and change from baseline 
to each evaluation. Listing of vital signs data will be provided.
15.5
Other Safety or Tolerability Evaluations
Safety 12-lead ECG data will be summarized by hepatic function group and time point using 
descriptive statistics for baseline (see definition in Section 9), each evaluation during the study, 
and change from baseline to each evaluation. Listings of ECG data will be provided. Overall 
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ECG assessments (normal, abnormal/not clinically significant, abnormal/clinically significant) 
will also be listed.
Clinically significant, abnormal findings from the physical examination are to be reported as 
AEs. Separate summary or listing of the physical examination will not be provided.
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
All statistical analyses and descriptive summaries of PK data will be performed on the PK 
Analysis Set. Pharmacokinetic parameters will not be summarized if more than 50% of the 
dataset are missing for a respective parameter.
16.1.1
Primary Endpoints
As the primary analysis, an analysis of variance (ANOVA) model including hepatic function 
group as a fixed effect will be applied to log-transformed tepotinib PK parameters AUC0-t, 
AUC0-∞, and Cmax of the subjects with Mild Impairment (Child-Pugh class A), Moderate 
Impairment (Child-Pugh class B) and the healthy subjects of the matched control group. Least-
squares means and corresponding 95% CIs by group, differences and corresponding 90% CIs 
between the hepatic impairment groups and control will be estimated on the log scale. Point 
estimates and CIs will be back-transformed to the original scale for presentation. 
Additionally, a generalized linear model including hepatic function group and sex (gender) as 
fixed effects, age and weight as covariates, will be applied to the same primary PK parameters. 
Boxplots will be prepared for AUC0-t, AUC0-! and Cmax of tepotinib by hepatic function group.
Primary endpoints will be descriptively summarized as described below for secondary endpoints.
In a further analysis, the subjects with liver impairment will be evaluated according to the 
Albumin-Bilirubin (ALBI) score and the Organ Dysfunction Working Group (ODWG) 
classification (1, 2). 
To categorize subjects based on the ALBI score (1), the following equation will be used: linear 
predictor = (log10(bilirubin) × 0.66) + (albumin × −0.085), where bilirubin is in μmol/L and 
albumin in g/L. Calculating the subject-level linear prediction (xb) and applying the cut points 
assigned each subject to one of three prognostic groups, named the ALBI grade, 1 to 3. The cut 
points are as follows: xb ≤ −2.60 (ALBI grade 1), more than −2.60 to ≤ −1.39 (ALBI grade 2), 
and xb more than −1.39 (ALBI grade 3). The linear prediction values will be derived for healthy 
subjects as well.
To categorize subjects based on the ODWG classification (2), the following will be followed: 
subjects will be assigned to four groups based on hepatic function, defined according to bilirubin 
and aspartate aminotransferase (AST) levels relative to the upper limit of normal (ULN) using 
the classification developed for organ dysfunction studies by the National Cancer Institute (NCI)
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ODWG. Normal function is defined as bilirubin and AST ≤ULN. Subjects with mild hepatic 
impairment have bilirubin ≤ULN and AST >ULN, or bilirubin >1.0–1.5 x ULN (with any AST). 
Moderate and severe hepatic impairments are defined as bilirubin >1.5–3 x ULN and >3 x ULN, 
respectively, with any AST.
The classifications for both ALBI and ODWG will be derived using the laboratory data obtained 
at Screening, while the same will be performed for laboratory data at Day 1 predose, for 
comparison purpose. These additional classifications will be presented in a listing.
Using the ALBI or ODWG classification, the generalized linear model including hepatic 
function group and sex (gender) as fixed effects, age and weight as covariates, will be applied to 
the same primary PK parameters. In addition, a similar model using the ALBI linear prediction 
values as a continuous variable, will also be performed.
16.1.2
Secondary Endpoints
Secondary endpoints are: Tepotinib (plasma) tmax, t1/2, CL/f, Vz/f, AUCextra%; unbound tepotinib 
parameters AUC0-∞,u, Cmax,u, and CL/f,u
Tepotinib metabolites MSC2571109 and MSC2571107 (plasma), AUC0-t, AUC0-∞, Cmax, tmax, 
t1/2, AUCextra%, MRAUC0-∞, and MRCmax.
All pharmacokinetic parameters data will be descriptively summarized using (refer to Section 9): 
n, Mean, SD, standard error of the mean (SEM), coefficient of variation (CV%), Min, Median, 
Max, Q1 and Q3 as appropriate, geometric mean (GeoMean), the geometric coefficient of 
variation (GeoCV%), and the 95% confidence interval (CI) for the GeoMean (LCI 95% GM, 
UCI 95% GM). 
Non-derived data will have the same precision as SDTM data (number of digits) for the 
following descriptive statistics: mean, median, Q1, Q3, Min, and Max. Statistics on derived data 
(i.e., SD) is to be presented with one digit more than the mean. 
PK parameter Cmax will be reported with the same precision as the source data and mean tmax (h) 
will be reported to two decimal places. All other PK parameters will be reported to 3 significant 
figures. Descriptive statistics of PK parameter data will be calculated using full precision values, 
and rounded for reporting purposes only. 
The following conventions will be applied when reporting individual values and descriptive 
statistics of PK parameter data:
Listings:
3 significant digits
Mean, Min, Median, Max, GeoMean, 95% CI, Q1 and Q3: 3 significant digits
SD, SEM:
4 significant digits
CV%, GeoCV%:
1 decimal place
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For the secondary PK parameters AUC0-t, AUC0-∞, and Cmax of the tepotinib metabolites, the 
primary ANOVA model including hepatic function group as a fixed effect as defined for the 
primary endpoints will be applied. Boxplots will also be provided as described for primary PK 
parameters included in the statistical analysis.
16.1.3
Concentration Data
A listing of PK blood sample collection times by individual, as well as derived sampling time 
and time deviations, will be provided. Actual elapsed sample collection times will be rounded to 
two decimal places with units of hours. All PK concentrations will be reported and analyzed with 
the same precision as the source data provided by the bioanalytical laboratory or clinical 
laboratory regardless of how many significant figures or decimal places the data carry. 
Pharmacokinetic parameters and actual elapsed sample collection times will be rounded for 
reporting purposes in by-subject listings. 
Plasma concentrations of tepotinib, its metabolites (MSC2571109 and MSC2571107) and the 
free-fraction of tepotinib in plasma will be listed and presented in summary tables by hepatic 
function group and/or nominal timepoint, as appropriate, showing: number of non-missing 
observations (n), Mean, SD, CV%, Min, median, and Max. Values below the lower limit of 
quantitation (LLOQ) will be identified as (BLQ), will be taken as zero for descriptive statistics. 
All data will be evaluated as observed; no imputation method for missing values will be used.
Descriptive statistics of PK concentration data will be calculated using values with the same
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting individual values and descriptive statistics of PK concentration 
data:
Listings:
3 significant digits
Mean, Min, Median, Max: 
3 significant digits
SD:
4 significant digits
CV%:
1 decimal place
Pharmacokinetic plasma concentrations which are erroneous due to a protocol deviation (as 
defined in the protocol), documented handling error or analytical error (as documented in the 
bioanalytical report) may be qualified as invalid if agreed with the Sponsor prior to performing a 
statistical analysis. In this case the rationale must be provided in the CSR. Invalid concentrations 
will be flagged within the listings. Any other PK concentrations that appear implausible to the 
Pharmacokineticist/PK Data Analyst must not be excluded from the analysis. Any implausible 
data will be documented in the CSR. 
Arithmetic mean plasma tepotinib (including free fraction tepotinib) and its metabolites 
(MSC2571109 and MSC2571107) concentration versus scheduled (nominal) time plots for all 
hepatic function groups will be provided using a linear and semi-logarithmic scale. Mean plots 
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will include SD bars (±SD) when plotted on a linear scale. The mean plasma concentration-time 
