Clinical trial NCT03531762
Conditions: Healthy
Keywords: Proton Pump Inhibitor Omeprazole Tepotinib Non-small cell lung cancer (NSCLC) Pharmacokinetics
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-05-14; Completion date: 2018-07-02
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This study was investigated in healthy participants (i) the effect of omeprazole (proton pump inhibitor) co-administration on the single dose pharmacokinetics (PK) of tepotinib under fed conditions, and (ii) the effect of food on the single dose PK of tepotinib after co-administration of omeprazole and tepotinib. Furthermore, the study assessed the safety and tolerability of tepotinib alone and upon co-administration of omeprazole.

Detailed description:

Arms: arm 1: Participants received single oral dose of 500 milligrams (mg) of Tepotinib alone in fed state on Day 1 of Treatment period 1 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 2 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment B) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 3 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment C). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations. arm 2: Participants received single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 1 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 2 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment C) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 3 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment B). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations. arm 3: Participants received single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 1 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment B) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 2 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 3 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment C). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations. arm 4: Participants received single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 1 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment B) followed by single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 2 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment C) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 3 (Treatment A). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations. arm 5: Participants received single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 1 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment C) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 2 (Treatment A) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 3 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 3 (Treatment B). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations. arm 6: Participants received single oral dose of 500 mg Tepotinib in fed state on Day 5 of Treatment period 1 with 40 mg omeprazole once daily on Day 1 to 5 of Treatment period 1 (Treatment C) followed by single oral dose of 500 mg Tepotinib in fasted state on Day 5 of Treatment period 2 with 40 mg of omeprazole once daily on Day 1 to 5 of Treatment period 2 (Treatment B) followed by single oral dose of 500 mg of Tepotinib alone in fed state on Day 1 of Treatment period 3 (Treatment A). A washout period of at least 14 days was maintained between the Tepotinib single dose administrations.
Interventions: intervention 1: Tepotinib intervention 2: Omeprazole
Intervention descriptions: intervention 1: Participants received single oral dose of 500 mg Tepotinib in Treatment A, B and C. intervention 2: Participants received omeprazole alone on Day 1 to 4 and co-administration of omeprazole with Tepotinib on Day 5 in Treatment B and C.

Protocol documents:
Prot_000.pdf: 
Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Effect of a pr ot o n p u m p i n hi bit or o n t he P K of T e p oti ni b
M S 2 0 0 0 9 5- 0 0 3 9
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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 9
Title
P hase I, O pe n -la bel, T hree -Peri o d Cr oss o ver St u d y 
t o I nvesti gate t he Effect of a Pr ot o n P u m p I nhi bit or 
( O me praz ole) o n t he P har mac o ki netics of Te p oti ni b 
i n Healt h y S u bjects
P h ase
I
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 7- 0 0 2 8 3 2- 1 8
Pri nci p al I n vesti g at or
,
 
, Ger ma n y
S p o ns or
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
Me dical Res p o nsi ble:
, 
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
P h o ne:
M o bile: 
Cli nic al Tri al Pr ot oc ol Versi o n
1 1 A pril 2 0 1 8 / 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 G a A, Dar msta dt, Ger ma n y, 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 m a y  not – i n f ull or part – be passe d o n, repr 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 G a A, Dar msta dt, Ger ma n y,  or its 
s u bsi diar y. C o p yri g ht © 2 0 1 8 b y  Merc k KG a A, Dar msta dt, Ger ma n y, or its s u bsi diar y. All ri g hts 
reser ve d.
D o c u me nt N o. 
O bject N o. 
0 9 0 0 ba be 8 0 d 1 6 d 7 4 v 2. 0
0 9 0 0 ba be 8 0f 4c 5 4 9
PI
PI
PI
PI
PI
PI
PI


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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................5
Table of In-Text Figures......................................................................................................5
List of Abbreviations ...........................................................................................................6
1
Synopsis................................................................................................9
2
Sponsor, Investigators and Trial Administrative Structure ................17
3
Background Information.....................................................................17
3.1
Trial Rationale ....................................................................................19
4
Trial Objectives ..................................................................................20
4.1
Primary Objective...............................................................................20
4.2
Secondary Objectives .........................................................................21
4.3
Exploratory Objectives .......................................................................21
5
Investigational Plan ............................................................................21
5.1
Overall Trial Design and Plan ............................................................21
5.2
Discussion of Trial Design .................................................................23
5.2.1
Inclusion of Special Populations ........................................................23
5.2.2
Scientific Rationale for Trial Design..................................................23
5.2.3
Justification for Dose..........................................................................24
5.2.4
Rationale for Endpoints......................................................................24
5.3
Selection of Trial Population..............................................................25
5.3.1
Inclusion Criteria ................................................................................25
5.3.2
Exclusion Criteria...............................................................................26
5.4
Criteria for Initiation of Trial Treatment ............................................27
5.5
Criteria for Subject Withdrawal..........................................................27
5.5.1
Withdrawal from Trial Treatment ......................................................27
5.5.2
Withdrawal from the Trial..................................................................27
5.6
Premature Termination of the Trial ....................................................29
5.7
Definition of End of Trial...................................................................29
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................29
6.1
Description of the Investigational Medicinal Product........................29
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6.2
Dosage and Administration ................................................................30
6.3
Assignment to Treatment Groups.......................................................31
6.4
Non-investigational Medicinal Products to be Used ..........................31
6.5
Concomitant Medications and Procedures .........................................31
6.5.1
Permitted Medicines...........................................................................32
6.5.2
Prohibited Medicines..........................................................................32
6.5.3
Permitted/Prohibited Procedures ........................................................32
6.5.4
Other Interventions .............................................................................33
6.5.5
Special Precautions.............................................................................33
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................33
6.6
Packaging and Labeling of the Investigational Medicinal Product....33
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................34
6.8
Investigational Medicinal Product Accountability.............................34
6.9
Assessment of Investigational Medicinal Product Compliance .........35
6.10
Blinding ..............................................................................................35
6.11
Emergency Unblinding.......................................................................35
6.12
Treatment of Overdose .......................................................................35
6.13
Medical Care of Subjects after End of Trial.......................................36
7
Trial Procedures and Assessments......................................................36
7.1
Schedule of Assessments....................................................................36
7.1.1
Screening Examination.......................................................................36
7.1.2
Treatment Periods...............................................................................37
7.1.3
End of Trial Visit................................................................................40
7.2
Demographic and Other Baseline Characteristics ..............................41
7.3
Efficacy Assessments .........................................................................41
7.4
Assessment of Safety..........................................................................41
7.4.1
Adverse Events ...................................................................................42
7.4.2
Pregnancy and In Utero Drug Exposure.............................................46
7.4.3
Clinical Laboratory Assessments .......................................................47
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............49
7.5
Pharmacokinetics................................................................................50
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7.5.1
Blood Sampling ..................................................................................50
7.5.2
Calculation of Pharmacokinetic Variables .........................................51
7.6
Biomarkers..........................................................................................52
7.7
Pharmacogenomics.............................................................................52
7.8
Other Assessments..............................................................................52
8
Statistics..............................................................................................52
8.1
Sample Size ........................................................................................52
8.2
Randomization....................................................................................53
8.3
Endpoints............................................................................................53
8.3.1
Primary Endpoint................................................................................53
8.3.2
Secondary Endpoints ..........................................................................54
8.3.3
Exploratory Endpoints........................................................................54
8.4
Analysis Sets.......................................................................................54
8.5
Description of Statistical Analyses.....................................................55
8.5.1
General Considerations.......................................................................55
8.5.2
Analysis of Primary Endpoint ............................................................55
8.5.3
Analysis of Secondary Endpoints.......................................................55
8.5.4
Analysis of Safety and Other Endpoints.............................................56
8.5.5
Analysis of Exploratory Endpoints.....................................................56
8.6
Interim and Additional Planned Analyses ..........................................56
9
Ethical and Regulatory Aspects..........................................................56
9.1
Responsibilities of the Investigator ....................................................56
9.2
Subject Information and Informed Consent .......................................57
9.3
Subject Identification and Privacy......................................................57
9.4
Emergency Medical Support and Subject Card..................................58
9.5
Clinical Trial Insurance and Compensation to Subjects.....................58
9.6
Independent Ethics Committee...........................................................58
9.7
Health Authorities...............................................................................59
10
Trial Management...............................................................................59
10.1
Case Report Form Handling...............................................................59
10.2
Source Data and Subject Files............................................................59
10.3
Investigator Site File and Archiving...................................................60
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................60
10.5
Changes to the Clinical Trial Protocol................................................61
10.6
Clinical Trial Report and Publication Policy......................................61
10.6.1
Clinical Trial Report...........................................................................61
10.6.2
Publication..........................................................................................61
11
References Cited in the Text...............................................................62
12
Appendices .........................................................................................63
Appendix I
Signature Pages and Responsible Persons for the Trial......................64
Signature Page – Protocol Lead.........................................................................................65
Signature Page – Principal Investigator.............................................................................66
Sponsor Responsible Persons not Named on the Cover Page ...........................................67
Appendix II
Planned Numbers of Blood Samples for Clinical Laboratory, PK, 
and PGx and Total Blood Sampling Volume .....................................68
Appendix III
Contraception Guidance .....................................................................69
Table of In-Text Tables
Table 1
Schedule of Assessments - Screening and End of Trial Visit ............13
Table 2
Schedule of Assessments – Treatment A (Administration of 
Tepotinib Alone).................................................................................14
Table 3 
Schedule of Assessments – Treatments B and C (Administration 
of Tepotinib and Omeprazole)............................................................15
Table 4
Safety Laboratory Evaluations ...........................................................48
Table 5
Time Windows....................................................................................50
Table 6
Definition of PK Parameters for Tepotinib after Single Dose 
Administration....................................................................................51
Table 7
90% Confidence Intervals for Estimated Test/Reference Ratios, 
n=12....................................................................................................53
Table of In-Text Figures
Figure 1
pH Dependent Solubility Profile of Tepotinib....................................20
Figure 2
Study Design, Exemplified for Sequence 1........................................22
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List of Abbreviations
Abbreviation
Definition of Terms
AE
Adverse event
anti-HCV
Hepatitis C virus antibody
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
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
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing 
time) extrapolated to infinity
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra / AUC0-∞x 100
beta-HCG
Beta-human chorionic gonadotrophin 
Bpm
Beats per minute 
CI
Confidence interval
CK MB
Creatinine phosphokinase myocardium/brain type
CL/f
Apparent total body clearance considering the fraction of dose (f) absorbed 
Cmax
Maximum plasma concentration observed
c-Met
Mesenchymal-epithelial transition factor
CRO
Contract research organization
CV
Coefficient of variation
DDI
Drug-drug interaction
ECG
Electrocardiogram 
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Abbreviation
Definition of Terms
eGFR
Estimated glomerular filtration rate
eCRF
Electronic Case Report Form
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone 
GeoCV%
Geometric coefficient of variation in percent
GeoMean
Geometric mean
H
Hour(s)
HBsAg
Hepatitis B surface antigen
HCC
Hepatocellular carcinoma
HGF
Hepatocyte growth factor
HIV1/HIV2
Human immunodeficiency virus 1 and 2 
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
λz
Terminal rate constant
LLOQ
Lower limit of quantification
Min
Minute(s)
MRAUC0-∞
Metabolite AUC0-∞to parent AUC0-∞ratio
MRCmax
Metabolite Cmax to parent Cmax ratio
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events (AEs)
NSCLC
Non-small cell lung cancer
PGx
Pharmacogenetics
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Abbreviation
Definition of Terms
PK
Pharmacokinetics
QTcF
Corrected QT interval per Fridericia’s formula
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SAP
Statistical analysis plan 
StD
Standard deviation 
t1/2
Terminal half-life
TEAE
Treatment emergent adverse event
TF2
Tablet formulation 2
tlag
Time prior to the first measurable (non-zero) concentration
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
T/R ratio
Test/Reference ratios
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal range
VZ/f
Apparent volume of distribution during the terminal phase
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Effect of a pr ot o n p u m p i n hi bit or o n t he P K of T e p oti ni b
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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 9
Title
P hase I, O pe n -la bel, T hree-Peri o d Cr oss o ver 
St u d y  t o I n vesti gate t he Effect of a Pr ot o n P u m p 
I n hi bit or ( O me praz ole) o n t he P har mac o ki netics 
of Te p oti ni b i n Healt h y S u bjects
Tri al P h ase
I
I N D N u m ber
N ot a p plica ble
F D A c o vere d T ri al
N o
E u dr a C T N u m ber
2 0 1 7- 0 0 2 8 3 2- 1 8
Pri nci p al I n vesti g at or
 
, Ger ma n y
S p o ns or 
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
Tri al C e nter
 
 Ger ma n y
Pl a n ne d T ri al P eri o d
(first s u bject i n - l ast s u bject o ut)
Q 2 -Q 3 2 0 1 8
Tri al Re gistr y
E U Cli nical Trials Re gister, Cli nical Trials. g o v
Pri m ar y O bjecti ve:

T o i n vesti gate t he effect of o me praz ole c o-a d mi nistrati o n o n t he si n gle d ose P K of 
te p oti ni b u n der fe d c o n diti o ns i n healt h y s u bjects.
Sec o n d ar y O bjecti ves:

T o i n vesti gate t he effect of f o o d o n t he si n gle d ose P K of te p oti ni b after c o-
a d mi nistrati o n of o me praz ole a n d te p oti ni b

T o assess t he safet y an d t olera bilit y of te p oti ni b al o ne a n d u p o n c o-a d mi nistrati o n of 
o me praz ole.
E x pl or at or y O bjecti ves:

T o i n vesti gate t he effect of o me praz ole c o-a d mi nistrati o n o n t he P K of meta b olites of 
te p oti ni b u n der fe d c o n diti o ns

T o e x pl ore t he effect of p har mac o ge netics ( P G x) a n d variati o ns of ass ociate d ge nes o n 
t he P K pr ofile of te p oti ni b ( if a p plica ble, partici pati o n is o pti o nal) .
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0 d 1 6 d 7 4 v 2. 0
0 9 0 0 ba be 8 0f 4c 5 4 9
PI
PI
PI


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
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Methodology: Phase I, open-label, 3-period, cross-over study.
The study will be divided into 3 periods. Each subject will receive all 3 treatments A, B and C, 
and will be randomized to one of 6 treatment sequences. In Treatment A, the PK of tepotinib
will be evaluated after oral single dose administration of 500 mg tepotinib under fed condition.
Under Treatments B and C, 40 mg omeprazole will be administered once per day for 5 days. 
On Day 5, omeprazole and tepotinib will be co-administered once under fasted (Treatment B),
and once under fed conditions (Treatment C). The washout period will be at least 14 days 
between tepotinib single dose administrations. Participants will be randomized in a balanced 
way to one of 6 treatment sequences.
The subjects will be admitted to the study site on Day -1 of each period. After administration 
of tepotinib alone (Treatment A) the subjects will be resident at the study site from Days -1 to 
4 and must visit the site on the morning of Days 5 to 7 for further blood sampling. In both 
periods with omeprazole co-administration (Treatments B and C) the subjects will be resident 
at the study site from Days -1 to 8 and must visit the site on the morning of Days 9 to 11 for 
further blood sampling.
Planned number of subjects: Overall, 12 healthy subjects are planned to be included.
Primary Endpoint:

