Clinical trial NCT03629223
Conditions: Healthy
Keywords: Tepotinib Pharmacokinetics Bioequivalence
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-08-23; Completion date: 2019-01-25
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main purpose of the study was to demonstrate bioequivalence between the new tablet formulation (TF3, test treatment) and the tablet formulation used in clinical studies (TF2, reference treatment) and to investigate effect of food on pharmacokinetics (PK) of tepotinib.

Detailed description:

Arms: arm 1: Participants received a single oral dose of 500 milligrams (mg) Tepotinib tablet formulation 2 (TF2, reference treatment) on Day 1 of treatment period 1 followed by a single oral dose of 500 mg (2 x 250 mg) Tepotinib tablet formulation 3 (TF3, test treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period. arm 2: Participants received a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 1 followed by a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period. arm 3: Participants received a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 1 under fasting conditions followed by a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 2 under fed conditions. The washout period was 21 days between Day 1 of each period. arm 4: Participants received a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 1 under fed conditions followed by a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period. arm 5: Participants received a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 1 under fasting conditions followed by a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 2 under fed conditions. The washout period was 21 days between Day 1 of each period. arm 6: Participants received a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 1 under fed conditions followed by a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period.
Interventions: intervention 1: Tepotinib TF2 intervention 2: Tepotinib TF3
Intervention descriptions: intervention 1: Participants received a single oral dose of 500 mg Tepotinib TF2 under fasting or fed conditions in treatment period 1 or 2. intervention 2: Participants received single oral dose of 500 mg (2 x 250 mg)Tepotinib TF3 under fasting or fed conditions in treatment period 1 or 2.

Protocol documents:
Prot_000.pdf: 
Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce ( T F 3/ T F 2) a n d Effect of F o o d o n t he P K of Te p oti ni b
M S 2 0 0 0 9 5- 0 0 4 4
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 6 8
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 4 4
Title
P hase 1 , O pe n -la bel, 3 - Parts St u d y  wit h Cr oss o ver 
Desi g n i n eac h part t o I n vesti gate t he Bi oe q ui vale nce 
of 
t he Ta blet 
F or m ulati o n 
of 
Te p oti ni b 
T F 3 
c o m pare d t o T F 2 ( Part A), a n d t o I n vesti gate t he 
I nfl ue nce of F o o d o n t he P har mac o ki netics of eac h 
Ta blet F or m ulati o n T F 2 ( Part B) a n d T F 3 ( Part C) of 
Te p oti ni b i n Healt h y  S u bjects
P h ase
1
I N D N u m ber
N ot a p plica ble
E u dr a C T N u m ber
2 0 1 7- 0 0 5 0 5 6- 2 9
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
2 9 Ma y
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  an d m a y  not – i n f ull or part – be passe d o n, re pr o d uce d, 
p u blis he d or use d wit h o ut e x press per missi o n of Merc k K G a A, Dar msta dt, Ger ma n y,  or its 
s u bsi diary. C o p y ri 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 diary . 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 0e d 6c 2 2 v 1. 0
0 9 0 0 ba be 8 0fc b 4 1f
Pa ge 2 of 6 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 .......................................................................................................6
Table of In-Text Figures......................................................................................................6
List of Abbreviations ...........................................................................................................7
1
Synopsis................................................................................................9
2
Sponsor, Investigators and Trial Administrative Structure ................15
3
Background Information.....................................................................15
3.1
Trial Rationale ....................................................................................17
4
Trial Objectives ..................................................................................18
4.1
Primary Objectives .............................................................................18
4.2
Secondary Objectives .........................................................................18
4.3
Exploratory Objectives .......................................................................18
5
Investigational Plan ............................................................................18
5.1
Overall Trial Design and Plan ............................................................18
5.2
Discussion of Trial Design .................................................................20
5.2.1
Inclusion of Special Populations ........................................................21
5.2.2
Scientific Rationale for Trial Design..................................................21
5.2.3
Justification for Dose..........................................................................21
5.2.4
Rationale for Endpoints......................................................................22
5.3
Selection of Trial Population..............................................................22
5.3.1
Inclusion Criteria ................................................................................22
5.3.2
Exclusion Criteria...............................................................................23
5.4
Criteria for Initiation of Trial Treatment ............................................24
5.5
Criteria for Subject Withdrawal..........................................................24
5.5.1
Withdrawal from Trial Therapy..........................................................24
5.5.2
Withdrawal from the Trial..................................................................25
5.6
Premature Termination of the Trial ....................................................26
5.7
Definition of End of Trial...................................................................26
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................27
6.1
Description of the Investigational Medicinal Products ......................27