profiles will be plotted for subjects included in the PK Analysis Set. 
Individual plasma tepotinib and its metabolites (MSC2571109 and MSC2571107) concentration 
versus actual time plots will be provided using a linear and semi-logarithmic scale. Plots of 
individual profiles of plasma tepotinib and its metabolites (MSC2571109 and MSC2571107) 
concentration versus actual time for all subjects within each hepatic function group, presented on 
a single plot (ie, spaghetti plots), will be provided by hepatic function group, separately, using a 
linear and semi-logarithmic scale. 
16.1.4
Estimation of Pharmacokinetic Parameters
For PK parameters, the standard rounding procedure will be as follows: in export datasets, as 
well as in the SDTM PP domain, PK parameters will be provided with full precision, and will 
not be rounded. 
For the PK analysis, predose and postdose sample concentrations that are BLQ will be assigned a 
numerical value of zero for the calculation of PK parameters.
Predose samples that occur before the first drug administration will be assigned a time of 0 hour, 
as if the sample had been taken simultaneously with the IMP administration.
Pharmacokinetic parameters will be calculated using standard non-compartmental methods. 
Pharmacokinetic parameters will be evaluated and listed for all subjects who provide sufficient 
concentration-time data. At least 3 quantifiable, postdose concentration points will be required in 
the PK profile to obtain any PK parameter estimate.
Pharmacokinetic parameters will be calculated using the actual elapsed time since dosing, given 
with a precision of 14 significant digits or the SAS format Best12. 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 other than for a missing predose concentration 
as stated above.
For each subject in the PK Analysis Set, the following PK parameters will be calculated for 
tepotinib and tepotinib metabolites MSC2571109 and MSC2571107, where appropriate:
Symbol
Definition
AUC0-t
The AUC from time zero (= dosing time) to the last sampling time (tlast) at 
which the concentration is at or above the LLOQ. Calculated using the mixed 
log linear trapezoidal rule (linear up, log down). Units: ng x h/mL.
AUC0-! 
The AUC from time zero (dosing time) extrapolated to infinity, based on the 
predicted value for the concentration at tlast, as estimated using the linear 
regression from λz determination. AUC0-∞_pred=AUC0-t+Clastpred/λz. 
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Symbol
Definition
Units: ng x h/mL.
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of 
AUC0→!. AUCextra% = (extrapolated area/AUC0→∞) *100. The predicted 
AUC0→∞ should be used. Units: %.
CL/f
The apparent total body clearance of drug following extravascular 
administration. (tepotinib only)
CL/f = Dosep.o./AUC0-∞_pred. Units: L/h.
Cmax
Maximum observed concentration, taken directly from the observed 
concentration-time profile. Units: ng/mL.
tmax
The time to reach the maximum observed concentration collected during a 
dosing interval (unless otherwise defined, the first occurrence in case of 
multiple/identical Cmax values will be used). Units: h.
t1/2
Apparent terminal half-life. t1/2 = ln (2)/λz. Units: h.
Vz/f
The apparent volume of distribution during the terminal phase following 
extravascular administration Vz/F = Dose/ (AUC0-∞_pred x λz) following single 
dose. (tepotinib only). Units: L.
∃z
Terminal elimination rate constant (lambda_z). Determined from the terminal 
slope of the log-transformed concentration curve using linear regression on 
terminal data points of the curve. Units: h-1.
MRAUC0-∞ 
Metabolite (MSC2571109 or MSC2571107) AUC0-∞_pred
to tepotinib 
AUC0-∞_pred ratio.
MRCmax 
Metabolite (MSC2571109 or MSC2571107) Cmax to tepotinib Cmax ratio.
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Symbol
Definition
fu
Fraction of analyte unbound. Free fraction will be calculated as the ratio of free 
concentration divided by total concentration at a given sampling point. Both 
unbound (ie, plasma ultrafiltrate) concentrations and unbound fractions will be 
listed for each scheduled sample collection. The average fu will represent the 
average of all available fractions (assuming concentration independent protein 
binding). If only a single unbound concentration is available, the derived 
fraction of the single timepoint for the respective analyte will be used for all 
calculations. If the unbound concentration is below the LLOQ at a given 
timepoint, that timepoint will be omitted from the calculation of the average 
and only the available timepoints will be used. If the unbound concentration 
falls below LLOQ in all 4 samples, fu and unbound PK parameters will not be 
presented. (tepotinib only)
Cmax,u
Maximum unbound plasma drug concentration, calculated as Cmax*fu (tepotinib 
only)
AUC0-!,u
Area under the concentration-time curve for unbound drug from time zero to 
infinity, calculated as AUC0-!%pred *fu (or AUC0-t*fu if AUC0-!%pred is not 
adequately estimable (tepotinib only);
CL/f,u
Unbound apparent oral clearance, calculated as CL/f,u = Dosep.o./AUC0-∞_pred/fu
(tepotinib only). Units: L/h
Note: Predicted estimates for AUC0-!∀ and all parameters derived (ie, AUCextrap%, AUC0-!,u CL/f, CL/f,u, and Vz/F) 
will be presented
If fu appears to be concentration dependent or time dependent, an alternate approach for 
calculation of unbound PK parameters may be employed and will be discussed in the CSR. 
The following PK parameters will be calculated for diagnostic purposes and listed, but will not 
be summarized:
# The time interval (h) of the log-linear regression (λz lower, λz upper) to determine λz
# Number of data points (Nλ) included in the log-linear regression analysis to determine λz
# Goodness-of-fit statistic (Rsq) for calculation of λz
# The AUC from time tlast extrapolated to infinity given as percentage of AUC0-!. Units: %.
The regression analysis for the terminal phase should contain data from at least 3 different 
timepoints consistent with the assessment of a straight line on the log-transformed scale. Phoenix 
WinNonlin best fit methodology will be used as standard. However, the PK scientist may adjust 
the regression analysis, if warranted by the data. The last quantifiable concentration should 
always be included in the regression analysis, while the concentration at tmax and any 
concentrations < LLOQ which occur after the last quantifiable data point should not be used. 
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The Rsq should be ≥ 0.800, or AUCextra% ≤ 20.0%. If these criteria are not met, then the rate 
constants and all derived parameters (eg, AUC0-∞, AUCextra%, CL/f, ∃z, MRAUC0-∞, MRCmax, t1/2,
Vz/f) will be included in the parameter output Listings and flagged as invalid for descriptive 
statistics. These exclusions are to be discussed appropriately. Any flags should be included in the 
study specific SDTM. 
The IMP dose administered is given for the monohydrate hydrochloride salt (ie, 500 mg IMP). A 
conversion factor for the freebase IMP was calculated and will be applied when ‘dose’ is used in 
deriving PK parameter formulas needing a dose value (CL/f).
Conversion factor = Molecular weight (MW) of base IMP divided by MW of salt form IMP 
492.574 g/mol / 547.05 g/mol = 0.9004 = conversion factor
Amount of dose * conversion factor = actual dose of IMP: 500 mg * 0.900 = 450 mg
No MW conversion factor for the parent-to-metabolite ratios will be applied.
A Phoenix WinNonlin NCA Core Output will be provided in a separate listing. Individual PK 
parameters will be calculated using actual sampling times. 
Missing concentrations (eg, no sample, insufficient sample volume for analysis, no result, or 
result not valid) will be reported and displayed generally as “N.R.”. 
16.2
Pharmacodynamics
There are no pharmacodynamic assessments planned
17
References
1. Johnson PJ, Berhane S, Kagebayashi C, et al. Assessment of liver function in patients with 
hepatocellular carcinoma: a new evidence-based approach-the ALBI grade. J Clin Oncol. 
2015; 33(6) 550-558.
2. LoRusso PM, Venkatakrishnan K, Ramanathan RK, et al. Pharmacokinetics and safety of 
bortezomib in patients with advanced malignancies and varying degrees of liver dysfunction: 
Phase 1 NCI Organ Dysfunction Working Group study NCI-6432. Clin Cancer Res. 2012;
18(10), doi:10.1158/1078-0432.CCR-11-2873.
18
Appendices
There are no appendices.
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 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-t (ng*h/mL) PARAMCD=AUCLST 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
26/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1497
 
