An Open-label, Single-dose, Randomized, 2-period, 2-sequence Cross-over, Single-center Phase I Trial in Healthy Subjects to Assess the Bioequivalence of Tepotinib TF3 Administered as 5 Tablets of 100 mg Versus 2 Tablets of 250 mg Dose Strength
Phase: PHASE1
Conditions: Healthy
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg 
TF3 of tepotinib
MS200095_0038
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
Appendix 16.1.1
List of Protocols and Protocol Amendments
Protocol Version 1.0, 05 September 2019
Page 1 of 66

Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 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/ 6 5
Cli nic al Tri al Pr ot oc ol
Cli nic al Tri al Pr ot oc ol N u m ber
M S 2 0 0 0 9 5 _ 0 0 3 8
Title
A n o pe n -la bel, si n gle-d ose, ra n d o mize d, 2-peri o d, 
2- se q ue nce cr oss -o ver, si n gle-ce nter P hase I trial i n 
healt h y  su bjects t o assess t he bi oe q ui vale nce of 
te p oti ni b ta blet f or m ulati o n 3 a d mi nistere d as 
5 ta blets of 1 0 0 m g vers us 2 ta blets of 2 5 0 m g d ose 
stre n gt h.
P h ase
1
I N D N u m ber
N ot a p plica ble
E u dr a C T N u m ber
2 0 1 9- 0 0 3 5 7 8- 1 3
Pri nci p al I n vesti g at or
 
 Ger ma n y
S p o ns or
Merc k Healt hcare K Ga A
a n affiliate of Merc k K Ga A, Dar msta dt, Ger ma n y
Fra n kf urter Str. 2 5 0
Dar msta dt, Ger ma n y
Me dical Res p o nsi ble:
 
Merc k Healt hcare 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: 
Cli nic al 
Tri al Pr ot oc ol D ate 
/ 
Versi o n
0 5- Se p - 2 0 1 9 / Versi o n 1. 0
Re pl aces Versi o n
N ot a p plica ble
- C o nfi de ntial -
T his d oc u me nt is t he pr o pert y  of Merc k K Ga A, Dar msta dt, Ger ma ny, or o ne of its s u bsi diaries. 
It is i nte n de d f or restricte d use o nl y a n d ma y n ot – i n f ull or part – be passe d o n, re pr o d uce d, 
p u blis he d or use d wit h o ut e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y, or its 
s u bsi diar y. C o p yri g ht © 2 0 1 9 b y  Merc k K Ga A, Dar msta dt, Ger ma ny, or its s u bsi diar y . All ri g hts 
reser ve d.
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 2 of 6 6
PI
PI
PI
PI
PI

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
2/65
Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................6
Table of In-Text Figures......................................................................................................6
List of Abbreviations ...........................................................................................................7
1
Synopsis................................................................................................9
2
Sponsor, Investigators and Trial Administrative Structure ................15
3
Background Information.....................................................................15
3.1
Trial Rationale ....................................................................................17
3.2
Risk/Benefit Assessment ....................................................................17
4
Trial Objectives ..................................................................................18
4.1
Primary Objectives .............................................................................18
4.2
Secondary Objectives .........................................................................18
4.3
Exploratory Objectives .......................................................................19
5
Investigational Plan ............................................................................19
5.1
Overall Trial Design and Plan ............................................................19
5.2
Discussion of Trial Design .................................................................20
5.2.1
Inclusion of Special Populations ........................................................21
5.2.2
Scientific Rationale for Trial Design..................................................21
5.2.3
Justification for Dose..........................................................................21
5.2.4
Rationale for Endpoints......................................................................22
5.3
Selection of Trial Population..............................................................22
5.3.1
Inclusion Criteria ................................................................................22
5.3.2
Exclusion Criteria...............................................................................23
5.4
Criteria for Initiation of Trial Treatment ............................................24
5.5
Criteria for Subject Withdrawal..........................................................24
5.5.1
Withdrawal from Trial Therapy..........................................................24
5.5.2
Withdrawal from the Trial..................................................................25
5.6
Premature Termination of the Trial ....................................................26
5.7
Definition of End of Trial...................................................................26
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................27
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 3 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
3/65
6.1
Description of the Investigational Medicinal Products ......................27
6.2
Dosage and Administration ................................................................27
6.3
Assignment to Treatment Groups.......................................................28
6.4
Non-investigational Medicinal Products to be Used ..........................28
6.5
Concomitant Medications and Therapies ...........................................28
6.5.1
Permitted Medicines...........................................................................29
6.5.2
Prohibited Medicines..........................................................................29
6.5.3
Permitted / Prohibited Procedures ......................................................29
6.5.4
Other Interventions.............................................................................30
6.5.5
Special Precautions.............................................................................30
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................30
6.6
Packaging and Labeling of the Investigational Medicinal Product....30
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................30
6.8
Investigational Medicinal Product Accountability.............................31
6.9
Assessment of Investigational Medicinal Product Compliance .........32
6.10
Blinding ..............................................................................................32
6.11
Emergency Unblinding.......................................................................32
6.12
Treatment of Overdose .......................................................................32
6.13
Medical Care of Subjects after End of Trial.......................................32
7
Trial Procedures and Assessments......................................................32
7.1
Schedule of Assessments....................................................................32
7.1.1
Screening Examination.......................................................................33
7.1.2
Treatment Periods...............................................................................34
7.1.3
End of Trial Visit................................................................................35
7.2
Demographic and Other Baseline Characteristics ..............................36
7.3
Efficacy Assessments .........................................................................36
7.4
Assessment of Safety..........................................................................36
7.4.1
Adverse Events...................................................................................37
7.4.2
Pregnancy and In Utero Drug Exposure.............................................41
7.4.3
Clinical Laboratory Assessments .......................................................42
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 4 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
4/65
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............45
7.5
Pharmacokinetics................................................................................46
7.5.1
Blood Sampling ..................................................................................46
7.5.2
Calculation of Pharmacokinetic Variables .........................................47
7.6
Biomarkers..........................................................................................47
7.7
Pharmacogenetics ...............................................................................48
7.8
Other Assessments..............................................................................48
8
Statistics..............................................................................................48
8.1
Statistical Hypotheses.........................................................................48
8.2
Sample Size ........................................................................................49
8.3
Randomization....................................................................................49
8.4
Endpoints............................................................................................50
8.4.1
Primary Endpoints ..............................................................................50
8.4.2
Secondary Endpoints ..........................................................................50
8.4.3
Exploratory Endpoints........................................................................50
8.5
Analysis Sets.......................................................................................50
8.5.1
Safety Analysis Set.............................................................................50
8.5.2
Definition of Pharmacokinetic Analysis Set.......................................50
8.6
Description of Statistical Analyses.....................................................51
8.6.1
General Considerations.......................................................................51
8.6.2
Analysis of Primary Endpoints...........................................................52
8.6.3
Analysis of Secondary Endpoints.......................................................52
8.6.4
Analysis of Safety and Exploratory Endpoints...................................52
8.7
Interim and Additional Planned Analyses ..........................................53
9
Ethical and Regulatory Aspects..........................................................53
9.1
Responsibilities of the Investigator ....................................................53
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 Trial Insurance and Compensation to Subjects.....................54
9.6
Independent Ethics Committee or Institutional Review Board ..........55
9.7
Health Authorities...............................................................................55
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 5 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
5/65
10
Trial Management...............................................................................55
10.1
Case Report Form Handling...............................................................55
10.2
Source Data and Subject Files............................................................56
10.3
Investigator Site File and Archiving...................................................56
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................57
10.5
Changes to the Clinical Trial Protocol................................................57
10.6
Clinical Trial Report and Publication Policy......................................57
10.6.1
Clinical Trial Report...........................................................................57
10.6.2
Publication..........................................................................................57
11
References Cited in the Text...............................................................58
12
Appendices .........................................................................................59
Appendix I
Signature Pages and Responsible Persons for the Trial......................59
Signature Page – Protocol Lead.........................................................................................60
Signature Page – Principal Investigator.............................................................................61
Sponsor Responsible Persons not Named on the Cover Page ...........................................62
Appendix II
Blood Volume Sampled in the Clinical Trial .....................................63
Appendix III
Contraception Guidance .....................................................................64
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 6 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
6/65
Table of In-Text Tables
Table 1
Schedule of Assessments....................................................................13
Table 2
Clinical Laboratory Evaluations.........................................................44
Table 3
Time Windows....................................................................................46
Table 4
Definition of PK Parameters for Tepotinib and its Metabolites 
After Single Dose Administration ......................................................47
Table 5
Overview of the PK-Variability Observed in Tepotinib Study 
MS200095-0044 .................................................................................49
Table of In-Text Figures
Figure 1
Overall Trial Design ...........................................................................20
Figure 2
Design of the Trial..............................................................................20
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 7 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
7/65
List of Abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ALU
Aluminum
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing 
time) extrapolated to infinity
AUC0-t
Area under the plasma concentration-time curve 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
AUCextra%
AUCextra / AUC0-∞in percent
beta-HCG
Beta-human chorionic gonadotropine
BMI
Body mass index
CI
Confidence interval
CK-MB
Creatine phosphokinase - myocardium/brain type
CL/f
Apparent total body clearance considering the fraction of dose (f) absorbed
Cmax
Maximum plasma concentration
c-Met
Mesenchymal-epithelial transition factor
CRO
Contract research organization
CTCAE
Common Terminology Criteria for AEs
CV
Coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EudraCT
European Union Clinical Trials Register
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GeoMean
Geometric mean 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 8 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
8/65
GMR
Geometric Mean Ratio
h
Hour(s)
HCC
Hepatocellular carcinoma
HGF
Hepatocyte growth factor
HIV1/HIV2
Human immunodeficiency virus 1 and 2
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation 
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
LLOQ
Lower limit of quantification
min
Minute(s)
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
PGx
Pharmacogenetics
PK
Pharmacokinetics
QTcF
Corrected QT interval according to Fridericia
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SUSAR
Suspected unexpected serious adverse reactions
T/R
Test/Reference
t1/2
Terminal half-life
TEAE
Treatment emergent adverse event
TF1; TF2; TF3
Tablet Formulation 1; Tablet Formulation 2; Tablet Formulation 3
tlast
The last sampling time at which the concentration is at or above the lower 
limit of quantification
tmax
Time to reach the maximum plasma concentration
ULN
Upper limit of normal range
VZ/f
Apparent volume of distribution during terminal phase (after 
oral/extravascular administration)
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 9 of 66

Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 8
C O N F I D E N T I A L
I N F O R M A T I O N
9/ 6 5
1
S y n o psis
Cli nic al Tri al Pr ot oc ol N u m ber
M S 2 0 0 0 9 5 _ 0 0 3 8
Title
A n o pe n -la bel, si n gle-d ose, ra n d o mize d, 
2 peri o d, 2 -se q ue nce cr oss-o ver, si n gle -ce nter 
P hase I trial i n healt h y s u bjects t o assess t he 
bi oe q ui vale nce of te p oti ni b ta blet f or m ulati o n 3 
a d mi nistere d as 5 ta blets of 1 0 0 m g vers us 
2 t a blets of 2 5 0 m g d ose stre n gt h.
Tri al P h ase
1
I N D N u m ber
N ot a p plica ble
F D A c o vere d tri al
N o
E u dr a C T N u m ber
2 0 1 9- 0 0 3 5 7 8- 1 3
Pri nci p al I n vesti g at or
 