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6.2
Dosage and Administration ................................................................27
6.3
Assignment to Treatment Groups.......................................................28
6.4
Non-investigational Medicinal Products to be Used ..........................29
6.5
Concomitant Medications and Therapies ...........................................29
6.5.1
Permitted Medicines...........................................................................29
6.5.2
Prohibited Medicines..........................................................................29
6.5.3
Permitted / Prohibited Procedures ......................................................30
6.5.4
Other Interventions.............................................................................30
6.5.5
Special Precautions.............................................................................31
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................31
6.6
Packaging and Labeling of the Investigational Medicinal Product....31
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................31
6.8
Investigational Medicinal Product Accountability.............................31
6.9
Assessment of Investigational Medicinal Product Compliance .........32
6.10
Blinding ..............................................................................................32
6.11
Emergency Unblinding.......................................................................32
6.12
Treatment of Overdose .......................................................................33
6.13
Medical Care of Subjects after End of Trial.......................................33
7
Trial Procedures and Assessments......................................................33
7.1
Schedule of Assessments....................................................................33
7.1.1
Screening Examination.......................................................................33
7.1.2
Treatment Periods...............................................................................34
7.1.3
End of Trial Visit................................................................................36
7.2
Demographic and Other Baseline Characteristics ..............................36
7.3
Efficacy Assessments .........................................................................37
7.4
Assessment of Safety..........................................................................37
7.4.1
Adverse Events ...................................................................................37
7.4.2
Pregnancy and In Utero Drug Exposure.............................................41
7.4.3
Clinical Laboratory Assessments .......................................................42
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............44
7.5
Pharmacokinetics................................................................................45
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7.5.1
Blood Sampling ..................................................................................45
7.5.2
Calculation of Pharmacokinetic Variables .........................................45
7.6
Biomarkers..........................................................................................46
7.7
Pharmacogenetics ...............................................................................46
7.8
Other Assessments..............................................................................47
8
Statistics..............................................................................................47
8.1
Statistical Hypotheses.........................................................................47
8.2
Sample Size ........................................................................................47
8.2.1
Part A (Bioequivalence) .....................................................................47
8.2.2
Parts B and C (Food Effect)................................................................50
8.3
Randomization....................................................................................50
8.4
Endpoints............................................................................................51
8.4.1
Primary Endpoints ..............................................................................51
8.4.2
Secondary Endpoints ..........................................................................51
8.4.3
Exploratory Endpoints........................................................................52
8.5
Analysis Sets.......................................................................................52
8.5.1
Safety Analysis Set.............................................................................52
8.5.2
Definition of Pharmacokinetic Analysis Set.......................................52
8.6
Description of Statistical Analyses.....................................................52
8.6.1
General Considerations.......................................................................52
8.6.2
Analysis of Primary Endpoints...........................................................53
8.6.3
Analysis of Secondary Endpoints.......................................................54
8.6.4
Analysis of Safety and Exploratory Endpoints...................................54
8.7
Interim and Additional Planned Analyses ..........................................55
9
Ethical and Regulatory Aspects..........................................................55
9.1
Responsibilities of the Investigator ....................................................55
9.2
Subject Information and Informed Consent .......................................55
9.3
Subject Identification and Privacy......................................................56
9.4
Emergency Medical Support and Subject Card..................................56
9.5
Clinical Trial Insurance and Compensation to Subjects.....................56
9.6
Independent Ethics Committee or Institutional Review Board..........57
9.7
Health Authorities...............................................................................57
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10
Trial Management...............................................................................57
10.1
Case Report Form Handling...............................................................57
10.2
Source Data and Subject Files............................................................58
10.3
Investigator Site File and Archiving...................................................58