 
Fit Statistics 
-2 Res Log Likelihood 
19.5 
AIC (Smaller is Better) 
21.5 
AICC (Smaller is Better) 
21.8 
BIC (Smaller is Better) 
22.2 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
10.0665
0.1580
15
63.73
<.0001 
0.05
9.7298
10.4032
GRP 
1 
0.1370
0.2234
15
0.61
0.5489 
0.05
-0.3391
0.6132
GRP 
2 
0.08370
0.2234
15
0.37
0.7131 
0.05
-0.3924
0.5599
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
0.19
0.8280 
 
 
27/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.05331
0.2234
15
-0.24
0.8146 
0.1
-0.4449
0.3383
Moderate vs Healthy 
-0.1370
0.2234
15
-0.61
0.5489 
0.1
-0.5286
0.2546
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.2035
0.1580
15
64.59
<.0001 
0.05
9.8668
10.5402
GRP 
2 
10.1502
0.1580
15
64.26
<.0001 
0.05
9.8135
10.4869
GRP 
3 
10.0665
0.1580
15
63.73
<.0001 
0.05
9.7298
10.4032
 

 

28/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-inf (ng*h/mL) PARAMCD=AUCIFP 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
29/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1434
 
 
Fit Statistics 
-2 Res Log Likelihood 
18.8 
AIC (Smaller is Better) 
20.8 
AICC (Smaller is Better) 
21.1 
BIC (Smaller is Better) 
21.5 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
10.0921
0.1546
15
65.29
<.0001 
0.05
9.7626
10.4216
GRP 
1 
0.1287
0.2186
15
0.59
0.5647 
0.05
-0.3372
0.5947
GRP 
2 
0.07732
0.2186
15
0.35
0.7285 
0.05
-0.3886
0.5433
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
0.18
0.8406 
 
 
30/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.05141
0.2186
15
-0.24
0.8173 
0.1
-0.4347
0.3318
Moderate vs Healthy 
-0.1287
0.2186
15
-0.59
0.5647 
0.1
-0.5120
0.2545
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.2208
0.1546
15
66.12
<.0001 
0.05
9.8913
10.5503
GRP 
2 
10.1694
0.1546
15
65.79
<.0001 
0.05
9.8399
10.4989
GRP 
3 
10.0921
0.1546
15
65.29
<.0001 
0.05
9.7626
10.4216
 

 

31/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=1 ANALYTE=Tepotinib PARM=Cmax (ng/mL) PARAMCD=CMAX 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
32/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.05441
 
 
Fit Statistics 
-2 Res Log Likelihood 
4.3 
AIC (Smaller is Better) 
6.3 
AICC (Smaller is Better) 
6.6 
BIC (Smaller is Better) 
7.0 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
5.6642
0.09523
15
59.48
<.0001 
0.05
5.4612
5.8671
GRP 
1 
0.3423
0.1347
15
2.54
0.0226 
0.05
0.05523
0.6293
GRP 
2 
0.3664
0.1347
15
2.72
0.0158 
0.05
0.07940
0.6535
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
4.63
0.0271 
 
 
33/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
0.02417
0.1347
15
0.18
0.8599 
0.1
-0.2119
0.2603
Moderate vs Healthy 
-0.3423
0.1347
15
-2.54
0.0226 
0.1
-0.5784
-0.1062
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
6.0064
0.09523
15
63.08
<.0001 
0.05
5.8035
6.2094
GRP 
2 
6.0306
0.09523
15
63.33
<.0001 
0.05
5.8276
6.2336
GRP 
3 
5.6642
0.09523
15
59.48
<.0001 
0.05
5.4612
5.8671
 