 Ger ma n y
S p o ns or
Merc k Healt hcare K Ga A, 
a n affiliate of Merc k K Ga A, Dar msta dt, 
Ger ma n y,
Fra n kf urter Strasse 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
Tri al ce nter
 
 Ger ma n y 
Pl a n ne d tri al peri o d
(first s u bject i n-l ast s u bject o ut)
Oct o ber t o Dece m ber 2 0 1 9
Tri al Re gistr y
Cli nical Trial. g o v, E U Cli nical Trials Re gister
Pri m ar y O bjecti ves:

T o de m o nstrate bi oe q ui vale nce bet wee n 5 ta blets of t he 1 0 0 m g d ose stre n gt h of te p oti ni b
ta blet f or m ulati o n 3 ( T F 3, test treat me nt) a n d 2 ta blets of t he 2 5 0 m g  d ose stre n gt h of T F 3 
(refere nce treat me nt) after si n gle d os e a d mi nistrati o n i n healt h y  su bjects u n der fasti n g 
c o n diti o ns
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
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 1 0 of 6 6
PI
PI
PI

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
10/65
To further assess the safety and tolerability of tepotinib TF3 under fasting conditions
Exploratory Objectives:
To investigate the PK of tepotinib metabolites 
To explore the effect of pharmacogenetics (PGx) and variations of associated genes on the 
PK profile of tepotinib (if applicable).
Methodology: This is an open-label, single-dose, randomized, 2-period, 2-sequence 
cross-over, single-center trial to investigate the bioequivalence of the 100 mg and 250 mg dose 
strengths of tepotinib tablet formulation 3 under fasted condition.
For each subject, the study consists of a screening period (Day -21 to Day -2) and 2 treatment 
periods including a washout of 21-days in each period. Eligible subjects will be admitted to the 
clinical unit on Day -1. Subjects who continue to meet the eligibility criteria will be randomized 
to 1 of 2 treatment sequences on Day 1 of Period 1. 
In each study period, the subjects will be hospitalized from Day -1 to Day 4 for safety 
assessments and PK blood sampling and return to the site on Days 5 - 8 for additional PK blood 
sampling and monitoring of AEs and concomitant medication. Study drug will be administered 
on Day 1 of each period. An End of Trial Visit will be performed at the end of Period 2 (21 days 
after dosing in Period 2).
Planned number of subjects: 
18 subjects.
Primary Endpoints:
Area under the plasma concentration-time curve (AUC) from time zero (= dosing time) to 
the last sampling time at which the concentration is at or above the lower limit of 
quantification (AUC0-t), AUC from time zero extrapolated to infinity (AUC0-∞) and 
maximum plasma concentration (Cmax) of tepotinib observed from time zero to 168 h post-
dose of each period.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 11 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
11/65
Secondary Endpoints:
Time to reach Cmax (tmax), terminal half-life (t1/2), apparent total body clearance considering 
the fraction of dose absorbed (CL/f) and apparent volume of distribution during terminal 
phase (Vz/f) of tepotinib observed from time zero to 168 h post-dose of each period
Occurrence of treatment-emergent adverse events (TEAEs; incidence, frequency, intensity 
and causality), occurrence of changes in safety laboratory assessments, 12-lead 
electrocardiograms (ECGs) and vital signs.
Exploratory Endpoints:
PK profiles of tepotinib metabolites: 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time zero to 168 h 
post-dose of each period
Genetic variants and mutations in genes that potentially influence PK of tepotinib.
Pharmacokinetics:
Plasma concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A 
will be determined in each study period from pre-dose until 168 h post-dose. PK parameters 
will be calculated using non-compartmental analysis.
Pharmacogenetics: PGx analysis on Day -1 of Period 1
Other assessments: Not applicable
Diagnosis and key inclusion and exclusion criteria:
Healthy males and females (of non-childbearing potential) between 18 to 55 years (inclusive) 
with a body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 and a total body weight between 50 
and 100 kg (inclusive) at the time of Screening examination may be enrolled in the trial.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule:
Tepotinib film-coated tablet TF3 containing 100 mg of drug substance for oral 
administration (test treatment)
Tepotinib film-coated tablet TF3 containing 250 mg of drug substance for oral 
administration (reference treatment)
Administration of single doses of 500 mg tepotinib per treatment period, administered as 
2 tablets of 250 mg, and 5 tablets of 100 mg, after overnight fasting.
The washout period between single doses will be at least 21 days.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable
Planned trial and treatment duration per subject: 
About 9 weeks each from Screening to End of Trial Visit, including 2 treatment periods of 
21 days each.
Statistical methods:
Primary Endpoints: 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 12 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
12/65
An analysis of variance (ANOVA) model will be fitted to the log-transformed PK parameters 
Cmax, AUC0-t, AUC0-∞based on the PK analysis set. The model will include treatment, period, 
sequence as fixed effects and subject within sequence as random effect. 
Treatment differences on the log scale of tepotinib will be estimated for Cmax, AUC0-t, AUC0-∞
together with their 90% CIs. 
The null hypothesis of non-bioequivalence will be rejected if the 90% CI for the ratio of the 
geometric mean lies within the bioequivalence acceptance interval of 0.8000 to 1.2500 for all 
primary PK parameters. 
Secondary and exploratory endpoints will be analyzed with summary statistics.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 13 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
13/65
Table 1
Schedule of Assessments
Assessment/ Activity
Screening
All periods
End of Trial Visit
Day
-21 to -2
-1
1
2 - 4
5 - 8
21 (± 1) after dosing in Period 2
Written informed consent a
Hospitalization
X ----------------------------------------------------------------- X
Ambulatory visits
X
X
X
In-/exclusion criteria
X
X (Period 1 only)
Randomization
X (predose, 
Period 1 only)
Demographic data (incl. height, weight, 
BMI)
X
Medical history
X
Physical examination
X
X
Day 2, Day 4 e
X
Vital signs (blood pressure, pulse rate, 
body temperature)
X
X
pre-dose, 2 h, 8 h
Day 2, Day 4 e
X
12-lead safety ECG
X
X
pre-dose b, 2 h, 
8 h
Day 2, Day 4 e
X
Clinical laboratory (hematology, 
biochemistry, urinalysis)
X
X
pre-dose
Day 2, Day 4 e
X
Coagulation
X
Serology (HIV/hepatitis)
X
Pregnancy test (in serum at Screening 
and End of Trial Visit, in urine on Day -1)
X
X
X
Urine drug screen; Alcohol breath test
X
X
Administration of tepotinib
X
PK blood sampling
X c
X c
X c
PGx blood sampling
X (Period 1 only)
Adverse events monitoring
X
X -----------------------------------------------------------------------------------------------------------------X d
(Prior and) concomitant medication
X
X -----------------------------------------------------------------------------------------------------------------X d
BMI = body mass index, ECG = electrocardiogram, h = hours, HIV = human immunodeficiency virus, min = minutes, PK = pharmacokinetics, 
PGx = pharmacogenetics
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 14 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
14/65
a
Written informed consent must be obtained prior to any screening activities 
b
ECGs at pre-dose will be recorded in triplicate
c
PK blood samples for determination of tepotinib and its metabolites will be collected at pre-dose (within 60 min prior to dosing) and 15, 30, 45, 60, 90 min, 
and 2, 3, 4, 6, 8, 12, 16 and (Day 2) 24, 36, (Day 3) 48, 60, (Day 4) 72, (Day 5) 96, (Day 6) 120, (Day 7) 144 and (Day 8) 168 h post-dose
d
Adverse events and concomitant medication will be assessed from signing of the informed consent form throughout the whole study until End of Trial.
e
All safety assessments on Day 4 before discharge.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 15 of 66

Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 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 5 /6 5
2
S p o ns or, I n vesti g at ors a n d Tri al A d mi nistr ati ve Str uct ure
T his cli nical trial will be s p o ns ore d b y:  
Merc k Healt hcare K Ga A a n affiliate of 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.
Si n gle trial site at 
, Ger ma ny.
T he Pri nci pal I n vesti gat or (
, 
 
, Ger ma n y) 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 trial desi g n a n d 
e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d si g n off of t he cli nical trial re p ort c o nsiste nt wit h 
t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) T o pic E 6 G o o d Cli nical Practice ( G C P; 
hereafter referre d t o as I C H G C P) [7 ]. 
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 nvesti gat or 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 I .
T he trial will a p pear i n t he f oll o wi n g cli nical trial re gistries: E ur o pea n U ni o n Cli nical Trials 
Re gister ( E u dra C T), Cli nical Trials. g o v.
N u visa n G m b H, We ge nerstrasse 1 3, 8 9 2 3 1 Ne u -Ul m, Ger ma n y , a c o ntract researc h or ga nizati o n 
( C R O), will co n d uct t he cli nical part of t he trial i ncl u di n g trial set- u p, c o or di nati o n, safety a n d 
a nal yt ical la b, m o nit ori n g, data ca pt ure, data ma na ge me nt, statistical a nal ysis, a n d cli nical trial 
re p orti n g. N u visa n 
G m b H 
will 
als o s u b mit t he necessar y  ap plicati o ns t o t he a p plica ble 
I n de pe n de nt Et hics C o m mittee (I E C) a n d re g ulat or y bo dies o n be half of a n d i n cl ose ali g n me nt 
wit h t he S p o ns or. 
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 will be prese nte d i n a se parate 
La b Ma n ual 
w hic h will be pre pa re d b y  Nu visa n G m b H i n c o o perati o n wit h t he S p o ns or. 
M o nit ori n g a n d data ma na ge me nt pr oce d ures will be defi ne d i n se parate M o nit ori n g a n d Data 
Ma na ge me nt Pla ns w hic h will be pre pare d b y N u visa n G m b H.
T he S p o ns or will pr o vi de t he I n vesti gati o nal Me dici nal P r o d uct (I M Ps) te p oti ni b. Pac ka gi n g, 
la beli n g a n d distri b uti o n of all I M Ps t o t he trial site will be c o n d ucte d b y  a desi g nate d c o ntract 
ma n ufact uri n g 
or ga nizati o n ( N u visa n G m b H). 
T he S p o ns or will 
s u per vise all o uts o urce d 
acti vities.
3
B ac k gr o u n d I nf or m ati o n
T he mese nc h y m al -e pit helial tra nsiti o n fact or (c-Met), al o n g wit h its li ga n d, t he he pat oc y te gr o wt h 
fact or ( H G F) ha ve bee n i m plicate d i n carci n o ge nesis a n d metastatic t u m or pr o gressi o n, beca use 
of t heir a bilit y t o e n ha nce a n gi o ge nesis, ca ncer cell pr oliferat i o n, mi grati o n a n d i n vasi o n, as well 
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 1 6 of 6 6
PI
PI
PI