PK profile of tepotinib following Treatments A and C in terms of area under the 
concentration-time curve (AUC) from time zero to the last sampling time 144 h 
postdose (AUC0-t), AUC from time zero extrapolated to infinity (AUC0-∞) and 
maximum plasma concentration (Cmax).
Secondary Endpoints: 

PK profile of tepotinib following Treatment B in terms of AUC0-t from time zero to 
144 h postdose, AUC0-∞and Cmax

PK profile of tepotinib following Treatments A, B and C in terms of time of the 
maximum drug concentration (tmax), terminal half-life (t1/2), time prior to the first 
measurable (non-zero) concentration (tlag), apparent total body clearance (CL/f), 
apparent volume of distribution during terminal phase (VZ/f)

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 in subjects receiving tepotinib alone 
and together with omeprazole assessed from Day -1 of Period 1 until the End of Trial
Visit.
Exploratory Endpoints: 

PK profiles of tepotinib metabolites: AUC0-t, AUC0-∞, Cmax, tmax, and t1/2

Ratios of tepotinib metabolites to tepotinib: MRAUC0-∞and MRCmax

Genetic variants and mutations in genes that potentially influence the PK of tepotinib.
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Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
11/70
Pharmacokinetics: 
Blood samples for determination of plasma concentrations of tepotinib and its metabolites 
MSC2571109A and MSC2571107A will be taken at predose until 144 hours (h) after dosing 
on Day 1 of Treatment A and Day 5 of Treatments B and C. PK parameters will be calculated 
using non-compartmental analysis. 
Other assessments: Not applicable.
Diagnosis and key inclusion and exclusion criteria: 
Healthy males and females (of non-childbearing potential) between 18 and 55 years of age 
(inclusive) with total body weight between 50 to 100 kg (inclusive) and body mass index 
(BMI) between 18.5 and 29.9 kg/m2 (inclusive) at the time of the Screening examination.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule:
Tepotinib film-coated tablet (Tablet Formulation 2, TF2) containing 500 mg of drug substance, 
oral administration.
Omeprazole, 40 mg gastro-resistant hard capsule.
Treatment A: A single oral dose of 500 mg tepotinib will be administered on Day 1 together 
with 240 mL still water at 30 minutes (min) after start of the breakfast which will have to be 
consumed completely within 25 min. 
Treatment B: Single doses of 40 mg omeprazole will be administered in the fasted state in the 
morning of Days 1 to 5. In the morning of Day 5, also a single oral dose of 500 mg tepotinib 
will be administered, in fasted state, 2 h after the omeprazole administration.
Treatment C: Single doses of 40 mg omeprazole will be administered in the fasted state in the 
morning of Days 1 to 5. In the morning of Day 5, also a single oral dose of 500 mg tepotinib 
will be administered in a fed state, 2 h after the omeprazole administration and 30 min after 
start of breakfast.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable
Planned trial and treatment duration per subject:
About 2 months from Screening to End of Trial Visit, treatment on Day 1 of Treatment A and 
Days 1 to 5 of Treatments B and C. 
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I N F O R M A T I O N
12/70
Statistical methods:
A linear model with TREATMENT, PERIOD, SEQUENCE and SUBJECT (SEQUENCE) as 
fixed effects will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞
based on the PK analysis set. Treatment differences C-A and C-B on the log scale will be 
estimated for Cmax, AUC0-t, and AUC0-∞together with their 90% confidence intervals (CIs). 
Point estimates and CIs will be back-transformed to the original scale.
The relative bioavailabilities C/A and C/B will be calculated for each subject.
Summary statistics will be provided for all parameters.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
13/70
Table 1
Schedule of Assessments - Screening and End of Trial Visit
Assessment / Activity
Screening
End of Trial Visit
Day
-21 to -2
7 (± 1) days after last drug 
administration in the final period
Written informed consent a
Ambulatory visits
X
X
In-/exclusion criteria
X
Demographic data (incl. height, weight, BMI)
X
Medical history
X
Physical examination
X
X
Vital signs (supine blood pressure, pulse rate, 
body temperature)
X
X
12-lead ECG
X
X
Clinical laboratory (hematology, biochemistry, 
urinalysis)
X
X
Serology (HIV/hepatitis)
X
Serum pregnancy test
X b
X b
Drugs of abuse test / Alcohol Breath Test
X
Adverse events (AEs)
X
X
Prior and concomitant medication
X
X
ECG = electrocardiogram, FSH: Follicle-stimulating hormone, HIV = human immunodeficiency virus
a
Written informed consent must be obtained prior to any Screening activities.
b
Women of non-childbearing potential must have a negative serum pregnancy test at Screening and at End of
Trial Visit. 
Females are considered postmenopausal if they have age-related amenorrhea ≥12 consecutive months and 
increased FSH > 40 mIU/mL, or if they have undergone irreversible surgical sterilization by hysterectomy or 
bilateral oophorectomy or bilateral salpingectomy.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
14/70
Table 2
Schedule of Assessments – Treatment A (Administration of Tepotinib Alone)
Assessment / Activity
Treatment A
Day
-1
1
2 – 4
5 - 7
Hospitalization
X ----------------------------------------------------------------X a
Ambulatory visits
X
In-/exclusion criteria (only in Period 1)
X
Physical examination
X
Vital signs (blood pressure, pulse rate, body 
temperature)
X
X b
X b
12-lead ECG
X
X c
X c
Clinical laboratory (hematology, biochemistry, 
urinalysis)
X d
X d
X d
Pregnancy test
X e
Drugs of abuse / Alcohol breath test
X
Administration of tepotinib
X f
PK blood sampling
X g
X g
X g
PGx blood sampling (optional, and only in Period 1)
X h
Adverse events monitoring
X ---------------------------------------------------------------------------------------------X j
Concomitant medication
X ---------------------------------------------------------------------------------------------X j
ECG = electrocardiogram, PK = pharmacokinetics, PGx = pharmacogenetics
a
Hospitalization from the morning of Day -1 until 72 h after administration of tepotinib and completion of respective clinical activities (= Day 4).
b
Vital signs (blood pressure and pulse rate) will be measured after at least 5 min rest at predose (within 60 min prior to dosing) and 2, 4, 8, 12, 
24, 48 and 72 h postdose.
c
12-lead ECGs will be recorded and printed out after at least 5 min rest in supine position at predose (within 60 min prior to dosing) and 2, 
4, 8, 12, 24, 48 and 72 h postdose.
d
Laboratory assessments will be performed on Day -1, before tepotinib administration on Day 1 and before discharge on Day 4.
e
Women of non-childbearing potential must have a negative urine pregnancy test at Day -1.
f
A standardized breakfast will be administered 30 min prior to administration of tepotinib and must be consumed completely within 25 min. 
30 min after start of the breakfast tepotinib will be taken together with 240 mL of water.
g
PK blood samples for determination of tepotinib and its metabolites will be collected on Day 1 at predose (within 60 prior to dosing), and 15, 
30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16 h, and on Day 2 at 24, 36 h, on Day 3 at 48, 60 h, on Day 4 at 72 h, on Day 5 at 96 h, on Day 6 
at 120 h, and on Day 7 at 144 h postdose.
h
PGx blood samples of 2 x 2 mL (optional) to be drawn at Day -1, in Period 1 only.
j
Adverse events and concomitant medication will be assessed from signing of the informed consent form (ICF) throughout the whole study 
until the End of Trial Visit.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
15/70
Table 3
Schedule of Assessments – Treatments B and C (Administration of Tepotinib and Omeprazole)
Assessment / Activity
Treatments B and C
Day
-1
1 - 4
5
6 – 8
9 - 11
Hospitalization 
X ------------------------------------------------------------------------------X a
Ambulatory visits
X
In-/exclusion criteria (only if Period 1)
X
Physical examination
X
X b
X b
Vital signs (blood pressure, pulse rate, 
body temperature)
X
X c
X c
12-lead ECG
X
X d
X d
Clinical laboratory (hematology, 
biochemistry, urinalysis)
X e
X e
X e
Pregnancy test
X f
Drugs of abuse / Alcohol breath test
X
Administration of tepotinib
X g
Administration of omeprazole
X
X g
PK blood sampling
X h
X h
X h
PGx blood sampling (optional, and only in 
Period 1)
X i
Adverse event monitoring
X ----------------------------------------------------------------------------------------------------------X j
Concomitant medication
X ----------------------------------------------------------------------------------------------------------X j
ECG = electrocardiogram, PK = pharmacokinetics, PGx = pharmacogenetics
a
Hospitalization from the morning of Day -1 until 72 h after administration of tepotinib and completion of respective clinical activities (= Day 8).
b
Physical examinations will be performed in on Day 4 and before discharge on Day 8.
c
Vital signs (blood pressure and pulse rate) will be measured after at least 5 min rest at predose (within 60 min prior to dosing of tepotinib) and 
at 2, 4, 8, 12, 24, 48 and 72 h after tepotinib administration.
d
12-lead ECGs will be recorded and printed out after at least 5 min rest at predose (within 60 min prior to dosing of tepotinib) and at 2, 4, 8, 
12, 24, 48 and 72 h after tepotinib administration.
e
Laboratory assessments will be performed on Day -1, before tepotinib administration on Day 5 and before discharge on Day 8.
f
Women of non-childbearing potential must have a negative urine pregnancy test at Day -1.
g
Treatment B: on Day 5 omeprazole will be given 2 h prior to the planned tepotinib dosing, 500 mg tepotinib will be administered together with 
240 mL of water in the fasted state;
Treatment C: on Day 5 omeprazole will be given 2 h prior to the planned tepotinib dosing, 500 mg tepotinib will be administered together with 
240 ml of water after a standardized breakfast which will be started 30 min prior to tepotinib administration and must be consumed completely 
within 25 min.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
16/70
h:
PK blood samples for determination of tepotinib and its metabolites will be collected on Day 5 at predose (within 60 min prior to administration
of tepotinib) and 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16 h and on Day 6 at 24, 36 h, on Day 7 at 48, 60 h, on Day 8 at 72 h, on Day 9
at 96 h, on Day 10 at 120 h and on Day 11 at 144 h after tepotinib administration.
i:
PGx blood samples of 2 x 2 mL (optional) to be drawn at Day -1, in Period 1 only.
j:
Adverse events and concomitant medication will be assessed from signing of the ICF throughout the whole study until the End of Trial Visit.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Effect of a pr ot o n p u m p i n hi bit or o n t he P K of T e p oti ni b
M S 2 0 0 0 9 5- 0 0 3 9
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 /7 0
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 K Ga A , Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma ny.
T he trial will be c o n d ucte d at o ne site i n Ger ma n y .
T he Pri nci pal I n vesti gat or (
, 
) will
pr o vi d e 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 nfere nce o n Har m o nisati o n
(IC 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).
Si g nat ure pa ges f or t he Pr ot oc ol Lea d s a n d t he Pri nci pal I n vesti gat or as well as a list of S p o ns or 
res p o nsi ble pers o ns f or t he trial are i n A p pe n di x I.
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, will c o 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 ys is, 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 p are 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 M e dici nal P r o d ucts
(I M Ps) te p oti ni b a n d 
o me praz ole. 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, We ge nerstrasse 
1 3, 8 9 2 3 1 
Ne u -Ul m, Ger ma n y ). 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 mal -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 t e 
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 oliferati o n, mi grati o n 
a n d 
i n vasi o n, as well as c o nferri n g resista nce t o a p o pt osis. P har mac ol o gical i nterfere nce wit h t he 
H G F/c -Met a xis is c o nsi dere d as a pr o misi n g strate g y to i n hi bit pri mar y  tu m or gr o wt h a n d 
metastasis.
I n pri mar y  phar mac o d y n a mic ( P D) st u dies, te p oti ni b ( M S C 2 1 5 6 1 1 9J) p ote ntl y i n hi bite d c-Met 
ki nase acti vit y in a d ose -de pe n de nt ma n ner. T his i n hi bit or y effect was c o nfir me d b ot h i n t u m or 
cells e x pressi n g f ull-le n gt h c-Met u p o n sti m ulati o n wit h H G F, a n d i n t u m or cells i n w hic h c Met 
was acti vate d i n a li ga n d i n de pe n de nt ma n ner, ie i n cells har b ori n g c-Met ge ne a m plificati o n or 
e x pressi n g t he o nc o ge nic f usi o n pr otei n tra nsl ocate d pr o m oter re gi o n ( T P R) Met.
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0 d 1 6 d 7 4 v 2. 0
0 9 0 0 ba be 8 0f 4c 5 4 9
PI
PI