 

34/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=2 ANALYTE=Metabolite 2571107A PARM=AUC0-t (ng*h/mL) PARAMCD=AUCLST 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
35/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.3645
 
 
Fit Statistics 
-2 Res Log Likelihood 
32.8 
AIC (Smaller is Better) 
34.8 
AICC (Smaller is Better) 
35.1 
BIC (Smaller is Better) 
35.5 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
6.9608
0.2465
15
28.24
<.0001 
0.05
6.4354
7.4861
GRP 
1 
0.05676
0.3486
15
0.16
0.8728 
0.05
-0.6862
0.7997
GRP 
2 
0.06146
0.3486
15
0.18
0.8624 
0.05
-0.6815
0.8044
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
0.02
0.9809 
 
 
36/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
0.004702
0.3486
15
0.01
0.9894 
0.1
-0.6063
0.6158
Moderate vs Healthy -0.05676
0.3486
15
-0.16
0.8728 
0.1
-0.6678
0.5543
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
7.0175
0.2465
15
28.47
<.0001 
0.05
6.4922
7.5429
GRP 
2 
7.0222
0.2465
15
28.49
<.0001 
0.05
6.4969
7.5476
GRP 
3 
6.9608
0.2465
15
28.24
<.0001 
0.05
6.4354
7.4861
 

 

37/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=2 ANALYTE=Metabolite 2571107A PARM=AUC0-inf (ng*h/mL) PARAMCD=AUCIFP 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
38/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.3549
 
 
Fit Statistics 
-2 Res Log Likelihood 
32.4 
AIC (Smaller is Better) 
34.4 
AICC (Smaller is Better) 
34.7 
BIC (Smaller is Better) 
35.1 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
6.9878
0.2432
15
28.73
<.0001 
0.05
6.4694
7.5062
GRP 
1 
0.03890
0.3440
15
0.11
0.9115 
0.05
-0.6942
0.7720
GRP 
2 
0.04692
0.3440
15
0.14
0.8933 
0.05
-0.6862
0.7801
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
0.01
0.9894 
 
 
39/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
0.008022
0.3440
15
0.02
0.9817 
0.1
-0.5950
0.6110
Moderate vs Healthy -0.03890
0.3440
15
-0.11
0.9115 
0.1
-0.6419
0.5641
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
7.0267
0.2432
15
28.89
<.0001 
0.05
6.5083
7.5452
GRP 
2 
7.0348
0.2432
15
28.92
<.0001 
0.05
6.5164
7.5532
GRP 
3 
6.9878
0.2432
15
28.73
<.0001 
0.05
6.4694
7.5062
 

 

40/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=2 ANALYTE=Metabolite 2571107A PARM=Cmax (ng/mL) PARAMCD=CMAX 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
41/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1691
 
 
Fit Statistics 
-2 Res Log Likelihood 
21.3 
AIC (Smaller is Better) 
23.3 
AICC (Smaller is Better) 
23.6 
BIC (Smaller is Better) 
24.0 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
2.3136
0.1679
15
13.78
<.0001 
0.05
1.9557
2.6715
GRP 
1 
0.3205
0.2374
15
1.35
0.1970 
0.05
-0.1856
0.8266
GRP 
2 
0.3836
0.2374
15
1.62
0.1270 
0.05
-0.1225
0.8897
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
1.50
0.2545 
 
 
42/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
0.06307
0.2374
15
0.27
0.7942 
0.1
-0.3532
0.4793
Moderate vs Healthy 
-0.3205
0.2374
15
-1.35
0.1970 
0.1
-0.7368
0.09571
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
2.6341
0.1679
15
15.69
<.0001 
0.05
2.2763
2.9920
GRP 
2 
2.6972
0.1679
15
16.07
<.0001 
0.05
2.3393
3.0551
GRP 
3 
2.3136
0.1679
15
13.78
<.0001 
0.05
1.9557
2.6715
 

 

43/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=3 ANALYTE=Metabolite 2571109A PARM=AUC0-t (ng*h/mL) PARAMCD=AUCLST 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
44/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.3431
 
 
Fit Statistics 
-2 Res Log Likelihood 
31.9 
AIC (Smaller is Better) 
33.9 
AICC (Smaller is Better) 
34.2 
BIC (Smaller is Better) 
34.6 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
9.8062
0.2391
15
41.01
<.0001 
0.05
9.2965
10.3159
GRP 
1 
-0.3118
0.3382
15
-0.92
0.3711 
0.05
-1.0327
0.4090
GRP 
2 
-0.5028
0.3382
15
-1.49
0.1578 
0.05
-1.2236
0.2181
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
1.13
0.3501 
 
 
45/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.1909
0.3382
15
-0.56
0.5807 
0.1
-0.7838
0.4019
Moderate vs Healthy 
0.3118
0.3382
15
0.92
0.3711 
0.1
-0.2810
0.9047
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
9.4944
0.2391
15
39.70
<.0001 
0.05
8.9847
10.0041
GRP 
2 
9.3034
0.2391
15
38.91
<.0001 
0.05
8.7937
9.8131
GRP 
3 
9.8062
0.2391
15
41.01
<.0001 
0.05
9.2965
10.3159
 

 

46/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=3 ANALYTE=Metabolite 2571109A PARM=AUC0-inf (ng*h/mL) PARAMCD=AUCIFP 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
47/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.3420
 
 
Fit Statistics 
-2 Res Log Likelihood 
31.8 
AIC (Smaller is Better) 
33.8 
AICC (Smaller is Better) 
34.2 
BIC (Smaller is Better) 
34.6 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
9.8232
0.2387
15
41.15
<.0001 
0.05
9.3143
10.3320
GRP 
1 
-0.3185
0.3376
15
-0.94
0.3604 
0.05
-1.0382
0.4011
GRP 
2 
-0.5127
0.3376
15
-1.52
0.1497 
0.05
-1.2323
0.2069
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
1.18
0.3355 
 
 
48/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.1942
0.3376
15
-0.58
0.5738 
0.1
-0.7860
0.3977
Moderate vs Healthy 
0.3185
0.3376
15
0.94
0.3604 
0.1
-0.2733
0.9104
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
9.5046
0.2387
15
39.81
<.0001 
0.05
8.9958
10.0135
GRP 
2 
9.3105
0.2387
15
39.00
<.0001 
0.05
8.8016
9.8193
GRP 
3 
9.8232
0.2387
15
41.15
<.0001 
0.05
9.3143
10.3320
 