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
16/65
as conferring resistance to apoptosis. Pharmacological interference with the HGF/c-Met axis is 
considered as a promising strategy to inhibit primary tumor growth and metastasis.
In primary pharmacodynamic studies, tepotinib (MSC2156119J) 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 translocated promoter region (TPR) Met.
Until 19-July-2019, 715 subjects have been exposed to tepotinib at doses up to 1400 mg, including 
195 healthy participants, and 12 subjects with Child-Pugh class A or B hepatic impairment in 8 
Clinical Pharmacology studies.
Four of the Clinical Pharmacology studies in healthy subjects (EMR200095-007, n = 27;
EMR200095-0012, n = 24; MS200095-0039, n = 12 and MS200095-0044, n = 66) were 
conducted as single-dose studies with 500 mg tepotinib, in one study (EMR200095-002, n = 28), 
single doses of 30 mg tepotinib were administered to healthy subjects. In two further studies, 
healthy subjects received multiple doses of 500 mg tepotinib over 11 days (MS200095-0030, 
n = 12) or 8 days (MS200095-0032, n = 20).
In all 7 studies performed in healthy subjects, the subjects well tolerated single doses of 30 mg or 
500 mg tepotinib, or multiple doses of 500 mg tepotinib. All treatment-emergent adverse events 
(TEAEs) were mild to moderate, except 2 Grade 3 asymptomatic lipase elevations in 2 subjects, 
and 2 Grade 3 TEAE (back pain and collum femoris fracture) that were not considered related to 
treatment. TEAEs did not show a pattern across the trials. No drug-related serious adverse events 
(SAEs) were reported and no subject died. No clinically significant findings regarding laboratory 
parameters, vital signs and electrocardiogram (ECG) including corrected QT interval according to 
Fridericia (QTcF) were noted.
In a further Clinical Pharmacology trial (MS200095-0028), 6 subjects with Child-Pugh Class A, 6 
subjects with Class B hepatic impairment, and 6 healthy subjects received single doses of 500 mg 
tepotinib. No subject had serious adverse events, Grade ≥ 3 TEAEs, or discontinued due to a 
TEAE, or died during the study
In 2 clinical studies (EMR200095-001 and EMR200095-003), 161 patients with different solid 
tumors received multiple doses up to 1400 mg tepotinib. In 2 studies, 138 patients with 
hepatocellular cancer (EMR200095-004 and EMR200095-005) received multiple doses of 
300 mg, 500 mg or 1000 mg tepotinib. In a clinical study in patients with MET-positive, non-
small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor mutations 
(EMR200095-006), 64 patients received multiple doses of 300 mg or 500 mg tepotinib.
Until 19-July-2019, 145 patients with NSCLC in the ongoing VISION trial (MS200095-0022) 
have received multiple doses of 500 mg tepotinib.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 17 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
17/65
Elevations in serum lipase and amylase are identified risks for tepotinib and were observed in 
healthy subjects and patients exposed to tepotinib. These increases were mild to moderate in 
severity (exception: 1 Grade 3 lipase elevation), transient and without apparent dose dependency. 
All increases of serum amylase/lipase were asymptomatic and not associated with pancreatitis. 
This study will investigate the bioequivalence of tepotinib tablet formulation 3 (TF3) administered 
as 5 tablets of 100 mg versus 2 tablets of 250 mg dose strength. A dose of 500 mg once daily is 
the recommended Phase 2 dose. Refer to the Investigator’s Brochure (IB) for further information 
about the nonclinical and clinical programs and the implemented Guidance for the Investigator.
For the PK of tepotinib refer to the IB.
3.1
Trial Rationale
This trial will investigate the bioequivalence of the 100 mg dose strength (test treatment) of the 
envisioned market formulation, TF3, compared to the 250 mg dose strength of the same 
formulation (reference treatment), both given at a single dose of 500 mg. The 250 mg dose strength 
of TF3 had been shown to be bioequivalent to the 500 mg dose strength of TF2, used in the Phase 2 
studies, and in a previous bioequivalence study (MS200095-0044).
While the recommended clinical dose of 500 mg for the treatment of patients with NSCLC can be 
administered using the 250 mg dose strength, the lower TF3 dose strength of 100 mg will be made 
available for individual dose adaptation and future development options.
The tablet cores of both TF3 dose strengths are identical. The tablet film-coating is a 
non-functional coating that differs only marginally in composition between both dose strengths.
However, owing to the different tablet sizes, the difference of coating material per surface area 
formally exceeds regulatory thresholds in certain regulatory regions. Clinical investigation of 
bioequivalence between the TF3 strengths will therefore be performed.
The trial design using an open-label 2-period, 2-sequence cross-over design under fasted 
conditions follows the regulatory guidelines of the Food and Drug Administration (FDA) [1, 2], 
the European Medicines Agency (EMA) [3] and the Pharmaceuticals and Medical Devices Agency 
(PMDA) [4, 5].
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP [7], 
and any additional applicable regulatory requirements.
Based on the available nonclinical and clinical data to date, the conduct of the trial specified in 
this protocol is considered justifiable.
3.2
Risk/Benefit Assessment
Based on the currently available nonclinical as well as clinical safety data, and the lack of 
genotoxicity in non-clinical studies, there is no objection against administration of single doses of 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 18 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
18/65
tepotinib to healthy subjects. It is recognized that healthy subjects will not get benefit by 
participating in this study. Subjects enrolled in this study might be exposed to a potential risk, 
including pancreatic enzyme elevation. However, inclusion of healthy subjects 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.
Since loss of c-Met induces teratogenic effects in c-Met knockout mice, and since a pilot embryo-
fetal development study in rabbits revealed maternotoxic effects and a dose-dependent increased 
number of skeletal malformations (teratogenicity), 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 due to hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) will be enrolled in this study (for details see Section 5.3.1). Male subjects will be 
required to take precautions with regards to female partners. 
To further mitigate any risk, a close monitoring of the safety laboratory parameters, ECG, and vital 
signs will be performed in all healthy subjects. Subjects will be admitted to the study site and 
remain resident there for at least 72 h after administration of a single dose in each treatment period, 
to allow continuous safety monitoring. In addition, frequent monitoring of subjects is ensured by 
subsequent ambulant visits and by choosing a CRO experienced in the conduct of clinical 
pharmacology studies.
In summary, healthy subjects will be included in the study to minimize variability, which is 
expected to be higher in a patient population. Non-clinical safety investigations did not reveal a 
genotoxicity potential or other findings with relevance for human use. Therefore, it is reasonable 
that tepotinib can be administered to healthy subjects such as in this study in which careful safety 
monitoring is conducted. Knowing that tepotinib shows teratogenic effects, only healthy women 
who are postmenopausal or surgically sterile (ie, due to hysterectomy, or bilateral oophorectomy, 
or bilateral salpingectomy) will be enrolled in this study and male subjects must and have their 
female partner of childbearing potential use methods of highly effective contraception.
4
Trial Objectives
4.1
Primary Objectives
To demonstrate bioequivalence between 5 tablets of the 100 mg dose strength of tepotinib TF3 
(test treatment) and 2 tablets of the 250 mg dose strength of TF3 (reference treatment) after 
single dose administration in healthy subjects under fasting conditions.
4.2
Secondary Objectives
To further investigate the PK of tepotinib.
To further assess the safety and tolerability of tepotinib TF3 under fasting conditions.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 19 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
19/65
4.3
Exploratory Objectives
To investigate the PK of tepotinib metabolites
To explore the effect of pharmacogenetics (PGx) and variations of associated genes on the PK
profile of tepotinib (if applicable).
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is an open-label, single-dose, randomized, 2-period, 2-sequence cross-over, single-center trial 
to investigate the bioequivalence of the 100 mg and 250 mg dose strengths of tepotinib TF3 when 
administered at the same dose under fasted condition.
For each subject, the study consists of a screening period (Day -21 to Day -2) and 2 treatment 
periods, including a 21-days washout in each period. Eligible subjects will be admitted to the 
clinical unit on Day -1. Subjects who continue to meet the eligibility criteria will be randomized 
to 1 of 2 treatment sequences on Day 1 of Period 1. 
In each study period, the subjects will be hospitalized from Day -1 to Day 4 for safety assessments 
and PK blood sampling and return to the site on Days 5 - 8 for additional PK blood sampling and 
monitoring of AEs and concomitant medication. Study drug will be administered on Day 1 of each 
period. An End of Trial Visit will be performed at the end of Period 2 (21 days after dosing in 
Period 2).
More details are given in Section 7.1. 
Common Visit Schedule
Trial procedures are the same for both periods. 
The washout period will be at least 21 days between Day 1 of each period (see Figure 2).
A screening period is implemented from Day -21 to Day -2.
Subjects will be admitted to the study site on Day -1 of each period and will be resident at the 
study site under medical supervision from Days -1 to 4. They must visit the site on the morning of 
Days 5 to 8 for further blood sampling. 
Blood and urine samples will be collected for laboratory assessments (hematology, biochemistry, 
urinalysis), which will be performed at Screening, throughout the in-patient period of each 
treatment period and for the End of Trial Visit. 
Serial blood samples for PK assessments will be collected for 168 h after tepotinib administration 
in all periods. 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 20 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
20/65
The End of Trial Visit is planned 21 days (± 1 day) after tepotinib administration in the second 
period. An Early Termination Visit will be conducted for subjects who withdraw prematurely. The 
same assessments as for the End of Trial Visit will be conducted at the Early Termination Visit.
Figure 1
Overall Trial Design
Test treatment: 5 tablets 100 mg tepotinib TF3, Reference treatment: 2 tablets 250 mg tepotinib TF3
Figure 2
Design of the Trial
Each Period
Day
Procedure
-1
1
2 to 4
5 to 8
21
Hospitalization
Tepotinib administration
PK blood sampling
Safety assessmentsa
AE monitoring
AE = adverse event, PK = pharmacokinetics
The washout period will be at least 21 days between Day 1 of each period.
a Safety assessments: Vital signs, 12-lead electrocardiogram, clinical laboratory during hospitalization and at the End 
of Trial Visit.
A detailed schedule of study procedures and assessments is provided in Table 1.
5.2
Discussion of Trial Design
The primary objective is to demonstrate bioequivalence between 5 tablets of the 100 mg dose 
strength of TF3 (test treatment) and 2 tablets of the 250 mg dose strength of TF3 (reference 
treatment) after single dose administration in healthy subjects under fasting conditions.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 21 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
21/65
The general trial design is strictly based on the regulatory guidelines of the FDA [1, 2], EMA [3] 
and PMDA [4, 5].
5.2.1
Inclusion of Special Populations
Not applicable.
5.2.2
Scientific Rationale for Trial Design
The trial design and endpoints are typical for bioequivalence studies of this type. The single dose 
design under fasted conditions is more sensitive in showing changes in the PK as compared to 
multiple dose designs and is generally recommended by the relevant guidelines [1-5].
As illustrated in Figure 1, the study will utilize a randomized open-label, 2-period, 2-sequence 
cross-over design to minimize the influence of covariates. 
In a recent clinical study with PK sampling up to 504 h after administration (MS200095-012), 
terminal elimination half-lives (t1/2) of about 30 h for the parent compound tepotinib and about 
45 h for the main metabolites MSC2571109A and MSC2571107A were observed (Study 
MS200095-0012). Due to the very sensitive bioanalytical method, very low concentrations (< 5% 
of the maximum plasma concentration [Cmax]) were observed after 14 days in study MS200095-
0012. No (or only negligible) concentrations above the detection limit are expected after 21 days 
following dosing. Accordingly, the washout period will be at least 21 days between Day 1 (study 
drug administration) of each treatment period to further minimize potential carry-over.
In a previous clinical study with single-dose administrations of 500 mg tepotinib as TF3 under 
fasted conditions (EMR200095-0044, Part A), the median time to reach the maximum plasma 
concentration (tmax) was 12 h (ranging from 8 h to 36 h), and the mean apparent half-life was 30.9 h 
(95% confidence interval: 29.4 h to 32.5 h). The PK sampling scheme (see Table 1) with sampling 
up to 168 h after administration is expected to adequately cover the absorption, distribution and 
elimination phases up to > 80% of the AUC from time zero (dosing time) extrapolated to infinity 
(AUC0-∞).
This trial will be performed in healthy volunteers to standardize the trial population and minimize 
inter-subject variability. 
5.2.3
Justification for Dose
The 500 mg single oral dose has been studied in previous studies in healthy subjects and was found 
to be safe and well tolerated. The tepotinib dose of 500 mg is the recommended Phase 2 dose
(RP2D) for the treatment of human malignant tumors.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 22 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
22/65
5.2.4
Rationale for Endpoints
The peak (Cmax) and extent (area under the plasma concentration-time curve [AUC0-t and AUC0-∞
]) of exposure after single dose administration are considered adequate endpoints to evaluate the 
bioequivalence. These endpoints are in line with the regulatory guidance of the FDA, EMA and 
PMDA (see Section 3.1).
5.3
Selection of Trial Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Prior to performing any trial assessments not part of the subject’s routine medical care, 
the Investigator will ensure that the subject has provided written informed consent following the 
procedure described in Section 9.2.
5.3.1
Inclusion Criteria
To be eligible, the subject must fulfill all the following criteria:
1.
Male or female, aged 18 to 55 years inclusive (at Screening)
2.
Body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 and body weight between 50 and 100 kg, 
inclusive (at Screening)
3.
A female participant is eligible to participate if she is not pregnant, not breastfeeding and of 
non-childbearing potential, confirmed at Screening, by fulfilling at least 1 of the following 
criteria (Appendix III
Contraception Guidance): 
Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL)
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy
4.
A male participant must agree to use and to have his female partner of childbearing potential 
to use highly effective methods of contraception (ie methods with a failure rate of less than 
1% per year) as detailed in the Clinical Trial Facilitation Group (CTFG) recommendations 
[6] during the period of participation in the study and for at least 3 months after the last IMP 
administration (see Appendix III). Males must also refrain from donating sperm during this 
period and should always use a barrier method such as condom concomitantly. The male 
participants will be asked to report pregnancies in their female partners up to 3 months after 
the last IMP intake.
5.
Subject must be healthy, as assessed by the Investigator, with no clinically significant 
abnormality identified on physical examination and no active clinically significant disorder, 
condition, infection or disease that would pose a risk to subject safety or interfere with the 
study evaluation, procedures, or completion (at Screening and Day -1).
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 23 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
23/65
6.
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. 
7.
All values for hematology, coagulation, and biochemistry tests of blood and urinalysis within 
the normal range (at Screening). Minor (solitary) non-clinically relevant deviation(s) are 
allowed as judged by the Investigator, however amylase and lipase should not exceed the 
upper limit of normal range (ULN); alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) should not exceed the ULN x 1.1.
5.3.2
Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:
1.
Participation in the treatment phase of a clinical study within 60 days or 5 half-lives after last 
dosing of the previous study drug, whatever is longer, before administration of study drug
2.
Whole blood donation or loss of > 450 mL within 60 days before administration of study drug
3.
Any surgical or medical condition, including findings in the medical history or in the pre-
study assessments, or any other significant disease, that in the opinion of the Investigator, 
constitutes a risk or a contraindication for the participation of the subject in the study or that 
could interfere with the study objectives, conduct, or evaluation
4.
Supine systolic blood pressure > 140 or < 90 mmHg, diastolic blood pressure > 90 or 
< 50 mmHg, and pulse rate > 90 or < 50 beats per minute (min) at Screening and at Admission 
on Day -1 (Any abnormal blood pressure results may be repeated once and if the repeat result 
is within the normal range, it is not considered to have met the exclusion criterion)
5.
12-Lead ECG showing a QTcF > 450 ms, PR > 215 ms, or QRS > 120 ms 
6.
Creatinine clearance estimated glomerular filtration rate (eGFR) < 90 mL/min as assessed by 
using the estimated measure with the Cockcroft-Gault equation (at Screening). In case of a 
borderline result between ≥80 and 90 mL/min, Cystatin C will be determined in addition, and 
the subject will only be included if the Cystatin C value is below the ULN. 
7.
Subjects with gall bladder removal or other relevant surgery of gastrointestinal tract. 
(Appendectomy is not considered as relevant)
8.
History of any malignancy except for adequately treated superficial basal cell carcinoma 
9.
History of epilepsy
10. Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or 
excipients; history of anaphylaxis to drugs or serious allergic reactions leading to 
hospitalization or any other allergy reaction in general, which the Investigator considers may 
affect the safety of the subject and/or outcome of the study
11. Positive screen for alcohol and drugs of abuse (at Screening and Day -1 of Period 1) 
12. Positive screen for hepatitis B surface antigen, hepatitis C virus antibody, and human 
immunodeficiency virus 1 and 2 antibodies (HIV1/HIV2 antibodies) (at Screening)
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 24 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
24/65
13. Excessive consumption of xanthine-containing food or beverages (> 5 cups of coffee or 
equivalent a day) or inability to stop consuming caffeine (at Screening and Day -1)
14. Receipt of any prescription or nonprescription medication within 14 days or 5 half-lives, 
whatever is longer, before study drug administration (apart from paracetamol up to 1500 mg 
per day, as judged appropriate by the Investigator)
15. Smoker (cigarettes, pipes, cigars, or others) or former smoker who stopped smoking for less 
than 6 months before the time of the Screening Visit
16. Intake of grapefruit, Seville orange, cranberry or juices of these fruits, or St John’s Wort, from 
14 days prior to Day -1 of Period 1
17. Inability to communicate or cooperate with the Investigator (eg, language problem, illiteracy, 
poor mental status) or to comply with the requirements of the entire study, including dietary 
restrictions 
18. Other factors, which in the opinion of the Investigator may interfere with study conduct (at 
Screening and Day -1 of Period 1 only)
19. Legal incapacity or limited legal capacity
20. Subjects kept in detention
5.4
Criteria for Initiation of Trial Treatment
Inclusion and exclusion criteria will be checked within the screening period and again on Day -1 
of Period 1. Subjects meeting all the inclusion and none of the exclusion criteria will be 
randomized to a treatment sequence on Day 1 of the first treatment period.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Therapy 
A subject must be withdrawn from IMP administration if any of the following occur:
The subject requires treatment with any medication suspected or known to interfere with the 
IMP 
The subject is suspected or known not to comply with the protocol directives (use of prohibited 
medication, noncompliance with the sampling schedule, nonadherence to dietary rules, and 
nonattendance at study assessments).
Withdrawal of a subject from study drug due to any of the above reasons means that this subject 
prematurely discontinues the study, ie before completion of the full profiling and all safety 
investigations. Subjects who dropped out, must be encouraged to attend the End of Trial 
examination for safety reasons (see Table 1).
Subjects who dropped out will not be replaced as per design specificity. A drop-out compensation 
of 2 subjects has been added. 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 25 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
25/65
5.5.2
Withdrawal from the Trial
Subjects must be withdrawn from the trial by the Investigator at any time for any of the following 
reasons:
Subject withdrew consent
Subject lost to Follow-up
Participation in another clinical study 
Relevant adverse events (AEs), especially SAEs, occur that do not justify the subject’s 
continuation in the study
Pregnancy
Protocol noncompliance judged as significant by the Investigator and/or Sponsor
Use of a non-permitted concomitant drug as defined in Section 6.5.2. However, any medications 
that are considered necessary for the subject’s well-being (eg paracetamol up to 1500 mg per 
day) may be given at the discretion of the Investigator
Subject is no longer able to participate for other medical reasons (eg surgery, intercurrent 
illness)
Any other condition which to the opinion of the Investigator no longer justifies or permits a 
safe participation of the subject
Any of the following individual stopping criteria is met unless deemed unrelated to the IMP by 
the Investigator with alternate etiology identified:
o Abnormal clinically relevant vital signs confirmed on 2 or more measurements 
(minimum 5 min intervals), including abnormal blood pressure 
-
hypotension defined as systolic < 80 mmHg and/or diastolic < 40 mmHg, or
-
hypertension defined as systolic > 160 mmHg and/or diastolic > 100 mmHg 
o Abnormal clinically relevant ECG findings, including a corrected QT-interval (ad modus 
Fridericia; QTcF) > 500 ms or an increase in QTcF > 60 ms compared to baseline, confirmed 
on ≥2 repeat measurements
o Marked increases in liver or renal parameters (ALT/AST ≥3 x ULN, total bilirubin ≥2 x 
ULN, creatinine ˃ 1.5 x ULN confirmed by ≥2 repeat measurements
o Any clinically relevant symptom or sign which in the opinion of the investigator and/or 
sponsor warrants subject withdrawal.
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 26 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
26/65
In case a subject should be withdrawn from the trial, the medical monitor and clinical trial leader 
at the Sponsor will be informed immediately. If there is a medical reason for the withdrawal, 
appropriate medical care will be provided.
In case of premature withdrawal from the trial, the assessments scheduled for the last End of Trial 
Visit should be performed, as Early Termination Visit, if possible with focus on the most relevant 
assessments (see Table 1). In any case, the appropriate electronic case report form (eCRF) section 
must be completed.
Subjects who withdraw from the trial prior to the first administration of IMPs, or for any reason 
do not have a full PK dataset may be replaced. A discussion should occur between the Investigator 
and the Sponsor regarding whether a replacement may be considered.
5.6
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for any IMP. 
The Sponsor may discontinue the trial if it becomes unjustifiable for medical or ethical reasons, 
for poor enrolment, or because of discontinuation of clinical development of an IMP or withdrawal 
of an IMP or comparator from the market for safety reasons.
Health Authorities and IECs will be informed about the discontinuation of the trial in accordance 
with applicable regulations.
5.7
Definition of End of Trial
The End of Trial is defined as the last contact (related to this trial) with the last subject who 
participates in this study (last subject’s End of Trial Visit, independent of whether the subject is in 
End of Trial Visit or discontinued from the study).
A clinical trial protocol may not be considered closed as long as:
Any subject is still receiving any IMP
Visits specified by the protocol are still taking place
Procedures or interventions according to the protocol are still being undertaken in any subject 
The post-treatment follow up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 27 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
27/65
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
6.1
Description of the Investigational Medicinal Products
Investigational Medicinal Products: 
Tepotinib 
(MSC2156119J), 
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-
benzyl}-1,6-dihydro-6-oxo-pyridazin-3-yl)-benzonitrile hydrochloride hydrate (HCl), is supplied 
as
250 mg white-pink, oval, biconvex tablet with embossment “M” on one side TF3 for oral 
administration (reference treatment)
Tepotinib 250 mg film-coated tablets (TF3) have a drug load of approximately 30% and contain 
the excipients D-mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, silica 
colloidal anhydrous, and Opadry® II pink.
100 mg white-yellow, round, biconvex tablets with embossment “M” on one side TF3 for oral 
administration (test treatment). 
Tepotinib 100 mg film-coated tablets (TF3) have a drug load of approximately 30% and contain 
the excipients D-mannitol, silica colloidal anhydrous, crospovidone, magnesium stearate, and 
Opadry II yellow.
All excipients used in the tablet formulations are of compendial grade. Supplier’s certificates show 
that there is no transmissible spongiform encephalopathy risk. Tepotinib is provided in aluminum 
(ALU/ALU) blisters and storage is at or below 25°C.
For dosage and administration see Section 6.2.
Reference product: Not applicable.
Specific rules for treatment modifications: Not applicable.
6.2
Dosage and Administration
In the two treatment periods, the subjects will receive the following single administrations of 
tepotinib in randomized order:
5 film-coated tablets TF3 containing 100 mg tepotinib, with a total dose of 500 mg (test 
treatment)
2 film-coated tablets TF3 containing 250 mg tepotinib, with a total dose of 500 mg (reference 
treatment)
Both treatments will be administered in the fasted state (after at least 10 h fasting) together with 
200 mL of water.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 28 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
28/65
The minimum washout period will be at least 21 days between Day 1 of each period to prevent 
any significant PK carryover effects between periods.
Subjects will be administered the tablet formulation in upright position. 
In both periods subjects will stay in a semi-recumbent position for 4 h post-dose, except for use of 
the toilet, when the subjects will be allowed to leave the bed without undue physical stress/activity.
Food intake is not allowed for 4 h after IMP administration. Further drinking is not allowed from 
1 h before to 1 h after IMP administration.
Standardized meals will be served approximately 4 h (lunch), 8 h (snack) and 10 h (dinner) after 
administration of tepotinib; thereafter, meals will be served at customary times during the in-
patient period.
6.3
Assignment to Treatment Groups
Only subjects who comply with all selection criteria will be included into the trial. Prior to the first 
administration, the subjects enrolled into the trial will be randomly assigned to 1 of 2 treatment 
sequences, via the random number on Day 1 of Period 1 (see Section 8.3).
According to CRO standard operational procedures (SOPs), the subjects will be assigned to the 
random number in the order of their registration to the study (first registration results in the lowest 
available random number, second registration results in the second lowest available random 
number, and so on). However, precedence will be given to subjects who participate in a trial at 
 for the first time and for subjects who served as “stand-by” during a preceding 
trial. 
The Investigator will keep a record relating the subjects’ random numbers and the names of all 
subjects (including screening number and the Nuvisan GmbH ID number) who have given their 
informed consent, to allow easy checking of data in subject files, when required. This record will 
also include the date of subject’s enrolment and completion, as well as subjects who could not be 
randomized for whatever reason.
6.4
Non-investigational Medicinal Products to be Used
Not applicable.
6.5
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
route, duration, regimen, status and indication of each drug. Nondrug interventions and any 
changes to a concomitant medication or other intervention should also be recorded in the eCRF.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 29 of 66
PI