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................59
10.5
Changes to the Clinical Trial Protocol................................................59
10.6
Clinical Trial Report and Publication Policy......................................59
10.6.1
Clinical Trial Report...........................................................................59
10.6.2
Publication..........................................................................................59
11
References Cited in the Text...............................................................60
12
Appendices .........................................................................................61
Appendix I
Signature Pages and Responsible Persons for the Trial......................62
Signature Page – Protocol Lead.........................................................................................63
Signature Page – Principal Investigator.............................................................................64
Sponsor Responsible Persons not Named on the Cover Page ...........................................65
Appendix II
Blood Volume Sampled in the Clinical Trial .....................................66
Appendix III
Contraception Guidance .....................................................................67
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Table of In-Text Tables
Table 1
Schedule of Assessments – Parts A, B and C.....................................13
Table 2
Clinical Laboratory Evaluations.........................................................43
Table 3
Time Windows....................................................................................45
Table 4
Definition of PK Parameters for Tepotinib and its Metabolites 
After Single Dose Administration ......................................................46
Table 5
Overview of the PK-Variability Observed in the Previous 
Tepotinib Studies................................................................................48
Table 6
Power and Mean n for Declaring Bioequivalence for Individual 
PK Parameters ....................................................................................49
Table 7
90% Confidence Intervals for Estimated Test/Reference Ratios, 
n = 12 per Group.................................................................................50
Table of In-Text Figures
Figure 1
Overall Trial Design ...........................................................................20
Figure 2
Design of the Trial Parts.....................................................................20
Figure 3
Diagram of Two-Stage Adaptive Design ...........................................48
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List of Abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine aminotransferase
ALU
Aluminum
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing 
time) extrapolated to infinity
AUC0-t
Area under the plasma concentration-time curve from time zero (= dosing 
time) to the last sampling time (tlast) at which the concentration is at or above 
the lower limit of quantification.
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra / AUC0-∞in percent
beta-HCG
Beta-human chorionic gonadotropine
BMI
Body mass index
CI
Confidence interval
CK-MB
Creatine phosphokinase - myocardium/brain type
CL/f
Apparent total body clearance considering the fraction of dose (f) absorbed
Cmax
Maximum plasma concentration
c-Met
Mesenchymal-epithelial transition factor
CRO
Contract research organization
CTCAE
Common Terminology Criteria for AEs
CV
Coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
EudraCT
European Union Clinical Trials Register
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GeoMean
Geometric mean 
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GMR
Geometric Mean Ratio
h
Hour(s)
HCC
Hepatocellular carcinoma
HGF
Hepatocyte growth factor
HIV1/HIV2
Human immunodeficiency virus 1 and 2
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation 
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
LLOQ
Lower limit of quantification
min
Minute(s)
NCI
National Cancer Institute
NSCLC
Non-small cell lung cancer
PGx
Pharmacogenetics
PK
Pharmacokinetics
QTcF
Corrected QT interval according to Fridericia
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard deviation
SUSAR
Suspected unexpected serious adverse reactions
T/R
Test/Reference
t1/2
Terminal half-life
TEAE
Treatment emergent adverse event
TF1; TF2; TF3
Tablet Formulation 1; Tablet Formulation 2; Tablet Formulation 3
tlast
The last sampling time at which the concentration is at or above the lower 
limit of quantification
tmax
Time to reach the maximum plasma concentration
ULN
Upper limit of normal range
VZ/f
Apparent volume of distribution during terminal phase (after 
oral/extravascular administration)
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
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M S 2 0 0 0 9 5- 0 0 4 4
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9/ 6 8
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 4 4
Title
P hase 
1, 
O pe n -la bel, 3 - Parts 
St u d y  
wit h 
Cr oss o ver Desi g n i n eac h part t o I n vesti gate t he 
Bi oe q ui vale nce of t he Ta blet F or m ulati o n of 
Te p oti ni b T F 3 c o m pare d t o T F 2 ( Part A), a n d t o 
I n vesti gate t he I nfl ue nce of 
F o o d 
o n 
t he 
P har mac o ki netics of eac h Ta blet F or m ulati o n T F 2 
( Part B) a n d T F 3 ( Part C) of Te p oti ni b i n Healt h y 
S u bjects
Tri al P h ase
1
I N D N u m ber
N ot a p plica ble
F D A c o vere d tri al
N o
E u dr a C T N u m ber
2 0 1 7- 0 0 5 0 5 6- 2 9
Pri nci p al I n vesti g at or
, M D
 
 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 ce nter
 
 Ger ma n y
Pl a n ne d tri al peri o d
(first s u bject i n-l ast s u bject o ut)
Q 3- Q 4 2 0 1 8
Tri al Re gistr y
Cli nical Trial. g o v, E U Cli nical Trials Re gister
Pri m ar y O bjecti ves:

Part A: T o de m o nstrate bi oe q ui vale nce bet wee n t he ne w ta blet f or m ulati o n ( T F 3, test 
treat me nt) a n d t he ta blet f or m ulati o n use d i n cli nical st u dies ( T F 2, refere nce treat me nt) after 
si n gle d ose a d mi nistrati o n i n healt h y s u bjects u n der fasti n g c o n diti o ns

Parts B a n d C: T o i n vesti gate t he f o o d effect, ie t he differe nce i n p har mac o ki neti cs (P K )
bet wee n a d mi nistrati o n after a hi g h -cal orie, hi g h -fat brea kfast a n d a d mi nistrati o n u n der 
fasti n g c o n diti o ns i n healt h y s u bjects, f or b ot h T F 3 a n d T F 2.