 

49/88


 
 
Supporting Document for Tables 15.4.3.1.1/2, 15.4.3.6.1/2, and 15.4.3.7.1/2 
 
The Mixed Procedure 
 
ANAL=Primary Model ANALYTEN=3 ANALYTE=Metabolite 2571109A PARM=Cmax (ng/mL) PARAMCD=CMAX 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
4 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
50/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1481
 
 
Fit Statistics 
-2 Res Log Likelihood 
19.3 
AIC (Smaller is Better) 
21.3 
AICC (Smaller is Better) 
21.6 
BIC (Smaller is Better) 
22.0 
 
 
Solution for Fixed Effects 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
5.1042
0.1571
15
32.49
<.0001 
0.05
4.7693
5.4391
GRP 
1 
-0.1380
0.2222
15
-0.62
0.5438 
0.05
-0.6116
0.3356
GRP 
2 
-0.2181
0.2222
15
-0.98
0.3418 
0.05
-0.6918
0.2555
GRP 
3 
0
 
 
 
Type 3 Tests of Fixed Effects 
Effect
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
15
0.49
0.6202 
 
 
51/88


 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.08011
0.2222
15
-0.36
0.7235 
0.1
-0.4696
0.3094
Moderate vs Healthy 
0.1380
0.2222
15
0.62
0.5438 
0.1
-0.2515
0.5276
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
4.9662
0.1571
15
31.61
<.0001 
0.05
4.6313
5.3011
GRP 
2 
4.8861
0.1571
15
31.10
<.0001 
0.05
4.5512
5.2210
GRP 
3 
5.1042
0.1571
15
32.49
<.0001 
0.05
4.7693
5.4391
 

 

52/88


 
Supporting Document for Tables 15.4.3.2.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 1 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-t (ng*h/mL) PARAMCD=AUCLST 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
8 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
53/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1353
 
 
Fit Statistics 
-2 Res Log Likelihood 
31.2 
AIC (Smaller is Better) 
33.2 
AICC (Smaller is Better) 
33.6 
BIC (Smaller is Better) 
33.7 
 
 
Solution for Fixed Effects 
Effect 
Sex 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t|
Alpha
Lower
Upper
Intercept  
 
8.6908
0.8762
12
9.92
<.0001
0.05
6.7816
10.6000
GRP 
 
1 
0.1863
0.2154
12
0.87
0.4039
0.05
-0.2829
0.6556
GRP 
 
2 
0.001881
0.2223
12
0.01
0.9934
0.05
-0.4824
0.4862
GRP 
 
3 
0
SEX 
F 
 
0.2845
0.2210
12
1.29
0.2224
0.05
-0.1971
0.7660
SEX 
M 
 
0
AGE 
 
 
0.02540
0.01327
12
1.91
0.0797
0.05
-0.00351
0.05431
BLWEIGHT 
 
 
-0.00224
0.007054
12
-0.32
0.7567
0.05
-0.01761
0.01313
 
 
54/88


 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
12
0.46
0.6442 
SEX 
1
12
1.66
0.2224 
AGE 
1
12
3.67
0.0797 
BLWEIGHT
1
12
0.10
0.7567 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.1845
0.2333
12
-0.79
0.4445 
0.1
-0.6003
0.2314
Moderate vs Healthy 
-0.1863
0.2154
12
-0.87
0.4039 
0.1
-0.5702
0.1975
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.3427
0.1718
12
60.21
<.0001 
0.05
9.9684
10.7169
GRP 
2 
10.1582
0.1634
12
62.17
<.0001 
0.05
9.8022
10.5142
GRP 
3 
10.1563
0.1666
12
60.98
<.0001 
0.05
9.7934
10.5192
 

 

55/88


 
 
Supporting Document for Tables 15.4.3.2.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 1 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-inf (ng*h/mL) PARAMCD=AUCIFP 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
8 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
56/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1290
 
 
Fit Statistics 
-2 Res Log Likelihood 
30.6 
AIC (Smaller is Better) 
32.6 
AICC (Smaller is Better) 
33.0 
BIC (Smaller is Better) 
33.1 
 
 
Solution for Fixed Effects 
Effect 
Sex 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t|
Alpha
Lower
Upper
Intercept  
 
8.7302
0.8555
12
10.21
<.0001
0.05
6.8663
10.5941
GRP 
 
1 
0.1766
0.2103
12
0.84
0.4173
0.05
-0.2815
0.6348
GRP 
 
2 
-0.00247
0.2170
12
-0.01
0.9911
0.05
-0.4753
0.4704
GRP 
 
3 
0
SEX 
F 
 
0.2832
0.2158
12
1.31
0.2140
0.05
-0.1870
0.7533
SEX 
M 
 
0
AGE 
 
 
0.02489
0.01295
12
1.92
0.0787
0.05
-0.00333
0.05312
BLWEIGHT 
 
 
-0.00205
0.006887
12
-0.30
0.7714
0.05
-0.01705
0.01296
 
 
57/88


 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
12
0.44
0.6547 
SEX 
1
12
1.72
0.2140 
AGE 
1
12
3.69
0.0787 
BLWEIGHT
1
12
0.09
0.7714 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.1791
0.2278
12
-0.79
0.4470 
0.1
-0.5851
0.2269
Moderate vs Healthy 
-0.1766
0.2103
12
-0.84
0.4173 
0.1
-0.5514
0.1981
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.3580
0.1677
12
61.77
<.0001 
0.05
9.9926
10.7234
GRP 
2 
10.1789
0.1595
12
63.81
<.0001 
0.05
9.8313
10.5265
GRP 
3 
10.1814
0.1626
12
62.61
<.0001 
0.05
9.8271
10.5357
 

 

58/88


 
 
Supporting Document for Tables 15.4.3.2.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 1 ANALYTEN=1 ANALYTE=Tepotinib PARM=Cmax (ng/mL) PARAMCD=CMAX 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
3
1 2 3 
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
8 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
59/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.05446
 
 
Fit Statistics 
-2 Res Log Likelihood 
20.3 
AIC (Smaller is Better) 
22.3 
AICC (Smaller is Better) 
22.7 
BIC (Smaller is Better) 
22.7 
 
 
Solution for Fixed Effects 
Effect 
Sex 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
 