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
29/65
6.5.1
Permitted Medicines
Paracetamol is the only permitted medication. Paracetamol will be permitted up to a maximum 
daily dosage of 1500 mg. 
Any medications that are considered necessary to protect subject welfare and that will not interfere 
with the IMP may be given at the Investigator’s discretion. The potential drug-drug interactions 
with tepotinib are still under evaluation. Therefore, medically required concomitant medication 
might have to be adjusted based on tolerability and the clinical response.
The Investigator will record, in the appropriate section of the eCRF, all previous/concomitant 
medications taken by the subject during the study from the date of signature of informed consent.
6.5.2
Prohibited Medicines
The subjects are prohibited from using prescription or over-the-counter medications (apart from 
paracetamol up to 1500 mg per day, as judged appropriate by the Investigator) within 14 days or 
5 half-lives, whichever is longer, prior to the first IMPs administration during the trial, and until 
after the End of Trial Visit.
6.5.3
Permitted / Prohibited Procedures
Subjects should drink about 2 L fluids per day during the hospitalization phase (as provided by the 
site) and will be reminded regularly.
Throughout the PK profiling day, the following restrictions must be met:
Subjects will be in the fasted state for at least 10 h before administration of tepotinib 
Drinking is not allowed 1 h before and after administration of tepotinib (except for the 
administration)
Chewing gum is not allowed during the PK profile days.
Throughout the study, the following restrictions must be met:
No smoking or use of tobacco products
No alcohol intake
No intake of food or beverages other than that provided to the subjects by the trial site during 
the in-patient period
No intake of caffeine- and xanthine-containing food and beverages (eg coffee, black or green 
tea, cola, cocoa, chocolate or chocolate-containing food or beverages) from 48 h before 
administration of tepotinib in each period until collection of last PK blood sampling of each 
period
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 30 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
30/65
No intake of herbs or fruits that can have an influence on the PK (eg St. John’s wort, Seville 
oranges, grapefruits, cranberry or the juice of these fruits), from 14 days prior to Day -1 of 
Period 1 until final examination
No intake of poppy seeds (eg poppy seed rolls, poppy seed cake, yoghurt containing poppy seed 
etc.) from 72 h before first administration of study drug until completion of final examination
No intake of concomitant medication within 14 days or 5 half-lives, whatever is longer, before 
first administration of study drug until final examination (except for paracetamol up to 1500 mg 
per day, may be given at the discretion of the Investigator) 
No intake of recreational drugs within 14 days or 5 half-lives, whatever is longer, before first 
administration of study drug until final examination
No exhausting physical activities (body building, sports) from at least 72 h before the first 
administration of study drug until the final examination 
No sun baths, solarium, or sauna at least 12 h before first administration of study drug until 
final examination.
6.5.4
Other Interventions
Not applicable.
6.5.5
Special Precautions
Not applicable.
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions
No specific measures are proposed at this stage. Standard medical care will be provided at the 
study site for all AEs occurring during the study.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
The investigational product tepotinib will be provided by the Sponsor packed in ALU/ALU blister.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
The pharmacy or designee will receive the IMPs labeled and packaged according to the local 
regulatory requirements and the storage requirements. Tepotinib will be supplied in ready to use 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 31 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
31/65
oral formulations. The responsible pharmacist will dispense the necessary amount of the IMPs. 
Detailed guidance will be provided in an IMP handling manual.
The IMP supplies will be recorded in an IMP inventory.
Tepotinib must be carefully stored at the trial site in a closed room or cabinet with restricted access, 
safely and separately from other drugs and protected from environmental extremes until used in 
the trial. Tepotinib should be stored at or below 25°C. Any deviations from the recommended 
storage conditions should be immediately reported to the Sponsor, and the IMP should not be used 
until authorization has been received from the Sponsor. The preparation, handling and storage of 
the IMP will be documented.
The IMPs must not be used for any purpose other than the trial in question.
It must be ensured at the trial site that the IMPs are not used after the use-by date. This is to be 
closely monitored by the responsible monitor.
6.8
Investigational Medicinal Product Accountability
The Clinical Trial Supply Department of Nuvisan GmbH is responsible for ensuring IMP 
accountability, including reconciliation of drugs and maintenance of records. Drug accountability 
will also be confirmed by the Trial Monitor.
Upon receipt of IMPs, 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
IMP dispensing will be recorded on the appropriate drug accountability forms so that accurate 
records will be available for verification at each monitoring visit.
Trial site IMP accountability records will include the following:
-
Confirmation of IMP receipt, in good condition and in the defined temperature range
-
The inventory of IMPs provided for the clinical trial and prepared at the site
-
The use of each dose by each subject
-
The disposition (including return, if applicable) of any unused IMP
-
Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP prepared 
at the site), and the individual subject trial numbers.
The Investigator site 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 trial. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
A Trial Monitor will periodically collect the IMP accountability forms. 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 32 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
32/65
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
During the treatment periods, drug administrations will be performed by a Nuvisan GmbH staff 
member in accordance with the specifications of the Investigator. This includes checking the oral 
and buccal cavity with the aid of a flashlight and tongue depressor. The proper administration of 
the trial medication will be documented on the individual eCRF.
6.10
Blinding
This is an open-label study by design. Therefore, blinding is not applicable. (Note: the bioanalytics 
will be performed without knowledge of treatment information. Access to treatment 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 trial 
protocol or planned for an individual subject enrolled in the trial. Even if it does not meet other 
criteria for an SAE, any overdose must be recorded in the trial 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 of tepotinib 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 judgment for the management of any clinical symptoms or evaluation results.
6.13
Medical Care of Subjects after End of Trial
Not applicable in a trial with healthy subjects.
7
Trial Procedures and Assessments 
7.1
Schedule of Assessments
Study procedures are the same for both periods. A detailed schedule of trial 
procedures/assessments is provided in Table 1.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 33 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
33/65
Prior to performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2.
7.1.1
Screening Examination
All subjects will undergo an entry examination to evaluate their health status and their eligibility 
for inclusion in the study. The Screening examination will be conducted not more than 21 days 
prior to the planned first drug administration, ie between Day -21 to Day -2 before commencing 
to first study period. Only subjects who meet the inclusion criteria and none of the exclusion 
criteria will be admitted to the trial. 
Prior to Screening examination, the subjects will receive a screening number for identification. 
Eligible subjects will receive a random number upon enrolment into the study. 
There is a notification on the subject’s card as well as in the electronic subjects’ data base on the 
last participation in a trial. In addition, all subjects are reported to a central checking organization 
(VIP Check) before inclusion into the trial.
Prior to any Screening examinations the subjects must sign the Informed Consent Form (ICF). 
At Screening (Days -21 to -2), the following assessments will be performed (Table 1):