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
18/70
Until 30 September 2017, 452 subjects have been exposed to tepotinib. 60 subjects of these were 
exposed to the tepotinib + gefitinib combination. Five studies have been completed; 3 of these 
were conducted as single dose studies in healthy subjects (EMR200095-002, EMR200095-007, 
and MS200095-0012; n = 79 subjects), and 2 as multiple dose studies in subjects with different 
solid tumors (EMR200095-001 and EMR200095-003; n = 161). In addition, 4 studies in subjects 
with hepatocellular carcinoma (HCC; EMR200095-004, EMR200095-005) or epidermal growth 
factor receptor (EGFR) mutated or c-Met mutated non-small cell lung cancer (NSCLC; 
EMR200095-006, and MS200095-0022) are ongoing. In the ongoing studies, subjects with HCC 
received tepotinib as multidose monotherapy, and subjects with NSCLC received either 
multidose tepotinib monotherapy or a multidose combination with gefitinib in Phase I or Phase 
Ib/II studies. Doses of tepotinib of up to 1400 mg daily in subjects with solid tumors 
(EMR200095-001) and up to 1000 mg daily in subjects with HCC (EMR200095-004) have been 
explored.
The 500 mg tepotinib single oral dose has been studied in previous studies with 36 healthy 
subjects in total (EMR200095-007: 12 subjects, MS200095-0012: 24 subjects, 2 single doses of 
500 mg) and was well tolerated. A dose of 500 mg once daily is the recommended Phase II dose 
(RP2D). Refer to the Investigator’s Brochure for further information about the nonclinical and 
clinical programs and the implemented Guidance for the Investigator.
Based on the currently available nonclinical as well as clinical safety data, there is no objection 
against administration of single doses of tepotinib to healthy subjects. It is recognized that 
healthy subjects will not get benefit by participating in this study. However, this study will 
generate mandatory human data about the potential of drug-drug interaction (DDI) of a proton 
pump inhibitor (omeprazole) on the PK of tepotinib, which is of importance in the context of 
concomitant medication in tumor patients with hepatic impairment treated with tepotinib. This is 
basic information to safeguard the further clinical development of tepotinib in patients suffering 
from malignancies such as HCC. During the development of tepotinib, in all 3 studies performed 
in healthy subjects (n = 79), the subjects well tolerated a single or 3 doses of tepotinib (different 
dose levels up to 500 mg single dose). All treatment emergent adverse events (TEAEs) were 
mild to moderate, except one Grade 3 asymptomatic lipase elevation in 1 subject. TEAEs did not 
show a pattern across all 3 trials. No serious adverse events (SAEs) were reported and no subject 
died. No clinically significant findings regarding laboratory parameters, vital signs and ECG 
including corrected QT interval according to Fridericia (QTcF) values were noted.
Elevations in serum lipase and amylase are considered as identified risks for subjects 
administered tepotinib. These elevations were observed in 5 of 79 healthy subjects exposed to 
tepotinib and were mild to moderate in severity (exception: one Grade 3 lipase elevation) and 
without apparent dose dependency. All increases of serum amylase/lipase were asymptomatic 
and not associated with a pancreatitis.
Subjects enrolled in this study might be exposed to a 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.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
19/70
Knowing that loss of c-Met induces teratogenic effects in c-Met knockout mice, stringent criteria 
are applied to ensure exclusion of women of childbearing potential in this study. A pilot embryo-
fetal development study in rabbits revealed maternotoxic effects and a dose-dependent increased 
number of skeletal malformations (teratogenicity). Only healthy women that are known to be 
postmenopausal or surgically sterile (ie due to hysterectomy, or bilateral oophorectomy, or 
bilateral salpingectomy) will be enrolled in this study (for details see Section 5, Investigational 
Plan). 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 tepotinib 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 contract research 
organization (CRO) experienced in the conduct of clinical pharmacology studies.
Omeprazole
Omeprazole reduces gastric acid secretion through a highly targeted inhibition of the H+K+-
ATPase - the proton pump expressed in the parietal cell. It is frequently used for the treatment of 
gastroesophageal reflux, peptic ulcer disease, and Zollinger-Ellison syndrome. For further 
information refer to the SmPC [1].
Oral dosing with omeprazole once daily leads to rapid and effective inhibition of daytime and 
nighttime gastric acid secretion with maximum effect being achieved within 4 days of daily 
treatment [1].
The recommended daily dose of omeprazole to treat patients with active duodenal or
intragastrical ulcer is 20 mg per day, but can be increased to 40 mg omeprazole per day as 
necessary. With omeprazole 20 mg, a mean decrease of at least 80% in 24-hour intragastrical
acidity is then maintained in duodenal ulcer patients, with the mean decrease in peak acid output 
after pentagastrin stimulation being about 70% 24 hours after dosing. Oral dosing with 
omeprazole 20 mg maintains an intragastrical pH of ≥3 for a mean time of 17 hours of the 24-
hour period in duodenal ulcer patients.
Likewise, omeprazole significantly reduced the percentage of time with pH < 5 postprandially. 
Omeprazole does not change 24-hour median intraduodenal pH significantly [2].
3.1
Trial Rationale
The impact of the proton pump inhibitor omeprazole on the bioavailability of tepotinib will be 
studied as the solubility of tepotinib is pH dependent, specifically tepotinib is slightly soluble at 
pH 4.5 whereas it is practically insoluble at pH 1.2, 6.8, and 7.4 (see Figure 1). In this study, the 
impact of the proton pump inhibitor omeprazole on the bioavailability of tepotinib will be 
studied. A 3-period, crossover study design will be used to investigate the effect of omeprazole 
on the PK of tepotinib under fasted and fed condition, and based on the regulatory guidelines of 
the Food and Drug Administration (FDA) [3] and the European Medicines Agency (EMA) [4].
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
20/70
Based to the known minor, but positive food effect on tepotinib exposure (EMR200095-003, see 
Tepotinib Investigator’s Brochure), tepotinib is developed in clinical studies with patients by 
administration under fed condition. Therefore, the PK of tepotinib after single dose 
administration under fed condition (Treatment A) will serve as reference in this study.
Figure 1
pH Dependent Solubility Profile of Tepotinib
Source: Analytical Report Re100004.
Data of 2 different batches are presented.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP 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. 
4
Trial Objectives
4.1
Primary Objective

To investigate the effect of omeprazole co-administration on the single dose PK of 
tepotinib under fed conditions in healthy subjects.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
21/70
4.2
Secondary Objectives

To investigate the effect of food on the single dose PK of tepotinib after co-
administration of omeprazole and tepotinib

To assess the safety and tolerability of tepotinib alone and upon co-administration of 
omeprazole.
4.3
Exploratory Objectives

To investigate the effect of omeprazole co-administration on the PK of metabolites of 
tepotinib under fed conditions

To explore the effect of pharmacogenetics (PGx) and variations of associated genes on 
the PK profile of tepotinib (if applicable, participation is optional).
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase I, open-label, 3-period, crossover study to investigate the effect of omeprazole on 
the PK of tepotinib in 12 healthy subjects under fasted and fed condition. A flowchart 
summarizing the overall study design is shown in Figure 2. Two subjects each will be 
randomized to one of the six possible treatment sequences.
The study will be divided into 3 periods: in one period, the PK of tepotinib will be evaluated 
after single dose administration under fed condition (Treatment A), and in two periods 
omeprazole will be administered for 5 days and a respective single dose of tepotinib will be co-
administered on Day 5. Thereby tepotinib will be administered 2 hours after omeprazole 
administration once under fasted (Treatment B) and once under fed conditions (Treatment C). 
The washout period will be at least 14 days between tepotinib single dose administrations (see 
Figure 2). Subjects will be randomized to one of six possible treatment sequences as detailed in 
Section 8.2.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
22/70
Figure 2
Study Design, Exemplified for Sequence 1
Sequence 1
Treatment A
WO a
Treatment B
WO a
Treatment C 
Day
Day
Day
Procedure
-1
1
2 - 4 5 - 7
-1
1 - 4
5
6 - 8 9 - 11
-1
1 - 4
5
6 - 8 9 - 11
Tepotinib 
administration
Omeprazole 
administration
PK blood 
sampling
Safety 
assessments b
AE monitoring
Hospitalization
Treatment A = tepotinib alone fed; Treatment B = tepotinib fasted with omeprazole; Treatment C = tepotinib fed with 
omeprazole
a:
WO = washout; the washout period will be at least 14 days between tepotinib single dose administrations.
b:
Safety assessments: Vital signs, 12-lead ECG, clinical laboratory.
A screening period will occur from Day -21 to Day -2.
Subjects will be admitted to the study site on Day -1 of each period. After administration of 
tepotinib alone the subjects will be resident at the study site under medical supervision from 
Days -1 to 4 and must visit the site on the morning of Days 5 to 7 for further blood sampling. In 
both periods with omeprazole co-administration the subjects will be resident at the study site 
under medical supervision from Days -1 to 8 and must visit the site on the morning of Days 9 to 
11 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 inpatient period of each 
treatment period as explained in detail in Table 2 and Table 3 (also see Figure 2) and for the End 
of Trial Visit. 
Serial blood samples for PK assessments will be collected for 144 h (7 days) after tepotinib 
administration in all 3 periods. 
The End of Trial Visit is planned 7 days (± 1 day) after tepotinib administration in the last 
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. 
A detailed schedule of study procedures and assessments is provided in Table 1, Table 2 and 
Table 3.
Document No. 
 
Object No. 
 
0900babe80d16d74v2.0
0900babe80f4c549


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
23/70
Primary Endpoint:

PK profile of tepotinib following Treatments A and C in terms of AUC from time zero to 
the last sampling time 144 h post-dose (AUC0-t), AUC from time zero extrapolated to 
infinity (AUC0-∞) and maximum plasma concentration (Cmax).
Secondary Endpoints: 

PK profile of tepotinib following Treatments B in terms of AUC0-t from time zero to 144 
h post-dose, AUC0-∞and Cmax

PK profile of tepotinib following Treatments A, B and C in terms of time of the 
maximum drug concentration (tmax), terminal half-life (t1/2), time prior to the first 
measurable (non-zero) concentration (tlag), apparent total body clearance (CL/f), and 
apparent volume of distribution during terminal phase (VZ/f) 

Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of 
changes in safety laboratory assessments, 12-lead ECGs and vital signs in subjects 
receiving tepotinib alone and together with omeprazole assessed from Day -1 of Period 1 
until the End of Trial Visit.
Exploratory Endpoints: 

PK profiles of tepotinib metabolites: AUC0-t, AUC0-∞, Cmax, tmax, and t1/2

Ratios of tepotinib metabolites to tepotinib: MRAUC0-∞and MRCmax

Genetic variants and mutations in genes that potentially influence the PK of tepotinib
Note: Pharmacogenetic sample collection is optional. The results of the pharmacogenetic 
analysis, as applicable, will be described in a separate report.
5.2
Discussion of Trial Design
The trial design is based on the regulatory guidelines of the FDA and the EMA (see Section 3.1).
5.2.1
Inclusion of Special Populations
Not applicable.
5.2.2
Scientific Rationale for Trial Design
The study design and endpoints are typical for a drug interaction study of this type. The single 
dose design is more sensitive in showing changes in the PK as compared to multiple dose 
designs. Considering that the main influence of the gastric pH change is on the absorption, a 
single dose design is preferred.
The study will utilize a crossover design to minimize the influence of covariates, with all 3 
treatments applied to each subject. Tepotinib has an elimination t1/2 of about 30 h and its main 
metabolite MSC2571109A has a t1/2 of approximately 45 h. Very low concentrations were 
observed after 14 days in study MS200095-0012, (ie, less than the 5% of Cmax as required in the 
Document No. 
 
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Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
C O N F I D E N T I A L
I N F O R M A T I O N
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bioequivalence guidance [5]). Therefore, a washout period of at least 14 days is considered 
appropriate to prevent any significant carryover effects between periods. 
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 that 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 take precautions 
with female partners.
This study is performed in healthy subjects to minimize variability that may be observed in a co-
morbid patient on concomitant treatments. Further, participation of tumor patients in this cross-
over study would delay their start of continuous tumor treatment due to study requirements. A 
close monitoring of the safety laboratory parameters, ECG, and vital signs will be performed in 
all subjects. Subjects will be admitted to the study site and remain resident there until at least 
72 h after the last administration, to allow continuous safety monitoring. A hospitalization period 
of 72 h after the last dose of tepotinib is regarded as sufficient to ensure close safety monitoring 
of the subjects during the initial elimination of about 70 - 80%. The End of Trial Visit is set at 
7 (1) days after last dose of tepotinib, hence covering full elimination of tepotinib. The 
Investigator can extend the inpatient period as appropriate. In addition, monitoring of subjects is 
ensured by choosing a CRO experienced in the conduct of clinical pharmacology studies.
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 well tolerated. The tepotinib dose of 500 mg is the RP2D for the treatment of human 
malignant tumors. 
Omeprazole will be administered as 40 mg gastro-resistant capsules, daily for 5 days. A 40 mg 
daily dose is the approved dose for 14 days for Helicobacter pylori eradication and it is the 
approved dose for 4 to 8 weeks for a gastric ulcer. For the long-term management of patients 
with healed reflux esophagitis, the recommended dose of omeprazole is up to 40 mg once daily. 
The anti-secretory effect of multiple doses of 20 and 40 mg of omeprazole in healthy subjects 
and in patients demonstrate a greater effect following a 40 mg daily dose compared to 20 mg. 
The maximum effect on the inhibition of gastric acid secretion is 2 to 6 h post-dose. The 
inhibitory effect of omeprazole on gastric acid secretion increases with repeated once-daily 
dosing, reaching a plateau after 4 days [6].
5.2.4
Rationale for Endpoints
The peak (Cmax) and extent (AUC) of exposure of tepotinib after single dose administration are 
considered adequate endpoints to evaluate the effect of omeprazole on the PK of tepotinib and its 
metabolites. These endpoints are in line with the regulatory guidance of the FDA and the EMA
(see Section 3.1).
Document No. 
 
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Tepotinib (MSC2156119J)
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MS200095-0039
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5.3
Selection of Trial Population
Only subjects meeting all inclusion criteria and no exclusion criteria may be enrolled into the 
trial as participants. Prior to performing any trial assessments, 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 to 100 kg, 
inclusive (at Screening)
3. A female participant is eligible to participate if she is of non-childbearing potential, 
confirmed at Screening, by fulfilling at least one of the following criteria: 

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, or bilateral 
oophorectomy, or bilateral salpingectomy
4. A male participant must agree to use and to have his female partner of childbearing potential 
to use a highly effective method of contraception (ie, methods with a failure rate of less than 
1% per year) as detailed in the Clinical Trial Facilitation Group (CTFG) recommendations
[7] during the period of participation in the study and for at least 3 months after the last 
investigational medicinal product (IMP) administration (see Appendix III). Males must also 
refrain from donating sperm during this period and should always use a barrier method such 
as a 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)
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 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; amylase and lipase should not exceed the upper limit of normal
(ULN); Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) should not 
exceed ULN x 1.1.
Document No. 
 
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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, whichever is longer, before administration of study 
drug within this study
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 (SBP) > 140 or < 90 mmHg, diastolic blood pressure (DBP) 
> 90 or < 50 mmHg, and pulse rate > 90 or < 50 beats per minute (bpm) at Screening and at 
Admission on Day-1. (Any abnormal vital signs 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 (at Screening)
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)
7.
Subjects with gall bladder removal or other relevant surgery of gastrointestinal tract
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 or drugs of abuse (at Screening and Day -1)
12. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-
HCV), and human immunodeficiency virus 1 and 2 antibodies (HIV1/HIV2 antibodies) (at 
Screening)
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 less 
than 6 months before the time of the Screening Visit
Document No. 
 
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MS200095-0039
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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 first Period only)
19. Legal incapacity or limited legal capacity
20. Subjects kept in detention
21. Subjects with history of rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption or sucrase-isomaltase insufficiency.
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 Treatment
A subject must be withdrawn from IMPs administration if any of the following occur:

The subject requires treatment with any medication suspected or known to interfere with 
the IMPs

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 with incomplete PK data must be replaced.
5.5.2
Withdrawal from the Trial
Subjects must be withdrawn from the study by the Investigator at any time for any of the 
following reasons:
Subject withdrew consent
Subject lost to Follow-up
Document No. 
 
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Participation in another clinical study
Relevant adverse events (AEs), especially serious adverse events (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. However, any medications 
that are considered necessary for the subject’s wellbeing (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 study 
drug(s) (IMPs) by the Investigator with alternate etiology identified:
-
Abnormal clinically relevant vital signs confirmed on 2 or more measurements (min. 
5 minute intervals), including abnormal blood pressure 
o
hypotension defined as systolic < 80 mmHg and/or diastolic < 40 mmHg, or
o
hypertension defined as systolic > 160 mmHg and/or diastolic > 100 mmHg 
-
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
-
Marked increases in liver or renal parameters (ALT/AST ≥3 x upper limit of normal 
range (ULN), total bilirubin ≥2 x ULN), creatinine ˃ 1.5 x (ULN) confirmed by ≥2 
repeat measurements
-
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.
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 with incomplete PK data must be replaced.
Document No. 
 