4.9944
0.5558
12
8.99
<.0001 
0.05
3.7833
6.2055
GRP 
 
1 
0.3604
0.1366
12
2.64
0.0217 
0.05
0.06269
0.6581
GRP 
 
2 
0.3267
0.1410
12
2.32
0.0390 
0.05
0.01950
0.6339
GRP 
 
3 
0
 
SEX 
F 
 
0.1918
0.1402
12
1.37
0.1964 
0.05
-0.1137
0.4973
SEX 
M 
 
0
 
AGE 
 
 
0.01072
0.008416
12
1.27
0.2270 
0.05
-0.00762
0.02905
BLWEIGHT 
 
 
-0.00008
0.004475
12
-0.02
0.9863 
0.05
-0.00983
0.009671
 
 
60/88


 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
2
12
4.33
0.0384 
SEX 
1
12
1.87
0.1964 
AGE 
1
12
1.62
0.2270 
BLWEIGHT
1
12
0.00
0.9863 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Healthy 
-0.03366
0.1480
12
-0.23
0.8239 
0.1
-0.2974
0.2301
Moderate vs Healthy 
-0.3604
0.1366
12
-2.64
0.0217 
0.1
-0.6039
-0.1169
 
 
Least Squares Means 
Effect 
Actual 
Treatment 
(N) 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
6.0850
0.1090
12
55.85
<.0001 
0.05
5.8476
6.3224
GRP 
2 
6.0514
0.1036
12
58.38
<.0001 
0.05
5.8255
6.2772
GRP 
3 
5.7246
0.1057
12
54.18
<.0001 
0.05
5.4944
5.9548
 

 

61/88


 
Supporting Document for Tables 15.4.3.3.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 2 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-t (ng*h/mL) PARAMCD=AUCLST 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
2
1 2 
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
7 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
62/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1329
 
 
Fit Statistics 
-2 Res Log Likelihood 
30.7 
AIC (Smaller is Better) 
32.7 
AICC (Smaller is Better) 
33.1 
BIC (Smaller is Better) 
33.3 
 
 
Solution for Fixed Effects 
Effect 
Sex
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
 
8.7925
0.8576
13
10.25
<.0001 
0.05
6.9398
10.6452
GRP 
 
1 
0.07693
0.1980
13
0.39
0.7040 
0.05
-0.3509
0.5048
GRP 
 
2 
0
 
SEX 
F 
 
0.2610
0.2177
13
1.20
0.2519 
0.05
-0.2093
0.7313
SEX 
M 
 
0
 
AGE 
 
 
0.02202
0.01279
13
1.72
0.1087 
0.05
-0.00561
0.04965
BLWEIGHT 
 
 
-0.00095
0.006651
13
-0.14
0.8883 
0.05
-0.01532
0.01342
 
 
Type 3 Tests of Fixed Effects 
63/88


 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
1
13
0.15
0.7040 
SEX 
1
13
1.44
0.2519 
AGE 
1
13
2.97
0.1087 
BLWEIGHT
1
13
0.02
0.8883 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Grade 2 vs Grade 1 -0.07693
0.1980
13
-0.39
0.7040 
0.1
-0.4276
0.2738
 
 
Least Squares Means 
Effect GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.2339
0.1155
13
88.57
<.0001 
0.05
9.9843
10.4836
GRP 
2 
10.1570
0.1826
13
55.61
<.0001 
0.05
9.7624
10.5516
 

 

64/88


 
 
Supporting Document for Tables 15.4.3.3.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 2 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-inf (ng*h/mL) PARAMCD=AUCIFP 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
2
1 2 
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
7 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
65/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1264
 
 
Fit Statistics 
-2 Res Log Likelihood 
30.1 
AIC (Smaller is Better) 
32.1 
AICC (Smaller is Better) 
32.4 
BIC (Smaller is Better) 
32.6 
 
 
Solution for Fixed Effects 
Effect 
Sex
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
 
8.8252
0.8362
13
10.55
<.0001 
0.05
7.0186
10.6318
GRP 
 
1 
0.07404
0.1931
13
0.38
0.7076 
0.05
-0.3432
0.4912
GRP 
 
2 
0
 
SEX 
F 
 
0.2601
0.2123
13
1.23
0.2422 
0.05
-0.1985
0.7187
SEX 
M 
 
0
 
AGE 
 
 
0.02162
0.01247
13
1.73
0.1066 
0.05
-0.00532
0.04856
BLWEIGHT 
 
 
-0.00079
0.006486
13
-0.12
0.9051 
0.05
-0.01480
0.01322
 
 
Type 3 Tests of Fixed Effects 
66/88


 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
1
13
0.15
0.7076 
SEX 
1
13
1.50
0.2422 
AGE 
1
13
3.01
0.1066 
BLWEIGHT
1
13
0.01
0.9051 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Grade 2 vs Grade 1 -0.07404
0.1931
13
-0.38
0.7076 
0.1
-0.4160
0.2680
 
 
Least Squares Means 
Effect GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.2536
0.1127
13
91.01
<.0001 
0.05
10.0102
10.4970
GRP 
2 
10.1796
0.1781
13
57.16
<.0001 
0.05
9.7948
10.5643
 

 

67/88


 
 
Supporting Document for Tables 15.4.3.3.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 2 ANALYTEN=1 ANALYTE=Tepotinib PARM=Cmax (ng/mL) PARAMCD=CMAX 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
GRP 
2
1 2 
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
7 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
68/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.05782
 
 
Fit Statistics 
-2 Res Log Likelihood 
19.9 
AIC (Smaller is Better) 
21.9 
AICC (Smaller is Better) 
22.3 
BIC (Smaller is Better) 
22.5 
 
 
Solution for Fixed Effects 
Effect 
Sex
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
 
5.3831
0.5657
13
9.52
<.0001 
0.05
4.1610
6.6052
GRP 
 
1 
0.3320
0.1306
13
2.54
0.0246 
0.05
0.04981
0.6143
GRP 
 
2 
0
 
SEX 
F 
 
0.1793
0.1436
13
1.25
0.2338 
0.05
-0.1309
0.4896
SEX 
M 
 
0
 
AGE 
 
 
0.007516
0.008436
13
0.89
0.3892 
0.05
-0.01071
0.02574
BLWEIGHT 
 
 
-0.00241
0.004387
13
-0.55
0.5916 
0.05
-0.01189
0.007065
 
 
Type 3 Tests of Fixed Effects 
69/88


 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
1
13
6.46
0.0246 
SEX 
1
13
1.56
0.2338 
AGE 
1
13
0.79
0.3892 
BLWEIGHT
1
13
0.30
0.5916 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Grade 2 vs Grade 1 
-0.3320
0.1306
13
-2.54
0.0246 
0.1
-0.5634
-0.1007
 