Recording of demographic information including body height, body weight and BMI

Recording of medical history

Physical examination

Measurement of vital signs

12-lead safety ECG recording

Blood and urine sampling for safety laboratory assessments

Serological tests for hepatitis B, C, and HIV1/HIV2 and coagulation tests

Serum Pregnancy test (for females)

Urine drug screen (including test for cotinine)

Alcohol breath test

Assessments of AEs

Documentation of prior and concomitant medication

Preliminary evaluation of inclusion and exclusion criteria.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 34 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
34/65
7.1.2
Treatment Periods
The subjects willing to participate in the trial will only be included when all Screening examination 
procedures have demonstrated that all inclusion criteria and none of the exclusion criteria apply. 
Subjects will be assigned to a random number within the trial prior to the first administration. 
For time points and assessments please refer to Table 1.
Day -1 (Admission)
Subjects will be admitted to the clinic in the morning of Day -1 until completion of the 72 h 
assessments in the morning of Day 4 of each period.
In each period, the following assessments will be performed:

Physical examination

Measurement of vital signs 

12-lead safety ECG recording (as triplicate)

Blood and urine sampling for safety laboratory assessments 

Pregnancy test (in urine)

Urine drug screen (including test for cotinine) 

Alcohol breath test

Assessment of AEs

Documentation of concomitant medication

Evaluation of inclusion and exclusion criteria (Period 1 only)

Blood sampling for PGx (Period 1 only).
Days 1 to 4 (inpatient)
Prior to dosing on Day 1 the following assessments will be done:

Measurement of vital signs 

12-lead safety ECG recording

Blood and urine sampling for safety laboratory assessments 

Pre-dose PK blood sample for determination of tepotinib and its metabolites. 
After completion of pre-dose assessments study drug will be administered in the morning of Day 1 
of each period as the following: 
Study drug will be administered in both periods in the fasted state together with 200 mL of water.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 35 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
35/65
A detailed guidance on dosage and administration is provided in Section 6.2.
After dosing the following assessments will be performed at the time points given in the Schedule 
of Assessments (Table 1):