Sec o n d ar y O bjecti ves:

T o f urt her i n vesti gate t he P K of te p oti ni b

T o assess t he safety a n d t olera bilit y of te p oti ni b (T F 3 a n d T F 2 ) u n der fasti n g a n d n o n-
fasti n g c o n diti o ns.
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0e d 6c 2 2 v 1. 0
0 9 0 0 ba be 8 0fc b 4 1f
Pa ge 1 0 of 6 9
PI
PI
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Tepotinib (MSC2156119J)
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib
MS200095-0044
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Exploratory Objectives:
Part A: To investigate the PK of metabolites after administration of both tablet formulations 
(TF3 and TF2) of tepotinib
Parts B and C: To investigate the effect of food on the PK of metabolites of tepotinib
To explore the effect of pharmacogenetics (PGx) and variations of associated genes on the 
PK profile of tepotinib (if applicable).
Methodology: This is a Phase 1, mono-center, single-dose, open-label trial in 3 parts (Parts A, 
B and C).
Part A investigates the bioequivalence of TF3 and TF2 under fasted condition and is designed 
in 2 stages. If the PK-variability in Stage 1 is larger than initially assumed, the sample size will 
be re-calculated (with alpha-correction) and additional subjects may be randomized in Stage 2.
Parts B and C investigate the effect of food on the PK of tepotinib after administration of TF2 
(Part B) and TF3 (Part C), respectively. 
Each trial part has a 2-period, 2-sequence cross-over design. All 3 trial parts may be performed 
concurrently.
For each subject, the study consists of a screening period (Day -21 to Day -2) and 2 treatment 
periods, each lasting 21 days. Eligible subjects will be admitted to the clinical unit on Day -1. 
Subjects who continue to meet the eligibility criteria will be randomized to 1 treatment 
sequence on Day 1 of Period 1. 
In each study period, the subjects will be hospitalized from Day -1 to Day 4 for safety 
assessments and PK blood sampling and return to the site on Days 5 - 8 for additional PK blood 
sampling and monitoring of AEs and concomitant medication. Study drug will be administered 
on Day 1 of each period. An End of Trial Visit will be performed at the end of Period 2 (21 days 
after dosing in Period 2).
Planned number of subjects: 
At least 64 subjects; more subjects may be enrolled in accordance with the adaptive study 
design (Part A: 40 subjects in Stage 1, additional subjects in Stage 2, if required; Parts B and 
C: 12 subjects each).
Primary Endpoints:
Part A: Area under the plasma concentration-time curve (AUC) from time zero (= dosing 
time) to the last sampling time at which the concentration is at or above the lower limit of 
quantification (AUC0-t), AUC from time zero extrapolated to infinity (AUC0-∞) and 
maximum plasma concentration (Cmax) of tepotinib observed from time zero to 168 h post-
dose of each period
Parts B and C: AUC0-t, AUC0-∞and Cmax of tepotinib observed from time zero to 168 h post-
dose of each period.