 
Least Squares Means 
Effect
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
6.0424
0.07622
13
79.28
<.0001 
0.05
5.8778
6.2071
GRP 
2 
5.7104
0.1205
13
47.40
<.0001 
0.05
5.4501
5.9707
 

 

70/88


 
Supporting Document for Tables 15.4.3.4.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 3 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-t (ng*h/mL) PARAMCD=AUCLST 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values 
GRP 
4
1 2 3 4
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
9 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
71/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.08508
 
 
Fit Statistics 
-2 Res Log Likelihood 
24.2 
AIC (Smaller is Better) 
26.2 
AICC (Smaller is Better) 
26.7 
BIC (Smaller is Better) 
26.6 
 
 
Solution for Fixed Effects 
Effect 
Sex
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
 
9.3885
0.7424
11
12.65
<.0001 
0.05
7.7545
11.0224
GRP 
 
1 
-0.1884
0.3126
11
-0.60
0.5588 
0.05
-0.8764
0.4995
GRP 
 
2 
-0.6956
0.3290
11
-2.11
0.0581 
0.05
-1.4197
0.02848
GRP 
 
3 
-0.2941
0.3782
11
-0.78
0.4533 
0.05
-1.1266
0.5384
GRP 
 
4 
0
 
SEX 
F 
 
0.2710
0.1777
11
1.52
0.1556 
0.05
-0.1202
0.6622
SEX 
M 
 
0
 
AGE 
 
 
0.01568
0.01134
11
1.38
0.1942 
0.05
-0.00928
0.04064
BLWEIGHT 
 
 
0.000633
0.005388
11
0.12
0.9086 
0.05
-0.01123
0.01249
 
72/88


 
 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
3
11
3.18
0.0671 
SEX 
1
11
2.32
0.1556 
AGE 
1
11
1.91
0.1942 
BLWEIGHT
1
11
0.01
0.9086 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Normal 
-0.5072
0.1779
11
-2.85
0.0158 
0.1
-0.8266
-0.1877
Moderate vs Normal 
-0.1057
0.2401
11
-0.44
0.6684 
0.1
-0.5369
0.3256
Severe vs Normal 
0.1884
0.3126
11
0.60
0.5588 
0.1
-0.3729
0.7498
 
 
Least Squares Means 
Effect GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.3293
0.09690
11
106.59
<.0001 
0.05
10.1160
10.5426
GRP 
2 
9.8222
0.1600
11
61.39
<.0001 
0.05
9.4700
10.1743
GRP 
3 
10.2237
0.2364
11
43.24
<.0001 
0.05
9.7032
10.7441
GRP 
4 
10.5177
0.3078
11
34.17
<.0001 
0.05
9.8402
11.1953
 

 

73/88


 
 
Supporting Document for Tables 15.4.3.4.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 3 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-inf (ng*h/mL) PARAMCD=AUCIFP 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values 
GRP 
4
1 2 3 4
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
9 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
74/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.08325
 
 
Fit Statistics 
-2 Res Log Likelihood 
24.0 
AIC (Smaller is Better) 
26.0 
AICC (Smaller is Better) 
26.4 
BIC (Smaller is Better) 
26.4 
 
 
Solution for Fixed Effects 
Effect 
Sex
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
 
9.3997
0.7343
11
12.80
<.0001 
0.05
7.7835
11.0159
GRP 
 
1 
-0.1909
0.3092
11
-0.62
0.5495 
0.05
-0.8713
0.4896
GRP 
 
2 
-0.6743
0.3254
11
-2.07
0.0625 
0.05
-1.3905
0.04188
GRP 
 
3 
-0.2966
0.3741
11
-0.79
0.4447 
0.05
-1.1201
0.5269
GRP 
 
4 
0
 
SEX 
F 
 
0.2699
0.1758
11
1.54
0.1530 
0.05
-0.1170
0.6569
SEX 
M 
 
0
 
AGE 
 
 
0.01571
0.01122
11
1.40
0.1890 
0.05
-0.00898
0.04040
BLWEIGHT 
 
 
0.000689
0.005330
11
0.13
0.8994 
0.05
-0.01104
0.01242
 
75/88


 
 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
3
11
2.99
0.0777 
SEX 
1
11
2.36
0.1530 
AGE 
1
11
1.96
0.1890 
BLWEIGHT
1
11
0.02
0.8994 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Normal 
-0.4834
0.1759
11
-2.75
0.0190 
0.1
-0.7994
-0.1675
Moderate vs Normal 
-0.1057
0.2375
11
-0.45
0.6648 
0.1
-0.5323
0.3208
Severe vs Normal 
0.1909
0.3092
11
0.62
0.5495 
0.1
-0.3643
0.7461
 
 
Least Squares Means 
Effect GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
10.3443
0.09585
11
107.92
<.0001 
0.05
10.1334
10.5553
GRP 
2 
9.8609
0.1583
11
62.31
<.0001 
0.05
9.5125
10.2092
GRP 
3 
10.2386
0.2339
11
43.78
<.0001 
0.05
9.7238
10.7534
GRP 
4 
10.5352
0.3045
11
34.60
<.0001 
0.05
9.8650
11.2054
 

 

76/88


 
 
Supporting Document for Tables 15.4.3.4.1/2 
 
The Mixed Procedure 
 
ANAL=Additional Model 3 ANALYTEN=1 ANALYTE=Tepotinib PARM=Cmax (ng/mL) PARAMCD=CMAX 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values 
GRP 
4
1 2 3 4
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
9 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
77/88


 
Number of Observations 
Number of Observations Used 
18 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.02465
 
 
Fit Statistics 
-2 Res Log Likelihood 
10.6 
AIC (Smaller is Better) 
12.6 
AICC (Smaller is Better) 
13.1 
BIC (Smaller is Better) 
13.0 
 
 
Solution for Fixed Effects 
Effect 
Sex
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
 
5.3757
0.3995
11
13.45
<.0001 
0.05
4.4963
6.2551
GRP 
 
1 
0.4928
0.1682
11
2.93
0.0137 
0.05
0.1225
0.8631
GRP 
 
2 
-0.03700
0.1771
11
-0.21
0.8383 
0.05
-0.4267
0.3527
GRP 
 
3 
0.3271
0.2036
11
1.61
0.1364 
0.05
-0.1209
0.7752
GRP 
 
4 
0
 
SEX 
F 
 
0.1597
0.09566
11
1.67
0.1233 
0.05
-0.05088
0.3702
SEX 
M 
 
0
 
AGE 
 
 
0.000470
0.006104
11
0.08
0.9400 
0.05
-0.01297
0.01391
BLWEIGHT 
 
 
0.001500
0.002900
11
0.52
0.6152 
0.05
-0.00488
0.007883
 
78/88


 
 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
GRP 
3
11
11.55
0.0010 
SEX 
1
11
2.79
0.1233 
AGE 
1
11
0.01
0.9400 
BLWEIGHT
1
11
0.27
0.6152 
 