PK blood samples for determination of tepotinib and its metabolites will be taken regularly 
until 72 h (Day 4) post-dose before discharge (for time points please refer to Table 1)

Measurement of vital signs and 12-lead safety ECG recordings on Day 1 (2 h and 8 h post-
dose), Day 2 and Day 4 before discharge

Blood and urine sampling for safety laboratory assessments on Day 2 and Day 4 before 
discharge

Physical examination (only on Day 2 and Day 4 before discharge)

Regular assessment of AEs and concomitant medication.
After completion of the Day 4 assessments (72 h measurements) subjects will be discharged.
Days 5 to 8 (ambulatory)
Subjects will return to the clinic for daily blood sampling to determine the PK of tepotinib and its 
metabolites. Additionally, AEs will be monitored and concomitant medications will be recorded.
The washout period will be at least 21 days between Day 1 of each period (see Figure 2).
Restrictions:
A detailed listing of restrictions during the trial is provided in Section 6.5.
7.1.3
End of Trial Visit
The End of Trial examination has to verify that all values tested in the Screening have remained 
within a clinically acceptable range. The assessments will be performed 21 days (± 1 day) after 
tepotinib administration in the second period. Unacceptable values and AEs will be followed up 
until they return to the reference ranges/resolved or there is an adequate explanation which is not 
related to the trial.
The following assessments will be performed:

Physical examination

Measurement of vital signs 

12-lead ECG recording

Blood and urine sampling for safety laboratory assessments 

Serum Pregnancy test (for females)
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 36 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
36/65