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Secondary Endpoints:
Time to reach Cmax (tmax), terminal half-life (t1/2), apparent total body clearance considering 
the fraction of dose absorbed (CL/f) and apparent volume of distribution during terminal 
phase (Vz/f) of tepotinib observed from time zero to 168 h post-dose of each period
Occurrence of treatment-emergent adverse events (TEAEs; incidence, frequency, intensity 
and causality), occurrence of changes in safety laboratory assessments, 12-lead 
electrocardiograms (ECGs) and vital signs.
Exploratory Endpoints:
PK profiles of tepotinib metabolites: 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time zero to 168 h 
post-dose of each period
Genetic variants and mutations in genes that potentially influence PK of tepotinib.
Pharmacokinetics:
Plasma concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A 
will be determined in each study period from pre-dose until 168 h post-dose. PK parameters 
will be calculated using non-compartmental analysis.
Pharmacogenetics: PGx analysis on Day -1 of Period 1
Other assessments: Not applicable
Diagnosis and key inclusion and exclusion criteria:
Healthy males and females (of non-childbearing potential) between 18 to 55 years (inclusive) 
with a body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 and a total body weight between 50 
and 100 kg (inclusive) at the time of Screening examination may be enrolled in the trial.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule:
Tepotinib film-coated tablet (Tablet Formulation 2, TF2) containing 500 mg of drug 
substance for oral administration
Tepotinib film-coated tablet (Tablet Formulation 3, TF3) containing 250 mg of drug 
substance for oral administration
Part A: Single doses of 500 mg tepotinib administered as 1 tablet of TF2 and 2 tablets of TF3
in fasted state.
Part B: Single dose of 1 tablet (500 mg) of TF2 will be administered in fasted state and with a
high-fat, high-calorie breakfast.
Part C: Single dose of 2 tablets (500 mg) of TF3 will be administered in fasted state and with 
a high-fat, high-calorie breakfast.
The washout period between single doses will be at least 21 days.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable
Planned trial and treatment duration per subject:
For Parts A, B and C about 9 weeks each from Screening to End of Trial Visit, including 2 
treatment periods of 21 days each.
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Statistical methods:
Primary Endpoints: 
Part A (Bioequivalence): An analysis of variance (ANOVA) model will be fitted for the log-
transformed PK parameters Cmax, AUC0-t, AUC0-∞based on the PK analysis set. The model 
will include treatment, period, sequence and subject within sequence as fixed effects. If a 
Stage 2 is required and the number of subjects in Stage 2 is sufficiently large, stage will be 
included as additional effect to the ANOVA model for the analysis of the pooled data of both 
stages.
Treatment differences on the log scale of tepotinib will be estimated for Cmax, AUC0-t, AUC0-∞
together with their CIs with coverage probability according to the planned 2-stage procedure. 
The variance estimate from Stage 1 will be used to evaluate the power at Stage 1.
Bioequivalence will be assessed after Stage 1 using Stage 1 data, or after Stage 2 using the 
pooled data of both stages. 
The null hypothesis will be rejected if the CI corresponding to the α-level (either 90% or 
94.12%) for the ratio of the geometric mean lies within the interval 0.8000 to 1.2500. 
Parts B and C (Food Effect): PK parameters will be compared between study drug
administration (Part B: TF2; Part C: TF3) in fasted vs fed state using a mixed model with 
treatment, period and sequence as fixed effects and a random effect for subject within sequence 
based on log-transformed PK parameters.
Treatment differences on the log scale of tepotinib 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 for the comparisons.
Secondary and exploratory endpoints will be analyzed with summary statistics.