 
Estimates 
Label 
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Mild vs Normal 
-0.5298
0.09573
11
-5.53
0.0002 
0.1
-0.7017
-0.3579
Moderate vs Normal 
-0.1657
0.1292
11
-1.28
0.2262 
0.1
-0.3977
0.06642
Severe vs Normal 
-0.4928
0.1682
11
-2.93
0.0137 
0.1
-0.7949
-0.1907
 
 
Least Squares Means 
Effect
GRP
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
GRP 
1 
6.1083
0.05215
11
117.12
<.0001 
0.05
5.9935
6.2231
GRP 
2 
5.5785
0.08611
11
64.78
<.0001 
0.05
5.3889
5.7680
GRP 
3 
5.9426
0.1273
11
46.70
<.0001 
0.05
5.6625
6.2227
GRP 
4 
5.6155
0.1657
11
33.89
<.0001 
0.05
5.2508
5.9801
 

 

79/88


 
Supporting Document for Tables 15.4.3.5.1 
 
The Mixed Procedure 
 
ANAL=Additional Model 4 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-t (ng*h/mL) PARAMCD=AUCLST 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
6 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
80/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1263
 
 
Fit Statistics 
-2 Res Log Likelihood 
30.7 
AIC (Smaller is Better) 
32.7 
AICC (Smaller is Better) 
33.1 
BIC (Smaller is Better) 
33.3 
 
 
Solution for Fixed Effects 
Effect 
Sex
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept
 
8.4293
0.9121
13
9.24
<.0001 
0.05
6.4587
10.3998
XB 
 
-0.1272
0.1391
13
-0.91
0.3771 
0.05
-0.4279
0.1734
SEX 
F 
0.2363
0.2142
13
1.10
0.2901 
0.05
-0.2265
0.6991
SEX 
M 
0
 
AGE 
 
0.02223
0.01238
13
1.80
0.0958 
0.05
-0.00451
0.04897
BLWEIGHT 
 
-0.00026
0.006382
13
-0.04
0.9680 
0.05
-0.01405
0.01353
 
 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
XB 
1
13
0.84
0.3771 
81/88


 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
SEX 
1
13
1.22
0.2901 
AGE 
1
13
3.23
0.0958 
BLWEIGHT
1
13
0.00
0.9680 
 

 

82/88


 
 
Supporting Document for Tables 15.4.3.5.1 
 
The Mixed Procedure 
 
ANAL=Additional Model 4 ANALYTEN=1 ANALYTE=Tepotinib PARM=AUC0-inf (ng*h/mL) PARAMCD=AUCIFP 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
6 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
83/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.1201
 
 
Fit Statistics 
-2 Res Log Likelihood 
30.1 
AIC (Smaller is Better) 
32.1 
AICC (Smaller is Better) 
32.4 
BIC (Smaller is Better) 
32.6 
 
 
Solution for Fixed Effects 
Effect 
Sex
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept
 
8.4720
0.8894
13
9.53
<.0001 
0.05
6.5505
10.3934
XB 
 
-0.1238
0.1357
13
-0.91
0.3780 
0.05
-0.4170
0.1693
SEX 
F 
0.2359
0.2089
13
1.13
0.2791 
0.05
-0.2154
0.6872
SEX 
M 
0
 
AGE 
 
0.02181
0.01207
13
1.81
0.0939 
0.05
-0.00426
0.04788
BLWEIGHT 
 
-0.00012
0.006224
13
-0.02
0.9849 
0.05
-0.01357
0.01333
 
 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
XB 
1
13
0.83
0.3780 
84/88


 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
SEX 
1
13
1.28
0.2791 
AGE 
1
13
3.27
0.0939 
BLWEIGHT
1
13
0.00
0.9849 
 

 

85/88


 
 
Supporting Document for Tables 15.4.3.5.1 
 
The Mixed Procedure 
 
ANAL=Additional Model 4 ANALYTEN=1 ANALYTE=Tepotinib PARM=Cmax (ng/mL) PARAMCD=CMAX 
 
Model Information 
Data Set 
WORK.PK 
Dependent Variable 
LNEST 
Covariance Structure 
Diagonal 
Estimation Method 
REML 
Residual Variance Method 
Profile 
Fixed Effects SE Method 
Model-Based 
Degrees of Freedom Method Residual 
 
 
Class Level 
Information 
Class
Levels
Values
SEX 
2
F M 
 
 
Dimensions 
Covariance Parameters 
1 
Columns in X 
6 
Columns in Z 
0 
Subjects 
1 
Max Obs per Subject 
18 
 
 
Number of Observations 
Number of Observations Read 
18 
Number of Observations Used 
18 
86/88


 
Number of Observations 
Number of Observations Not Used 
0 
 
 
Covariance 
Parameter 
Estimates 
Cov Parm
Estimate
Residual
0.05756
 
 
Fit Statistics 
-2 Res Log Likelihood 
20.5 
AIC (Smaller is Better) 
22.5 
AICC (Smaller is Better) 
22.9 
BIC (Smaller is Better) 
23.1 
 
 
Solution for Fixed Effects 
Effect 
Sex
Estimate
Standard
Error
DF
t Value
Pr > |t| Alpha
Lower
Upper
Intercept  
4.6364
0.6158
13
7.53
<.0001 
0.05
3.3061
5.9667
XB 
 
-0.2404
0.09394
13
-2.56
0.0238 
0.05
-0.4433
-0.03746
SEX 
F 
0.1546
0.1446
13
1.07
0.3044 
0.05
-0.1578
0.4671
SEX 
M 
0
 
AGE 
 
0.009421
0.008355
13
1.13
0.2799 
0.05
-0.00863
0.02747
BLWEIGHT 
 
0.000026
0.004309
13
0.01
0.9952 
0.05
-0.00928
0.009334
 
 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
XB 
1
13
6.55
0.0238 
87/88


 
Type 3 Tests of Fixed Effects 
Effect 
Num 
DF
Den 
DF
F Value
Pr > F 
SEX 
1
13
1.14
0.3044 
AGE 
1
13
1.27
0.2799 
BLWEIGHT
1
13
0.00
0.9952 
 

 

88/88