Assessment of AEs

Documentation of concomitant medication.
No medical treatment is planned after the End of Trial.
The End of Trial is defined as the last contact (related to this trial) of the last subject undergoing 
the trial.
7.2
Demographic and Other Baseline Characteristics
At Screening, the following demographic data will be collected: date of birth, sex (gender), race, 
ethnicity, height, weight, and BMI.
Furthermore, the following will be documented:
Clinically relevant findings in the medical history are recorded
Prior medication within 14 days of Screening and concomitant medication at Screening (any 
prescribed medicine or over-the-counter drug or dietary supplement including herbal remedies, 
vitamins, and minerals)
Smoking status, alcohol intake
Female status (postmenopausal, sterilization).
7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. 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.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 37 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
37/65
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 Investigator is required to grade the severity or toxicity of each AE. Investigators will 
reference the National Cancer Institute (NCI) - Common Terminology Criteria for AEs 
(CTCAE), version 5.0 (publication date: 27 Nov 2017), a descriptive terminology that can be used 
for AE reporting. A general grading (severity/intensity; hereafter referred to as severity) scale is 
provided at the beginning of the above referenced document, and specific event grades are also 
provided. If the severity of a particular AE is not specifically graded by the guidance document, 
the Investigator is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 
following his or her best medical judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe 
Grade 4 or Life-threatening 
Grade 5 or Death. 
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as hemoglobin decreased 
or neutrophils count decreased, 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 (eg, 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 (including 
any other non-IMPs, or medical procedures, as applicable, etc.) using the following definitions. 
Decisive factors for the assessment of causal relationship of an AE to the IMP include, but may 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 38 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
38/65
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, trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under trial in 
this clinical trial protocol. A reasonable alternative explanation must be available
Related:
Reasonably related to the IMP. AE could medically (pharmacologically/clinically) 
be attributed to the IMP/study treatment under trial in this clinical trial 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 Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) 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
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
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 39 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
39/65
Elective hospitalizations to administer, or to simplify trial treatment or trial 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 initial study 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.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial 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. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs and all non-serious AEs of special interest 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 trial treatment, 
any other potential causal factors, any treatment given or other action taken, including dose 
modification or 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 and Monitoring Conventions.
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 
trial (date of first signature of informed consent) and continues until the End of Trial 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. 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 40 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
40/65
7.4.1.4
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 h after becoming aware of the event) inform the Sponsor 
or its designee in writing. All written reports should be transmitted using the SAE Report Form, 
which must be completed by the Investigator following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the trial-specific 
SAE Report Form. 
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.
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.
Adverse Events of Special Interest
Healthy subjects might experience asymptomatic elevations in serum lipase and amylase. Any 
elevation in serum lipase and amylase of Grade ≥3 will lead to the recording of an AE of special 
interest (AESI). The severity of these AEs should be defined based on clinical judgment of the 
Investigator and defined according to NCI-CTCAE Severity Scale. 
In the event of a non-serious AESI, the Investigator will complete the AESI Report Form and send 
it to the sponsor/designee within 24 h after becoming aware of the event. Serious AESIs must be 
reported in an expedited manner as SAEs as outlined above.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 41 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
41/65
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC that approved the trial.
In accordance with ICH GCP [7], the Sponsor/designee will inform the Investigator of “findings 
that could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s 
approval/favorable opinion to continue the trial. In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” [SUSARs]). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications. When direct reporting is not clearly defined by national or site-specific regulations, 
the Investigator will be responsible for promptly notifying the concerned IEC of any Safety 
Reports provided by the Sponsor/designee and of filing copies of all related correspondence in the 
Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive 
and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
AEs are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) and are 
assessed for final outcome at the End of Trial Visit. All SAEs ongoing at the End of Trial Visit 
must be monitored and followed up by the Investigator until stabilization or until the outcome is 
known, unless the subject is documented as “lost to follow-up”. Reasonable attempts to obtain this 
information must be made and documented. It is also the responsibility of the Investigator to ensure 
that any necessary additional therapeutic measures and follow-up procedures are performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example, 
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. This 
study does not allow inclusion of females of child-bearing potential under hormonal contraception.
However, all 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 same rule applies 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 42 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
42/65
to pregnancies in female partners of male subjects. The Investigator must notify the 
Sponsor/designee in an expedited manner of any pregnancy using the Pregnancy Report Form, 
which must be transmitted according to the same process as described for SAE reporting in Section 
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 trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Fasted blood and urine samples will be collected for the clinical laboratory tests (hematology, 
biochemistry, coagulation, virology, drugs of abuse, hormones, and urinalysis) following the 
timing noted in the Schedule of Assessments (Table 1). Additional laboratory safety examinations 
during the course of the trial are at the discretion of the Investigator. 
All blood and urine samples must be clearly identified and will be worked up and analyzed in 
Nuvisan's clinical laboratory. Any abnormalities in any of the laboratory parameters will be judged 
by a physician individually in relation to the reference ranges from the laboratory.
The Sponsor should receive a list of laboratory normal ranges before shipment of the IMP. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor, including 
laboratory certificates.
All safety laboratory examinations will be carried out under fasting conditions. Some additional 
parameters may be routinely analyzed by the laboratory after abnormal findings, or requested by 
the Investigator, including but not limited to eg microscopic differential blood count, direct 
bilirubin and creatine phosphokinase myocardium/brain type.
In case of positive findings of blood, protein, nitrite or leucocytes in the urinalysis, a subsidiary 
microscopic examination of the sediment will be performed.
For all findings with major deviation and/or possible pathological relevance, follow-up 
examinations will be carried out until the deviation returns to normal or the absence of pathological 
relevance can be confirmed. If a deviation considered clinically relevant has not returned to a 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 43 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
43/65
normal or not clinically relevant value when it is checked during the screening laboratory tests, the 
subject will not be included in the trial. Laboratory abnormalities considered clinically relevant by 
the Investigator will be reported as AE. 
Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at Screening, on Day -1 and at the end of relevant systemic exposure of the study 
intervention to confirm non-pregnant status of female participants as per Inclusion Criteria
(Section 5.3.1) the study.
The following parameters will be determined as summarized in Table 2.
The amount of blood sampled in this trial is specified in Appendix II.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 44 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
44/65
Table 2
Clinical Laboratory Evaluations
Biochemistry
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyl-transferase
Lactate dehydrogenase
Creatine phosphokinase b
Amylase
Lipase
Bilirubin (total) a
Cholesterol
Triglycerides
Uric acid
Sodium
Potassium
Creatinine
Urea
Glucose
Cystatin C (if applicable)
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 c:
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils 
Coagulation
Prothrombin Time (PT) 
International Normalized Ratio (INR)
Activated partial thromboplastin time (aPTT)
Urinalysis 
pH
Nitrite
Protein 
Glucose
Ketone bodies
Urobilinogen 
Bilirubin
Urine pregnancy 
test, females only
Leucocytes
Blood
Microscopic examination d
Urine drug screen
Cocaine
Amphetamines
Methamphetamines
Opiates
Barbiturates
Benzodiazepine
Methadone
Cannabinoids
Tricyclic antidepressants
Cotinine
Ecstasy
Other tests
Hepatitis B surface antigen
Hepatitis C antibody
HIV1/HIV2 antibodies
Follicle stimulating hormone (if applicable, females only to confirm post-menopausal status)
Thyroid stimulating hormone
Serum beta-HCG pregnancy test (females only)
eGFR e
Alcohol breath test
eGFR = estimated glomerular filtration rate, HIV = human immunodeficiency virus, beta-HCG = beta-human chorionic 
gonadotropine
a
In case of an increased bilirubin (total) the direct bilirubin will be determined. 
b
In case of an increased creatine phosphokinase (CK), myocardium/brain type (CK-MB) will be determined; if 
the ratio of CK/CK-MB is above 6, troponin will be determined as well.
c
In case of abnormal findings, manual differential blood count can be requested by the Investigator.
d
Only if blood, protein, nitrite, or leukocytes are positive on the dipstick.
e
Estimated glomerular filtration rate calculated using the Cockcroft-Gault equation.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 45 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
45/65
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Blood pressure (systolic blood pressure [mmHg] and diastolic blood pressure [mmHg]) will be 
measured per the oscillometric method using an automated device, which also indicates the 
corresponding pulse rate. Blood pressure and pulse rate will be measured after at least 5 min in a 
supine position, according to the Schedule of Assessments (see Table 1).
Body temperature will be measured auricular.
Further vital sign measurements during the trial are at the discretion of the Investigator.
7.4.4.2
Physical Examination
A standard examination will be performed including general appearance, skin, head, neck 
(including thyroid), eyes, ears, nose, throat, abdomen, as well as neurological, peripheral vascular, 
musculoskeletal, cardiovascular and pulmonary system. 
Physical examination will be scheduled according to the Schedule of Assessments (see Table 1). 
Further physical examinations during the trial are at the discretion of the Investigator. Any relevant 
findings are to be recorded on the Medical History form in the eCRF (for findings from the past 
that occurred prior to ICF signature) or on the AE form in the eCRF (for findings presently 
occurring; events existing but unresolved prior to drug administration).
7.4.4.3
Electrocardiogram 
12-lead ECGs will be recorded according to the Schedule of Assessments (see Table 1) using the 
ECG system Cardio Perfect®, Welch Allyn. The ECGs will be recorded in a supine position after 
at least 5 min rest. 
Per time-point, the ECG will be stored electronically, printed and reviewed in a timely manner by 
the Investigator. The original printout will be stored with the subject’s source data. Electronic data 
may be transferred to a central ECG laboratory for central reading and further analysis; these 
results would be reported separately.
ECG printouts will be signed and dated electronically by the person evaluating the ECG. The ECG 
will be interpreted by the Investigator (normal/abnormal). For abnormal ECGs, the clinical 
significance (yes/no) must be judged by the Investigator and the abnormality is to be specified.
Additional ECGs during the trial are at the discretion of the Investigator.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 46 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
46/65
7.4.4.4
Alcohol Breath Test
A commercially available breath analyzer (Alcotest 6510, Draeger Safety GmbH) will be used to 
determine the concentration of alcohol in the subject’s breath according to the Schedule of 
Assessments (see Table 1). 
Additional alcohol breath tests during the trial are at the discretion of the Investigator.
7.5
Pharmacokinetics
7.5.1
Blood Sampling
On the PK profiling day, an indwelling venous catheter will be positioned in a suitable forearm 
vein for blood sampling and should be kept, if possible, until at least 24 h after dosing. After 
removing the indwelling venous cannula, samples will be taken by venipuncture.
At visits where assessment time points coincide with each other, the vital signs and ECG 
assessments should be performed slightly before the specific time point and the PK blood sampling 
should be performed on time.
Plasma concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A will 
be determined in each period according to the sampling schedule outlined in the Schedule of 
Assessments (see Table 1). The exact date and time of sample collection must be recorded in the 
eCRF and will be used in the calculation of PK parameters. Blood samples should be taken as 
close as possible to the scheduled time points. Samples taken outside of the time periods shown in 
Table 3 need an explanation and will be considered as protocol violation.
Table 3
Time Windows
Planned Blood Sampling
Time Windows (min)
Pre-dose
- 60
0.25 - 1 h post-dose
± 2
> 1 h - 12 h post-dose
± 5
> 12 h - 48 h post-dose
± 15
> 48 h - 168 h post-dose
± 30
Concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A will be 
measured using a validated liquid chromatography-tandem mass spectrometry method at Nuvisan. 
The assays will be carried out in accordance with the applicable Good Clinical Practice and Good 
Laboratory Practice regulations and the EMA reflection paper. A separate bioanalytical protocol 
will be provided before the start of the analytical part of the trial. Full details of the bioanalytical 
method used will be described in a separate bioanalytical report.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 47 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
47/65
7.5.2
Calculation of Pharmacokinetic Variables
Noncompartmental computation of PK parameters will be performed using the software Phoenix® 
WinNonlin® 6.4 or higher (Certara, L.P., Princeton, New Jersey). For definitions of PK 
parameters, see Table 4.
Table 4
Definition of PK Parameters for Tepotinib and its Metabolites After 
Single Dose Administration
Symbol
Definition
AUC0-t
Area under the plasma concentration-time curve (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 (LLOQ), calculated per the mixed log linear trapezoidal rule (ie linear up/log 
down)
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing time) 
extrapolated to infinity, calculated as AUC0-t + AUCextra. AUCextra represents the 
extrapolated part of AUC0-∞ calculated by Clastpred/λz, where Clastpred is the predicted plasma 
concentration at the last sampling time point, calculated from the log-linear regression line 
for λz determination at which the measured plasma concentration is at or above LLOQ
Cmax
Maximum plasma concentration observed
tlast
The last sampling time at which the concentration is at or above the lower limit of 
quantification
tmax
Time to reach the maximum plasma concentration
t1/2
Terminal half-life, calculated as ln2/λz
λz
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 
Apparent total body clearance of drug from plasma following oral/extravascular 
administration, calculated as dose/AUC0-∞, only parent drug, will not be calculated for the 
metabolites
Vz/f 
Apparent volume of distribution during the terminal phase following oral/extravascular 
administration, will not be calculated for the metabolites
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra% = (AUCextra / AUC0-∞) x 100
Individual PK parameters will be calculated using actual sampling times. The pre-dose sample will 
be considered as if it had been taken simultaneously with the administration of study drug. PK 
variables will be evaluated and listed for all subjects who provide sufficient concentration-time 
data.
Concentrations below the lower limit of quantification (< LLOQ), which are before the last 
quantifiable data point, will be taken as zero for calculating the AUC.
7.6
Biomarkers
Biomarkers are not determined in this trial.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 48 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
48/65
7.7
Pharmacogenetics
Pharmacogenetic sampling is mandatory for trial participation. An additional separate ICF will be 
used. One blood sample should be collected in duplicate on Day -1 of the first treatment period 
prior to administration. The pharmacogenetic samples will be analyzed conditionally in case of 
unexpected PK profiles. The results of the PGx analysis, as applicable, will be described in a 
separate report.
Storage and analyses of samples will be handled according to the specifications described in the 
ICF.
7.8
Other Assessments
Not applicable.
8
Statistics
8.1
Statistical Hypotheses
The following null hypothesis for the ratio of the geometric means (GeoMean) will be used to 
assess bioequivalence
H0:
µT/µR ≤
or 1.2500 ≤µT/µR for at least one parameter (AUC0-t
or 
AUC0-∞or Cmax)
H1:
00 < µT/µR < 1.2500 for all parameters (AUC0-t and AUC0-∞and Cmax)
where µT and µR are the geometric means for the test and reference treatment respectively.
The test treatment is 5 tablets of the 100 mg dose strength of TF3 and reference treatment is 
2 tablets of the 250 mg dose strength of TF3, both under fasting condition. 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 49 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
49/65
8.2
Sample Size
The total and mixed intrasubject variability CVs (%) observed in study MS200095-0044 for
AUC0-t and Cmax of tepotinib are summarized in Table 5 (total and mixed intra-individual CV for 
AUC0-∞was very similar to that of AUC0-t and is not listed separately).
Table 5
Overview of the PK-Variability Observed in Tepotinib Study 
MS200095-0044
Study Part
Formulation
(Condition)
Arm
AUC0-t
Cmax
Total 
Geometric 
CV%
Mixed intra-
individual 
CV%
Total 
Geometric 
CV%
Mixed intra-
individual 
CV%
Part A
TF3 vs TF2 (fasted)
TF3 (fasted)
21.0
22.5
TF2 (fasted)
23.4
15.77
20.6
13.94
Part B
TF2 (fed versus fasted) 
TF2 (fed)
25.1
19.6
TF2 (fasted)
38.1
17.96
29.5
12.67
Part C
TF3 (fed versus fasted)
TF3 (fed)
25.0
17.0
TF3 (fasted)
19.8
14.93
15.3
16.79
AUC0-t = area under the plasma concentration-time curve from time zero to the last sampling time at which the 
concentration is at or above the lower limit of quantification, TF2/3 = tablet formulation 2/3; Cmax = maximum plasma 
concentration, CV = coefficient of variation.
Overall, the total variability in AUC and Cmax was between 15.3% and 25.0% for TF3. The mixed 
intrasubject variabilities of AUC and Cmax ranged between 12.67% and 17.96% across all 
investigated combinations of formulation and condition. 
Assuming that the within-subject variability for the comparison between the test and reference 
treatment will be similar to that of Part A in MS200095-0044 (i.e., CV% = 15.77), and with an 
assumed geometric mean ratio Test/Reference (GMR T/R) of 0.95, a one-sided alpha level of 0.05, 
16 evaluable subjects will be needed to provide approximatively 90% power to show 
bioequivalence. A drop-out compensation of 2 subjects will be added. In total, 18 subjects will be 
randomized. If the actual CV is up to 18.4%, the sample size of 16 evaluable subjects would still 
result in approximately 80% power to show bioequivalence.
8.3
Randomization
Refer to Section 6.3 for the technical and logistical aspects of treatment allocation. 
A total of 18 subjects will be randomized. Subjects will be randomized to 1 of 2 sequences at a 
ratio of 1:1:
Sequence 1: 5 x 100 mg (Test) – 2 x 250mg (Reference)
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 50 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
50/65
Sequence 2: 2 x 250 mg (Reference) – 5 x 100 mg (Test)
A computer-generated randomization scheme will be provided by Nuvisan GmbH CTS 
Department. 
8.4
Endpoints
8.4.1
Primary Endpoints
AUC0-t, AUC0-∞and Cmax of tepotinib calculated from concentration data obtained from time 
zero to 168 h post-dose of each period
8.4.2
Secondary Endpoints
tmax, t1/2, apparent total body clearance considering the fraction of dose absorbed (CL/f), and 
apparent volume of distribution during terminal phase (Vz/f) of tepotinib observed from time 
zero to 168 h post-dose of each period
Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of changes in 
safety laboratory assessments, 12-lead ECGs and vital signs.
8.4.3
Exploratory Endpoints
PK profiles of tepotinib metabolites: 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time zero to 168 h post-
dose of each period
Genetic variants and mutations in genes that potentially influence PK of tepotinib.
8.5
Analysis Sets
8.5.1
Safety Analysis Set
The Safety analysis set will be defined for each part and will include all subjects who have received 
at least 1 dose of planned IMP and have had 1 subsequent safety assessment. 
8.5.2
Definition of Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects without any relevant protocol deviations with respect 
to PK and absence of factors likely to affect the comparability of PK results, with adequate trial 
medication compliance, and who have valid primary endpoints for both treatments. 
All PK analyses will be based on this analysis set.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 51 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
51/65
8.6
Description of Statistical Analyses
8.6.1
General Considerations
Statistical analyses will be performed using the computer program package SAS® System for 
Windows™ (Version 9.4 or later; SAS Institute, Cary, North Carolina, USA).
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment and/or scheduled time point, as appropriate.
For demographic, baseline and safety assessments, continuous measurements will be summarized 
by means of descriptive statistics (ie number and percentage of observations, number and 
percentage of missing observations, mean, standard deviation [SD], median, 25th and 75th
percentiles, minimum, and maximum) and categorical data will be summarized by means of 
frequency tables (ie count and percentages), if not stated otherwise.
Concentrations of tepotinib and its metabolites in plasma will be presented in tables and 
descriptively summarized by treatment and nominal time point using n, arithmetic mean, SD, 
standard error of the mean, median, minimum, maximum, and CV%. Values below the LLOQ will 
be taken as zero for descriptive statistics of PK concentrations. Descriptive statistics of PK 
parameters will additionally show the GeoMean, the geometric coefficient of variation (GeoCV%), 
and the 95% CI for the GeoMean.
Graphical displays will be given, where appropriate. PK variables will be evaluated and listed for 
all subjects who provide sufficient concentration-time data. Invalid data will be flagged 
accordingly. 
Missing values will be handled as such and not be replaced by estimates.
Details of the statistical analysis will be described in the statistical analysis plan.
Changes in the conduct of the trial or planned analyses, if any, will be reported in the appropriate 
section of the statistical analysis plan (SAP) and in the clinical trial report.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 52 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
52/65
8.6.2
Analysis of Primary Endpoints
An analysis of variance (ANOVA) model will be fitted for the log-transformed PK parameters 
Cmax, AUC0-t, AUC0-∞based on the PK analysis set. The model will include treatment, period, 
sequence as fixed effects and subject within sequence as a random effect. 
Treatment differences on the log scale will be estimated for Cmax, AUC0-t, AUC0-∞together with 
their 90% CIs. Point estimates and CIs will be back-transformed to the original scale for the 
comparisons. 
The comparison will be the test treatment (5 x 100 mg TF3) vs the reference treatment (2 x 250 mg 
TF3) under fasting condition. 
The null hypothesis for non-bioequivalence will be rejected if the 90% CI for the ratio of the 
GeoMean lies within the interval 0.8000 to 1.2500 for all primary pharmacokinetic parameters. 
8.6.3
Analysis of Secondary Endpoints
Summary statistics will be provided for all secondary PK parameters in plasma by time point. 
Graphical displays will be given, where appropriate. Details of the statistical analysis will be 
described in the SAP.
8.6.4
Analysis of Safety and Exploratory Endpoints
Safety data analysis will be conducted on the Safety Analysis Set of each part. The number and 
percentage of subjects experiencing at least 1 TEAE will be summarized by treatment as will the 
number of events. Tables by relationship to study drug and by severity will be generated. AEs will 
be coded using Medical Dictionary for Regulatory Activities terminology. All laboratory data will 
be reported with SI units. 
Laboratory parameters will be summarized using descriptive statistics for absolute values and 
change from baseline over time, by post-dose shifts relative to baseline, and data listings of 
laboratory values/out of the normal range. 
Vital signs and ECG data will be summarized by changes from baseline values by treatment using 
descriptive statistics. Clinically significant ECG findings for individual subjects will be listed and 
summarized as appropriate.
PK concentrations will be descriptively summarized. Individual and mean concentration-timeplots 
will be produced in linear and log-linear scale.
Exploratory endpoints will be analyzed with descriptive statistics.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 53 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
53/65
8.7
Interim and Additional Planned Analyses
Not applicable.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP [7], and any other applicable regulations. The Investigator must ensure that 
only subjects who have given informed consent are included in the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which must be given before any trial-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 
[7] 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 trial, 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.
After the information is provided by the Investigator, the ICF 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 site, 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 
ICF 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 IEC 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 trial subject and obtain new written consent for continued 
participation in the trial. 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.
A separate subject information sheet will be prepared for the PGx testing. The subjects will be 
informed in the written form and verbally about pertinent aspects of the planned PGx testing 
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 54 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
54/65
including an explanation that this additional examination is mandatory for subjects’ participation 
in this clinical trial. Only subjects who have signed and dated the ICF for PGx testing will be 
included in this clinical trial.
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 trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial data to an individual subject via an identification list 
kept at the site. 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 Nuvisan GmbH for 
use during trial participation in order to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial 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 information provided on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, he/she will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators.
In cases where the Investigator is not available, the Phase 1 facility 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 Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for this trial. Insurance conditions will meet good local 
standards, as applicable.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 55 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
55/65
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents (including but not limited to Subject Information and ICF, 
insurance certificate, Investigator’s Brochure) to the responsible IEC 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.
The IEC 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 trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC, before 
implementation of substantial changes (see Section 10.5). Relevant safety information will be 
submitted to the IEC during the course of the trial in accordance with national regulations and 
requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, IMP Dossier, Subject 
Information and ICF) will be submitted or notified to the Health Authorities in accordance with 
all local and national regulations for each site.
10
Trial 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 trial 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 
trial 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 Sponsor or its designated organization contain no mention of any subject names.
The data will be entered into a validated database. Nuvisan GmbH 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 trial.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 56 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
56/65
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 trial. 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. 
Subject’s full name, date of birth, sex, height, weight
Medical history and concomitant diseases
Prior and concomitant therapies (including changes during the trial)
Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number
Dates for entry into the trial (informed consent) and visits to the site
Any medical examinations and clinical findings predefined in this clinical trial protocol
All AEs
Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
All documents containing source data must be filed, including, but not limited to 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.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial 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 trial, and must be safely archived for at least 
15 years after the end of the trial. The documents to be archived include the Subject Identification 
List and the signed subject ICFs. If archiving of the Investigator Site File is no longer possible at 
the site, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines [7], 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.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 57 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
57/65
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP [7] and any other applicable 
regulations. The site Monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, 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 Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantial amendments will 
usually require submission to the Health Authorities and to the relevant IEC for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by Nuvisan GmbH following the 
guidance in ICH Topic E3 [8].
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints. The results 
of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This 
allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results.
Posting of data on ClinicalTrials.gov and EudraCT is planned and will occur 12 months after the 
last clinic visit of the final trial subject or another appropriate date to meet applicable requirements.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 58 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
58/65
11
References Cited in the Text
1. Guidance for Industry; Bioavailability and Bioequivalence Studies submitted for NDAs or 
INDs – General Considerations. FDA CDER Office of Clinical Pharmacology, Mar 2014.
2. Guideline for Industry: Food-Effect Bioavailability Fed Bioequivalence Studies. FDA 
CDER. Dec 2002. 
3. EMA 
GUIDELINE 
ON 
THE 
INVESTIGATION 
OF 
BIOEQUIVALENCE. 
CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** London, 20 January 2010.
4. Guideline for Bioequivalence Studies for Different Strengths of Oral Solid Dosage Forms, 
PMDA 2012.
5. Guideline for Bioequivalence Studies of Generic Products, PMDA 2012.
6. Recommendations related to contraception and pregnancy testing clinical trials. Clinical 
Trial Facilitation Group (CTFG), Heads of Medicines Agencies. 15 September 2014. 
Downloaded from ‘www.hma.eu’ on 07 November 2017.
7. ICH 
Topic 
E6(R2) 
Guideline 
for 
good 
clinical 
practice 
E6(R2). 
EMA/CHMP/ICH/135/1995. London, 1 December 2016. 1-70.
8. ICH Topic E3. Structure and Content of Clinical Study Reports. CPMP/ICH/137/95, 
London July 1996. 1-47.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 59 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
59/65
12
Appendices
Appendix I
Signature Pages and Responsible Persons for the Trial
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 60 of 66