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Table 1
Schedule of Assessments – Parts A, B and C
Assessment/ Activity
Screening
All periods
End of Trial Visit
Day
-21 to -2
-1
1
2 - 4
5 - 8
21 (± 1) after 
dosing in Period 2
Written informed consent a
Hospitalization
X -------------------------------------------------------------------- X
Ambulatory visits
X
X
X
In-/exclusion criteria
X
X (Period 1 only)
Demographic data (incl. height, weight, 
BMI)
X
Medical history
X
Physical examination
X
X
Day 2, Day 4 e
X
Vital signs (blood pressure, pulse rate, 
body temperature)
X
X
pre-dose, 2 h, 
8 h
Day 2, Day 4 e
X
12-lead safety ECG
X b
X
pre-dose, 2 h, 
8 h
Day 2, Day 4 e
X
Clinical laboratory (hematology, 
biochemistry, urinalysis)
X
X
pre-dose
Day 2, Day 4 e
X
Serology (HIV/hepatitis)
X
Pregnancy test (in serum at Screening 
and End of Trial Visit, in urine on Day -1)
X
X
X
Urine drug screen; Alcohol breath test
X
X
Administration of tepotinib
X
PK blood sampling
X c
X c
X c
PGx blood sampling
X (Period 1 only)
Adverse events monitoring
X
X -----------------------------------------------------------------------------------------------------------------X d
(Prior and) concomitant medication
X
X -----------------------------------------------------------------------------------------------------------------X d
BMI = body mass index, ECG = electrocardiogram, h = hours, HIV = human immunodeficiency virus, min = minutes, PK = pharmacokinetics, 
PGx = pharmacogenetics
a
Written informed consent must be obtained prior to any screening activities 
b
ECGs at screening will be recorded in triplicate
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c
PK blood samples for determination of tepotinib and its metabolites will be collected at pre-dose (within 60 min prior to dosing) and 15, 30, 45, 60, 90 min, 
and 2, 3, 4, 6, 8, 12, 16 and (Day 2) 24, 36, (Day 3) 48, 60, (Day 4) 72, (Day 5) 96, (Day 6) 120, (Day 7) 144 and (Day 8) 168 h post-dose
d
Adverse events and concomitant medication will be assessed from signing of the informed consent form throughout the whole study until End of Trial.
e
All safety assessments on Day 4 before discharge.
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce ( T F 3/ T F 2) a n d Effect of F o o d o n t he P K of Te p oti ni b
M S 2 0 0 0 9 5- 0 0 4 4
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 /6 8
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 n y .
Si n gle trial site at 
, Ger ma ny.
T he Pri nci pal I n vesti gat or (
, 
 
, Ger ma n y ) will pr o vi de e x pert me dical i n p ut a n d a d vice relati n g t o trial desi g n a n d 
e xec uti o n a nd is res p o nsi ble f or t he re vie w a n d si g n off of t he cli nical trial re p ort c o nsiste nt wit h 
t he I nter nati o nal C o u ncil
f or Har m o nisati o n (I C H) T o pic E 6 G o o d Cli nical Practice ( G C P; 
hereafter referre d t o as I C H G C P) [ 7].
Si g nat ure pa ges f or t he Pr ot oc ol Lea d a n d t he Pri nci pal I nvesti gat or as well as a list of S p o ns or 
res p o nsi ble pers o ns are i n A p pe n di x I.
T he trial will a p pear i n t he f oll o win g cli nical trial re gistries: E ur o pea n U ni o n
Cli nical Trials 
Re gister ( E u dra C T), Cli nical Trials. g o v.
N u visa n G m b H , We ge nerstrasse 1 3, 8 9 2 3 1 Ne u-Ul m, Ger ma n y , a c ontract researc h or ga nizati o n 
( C R O), 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 ysis, a n d cli nical trial 
re p orti n g. N u visa n 
G m b H 
wil l 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 pare 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 wi ll pr o vi de t he I n vesti gati o nal Me dici nal Pr o d uct (I M Ps) te p oti ni b. Pac ka gi n g, 
la beli n g a n d distri b uti o n of all I M Ps t o t he trial site will be c o n d ucte d b y  a desi g nate d c o ntract 
ma n ufact u ri n g or ga nizati o n ( N u visa n G m b H ). T he S p o ns or will 
s u per vise all o uts o urce d 
acti vities.
3
B ac k gr o u n d I nf or m ati o n
T he mese nc h y m al -e pit helial tra nsiti o n fact or (c-Met), al o n g wit h its li ga n d, t he he pat oc y te gr o wt h 
fact or ( H G F) ha ve bee n i m plicate d i n carci n o ge nesis a n d metastatic t u m or pr o gressi o n, beca use 
of t heir a bilit y t o e nha 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  t o i n hi bit pri mar y t u m or gr o wt h a n d metastasis.