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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 enrollment, 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 by the last contact (related to this trial) with the last subject who 
participates in this trial (last subject’s End of Trial Visit or telephone call, independent of 
whether the subject is in End of Trial Visit or discontinued from the study).
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term “Investigational Medicinal Product” refers to any active substance or a placebo being 
tested or used as a reference treatment or therapy in a clinical trial, including products that have a 
marketing authorization but are formulated, packaged, or administered differently from the 
authorized form, used for an unauthorized indication, or used to gain further information about 
the authorized form.
6.1
Description of the Investigational Medicinal Product
Investigational Medicinal Product: 

Tepotinib (MSC2156119J), 3-(1-{3-[5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl]-
benzyl}-1,6-dihydro-6-oxo-pyridazin-3-yl)-benzonitrile hydrochloride (HCl) hydrate, is 
supplied as 500 mg (oblong, light yellow) film-coated tablets (Tablet Formulation 2, 
TF2) for oral administration 
Tepotinib 500 mg film-coated tablets have a drug load of approximately 50% and contain 
the excipients D-mannitol, silica colloidal anhydrous, crospovidone, magnesium stearate, 
and Opadry® II yellow
All excipients used in the tablet formulation 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 at or below 25°C

Omeprazole: Commercially available omeprazole will be used, eg “Omeprazol-
ratiopharm® NT 40 mg magensaftresistente Hartkapseln (gastro-resistant hard capsule)“.
Reference product: Not applicable.
Specific rules for treatment modifications: Not applicable.
Document No. 
 
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Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
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6.2
Dosage and Administration
Subjects will receive the following 3 treatments. The minimum washout period will be at least 
14 days between the tepotinib single dose administrations to prevent any significant PK 
carryover effects between periods.
Treatment A - 500 mg Tepotinib fed 
A single oral dose of 500 mg tepotinib film-coated tablet (TF2) will be administered together 
with 240 mL still water at 30 min after start of a standardized breakfast which will have to be 
consumed completely within 25 min.
The standardized breakfast will be a continental breakfast consisting of: 2 rolls, 20 g butter, 25 g 
jam, 1 slice of cheese, 1 slice of cold cut, fruit tea or decaffeinated coffee without milk and 
sugar.
Subjects will stay in a semi-recumbent position for 4 h post-dose, subjects will be allowed to 
leave the bed without undue physical stress/activity for use of toilet only.
Further standardized meals will be served 4 h (lunch), 8 h (snack) and 10 h (dinner) after 
administration of tepotinib; thereafter, meals will be served at customary times during the 
inpatient period.
Treatment B – 500 mg Tepotinib fasted + Omeprazole
In the morning of Days 1 to 5, 40 mg omeprazole will be administered in the fasted state. In the 
morning of Day 5, a single oral dose of 500 mg tepotinib film-coated tablet (TF2) will be 
administered, in a fasted state, 2 h after the omeprazole administration.
On Days 1 to 4, omeprazole will be administered in fasted state together with 240 mL water.
A standardized breakfast will be served 30 min after omeprazole administration
On Day 5, 40 mg omeprazole will be taken in fasted state with 240 mL still water 2 h prior to 
the planned tepotinib dosing. 500 mg tepotinib will be administered in the fasted state 
together with 240 mL of still water.
On Day 5, subjects will stay in a semi-recumbent position for 4 h post-dose of tepotinib 
administration, except for use of the toilet, when the subjects will be allowed to leave the bed 
without undue physical stress/activity.
Standardized meals will be served 4 h (lunch), 8 h (snack) and 10 h (dinner) after administration 
of tepotinib on Day 5; meals, except for breakfast on Days 1 to 4, will be served at customary 
times on the other days during the inpatient period.
Treatment C – 500 mg Tepotinib fed + Omeprazole
In the morning of Days 1 to 5, 40 mg omeprazole will be administered in the fasted state. In the 
morning of Day 5, a single oral dose of 500 mg tepotinib film-coated tablet (TF2) will be 
Document No. 
 
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Tepotinib (MSC2156119J)
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MS200095-0039
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administered, in a fed state, 2 h after the omeprazole administration and 30 min after start of 
breakfast.
On Days 1 to 4, omeprazole will be administered in the fasted state together with 240 mL
water. A standardized breakfast will be served 30 min after omeprazole administration
On Day 5, 40 mg omeprazole will be taken in fasted state with 240 mL still water 2 h prior to 
the planned tepotinib dosing. A standardized breakfast (see above) will be administered 
30 min prior to tepotinib administration and must be consumed completely within 25 min. 
30 min after start of the breakfast, 500 mg tepotinib will be administered together with 
240 mL of water.
On Day 5, subjects will stay in a semi-recumbent position for 4 h post-dose of tepotinib 
administration, except for use of the toilet, when the subjects will be allowed to leave the bed 
without undue physical stress/activity.
Standardized meals will be served 4 h (lunch), 8 h (snack) and 10 h (dinner) after administration 
of tepotinib on Day 5; meals, except for breakfast on Days 1 to 4, will be served at customary 
times on the other days during the inpatient period.
6.3
Assignment to Treatment Groups
Subjects will be randomly assigned to one of six treatment sequences (see Section 8.2). Only 
subjects who comply with all selection criteria will be included into the trial. Prior to the first 
administration the subjects will be assigned to a treatment sequence via the random number on 
Day 1. 
According 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 Procedures
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, 
Document No. 
 
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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.
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’s welfare and that will not 
interfere with the IMPs may be given at the Investigator’s discretion. The potential DDIs 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 trial, from the date of signature of informed consent.
6.5.2
Prohibited Medicines
The following treatments and therapies are not permitted during this trial:
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 IMP 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 and will be 
reminded regularly.
Throughout the PK profiling days, the following restrictions must be met:

Subjects will be fasting for at least 10 h before administration of tepotinib (except for the 
breakfast in Treatments A and C) and before administration of omeprazole

Drinking is not allowed 1 h after administration of tepotinib

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 CRO 
during the inpatient period
Document No. 
 
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
No intake of caffeine- and xanthine-containing food and beverages (eg coffee, black or 
green tea, chocolate or chocolate-containing food or beverages) from 48 h before 
administration of tepotinib in each period until collection of last PK blood sample of each 
period

No intake of herbs/fruits that can have an influence on 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 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 
trial site for all AEs occurring during the trial.
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.
Omeprazole will be purchased from commercially available supplies.
Document No. 
 
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Tepotinib (MSC2156119J)
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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 and the interaction drug will be 
supplied in ready to use 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.
Detailed recommendations for the use and storage of omeprazole are described in the Summary 
of Product Characteristics. 
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, kit numbers, expiry dates, formulation (for IMP 
prepared at the site), and the individual subject trial numbers.
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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.
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 Patient 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.
There is limited information available on the effects of overdoses of omeprazole in humans. In 
the literature, doses of up to 560 mg have been described, and occasional reports have been 
received when single oral doses have reached up to 2400 mg omeprazole (60 times the usual 
recommended clinical dose of 40 mg). Nausea, vomiting, dizziness, abdominal pain, diarrhea 
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and headache have been reported. Also, apathy, depression and confusion have been described in 
single cases.
The symptoms described have been transient, and no serious outcome has been reported. The 
rate of elimination was unchanged (first order kinetics) with increased doses. Treatment, if 
needed, is symptomatic.
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
Detailed schedule of trial procedures/assessments is provided in Table 1 (Screening and End of 
Trial Visit), Table 2 (Treatment A) and Table 3 (Treatments B and C).
Prior to performing any trial assessments, 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 enrollment 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. This 
Screening examination will consist of the following:

Demographic information including body height, body weight and BMI

Medical history

Physical examination

Vital signs (supine blood pressure, pulse rate, and body temperature)

12-lead ECG

Blood and urine samples for safety laboratory assessments 
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
Serological tests for hepatitis B, C, and HIV1/HIV2

Serum pregnancy test for women 

Urine drug screen (including test for cotinine) and an alcohol breath test

Prior medication and concomitant medication

Assessment of AEs

Preliminary evaluation of inclusion and exclusion criteria.
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 2 (Treatment A) and Table 3 (Treatments 
B and C).
Adverse event monitoring is generally assessed between Day -1 and Day 7.
Treatment A (Tepotinib alone)
Day -1 (admission)
Subjects will be hospitalized from the morning of Day -1 until completion of the 72 h 
assessments in the morning of Day 4. 
On admission on Day -1 the following will be done:

Physical examination 

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments (including drugs of abuse and 
a urine pregnancy test in females)

Alcohol breath test

Drugs of abuse

Blood sample for PGx (optional, and only if this is the first treatment period)

Evaluation of inclusion and exclusion criteria (if this is the first treatment period)

Subjects will be asked about their well-being and any concomitant medication taken 
during the previous days. 
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Days 1 to 4 (inpatient)
Prior to dosing on Day 1 the following will be done:

Vital signs

12-lead ECG 

Blood and urine samples for safety laboratory assessments 

Pre-dose PK blood sample for determination of tepotinib and its metabolites. 
After completion of the predose assessments breakfast will be served and tepotinib will be 
administered together with 240 mL water 30 min after start of breakfast. At 4 h after 
administration the subjects will consume a standardized lunch.
After dosing on Day 1 the following will be done:

PK blood samples for determination of tepotinib and its metabolites will be taken 
regularly until 72 h post-dose (for time points please refer to Table 2)

Vital signs will be measured and 12-lead ECGs will be recorded until 72 h post-dose (for 
time points please refer to Table 2)

Blood and urine samples for safety laboratory assessments will be taken on Day 1 and 
Day 4 before discharge

Subjects will be asked regularly about their well-being and any concomitant medication 
taken. 
After completion of the Day 4 measurements (72 h measurements) subjects will be discharged.
Days 5 to 7 (ambulatory)
Subjects will return to the study center in the morning of Day 5, Day 6 and Day 7 and PK blood 
samples for determination of tepotinib and its metabolites will be taken. Moreover, the subjects 
will be asked about their well-being and any medication taken.
Treatments B and C (Tepotinib together with Omeprazole)
Day -1 (admission)
Subjects will be hospitalized from the morning of Day -1 until completion of the assessments 
72 h after administration of tepotinib in the morning of Day 8. 
On admission on Day -1 the following will be done:

Physical examination 

Vital signs

12-lead ECG
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
Blood and urine samples for safety laboratory assessments (including drugs of abuse and 
a urine pregnancy test in females) 

Alcohol breath test
Drugs of abuse

Blood sample for PGx (optional, and only if this is the first treatment period)

Evaluation of inclusion and exclusion criteria (if this is the first treatment period)

Subjects will be asked about their well-being and any medication taken during the 
previous days.
Days 1 to 4 (inpatient)
The following activities will be done on Days 1 to 4:

40 mg omeprazole will be administered in the fasted state together with 240 mL water in 
the morning of Days 1 to 4 

Physical examination (on Day 4 only).
Days 5 to 8 (inpatient)
Prior to dosing of tepotinib on Day 5 the following will be done:

40 mg omeprazole will be administered in the fasted state together with 240 mL water in 
the morning 2 h prior to planned tepotinib dosing

Vital signs 

12-lead ECG 

Blood and urine samples for safety laboratory assessments 

Pre-dose PK blood sample for determination of tepotinib and its metabolites. 
Treatment B: 2 hours after omeprazole administration, 500 mg tepotinib will be administered in 
the fasted state together with 240 mL of water. 
Treatment C: 1.5 hours after omeprazole administration, a standardized breakfast will be served 
(ie, 30 min prior to tepotinib administration), which must be consumed completely within 
25 min. Thereafter, 500 mg tepotinib will be administered together with 240 mL of water.
After dosing of tepotinib on Day 5 the following will be done:

PK blood samples for determination of tepotinib and its metabolites will be taken 
regularly until 72 h post-dose (for time points please refer to Table 3)

Vital signs will be measured and 12-lead ECGs will be recorded until 72 h post-dose (for 
time points please refer to Table 3)

Blood and urine samples for safety laboratory assessments will be taken on Day 8 before 
discharge
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
Physical examination (on Day 8 only before discharge)

Subjects will be asked regularly about their well-being and any medication taken. 
After completion of the Day 8 measurements (72 h measurements after tepotinib administration) 
subjects will be discharged.
Days 9 to 11 (ambulatory)
Subjects will return to the study center in the morning of Day 9, Day 10 and Day 11 and PK 
blood samples for determination of tepotinib and its metabolites will be taken. Moreover, the 
subjects will be asked about their well-being and any medication taken.
Details about the measurements are provided in Sections 7.4 and 7.5.1.
Subjects should drink about 2 L fluids per day during the hospitalization phase (as provided by 
the site) and will be reminded regularly (for restrictions of fluids see below).
Restrictions:
Foods, sweets and beverages:
Intake of herbs/fruits that can have an influence on PK (eg St. John’s Wort, Seville oranges, 
grapefruits, cranberry or the juice of these fruits) are not allowed from 14 days before to Day -1 
of Period 1 until final examination. Methylxanthines (eg coffee, tea, cola, cocoa) and alcohol 
containing food or beverages are not allowed from 48 h before administration of tepotinib in 
each period until last PK blood sampling of each treatment period. Poppy seeds (eg poppy seed 
rolls, poppy seed cake, yoghurt containing poppy seed etc.) will not be allowed from 72 h prior 
to dosing until completion of final examinations.
Drinking of fluids:
Drinking of fluids is not allowed 1 h after administration of tepotinib.
Smoking:
Only non-smokers or smokers who stopped smoking at least 6 months before the time of the 
Screening Visit will be included in the trial. Moreover, smoking is not allowed from Screening 
Visit until completion of End of Trial Visit.
Exercise Regimen:
Subjects will be advised to avoid heavy physical exertion 72 h prior to first drug administration 
until completion of all post trial examinations.
7.1.3
End of Trial Visit
The End of Trial examination must verify that all values tested in the Screening have remained 
within a clinically acceptable range. The assessments will be performed 7 ± 1 days after last drug 
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administration in Period 3 or upon premature termination. 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 End of Trial examination will consist of the following:

Physical examination

Vital signs (supine blood pressure, pulse rate)

12-lead ECG

Blood and urine samples for safety laboratory assessments (including a serum pregnancy 
test)

Concomitant medication

Assessment of AEs.
No medical treatment is planned after the end of the trial.
The end of the 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: age (year of birth), height, 
weight, BMI, gender, race and ethnicity. 
Furthermore, the following will be documented:

Clinically relevant findings in the medical history are recorded

Prior medication within 14 days (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, ECGs 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 
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will report any AEs, whether observed by the Investigator or reported by the subject (see Section 
7.4.1.2). The reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE. Investigators will 
reference the National Cancer Institute - Common Terminology Criteria for AEs (NCI-
CTCAE), Version 4.03 (publication date: 14 June 2010), 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 for an AE is not specifically graded by NCI-CTCAE, the 
Investigator is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5, using 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
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 specified 
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 IMPs (including 
any other non-IMPs, radiation therapy, etc.) using the following definitions. Decisive factors for 
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the assessment of causal relationship of an AE to the IMPs include, but may not be limited to, 
temporal relationship between the AE and the IMPs known side effects of IMPs, medical history, 
concomitant medication, course of the underlying disease, trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMPs. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP/trial treatment under trial in 
this clinical trial protocol. A reasonable alternative explanation must be available.
Related:
Reasonably related to the IMPs. AE could medically (pharmacologically/clinically) 
be attributed to the IMPs 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.
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Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an
overnight stay to facilitate chemotherapy and related intravenous fluid 
administration) 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.
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 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 IMPs must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of IMPs. 
7.4.1.4
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest and Dose Limiting Toxicities
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE 
Report Form, which must be completed by the Investigator following specific completion 
instructions.
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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 adverse event 
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.
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, 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 line with respective regulations, the 
Sponsor/designee will inform the Investigator of AEs that are both serious and unexpected and 
are considered to be related to the administered product (“suspected unexpected serious adverse 
reactions” or SUSARs). The Investigator should place copies of Safety Reports in the 
Investigator Site File. National regulations with regards to Safety Report notifications to 
Investigators will be taken into account.
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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 AEs 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. 
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 to pregnancies in female subjects and to pregnancies in female partners of male subjects. 
The Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy 
using the Pregnancy Report Form, which must be transmitted according to the same process as 
described for SAE reporting in Section 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.
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7.4.3
Clinical Laboratory Assessments
Fasted blood samples and urine samples will be collected for the clinical laboratory tests 
(hematology, biochemistry, virology, drugs of abuse, hormones, and urinalysis, Table 4) 
following the timing noted in the Schedule of Assessments (Table 1, Table 2 and Table 3). 
Additional laboratory safety examinations during the trial are at the discretion of the Investigator. 
All blood and urine samples 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.
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 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. The following parameters will be determined as summarized in Table 4.
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.
For the amount of blood taken in this study see Appendix II.
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Table 4
Safety Laboratory Evaluations
Biochemistry
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyl-transferase
Lactate dehydrogenase
Creatine phosphokinase a
Amylase
Lipase
Bilirubin (total) b
Cholesterol
Triglycerides
Uric acid
Sodium
Potassium
Creatinine
Urea
Glucose
Hematology
Hematocrit
Hemoglobin
Red blood cell count 
Mean corpuscular volume
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration
Platelet count
White blood cell count
White blood cell differentials 
and absolute counts: c
Basophiles
Eosinophils
Lymphocytes 
Monocytes 
Neutrophils
Urinalysis
pH
Nitrite
Protein
Glucose
Leukocytes
Blood
Ketone bodies
Urobilinogen
Bilirubin
Urine pregnancy test, 
females only
Microscopic examination d
Urine drug screen
Cocaine
Amphetamines
Methamphetamines
Opiates
Barbiturates
Benzodiazepines
Methadone
Cannabinoids
Tricyclic antidepressants
Cotinine
Ecstasy
Other tests
Hepatitis B surface antigen
Hepatitis C antibody
HIV1/HIV2 antibodies 
Follicle stimulating hormone (if applicable)
Thyroid stimulating hormone
Serum pregnancy test (beta-HCG), females only
eGFR e
Alcohol breath test (at Screening and each Admission)
HIV = human immunodeficiency virus, HCG = human chorionic gonadotropin
a
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.
b
In case of an increased Bilirubin (total) the direct Bilirubin will be determined.
c
In case of abnormal findings, manual differential blood count can be requested by the Investigator.
d
Only if blood, protein, nitrite, or leucocytes are positive on the dipstick.
e
Estimated glomerular filtration rate (eGFR) calculated using the Cockcroft-Gault equation
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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 according to 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 (Table 1, Table 2 and Table 3).
Body temperature will be measured auricular.
Further vital sign measurements during the course of the trial are at the discretion of the 
Investigator.
7.4.4.2
ECG
Twelve-lead ECGs will be recorded as scheduled in the trial schedule of assessments (Table 1, 
Table 2 and Table 3) using the ECG system (CardioPerfect®, Welch Allyn). The ECGs will be 
recorded in supine position after at least 5 min rest.
ECGs will be plotted with a paper speed of 50 mm/s and 10 mm/mV amplitude, with 10 seconds 
recording duration for all leads and at least 3 complexes, but preferably 5 complexes in each 
lead. 
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 course of the trial are at the discretion of the Investigator.
7.4.4.3
Physical Examination
The physical examination comprises 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 study flow chart (see Table 1, Table 2
and Table 3). Further physical examinations during the course of 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). 
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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 per study flow chart (see Table 1, 
Table 2 and Table 3). 
Additional alcohol breath tests during the course of 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. 
Blood samples will be taken and plasma levels of tepotinib and its metabolites MSC2571109A 
and MSC2571107A will be determined as closely as possible to the following time points: 
Treatment A: 
on Day 1 at predose (within 60 min prior to administration of
tepotinib) and 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16 h and on 
Day 2 at 24, 36 h, on Day 3 at 48, 60 h, on Day 4 at 72 h, on Day 5 at 
96 h, on Day 6 at 120 h and on Day 7 at 144 h post-dose.
Treatments B and C: 
on Day 5 at predose (within 60 min prior to administration of 
tepotinib) and 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16 h and on 
Day 6 at 24, 36 h, on Day 7 at 48, 60 h, on Day 8 at 72 h, on Day 9 at 
96 h, on Day 10 at 120 h and on Day 11 at 144 h post-dose
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 5 need an 
explanation and will be considered a protocol violation.
Table 5
Time Windows 
Planned Blood Sampling 
Time Windows (min)
Predose
- 60
0.25 - 1 h postdose
± 2
> 1 h - 12 h postdose
± 5
> 12 h - 48 h postdose
± 15
> 48 h - 144 h postdose
± 30
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.
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Details of blood sample collection, labeling, processing, storage and shipment requirements will 
be described in a separate laboratory manual. For the amount of blood taken in this study see 
Appendix II.
All sample handling procedures, including the time of each sample collection, the time of 
placement into frozen storage (at the end of the sample preparation), and the date of transfer or 
shipment of the samples to the responsible analyst will be documented in detail. 
Concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A will be 
measured using validated liquid chromatography and tandem mass spectrometry methods at 
Nuvisan. The assays will be carried out in accordance with 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 study. Full details of the bioanalytical method used 
will be described in a separate bioanalytical report.
7.5.2
Calculation of Pharmacokinetic Variables
The following non-compartmental PK parameters (see Table 6) will be calculated from the 
individual plasma tepotinib concentration-time data using commercial software such as 
Phoenix®/WinNonlin® (Version 6.2 or higher) at Nuvisan GmbH.
Table 6
Definition of PK Parameters for Tepotinib
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 using 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 plasma concentration is at or above the lower limit of 
quantification
tmax
Time to reach the maximum observed plasma concentration
t1/2
Terminal half-life, calculated as ln(2)/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 extravascular administration,
calculated as dose/AUC0-∞
Vz/f 
Apparent volume of distribution during the terminal phase following extravascular administration
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra / AUC0-∞x 100.
MRAUC0-∞
Metabolite AUC0-∞to parent AUC0-∞ratio
MRCmax
Metabolite Cmax to parent Cmax ratio
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Individual PK parameters will be calculated using actual sampling times. The predose 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.
Plasma concentrations below LLOQ before the last quantifiable data point will be taken as zero 
for calculating the AUC (ie embedded below the limit of quantitation values set to zero). Plasma 
concentrations below LLOQ after the last quantifiable data point will not be considered for the 
determination of λz.
7.6
Biomarkers
Not applicable.
7.7
Pharmacogenomics 
Pharmacogenetic sample collection is optional. An additional separate Informed Consent Form 
(ICF) will be used. One blood sample should be collected in duplicate on Day -1 of Period 1. The 
pharmacogenetic samples will be analyzed conditionally in case of unexpected PK profiles. The 
results of the pharmacogenetic analysis, as applicable, will be described in a separate report.
7.8
Other Assessments
Not applicable.
8
Statistics
8.1
Sample Size
A total of 12 subjects will be randomized into this study. To obtain at least 12 evaluable subjects 
for the primary endpoint analysis, every drop-out with incomplete data must be replaced.
The statistical analysis of study data will be descriptive; no hypothesis tests will be performed. 
Nevertheless, the relative bioavailability should be estimated with a reasonable precision. 
The half-width of the 90% confidence interval (CI) will be taken as a measure of precision.
The precision for the test/reference ratios (T/R ratio) to be estimated for AUC and Cmax for a 
series of coefficients of variation (CV) and a fixed sample size of 12 subjects is shown in Table 
7. The CVs observed most recently for AUC and Cmax of tepotinib in a relative bioavailability in 
the fed condition study comparing two tepotinib tablet formulations (MS200095-0012) ranged 
between 10% and 13%. An increase in variability up to 20% is expected under fasting 
conditions.
A two-sided alpha = 0.10 was used in the calculations, and the probability of achieving a pre-
defined half-width (precision) was set to 0.80.
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Based on these assumptions, the CI half-width for the estimated T/R ratios will be between 9% 
and 18% for both AUC and Cmax. Considering the envisaged therapeutic window of tepotinib, 
this precision is sufficient to meet the study objectives. 
Table 7
90% Confidence Intervals for Estimated Test/Reference Ratios, n=12
CV
Half-width 90% CI
T/R Ratio
90% LCL
90% UCL
10%
8.8%
0.50
0.46
0.54
0.75
0.69
0.82
1.25
1.15
1.36
1.50
1.38
1.63
15%
13.4%
0.50
0.44
0.57
0.75
0.66
0.85
1.25
1.10
1.42
1.50
1.32
1.70
20%
18.2%
0.50
0.42
0.59
0.75
0.63
0.89
1.25
1.06
1.48
1.50
1.27
1.77
EAST 6.4 software was used to perform the calculations.
CI = Confidence Interval, LCL = Lower Confidence Limit, R = reference, T = test, UCL = Upper Confidence Limit
8.2
Randomization
A computer-generated randomization scheme will be provided by Nuvisan GmbH CTS 
Department. Two subjects each will be randomized to one of six possible treatment sequences:
Sequence 1: A-B-C
Sequence 2: A-C-B
Sequence 3: B-A-C
Sequence 4: B-C-A
Sequence 5: C-A-B
Sequence 6: C-B-A.
8.3
Endpoints
8.3.1
Primary Endpoint

PK profile of tepotinib following Treatments A and C in terms of AUC from time zero to 
the last sampling time 144 h postdose (AUC0-t), AUC from time zero extrapolated to 
infinity (AUC0-∞) and maximum plasma concentration (Cmax).
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8.3.2
Secondary Endpoints

PK profile of tepotinib following Treatment B in terms of AUC0-t, Cmax from time zero to 
144 h postdose, and AUC0-∞

PK profile of tepotinib following Treatments A, B and C in terms of time of the 
maximum drug concentration (tmax), terminal half-life (t1/2), time prior to the first 
measurable (non-zero) concentration (tlag), apparent total body clearance (CL/f), and 
apparent volume of distribution during terminal phase (VZ/f) 

Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of 
changes in safety laboratory assessments, 12-lead ECGs and vital signs in subjects 
receiving tepotinib alone and together with omeprazole assessed from Day -1 of Period 1 
until the End of Trial Visit.
8.3.3
Exploratory Endpoints

PK profiles of tepotinib metabolites: AUC0-t, AUC0-∞, Cmax, tmax, and t1/2

Ratios of tepotinib metabolites to tepotinib: MRAUC0-∞and MRCmax

Genetic variants and mutations in genes that potentially influence the PK of tepotinib
Note: Pharmacogenetic sample collection is optional. The results of the pharmacogenetic 
analysis, as applicable, will be described in a separate report.
8.4
Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Screening
The screening analysis set will include all subjects who provided signed 
informed consent, regardless of treatment status in the trial. This set will 
be used for subject disposition.
Safety
The Safety Analysis Set will include all subjects who have received at 
least 1 dose of planned IMP and have had 1 subsequent safety assessment. 
Subjects will be analyzed according to the actual treatment they receive.
Pharmacokinetic
The PK Analysis Set will consist of all subjects who receive at least one 
dose of IMP, have no clinically important protocol deviations or important 
events affecting PK, and provide at least one measurable postdose
concentration. Subjects will be analyzed according to the actual treatment 
they received. All PK analyses will be based on this analysis set.
Subjects may be excluded after vomiting or following diarrhea in a 
particular period as this could render the plasma concentration-time 
profile unreliable. The use of a concomitant medication that might 
interfere with the PK of any investigational drug could be a reason for 
excluding a subject.
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8.5
Description of Statistical Analyses
8.5.1
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 [StD], median, 25th 
and 75th percentiles [Q1 and Q3], 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, StD, 
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 geometric mean (GeoMean), the geometric coefficient of 
variation (GeoCV%), and the 95% CI for the GeoMean.
Missing data will be handled as such and not be replaced by estimates. A subject who withdraws 
prior to the last planned observation in a trial period will be included in the analyses up to the 
time of discontinuation.
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.
8.5.2
Analysis of Primary Endpoint
A linear model with TREATMENT, PERIOD, SEQUENCE and SUBJECT(SEQUENCE) as 
fixed effects will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞based 
on the PK analysis set. Treatment differences C-A and C-B on the log scale will be estimated for 
Cmax, AUC0-t, and AUC0-∞together with their 90% CIs. Point estimates and CIs will be 
back-transformed to the original scale. 
The relative bioavailabilities C/A and C/B will be calculated for each subject and summarized.
Graphical displays will be given, where appropriate. Details of the statistical analysis will be 
described in the SAP.
8.5.3
Analysis of Secondary Endpoints
Summary statistics will be provided for all secondary PK parameters in plasma by time point. 
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PK variables will be listed for all subjects who provide sufficient concentration-time data. 
Invalid data will be flagged accordingly.
Graphical displays will be given, where appropriate. Details of the statistical analysis will be 
described in the SAP.
8.5.4
Analysis of Safety and Other Endpoints
Safety data analysis will be conducted on the Safety Analysis Set. The number and percentage of 
subjects experiencing at least 1 TEAE will be summarized by treatment as well as the number of 
events. Tables by relationship to trial 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 postdose
shifts relative to baseline, and data listings of abnormalities as per NCI-CTCAE severity scale.
Vital signs and ECG data will be summarized by changes-from-baseline values by treatment 
using descriptive statistics. Clinical noteworthy ECG findings for individual subjects will be 
listed and summarized as appropriate.
PK concentrations will be descriptively summarized. Individual and mean concentration-time 
plots will be produced in linear and log-linear scale. 
8.5.5
Analysis of Exploratory Endpoints
Summary statistics will be provided for all exploratory PK parameters as well as for the 
concentrations of the tepotinib and metabolites in plasma by time point. PK variables of tepotinib 
and the metabolites will be listed for all subjects with data. Graphical displays will be given, 
where appropriate. Further details of the statistical analysis will be described in the SAP.
8.6
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, and any other applicable regulations. The Investigator must ensure that 
only subjects who have given informed consent are included in the trial.
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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 before informed 
consent is obtained. 
A subject information sheet must be prepared in the local language in accordance with ICH GCP
and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or a designate will 
inform the subject verbally of all pertinent aspects of the 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 Informed Consent Form must be signed 
and dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s 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 Informed Consent 
Form should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed
consent, the Investigator will revise the subject information sheet and any other written 
information to be provided to the subjects and submit them to the 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 and Informed Consent Form will be prepared and signed by the 
subjects for pharmacogenomic examination. 
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 
subject confidentiality will be strictly maintained.
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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 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 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 I facility will provide the appropriate 
means to contact a physician. This includes the provision of a 24 h 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 the trial. Insurance conditions will meet good local 
standards, as applicable.
9.6
Independent Ethics Committee 
Prior to commencement of the trial, this clinical trial protocol will be submitted together with its 
associated documents (for example, Informed Consent Form, insurance certificate) 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 document the date at which the favorable opinion or approval was given. A 
members list of the IEC will be provided. Written evidence of favorable opinion or approval that 
clearly identifies the clinical trial protocol version and the Subject Information and Informed 
Consent Form version reviewed will 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.
Document No. 
 