T e p o t i n i b  (  M S C 2 1 5 6 1 1 9 J )
M S 2 0 0 0 9 5 _ 0 0 3 8
Bi o e q ui v al e n c e of 5 t a bl et s of 1 0 0 m g v s 2 t a bl et s of 2 5 0 m g T F 3 of
t e p oti ni b
Si g n at ur e  P a g e  -  Pr ot o c ol  L e a d
T r i a l  T i t l e :
E u d r a C T  N u m b e r :
A n o p e n-l a b el, si n gl e- d o s e, r a n d o mi z e d, 2- p eri o d, 2-
s e q u e n c e  cr o s s- o v er,  si n gl e- c e nt er  P h a s e  I  tri al  i n
h e alt h y  s u bj e ct s  t o  a s s e s s  t h e  bi o e q ui v al e n c e  of
t e p oti ni b t a bl et f or m ul ati o n 3 a d mi ni st er e d a s 5 t a bl et s
of 1 0 0 m g v ers us 2 t a bl ets of 2 5 0 m g d os e str e n gt h.
2 0 1 9 - 0 0 3 5 7 8 - 1 3
Cli ni c al  Tri al  Pr ot o c ol  D at e  /  0 5- S e p- 2 0 1 9  /  V er si o n  1. 0
V e r si o n :
P r ot o c ol  L e a d:
I a p pr o v e t h e d e si g n of t h e cli ni c al tri al:
Si g n at ur e
N a m e, a c a d e mi c d e gr e e: 
D at e of Si g n at ur e
F u n cti o n  /  Titl e:
I n stit uti o n:
A d d r e s s:
Tel e p h o n e  n u m b er:
E- m ail  a d dr e s s:
M e di c al R e s p o n si bl e / 
M e r c k  H e a l t h c a r e  K  G a A
Fr a nkf urt er Str ass e 2 5 0, 6 4 2 9 3 D ar mst a dt, G er m a ny
D o c u m e nt  N o.  0 9 0 0 b a b e 8 1 2 c d 5 a 9 v  1. 0
O bj e ct  N o.  0 9 0 0 b a b e 8l 2 d 9 4 8 a
C
O
N
F I
D
E
N
T I
A
L
I
N
F
O
R
M
A
T I
O
N
6 0/ 6 5
PI
PI
PI
PI
PI
PI

PI
PI
PI
PI
PI
PI
PI
PI

Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce of 5 t a blets of 1 0 0 m g vs 2 t a blets of  25 0 m g T F 3 of 
te p oti ni b
M S 2 0 0 0 9 5 _ 0 0 3 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 2 /6 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:
F u ncti o n / Title:
I nstit uti o n:
Merc k Healt hcare 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:
E- mail a d dress:
Na me:
F u ncti o n / Title:
I nstit uti o n:
Merc k Healt hcare 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:
E- mail a d dress:
D oc u me nt N o. 0 9 0 0 ba be 8 1 2c d 5a 9 v 1. 0
O bject N o. 0 9 0 0 ba be 8 1 2 d 9 4 8a
Pa ge 6 3 of 6 6
PI
PI
PI
PI
PI
PI

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
63/65
Appendix II
Blood Volume Sampled in the Clinical Trial
Blood sample for
Amount 
per 
sample 
(mL)
Number of Scheduled Blood Samples per Subject
Total 
amount 
per 
Subject
(mL)
Screening Per Period
No. of 
Periods 
per Part
End of Trial 
Visit
Total
Clinical laboratory tests 
Biochemistry (incl. viral 
serology, TSH and FSH 
levels, if applicable)
4.7
1
4 a
2
1
10
47.0
Hematology
2.7
1
4 a
2
1
10
27.0
Coagulation
3.0
1
3.0
PK
2.0
22 b
2
44
88.0
PGx
2.0
2 c
2
4.0
Total
2
32
2
66
169.0
Note: the number of blood samples may increase above the scheduled number. Blood samples for 
clinical laboratory follow-up determinations may become necessary. Technical failure of PK/PGx blood 
drawing may lead the Investigator to decide immediately to repeat a single blood drawing to have a 
sample. 
Maximal blood volume drawn: Estimate per Subject in this Study 
that will not be exceeded in this planned trial as by experience of the Investigating Institution: 
200
FSH = follicle stimulating hormone, PGx = pharmacogenetics, PK = pharmacokinetics, TSH = thyroid stimulating 
hormone.
Clinical laboratory (biochemistry and hematology) blood samples:
a
Each period: on Day -1, pre-dose on Day 1, on Day 2 and before discharge on Day 4 = 4 samples;
PK blood samples for determination of tepotinib and its metabolites:
b
Each period: pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 
168 h post-dose = 22 samples;
PGx blood samples:
c
PGx blood samples of 2 x 2 mL to be drawn on Day 1 of Period 1 at pre-dose = 2 samples.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 64 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
64/65
Appendix III
Contraception Guidance
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, consider additional evaluation.
A WOCBP is not:
1. Premenarchal
2. A premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion applies to 
determine study entry.
3. A postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.

A high follicle-stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in a female not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, more than 1 FSH measurement is required in the 
postmenopausal range.

A female on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 65 of 66

Tepotinib (MSC2156119J)
Bioequivalence of 5 tablets of 100 mg vs 2 tablets of 250 mg TF3 of 
tepotinib
MS200095_0038
C O N F I D E N T I A L
I N F O R M A T I O N
65/65
Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency

Implantable progestogen-only hormone contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion

Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User DependentCombined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation

Oral

Intravaginal

Transdermal

Injectable

Progestogen-only hormone contraception associated with inhibition of ovulation

Oral

Injectable

Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study.
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study subjects.
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly.
Hormonal contraception may be susceptible to interaction with the study intervention(s), which may reduce the 
efficacy of the contraceptive method. As such, male condoms must be used in addition to hormonal 
contraception. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom cannot be used together (due to risk of failure with friction).
Document No. 0900babe812cd5a9v1.0
Object No. 0900babe812d948a
Page 66 of 66