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Effect of a proton pump inhibitor on the PK of Tepotinib
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9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information and Informed Consent Form) will be submitted 
or notified to the Health Authorities in accordance with all local and national regulations for each 
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. 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 data management
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.
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’s
screening 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
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
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’s screening 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 
Informed Consent Forms. 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, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP 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 IMPs and IMP accountability records, and the original medical records or files for 
each subject.
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10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive 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 EU Clinical Trials Register (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. 
 
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Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
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I N F O R M A T I O N
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11
References Cited in the Text
1. Summary of product characteristics (Fachinformation) Omeprazol-ratiopharm, February 
2016.
2. Gan KH, Geus WP, Lamers CBHW et al. Effect of Omeprazole 40 mg Once Daily on 
Intraduodenal and Intragastric pH in H. Pylori-Negative Healthy Subjects. Digestive 
Diseases and Sciences 1997;42:2304-09.
3. Guidance for Industry; Drug Interaction Studies - Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations, 2012.
4. Guideline on the Investigation of Drug Interactions, CPMP/EWP/560/95/Rev. 1 Corr. 
2**, 2012.
5.
Guideline on the investigation of bioequivalence CPMP/QWP/EWP/1401/98 Rev. 1, 
2010.
6. Omeprazole, www.drugs.com/omeprazole.html, down-loaded January 2018.
7. 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.
8. ICH Topic E 3 Note for Guidance on Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95); July 1996.
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12
Appendices
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Appendix I
Signature Pages and Responsible Persons for the Trial
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T c p oti ni b ( M C 2 1 5 6 1 1 9 J) 
M S 2 0 0 0 9 5- 0 0 3 9 
Eff e ct of a p r ot o n p u m p i n hi bit o r o n t he P K of T e p oti ni b 
Si g n a t u r e P a g e - P r ot o c ol L e a d 
T ri al Titl e: 
P h as e I O p e n-l a b el, T hr 
- P eri o d Cr oss o 
r t u d y t o 
I n v esti g at e t he Effi ct of a Pr ot o n P u m p l n hi bit or 
( O m e pr a z ol e) o n t he P h a n n a c o ki n eti cs of T e p oti ni b i n 
H e alt h y S u bj e cts 
E u d r a C T N u m b e r: 
2 0 1 7- 0 0 2 8 3 2- 1 8 
Cli ni c al 
T ri al 
P r ot o c ol 
D at e 
/ 
1 1 
pril 2 0 1 8 / V ersi o n 1. 0 
Versi o n: 
P r ot o c ol L e a d: 
l a p pr o v e t h e de i g n of t he cli ni c al trial: 
ig n at ur e 
Date of i g n at ur 
Na me a c a d e mi c d e gr e e: 
 
 
F u n cti o n / Titl e: 
M e di c al R es p o nsi bl 
/ 
 
[ nstit uti o n: 
er c k K G a A 
A d dress: 
Fr a n kf urt er Str ass e 2 5 0 , 6 4 2 9 3 D ar m t a dt G er m a n y 
Tele p h o ne n u m ber: 
 
- mai l a d dr es : 
D oc u me nt N o. 0 9 0 0 ba b c 8 0 d 1 6 d 7 4 v 2. 0 
O bject >J o . 0 9 0 0 ba bc 8 0f 4c 5 4 9 
6 5/ 7 0 
PI
PI
PI
PI
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T e p oti ni b ( M C 2l 5 6 1 1 9J) 
M S 2 0 0 0 9 5- 0 0 3 9 
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Si g n at u r e P a g e - P ri n ci p al I n v esti g at o r 
T ri al Tit le 
P hase I O pe n-la bel, T hree- Peri o d 
r oss o ver St u d y t o 
I n vesti gate t he Effect of a Pr ot o n P u m p I n hi bit or 
( O me praz ole) o n t he P har mac o ki netics of Te p oti ni b i n 
Healt h 
u bjects 
E u d r a C T N u m b e r 
2 0 1 7- 0 0 2 8 3 2-l 8 
Cli ni c al 
T ri al 
P r ot o c ol 
D at e 
/ I I A pri I 2 0 1 8 / Versi o n 1. 0 
V e rsi o n 
C e nt e r N u m b e r 
P ri n ci p al I n e ti g at o r 
 
I t he u n dersi g ne d , a m res p n i bl 
f or t he c o n d uct of t he trial at t hi 
ite a n d affir m t hat I 
u n dersta n d a n d will c o n d uct t he trial acc or di n g t o t he cli nical trial pr ot oc ol , a n y a p pr o e d 
pr ot oc ol a me n d me nts , I nter nati o nal C o u ncil of Har m o nizati o n G o o d Cli nical Practice ( T o pic 6) 
and all app li
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Si g nat ure 
Date of Si g nat ur 
a me, aca de mic de gree : 
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F u ncti o n I Title: 
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L nstit uti o n : 
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E - mail a d dress: 
 
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Effect of a pr ot o n p u m p i n hi bit or o n t he P K of T e p oti ni b
M S 2 0 0 0 9 5- 0 0 3 9
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 /7 0
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:
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A d dress:
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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 K Ga A 
A d dress:
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Tele p h o ne n u m ber:
E- mail a d dress:
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0 d 1 6 d 7 4 v 2. 0
0 9 0 0 ba be 8 0f 4c 5 4 9
PI
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PI


Tepotinib (MSC2156119J)
Effect of a proton pump inhibitor on the PK of Tepotinib
MS200095-0039
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Appendix II
Planned Numbers of Blood Samples for Clinical Laboratory, 
PK, and PGx and Total Blood Sampling Volume
Blood sample for
Amount 
per 
sample 
(mL)
Number of Scheduled Blood Samples per Subject
Total 
amount 
per 
Subject 
(mL)
Screening
Tepotinib 
alone
Tepotinib 
with 
omepra-
zole fasted
Tepotinib 
with 
omepra-
zole fed
End of 
Trial 
Visit
Total
Clinical laboratory tests 
Biochemistry (incl. viral 
serology, TSH and FSH 
levels, if applicable)
4.7
1
3 a
3 b
3 b
1
11
51.7
Hematology
2.7
1
3 a
3 b
3 b
1
11
29.7
PK
2.0
21 c
21 d
21 d
63
126.0
PGx (optional)
2.0
2 e
2
4.0
Total
2
29
27
27
2
87
211.4
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: 
250
FSH = follicle stimulating hormone, PK = pharmacokinetics; PGx = pharmacogenetics, TSH = thyroid stimulating 
hormone.
Clinical laboratory (biochemistry and hematology) blood samples:
a
Tepotinib alone: before drug administration on Day -1, before tepotinib administration on Day 1 and before 
discharge on Day 4 = 3 samples.
b
Tepotinib with omeprazole: Day -1, before tepotinib administration on Day 5, and before discharge on Day 8 = 3 
samples.
PK blood samples for determination of tepotinib and its metabolites:
c
Tepotinib alone: predose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 and 144 h 
postdose = 21 samples.
d
Tepotinib with omeprazole: predose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120 
and 144 h postdose = 21 samples.
PGx blood samples:
e
PGx blood samples of 2 x 2 mL (optional) to be drawn on Day -1, in Period 1 only = 2 samples.
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Appendix III
Contraception Guidance
Definitions
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered women of childbearing potential
1.
Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
2.
Premenarchal
3.
Postmenopausal female
Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy are 
exempt from pregnancy testing. If necessary to confirm postmenopausal status, FSH 
will be re-tested at Screening.
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
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Contraceptive Guidance for Women of Childbearing Potential:
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly. 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation b

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulation b

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of ovulation b

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion

Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. In this case another highly effective (not hormone based) method of contraception 
must be utilized during the treatment period and for at least 3 months after the last dose of study treatment 
Document No. 
 
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SAP_001.pdf: 
 
I nte gr ate d A n al ysis Pl a n 
Cli nic al Tri al Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 0 0 9 5- 0 0 3 9  
Title  
P hase I, O pe n -la bel, T hr ee-Peri o d Cr oss o ver St u d y  
t o I n vesti gat e t he Eff ect of a Pr ot o n P u m p I n hi bit or 
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i n Healt h y S u bjects 
Tri al P h ase  
I 
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
Te p oti ni b ( M S C 2 1 5 6 1 1 9J)  
Cli nic al Tri al Pr ot oc ol 
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1 1 A pril 2 0 1 8 / Versi o n 1. 0 
I nte gr ate d A n al ysis Pl a n 
A ut h or  
 
C o or di n ati n g A ut h or  
 
, M er c k 
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
, N u vi s a n 
 
 
 
 
I nte gr ate d A n al ysis Pl a n 
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, 
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C o p y ri g ht © 2 0 1 8  b y M erc k K G a A, D ar mst a dt, Ge r m a n y or its aff ili ate. All ri g hts reser ve d. 
Pa ge 2 of 3 3 3
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M S 2 0 0 0 9 5- 0 0 3 9 v ersi o n 1. 0 
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I nt e gr at e d A n al ysis Pl a n: M S 2 0 0 0 9 5- 0 0 3 9 
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I n hi bit or ( O me praz ole) o n t he P har mac o ki netics of T e p oti ni b i n Healt h y S u bjects 
, 
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2124 
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1 
Table of Contents 
Integrated Analysis Plan ......................................................................................................1 
Signature Page 
2 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................5 
3 
Modification History ............................................................................6 
4 
Purpose of the Integrated Analysis Plan ...............................................6 
5 
Objectives and Endpoints .....................................................................7 
6 
Overview of Planned Analyses .............................................................7 
7 
Changes to the Planned Analyses in the Clinical Trial Protocol ..........7 
8 
Protocol Deviations and Analysis Sets .................................................8 
8.1 
Definition of Protocol Deviations and Analysis Sets ...........................8 
8.2 
Definition of Analysis Sets and Subgroups ..........................................9 
9 
General Specifications for Data Analyses ............................................9 
10 
Trial Subjects ......................................................................................10 
10.1 
Disposition of Subjects and Discontinuations ....................................10 
10.2 
Protocol Deviations ............................................................................11 
10.2.1 
Important Protocol Deviations ............................................................11 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................11 
11 
Demographics and Other Baseline Characteristics .............................12 
11.1 
Demographics .....................................................................................12 
11.2 
Medical History ..................................................................................12 
11.3 
Other Baseline Characteristics ............................................................12 
12 
Previous or Concomitant Medications/Procedures .............................13 
13 
Treatment Compliance and Exposure .................................................13 
14 
Efficacy Analyses ...............................................................................13 
15 
Safety Analyses ..................................................................................13 
15.1 
Adverse Events ...................................................................................14 
15.1.1 
All Adverse Events .............................................................................14 
15.1.2 
Adverse Events Leading to Treatment Discontinuation .....................15 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................16 
Page 4 of 333


15.2.1 
Deaths .................................................................................................16 
15.2.2 
Serious Adverse Events ......................................................................16 
15.2.3 
Other Significant Adverse Event ........................................................16 
15.2.3.1 
Adverse Events of Special Interest .....................................................16 
15.3 
Clinical Laboratory Evaluation ...........................................................16 
15.4 
Vital Signs ..........................................................................................17 
15.5 
ECG Evaluation ..................................................................................17 
16 
Analyses of Other Endpoints ..............................................................18 
16.1 
Pharmacokinetics ................................................................................18 
General Specifications for Plasma Concentration Data .....................................................18 
General Specifications for PK Parameter Data ..................................................................19 
16.1.1 
Primary Endpoints ..............................................................................19 
16.1.2 
Secondary Endpoints ..........................................................................20 
16.1.3 
Exploratory Endpoints ........................................................................20 
16.1.4 
Plasma Concentration Data .................................................................21 
16.1.5 
Estimation of Individual Pharmacokinetic Parameters .......................21 
16.2 
Pharmacogenetics ...............................................................................24 
17 
References ...........................................................................................24 
18 
Appendices .........................................................................................24 
 
Page 5 of 333


2 
List of Abbreviations and Definition of Terms 
AE 
Adverse Event 
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 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero (= 
dosing time) extrapolated to infinity 
AUCextra 
The AUC from time tlast extrapolated to infinity 
AUCextra% 
AUCextra / AUC0-∞ x 100 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CL/f 
Apparent total body clearance considering the fraction of dose (f) 
absorbed  
Cmax 
Maximum plasma concentration observed 
CSR 
Clinical Study Report 
CV% 
Coefficient of Variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
GeoCV% 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
IAP 
Integrated Analysis Plan 
ICH 
International Conference on Harmonization 
LCI 
Lower Confidence Interval 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
PD 
Pharmacodynamics 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
Page 6 of 333


Q 1  
2 5t h Perce ntile  
Q 3  
7 5t h Perce ntile  
Q Tc F  
C orrecte d Q T i nter val per Fri dericia’s f or m ula  
S A E  
Seri o us A d verse E v e nt  
S E M  
Sta n dar d Err or of t he Mea n  
S O C  
S yste m Or ga n Class  
S D  
Sta n dar d De viati o n  
t1/ 2 
Ter mi nal half -life 
T E A E  
Treat me nt E mer ge nt A d v erse E ve nt  
tla g 
Ti me pri or t o t he first meas ura ble ( n o n -zer o) c o nce ntrati o n  
tlast 
T he  last  sa m pli n g  ti me  at  w hic h  t he  c o nce ntrati o n  is  at  or  a b o ve  t he 
l o wer li mit of q ua ntificati o n 
tma x  
Ti me t o reac h t he m a xi m u m plas ma c o nce ntr ati o n  
U L O Q  
U p per Li mit of Q ua ntificati o n  
U CI  
U p per C o nfi de n ce I nter v al  
V Z /f 
A p pare nt v ol u me of distri b uti o n d uri n g t he ter mi n al p hase 
 
3  
M o dific ati o n Hist or y  
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
1. 0  
2 7 -J U L -2 0 1 8  
 
Ori gi n al d o c u m e nt  
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n 
T he p ur p ose of t his I A P is t o d oc u me nt tec h nical a n d detaile d s pecificati o ns f or t he fi nal a nal ysis 
of data c ollect e d f or pr ot oc ol M S 2 0 0 0 9 5- 0 0 3 9 . Res ults of t he a nal ys es des cri be d i n t his I A P will 
b e i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R). A d diti o nall y, t he pla n ne d a nal yses  i de ntifie d i n 
t his I A P will  be  i ncl u de d  i n  re g ulat or y  s u b missi o ns  or  f ut ure  ma n uscri pts.  A n y  p ost -h o c,  or 
u n pla n ne d a n al yses p erf or me d t o pr o vi d e r es ults f or i n cl usi o n i n t he C S R b ut n ot i de ntifie d i n 
t his pr os pecti ve I A P will be clearl y i d e ntifie d i n t he  C S R.  
T he I A P is bas e d u p o n s ecti o n 8 ( Statistics) of t h e trial pr ot oc ol a n d pr ot o c ol a me n d me nts a n d is 
pre pare d i n c o m plia nce w it h I C H E 9.  
 
 
Pa ge 7 of 3 3 3
PI


5 
Objectives and Endpoints 
 
Objective 
Endpoint 
IAP 
section 
Primary 
Objective 
To investigate the effect of 
omeprazole co-administration 
on the single dose PK of 
tepotinib under fed conditions 
in healthy subjects. 
PK profile of tepotinib following Treatments A and C in 
terms of area under the concentration-time curve (AUC) 
from time zero to the last sampling time 144 h postdose 
(AUC0-t), AUC from time zero extrapolated to infinity 
(AUC0-∞) and maximum plasma concentration (Cmax). 
16.1.1 
 
 
 
 
Secondary 
Objective 
To investigate the effect of food 
on the single dose PK of 
tepotinib after co-administration 
of omeprazole and tepotinib 
PK profile of tepotinib following Treatment B in terms of 
AUC0-t from time zero to 144 h postdose, AUC0-∞ and 
Cmax PK profile of tepotinib following Treatments A, B 
and C in terms of time of the maximum drug 
concentration (tmax), terminal half-life (t1/2), time prior to 
the first measurable (non-zero) concentration (tlag), 
apparent total body clearance (CL/f), apparent volume 
of distribution during terminal phase (VZ/f) 
16.1.2 
 
To assess the safety and 
tolerability of tepotinib alone 
and upon co-administration of 
omeprazole. 
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 in subjects receiving tepotinib alone and 
together with omeprazole assessed from Day -1 of 
Period 1 until the End of Trial Visit. 
15 
Exploratory 
Objective 
To investigate the effect of 
omeprazole co-administration 
on the PK of metabolites of 
tepotinib under fed conditions 
PK profiles of tepotinib metabolites: AUC0-t, AUC0-∞, 
Cmax, tmax, and t1/2 
Ratios of tepotinib metabolites to tepotinib: MRAUC0-∞ 
and MRCmax 
16.1.3 
 
To explore the effect of 
pharmacogenetics (PGx) and 
variations of associated genes 
on the PK profile of tepotinib (if 
applicable, participation is 
optional). 
Genetic variants and mutations in genes that potentially 
influence the PK of tepotinib. 
16.2 
6 
Overview of Planned Analyses 
All final, planned analyses identified in the Clinical Trial Protocol and in this IAP will be 
performed only after the last subject has completed the last visit, ie, end of trial visit/early 
termination visit with all trial data in-house, all data queries resolved, and the database locked.  
A data review meeting will be held prior to database lock. In addition, no database can be locked 
until this IAP has been approved. 
7 
Changes to the Planned Analyses in the Clinical Trial 
Protocol 
The statistical methods as described in the protocol were adopted.  
 
Page 8 of 333


8 
Protocol Deviations and Analysis Sets 
8.1 
Definition of Protocol Deviations and Analysis Sets 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being.  
The following deviations will be identified and confirmed prior to or at the Data Review Meeting 
at the latest.  
Important protocol deviations include 
• Deviations from the inclusion and exclusion criteria 
• Concomitant medication violations (see Section 6.5.1 of the protocol) 
• Use of prohibited medicines (see Section 6.5.2. of the protocol) 
• Subjects that receive incorrect treatment or dose 
• Sample processing errors that may lead to inaccurate bioanalytical results 
• Vomiting or diarrhea following oral dosing (these instances will be discussed on a case-
by-case basis) 
• Deviation from Good Clinical Practice 
• Non-compliance to study procedures or deviations from study procedures likely to affect 
the primary endpoints (e.g. subject develops withdrawal criteria whilst on the study but is 
not withdrawn) 
• Deviation from study medication compliance in terms of medical conditions and/or AEs 
that may have interfered with drug disposition or with respect to factors likely to affect 
the primary endpoints 
All important protocol deviations will be documented in CDISC datasets whether identified 
through sites monitoring or medical review.  
 
 
Page 9 of 333


8.2 
Definition of Analysis Sets and Subgroups 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screening 
The screening analysis set will include all subjects who provided signed 
informed consent, regardless of treatment status in the trial. This set will 
be used for subject disposition.  
Safety 
The Safety Analysis Set will include all subjects who have received at 
least 1 dose of planned IMP and have had 1 subsequent safety assessment. 
Subjects will be analyzed according to the actual treatment they receive.  
Pharmacokinetic 
The PK Analysis Set will consist of all subjects who receive at least one 
dose of IMP, have no clinically important protocol deviations or important 
events affecting PK, and provide at least one measurable postdose 
concentration. Subjects will be analyzed according to the actual treatment 
they received. All PK analyses will be based on this analysis set. 
Subjects may be excluded after vomiting or following diarrhea in a 
particular period as this could render the plasma concentration-time 
profile unreliable. The use of a concomitant medication that might 
interfere with the PK of any investigational drug could be a reason for 
excluding a subject. 
 
9 
General Specifications for Data Analyses 
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, Q1 and 
Q3, minimum, and maximum) and categorical data will be summarized by means of frequency 
tables (ie, count and percentages), if not stated otherwise. Mean, Median, Q1, Q3, Min, Max will 
have the same precision as the SDTM data (decimal places). SD will be presented with one 
decimal place more than the mean.  F or subject disposition and demographic tables the 
denominator will be the number of subjects in the analysis set. Counts of missing observations 
will be included as a separate category. 
If not otherwise specified, ‘baseline’ refers to the last scheduled measurement before 
administration of the first drug in each period. However, if a subject is missing the baseline 
Page 10 of 333


collection, the previous non-missing evaluation within the same period predose could become 
the baseline value. If no baseline or previous to baseline evaluations exist then the baseline value 
will be treated as missing. 
The following calculations and derivations, as applicable, will be used:  
• Change from baseline: post-baseline visit value - baseline value  
• Duration of AE (in days hh:mm) = end date and time - start date and time of the AE, if 
missing time for either the beginning or end then = end date – start date + 1 
• Days hh:mm from dosing = start date and time of the event - date and time dose 
administration; (for treatment-emergent AEs), if missing time for either the dosing or event 
then = event start date – date of dose administration + 1 
• Rel. Day in study of AE = start date of the event – date of First Admin + 1 (for AEs on or 
after the day of dosing)  
• Rel. Day in study of AE = start date of the event – date of First Admin (for pre-treatment AEs 
only)  
Repeated laboratory assessments will be flagged as repeats in the subject data listings and not 
included in summary tables statistics (unless the scheduled measurement was considered 
unreliable, e.g. due to technical reasons, and needed to be replaced by an unscheduled repeat 
measurement). 
In this phase 1 PK study missing observations will be assumed to be missing completely at 
random (MCAR). No action will be taken to handle missing data. A subject who withdraws prior 
to the last planned observation in a trial period will be included in the analyses up to the time of 
discontinuation. 
The following treatment labels will be used in listing and tables: 
• tepotinib, fed 
• tepotinib + omeprazole, fasted 
• tepotinib + omeprazole, fed 
10 
Trial Subjects 
10.1 
Disposition of Subjects and Discontinuations 
This following will be presented in a summary table:  
• Total number of subjects screened (ie, subjects who gave informed consent) 
Page 11 of 333


• Number of screened subjects who discontinued from the trial prior to treatment overall and 
grouped by the main reason for discontinuation: 
o Subject did not meet all eligibility criteria 
o Withdrew consent 
o Other  
• Number of treated subjects 
• Number and percentage of treated subjects who completed study 
• Number and percentage of treated subjects who discontinued the study, with the primary 
reason of discontinuation: 
o Adverse event 
o Lost to follow-up 
o Protocol non-compliance 
o Death 
o Withdrew consent 
o Other 
• Number and percentage of subjects who completed period (for periods 1, 2 and 3) 
• Number and percentage of subjects who discontinued period and reason for discontinuation 
(for periods 1, 2 and 3) 
A listing of discontinued subjects will be provided. 
 
10.2 
Protocol Deviations 
10.2.1 
Important Protocol Deviations 
Listings of important protocol deviations will be provided including the date and relative day in 
relation to dosing in the relevant period. 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set 
All criteria/reasons leading to the exclusion of a subject from an analysis set will be listed based 
on the safety set.  
Page 12 of 333


Reasons for excluding individual PK concentrations will also be listed separately and flagged in 
the main listing based on the safety analysis set. 
11 
Demographics and Other Baseline Characteristics 
11.1 
Demographics 
Summaries will be given for both the safety and the pharmacokinetic set, if different. 
Demographic characteristics will be listed by subject and summarized using the following 
information from the Screening/Baseline Visit CRF pages.  
Demographic characteristics: 
• Sex: male, female  
• Race: Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or other Pacific Islander, White, Other 
• Ethnic origin: Hispanic or Latino , Not Hispanic or Latino  
• Age (years): summary statistics 
• Height (cm) at Baseline: summary statistics 
• Weight (kg) at Baseline: summary statistics 
• BMI (kg/m²) at Baseline: summary statistics 
Age will be taken from the eCRF and cannot be derived from the data because only the year of 
birth is collected in the eCRF. 
BMI will be re-derived (ie, not taken directly from the database) according to the following 
formula: 
• BMI (kg/m²) = weight (kg) / (height (m) * height (m)) 
11.2 
Medical History 
The medical history will be listed by subject including the preferred term and MedDRA system 
organ class (SOC) body using MedDRA, current version. 
11.3 
Other Baseline Characteristics 
Other baseline characteristics will be listed by subject and summarized using the following 
information from the Screening/Baseline Visit eCRF pages.  
Other baseline characteristics: 
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• Smoking status 
• Alcohol consumption 
12 
Previous or Concomitant Medications/Procedures 
Previous medications are medications, other than trial medications and pre-medications for trial 
drug, which started and stopped before first administration of trial drug.  
Concomitant treatments are medications, other than trial medications, which are taken by 
subjects any time on-trial (on or after the first day of trial drug treatment for each subject).  
In case the date values will not allow to unequivocally allocating a medication to previous or 
concomitant medication the medication will be considered as concomitant medication 
Any previous and concomitant medication will be encoded with WHO-DD, latest version. Prior 
and concomitant medications will be listed by subject (all subjects). 
The following information will be displayed in a listing: generic or trade name (as reported in 
eCRF), WHO drug name (including ATC-2nd level and preferred term), dose/unit, route, 
frequency, reason for use, start/end date and time. 
Concomitant procedures will be presented in a data listing. 
 
13 
Treatment Compliance and Exposure 
A listing of date and time of each drug administration and each blood sampling including time 
deviations will be provided sorted by subject. 
  
14 
Efficacy Analyses 
Not applicable. 
15 
Safety Analyses 
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs. 
Safety data analysis will be conducted on the Safety Analysis Set.  
 
Page 14 of 333


15.1 
Adverse Events 
The number and percentage of subjects experiencing at least one TEAE will be summarized by 
treatment as well as the number of events. A TEAE is an AE with onset after start of treatment.  
Tables by relationship to trial drug and by severity will be generated. AEs will be coded using 
Medical Dictionary for Regulatory Activities terminology, latest version.  
Incomplete TEAE-related dates will be handled as follows: 
• In case the onset date is missing completely or missing partially but the onset month and year, 
or the onset year are equal to the start of trial treatment then the onset date will be replaced by 
the minimum of start of trial treatment and TEAE resolution date.  
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop dates will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of subject's death. In the latter case, the date of death 
will be used to impute the incomplete stop date.  
• In all other cases the incomplete stop date will not be imputed.  
 
15.1.1 
All Adverse Events 
All AEs recorded during the course of the trial (ie, assessed from signature of informed consent 
until the end of the Follow-up/End of Trial visit) will be coded according to MedDRA latest 
version and assigned to a SOC and PT. 
TEAEs will be summarized by worst severity, using MedDRA latest version preferred term as 
event category and MedDRA primary system organ class (SOC) body term as Body System 
category. The severity of AEs will be graded using the “National Cancer Institute - Common 
Terminology Criteria for Adverse Events” (NCI-CTCAE) guideline, as detailed in the study 
protocol. 
TEAEs related to trial treatment are those events with relationship missing, unknown or related. 
The following will be summarized in an overview table with the number and percentage of 
subjects (and the number of events) by treatment and overall: 
• Any TEAE  
• Any trial treatment related TEAEs 
• Any TEAE related to omeprazole 
• Any TEAE related to tepotinib  
• Any serious TEAEs  
Page 15 of 333


• Any trial treatment related serious TEAEs  
• Any omeprazol related serious TEAEs  
• Any tepotinib related serious TEAEs  
• Any severe TEAE (grade >=3) 
• Any trial treatment related severe TEAE (grade >=3)  
• Any omeprazol related severe TEAE (grade >=3)  
• Any tepotinib related severe TEAE (grade >=3)  
• Any TEAEs leading to death 
• Any trial treatment related TEAEs leading to death 
• Any omeprazole related TEAEs leading to death 
• Any tepotinib related TEAEs leading to death 
 
TEAEs will be summarized by treatment and overall in tables with: 
• The number and percentage of subjects by treatment with at least one TEAE and the number 
of events overall and by SOC and PT. Group/SOC terms will be sorted alphabetically and PTs 
within each group/SOC term will be sorted by descending frequency.  
• The number and percentage of subjects by treatment with at least one non-serious TEAE and 
the number of non-serious TEAE applying frequency threshold of 5%. Group/SOC terms will 
be sorted alphabetically and PTs within each group/SOC term will be sorted by descending 
frequency. 
In addition the following tables will be provided. Group/SOC terms will be sorted alphabetically 
and PTs within each group/SOC term will be sorted by descending frequency (based on all 
treatment groups combined):  
• A table by severity of TEAEs with the number and percentage of subjects by treatment with at 
least one TEAE and the number of events by SOC and PT.  
• A table by relationship to trial treatment with the number and percentage of subjects by 
treatment with at least one TEAE and the number of events by SOC and PT.  
Pre-treatment AEs (AEs with onset after informed consent but before start of treatment) and 
TEAEs will be listed separately. 
 
15.1.2 
Adverse Events Leading to Treatment Discontinuation 
TEAEs leading to permanent discontinuation of trial treatment will be summarized by treatment 
and overall including number of subjects, percentage and number of events. 
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A listing of TEAEs leading to permanent discontinuation of a trial treatment will additionally be 
provided. 
 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events 
15.2.1 
Deaths 
All deaths as well as reason for death will be based on information from the “Report of Subject 
Death” eCRFs.  
Listing of deaths, if any, will be provided displaying date and cause of death (including TEAE 
leading to death and relatedness to trial treatment, when applicable), and date and time of 
treatment administration. 
 
15.2.2 
Serious Adverse Events 
A summary table of SAEs, if any, by treatment and overall will be provided displaying the 
number and percentage of subjects by treatment with at least one SAE and the number of SAE 
overall and by system organ class and preferred term. Group/SOC terms and PTs within each 
group/SOC term will be sorted alphabetically. 
Listing of SAEs, if any, will be provided in addition. 
15.2.3 
Other Significant Adverse Event 
15.2.3.1 
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 adverse event 
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. 
Adverse events of special interest will be presented in a separate data listing. 
15.3 
Clinical Laboratory Evaluation 
All laboratory data will be reported with SI units. Laboratory parameters will be listed by subject 
and time-point and summarized indicating the treatment at the respective time-point using 
descriptive statistics for absolute values and change from baseline over time.. Data listings of 
abnormalities as per the NCI-CTCAE guideline will be provided. Shift tables for laboratory tests 
will be presented by treatment. Shift tables will be based on NCI-CTCAE grades, where 
possible, and on normal ranges otherwise. They will be produced for 
Page 17 of 333


- 
End of Trial versus Screening 
- 
Discharge versus Pre-dose (Tepotinib admistration) within periods. 
 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges and NCI-CTCAE grade and will additionally be listed 
separately.  
See section 7.4.3 of the clinical study protocol for a table of the safety laboratory evaluations. 
Safety laboratory values are separated into: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Other tests 
 
15.4 
Vital Signs 
Vital signs will be listed by subject and time-point and summarized for absolute values and 
changes-from-baseline by visit and treatment using descriptive statistics. Descriptive statistics 
tables will start at baseline. 
 
15.5 
ECG Evaluation 
ECG data will be listed by subject and time-point and summarized by absolute values and 
changes-from-baseline by treatment group using descriptive statistics. Descriptive statistics 
tables will start at baseline. Clinically significant ECG findings for individual subjects will be 
listed and summarized. 
The time intervals [PR, QRS, RR, QT and corrected QT intervals [based on Fridericia’s formula, 
QTcF] will be summarized descriptively by treatment. 
The Fridericia’s Correction (QTcF) is derived as follows:  
 
Fridericia’s Correction (QTcF)  
3 RR
QT
QTc f =
 
 
Page 18 of 333


where: RR = RR-interval measured in seconds. 
Observed QTcF values will be categorized according to their absolute values into the categories 
• ≤ 430 ms, 
• > 430 and ≤ 450 ms, 
• > 450 and ≤  480 ms, 
• > 480 and ≤  500 ms, and 
• > 500 ms, 
 
and categorized according to their absolute change from baseline into the categories 
 
• ≤ 30 ms, 
• > 30 and ≤  60 ms, and 
• > 60 ms. 
The number and percentage of subjects by these categories at any post-dose assessment will be 
tabulated by treatment group. All ECG measurements will be listed, with abnormalities 
indicated. 
Investigator reported interpretation results will also be listed and tabulated treatment using the 
number and percentage of subjects for each interpretation category (Normal, Abnormal Not 
Clinically Significant [NCS], Abnormal Clinically Significant [CS]. 
16 
Analyses of Other Endpoints 
16.1 
Pharmacokinetics 
General Specifications for Plasma Concentration Data 
PK concentration data will be descriptively summarized using nominal times: number of 
observations (n), arithmetic mean (Mean), standard deviation (SD), standard error of the mean 
(SEM), coefficient of variation (CV%), minimum (Min), median (Median) and maximum (Max). 
Descriptive statistics of PK concentration data will be calculated using values with the same 
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK concentration data: 
Mean, Min, Median, Max:  
 
 
 
3 significant digits 
SD, SEM 
 
 
 
 
 
 
4 significant digits 
CV%:  
 
 
 
 
 
1 decimal place  
Values below the lower limit of quantification of the assay (LLOQ) will be taken as zero for 
summary statistics of PK concentration data. For final evaluations values greater than the upper 
limit of quantification (ULOQ) are not accepted and should be replaced by valid numeric values 
Page 19 of 333


from dilution measurement. Missing concentrations (e.g. no sample, insufficient sample volume 
for analysis, no result or result not valid) will be reported and used generally as “N.R.”. Pre-dose 
samples that occur before the first drug administration will be assigned a time of 0 hours, as if 
the sample had been taken simultaneously with the study drug administration. 
General Specifications for PK Parameter Data  
PK parameter data will be descriptively summarized: number of observations (n), Mean, SD, 
SEM, CV%, Min, Median, Max, geometric mean (GeoMean), the geometric coefficient of 
variation (GeoCV) and the 95% confidence interval for the GeoMean (LCI 95% GM, UCI 95% 
GM).  
PK parameter Cmax will be reported with the same precision as the source data. All other PK 
parameters will be reported to 3 significant figures. In export datasets, as well as in the SDTM 
PP domain, PK parameters will be provided with full precision, and will not be rounded. 
Descriptive statistics of PK parameter data will be calculated using full precision values, and 
rounded for reporting purposes only.  
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data: 
Mean, Min, Median, Max, GeoMean, 95% CI:  
3 significant digits 
SD, SEM: 
 
 
 
 
 
 
4 significant digits 
CV%, GeoCV%: 
 
 
 
 
1 decimal place  
Ratio of GeoMean and 95% CI 
 
 
4 decimal places 
To ensure a reliable estimate of the extent of exposure, AUCextra should be less than or equal to 
20%. If AUCextra is greater than 20%, all parameters derived using λz (ie, λz, t1/2, AUC0-∞ AUCextra, 
Vz/f, CL/f) will be listed, but set to missing for the calculation of descriptive statistics.  
All statistical analyses and descriptive summaries of pharmacokinetic data will be performed on 
the PK Analysis Set. All available PK data will be listed. Data of subjects not in the PK analysis 
set or invalid data will be flagged accordingly. 
In this phase 1 P K study missing observations will be assumed to be missing completely at 
random (MCAR). No action will be taken to handle missing data. A subject who withdraws prior 
to the last planned observation in a trial period will be included in the analyses up to the time of 
discontinuation. 
16.1.1 
Primary Endpoints 
The effect of omeprazole co-administration on t he single dose PK of tepotinib under fed 
conditions will be investigated by comparing treatments A and C.  
Page 20 of 333


A linear model with TREATMENT, PERIOD, SEQUENCE and SUBJECT(SEQUENCE) as 
fixed effects will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞ of 
tepotinib based on the PK analysis set. Treatment differences C-A on the log scale will be 
estimated for Cmax, AUC0-t, and AUC0-∞ together with their 90% CIs. Point estimates and CIs 
will be back-transformed to the original scale.  
 
The primary endpoints will be descriptively summarized. Scatter plots will be produced for each 
primary endpoint by treatment group indicating the geometric means within each treatment 
group. 
16.1.2 
Secondary Endpoints 
The effect of food on the single dose PK of tepotinib after co-administration of omeprazole and 
tepotinib will be investigated by comparing treatments B and C using the linear model described 
above in 16.1.1, again applied to log-transformed Cmax, AUC0-t, and AUC0-∞ of tepotinib. Cmax, 
AUC0-t, and AUC0-∞ of tepotinib under treatment B will be summarized together with treatments 
A and C in one table. The scatterplots for treatment B will be included in the scatterplots 
produced for the primary endpoints (16.1.1)  
The relative bioavailabilities C/B and C/A will be calculated for each subject and summarized. 
Summary statistics will also be provided for tmax, t1/2, tlag, CL/f and Vz/f of tepotinib (all 
treatments). For tmax, the Hodges-Lehmann shift estimates will be given for C-B and C-A 
together with the 90% confidence intervals according to Tukey. PK variables will be evaluated 
for all subjects of the PK population, but listed for all subjects with available data. 
16.1.3 
Exploratory Endpoints 
The effect of omeprazole co-administration on t he PK of metabolites of tepotinib under fed 
conditions will be investigated. 
A linear model with the same terms as for the primary analysis will be fitted for the log 
transformed exploratory PK parameters AUC0-t, AUC0-∞, Cmax for the metabolites.  Treatments A 
and C will be compared. 
The relative bioavailabilities C/A will be calculated for each subject and summarized. 
Summary tables will be presented for PK parameters AUC0-t, AUC0-∞, Cmax, tmax, and t1/2 based 
on tepotinib metabolites MSC2571109A and MSC2571107A. 
Ratios of tepotinib metabolites to tepotinib: MRAUC0-∞ and MRCmax will also be summarized 
descriptively. 
 
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16.1.4 
Plasma Concentration Data 
Concentrations of tepotinib and its metabolites will be tabulated and displayed graphically. 
Summary statistics will be provided by treatment and nominal timepoint. 
The following figures will be produced, separately for tepotinib, MSC2571109A and 
MSC2571107A: 
• Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear and 
semi-logarithmic scale 
• Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear scale 
including SD error bars 
• Individual plasma concentration-time profiles overlaying subjects, for each treatment 
separately on linear and semi-logarithmic scale 
• Individual plasma concentration-time profiles overlaying all treatments, separately for each 
subject on linear and semi-logarithmic scale 
 
The following listing will be produced: 
• Plasma concentrations will be listed for each analyte by treatment, subject, and nominal 
time. Excluded plasma concentrations will be flagged. 
 
16.1.5 
Estimation of Individual Pharmacokinetic Parameters 
The following non-compartmental PK parameters (see Table 1) will be calculated from the 
individual plasma total tepotinib its metabolites MSC2571109A and MSC2571107A 
concentration-time data using commercial software such as Phoenix®/WinNonlin® (Version 6.2 
or higher) at Nuvisan GmbH. 
 
Table 1 
Definition of PK Parameters for Tepotinib and 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 o f quantification (LLOQ), calculated using the mixed log linear 
trapezoidal rule (ie linear up/log down) 
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Symbol 
Definition 
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 plasma concentration is at or above the lower 
limit of quantification 
tmax  
Time to reach the maximum observed plasma concentration 
t1/2 
Terminal half-life, calculated as ln(2)/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 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 extravascular 
administration, only parent drug, will not be calculated for the metabolites 
AUCextra 
The AUC from time tlast extrapolated to infinity 
AUCextra% 
AUCextra / AUC0-∞ x 100. 
MRAUC0-∞  
Metabolite AUC0-∞ to parent AUC0-∞ ratio 
MRCmax  
Metabolite Cmax to parent Cmax ratio 
Frel,C/A 
Frel,B/A 
Relative bioavailability (Test versus Reference), defined as AUC0-∞,C/AUC0-∞,A 
and AUC0-∞,B/AUC0-∞,A, where AUC0-∞,C is AUC0-∞ under co-administration of 
omeprazole under fed conditions, AUC0-∞,B is AUC0-∞ under co-administration of 
omeprazole under fasted conditions and AUC0-∞,A is AUC0-∞ for tepotinib alone 
und fed condition.  
F = 
reference
AUC
∞
−
∞
0
 test
-
0
AUC
 * 100 
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Individual PK parameters will be calculated using actual sampling times. The predose 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. 
Plasma concentrations below LLOQ before the last quantifiable data point will be taken as zero 
for calculating the AUC (ie embedded below the limit of quantitation values set to zero). Plasma 
concentrations below LLOQ after the last quantifiable data point will not be considered for the 
determination of λz. 
The following PK parameters will be calculated for diagnostic purposes and listed, but will not 
be summarized: 
• The time interval (h) of the log-linear regression (λz low, λz upp) to determine λz.  
• Number of data points included in the log-linear regression analysis to determine λz. 
• Goodness of fit statistic (Rsq) for calculation of λz.   
The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on t he log-transformed scale. Phoenix 
WinNonlin best fit methodology will be used as standard. The last quantifiable concentration 
should always be included in the regression analysis, while the concentration at tmax and any 
<LLOQ concentrations that occur after the last quantifiable data point should not be used.  
The coefficient of correlation (R²) should be ≥0.8 and the observation period over which the 
regression line is estimated should be at least twofold the resulting t1/2 itself. If these criteria are 
not met, then the corresponding values should be flagged in the listing displaying Individual 
Plasma Pharmacokinetic Diagnostic Parameters for Each Treatment. Any flags should be 
included in the study specific SDTM. Then the rate constants and all derived parameters (e.g. 
AUC0-∞, %AUCextra, CL/f, t1/2, and VZ/f) will be included in the parameter listings and will be 
discussed appropriately in alignment with the protocol lead and quantitative pharmacology 
representative. 
Partial areas AUCτ should be calculated using the scheduled dosing interval, as defined in the 
Clinical Trial Protocol. The actual dosing interval calculated from eCRF time data should not be 
used. The following rules apply when calculating the partial area AUCτ within the observed time 
interval fromT1 to T2:  
• If the start time of the interval (T1) occurs before the first observation, the observation at 
T1 will be estimated using the linear interpolant between the first datapoint and C0. For 
single dose data C0= 0 when the drug was administered via an extravascular route. For 
steady state models, C0 is the minimum concentration value occurring within the time 
interval T1 to T2. 
• If either T1 or T2 falls within the time range in which samples were taken, but does not 
coincide with an observed data point, then a linear or logarithmic interpolation is 
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performed to estimate the corresponding concentration value. Whether a linear or 
logarithmic interpolation is used will depend on the method of AUC calculation e.g. 
linear up log down.  
• If the end time of the interval (T2) occurs after the last measurable concentration and the 
terminal regression (λz) is estimable, then λz is used to estimate the concentration at time 
T2. The log trapezoidal rule will be used to calculate the area from the last observation 
time to the end time of the partial area (T2). If λz cannot be estimated the partial area will 
not be calculated. 
The IMP dose administered is given for the monohydrate hydrochloride salt (ie, 500 mg IMP). A 
conversion factor for the freebase IMP was calculated and will be applied when ‘dose’ is used in 
deriving PK parameter formulas needing a dose value (CL/f). 
Conversion factor = Molecular weight (MW) of base IMP divided by MW of salt form IMP = 
492.574 g/mol / 547.05 g/mol = 0.9004  
Amount of dose * conversion factor = actual dose of IMP:  500 mg * 0.900 = 450 mg 
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing. 
 
16.2 
Pharmacogenetics 
The results of the pharmacogenetic analysis, as applicable, will be described in a separate report. 
 
17 
References 
None. 
 
18 
Appendices 
None. 
 
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