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0e d 6c 2 2 v 1. 0
0 9 0 0 ba be 8 0fc b 4 1f
Pa ge 1 6 of 6 9
PI
PI
PI


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In primary pharmacodynamic studies, tepotinib (MSC2156119J) potently inhibited c-Met kinase 
activity in a dose-dependent manner. This inhibitory effect was confirmed both in tumor cells 
expressing full-length c-Met upon stimulation with HGF, and in tumor cells in which c-Met was 
activated in a ligand independent manner, ie in cells harboring c-Met gene amplification or 
expressing the oncogenic fusion protein translocated promoter region (TPR) Met.
Until 30 September 2017, 452 subjects have been exposed to tepotinib. Sixty subjects of these 
were exposed to a 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 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 1 or Phase 1b/2 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 single dose of tepotinib 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 2 dose. Refer to 
the Investigator’s Brochure (IB) for further information about the nonclinical and clinical 
programs and the implemented Guidance for the Investigator.
Based on the currently available nonclinical as well as clinical safety data, and the lack of 
genotoxicity in non-clinical studies, there is no objection against administration of single doses of 
tepotinib to healthy subjects. It is recognized that healthy subjects will not get benefit by 
participating in this study. However, this study will investigate the bioequivalence of a new tablet 
formulation (tablet formulation 3, TF3) of tepotinib, which is the envisaged market formulation, 
compared to the formulation used in Phase 2 studies (tablet formulation 2, TF2). Moreover, the 
study will generate mandatory human data about the potential influence of food on 
pharmacokinetics (PK) of tepotinib. 
Further, justification based on the accumulated safety experience is provided. 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 1 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 electrocardiogram (ECG) including corrected QT 
interval according to Fridericia (QTcF) values were noted.
Elevations in serum lipase and amylase are considered as the only identified risks for subjects 
administered tepotinib so far. These elevations were observed in 5 of 79 healthy subjects exposed 
to tepotinib and were mild to moderate in severity (exception: 1 Grade 3 lipase elevation), transient 
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and without apparent dose dependency. All increases of serum amylase/lipase were asymptomatic 
and not associated with pancreatitis. 
Subjects enrolled in this study might be exposed to a potential risk, including pancreatic enzyme 
elevation. However, inclusion of healthy subjects is justified when the administration of tepotinib 
is limited to a single dose or short term multiple administrations that will be given under close 
monitoring conditions to reduce the risk for untoward effects.
Since loss of c-Met induces teratogenic effects in c-Met knockout mice, and since a pilot embryo-
fetal development study in rabbits revealed maternotoxic effects and a dose-dependent increased 
number of skeletal malformations (teratogenicity), stringent criteria are applied to ensure exclusion 
of women of childbearing potential in this study. Only healthy women that are known to be 
postmenopausal or surgically sterile (ie due to hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) will be enrolled in this study (for details see Section 5.3.1). Male subjects will be 
required to take precautions with regards to female partners. 
To further mitigate any risk, a close monitoring of the safety laboratory parameters, ECG, and vital 
signs will be performed in all healthy subjects. Subjects will be admitted to the study site and 
remain resident there for at least 72 h after administration of a single dose in each treatment period, 
to allow continuous safety monitoring. In addition, frequent monitoring of subjects is ensured by 
subsequent ambulant visits and by choosing a CRO experienced in the conduct of clinical 
pharmacology studies.
For the PK of tepotinib refer to the IB.
3.1
Trial Rationale
This trial will investigate the bioequivalence of a new tablet formulation (Tablet Formulation 3,
TF3, test treatment) of tepotinib, which is the envisaged market formulation, compared to the 
formulation used in Phase 2 studies (Tablet Formulation 2, TF2, reference treatment). In addition, 
the study will generate human data about the potential influence of food on the PK of tepotinib. 
This trial consists of 3 parts: the bioequivalence part (Part A with 2 stages) and the food effect 
parts (Parts B and C). 
Part A of the trial will investigate the bioequivalence of a new tablet formulation of tepotinib (TF3) 
in comparison to the tablet formulation used in the Phase 2 studies (TF2) using an open-label, 2-
period crossover, 2-stage design under fasted conditions. 
In Parts B and C of the study the effect of food on the PK of tepotinib will be investigated using 
an open-label, 2-period crossover design in Part B (TF2) and Part C (TF3) each. Tepotinib drug 
substance is a hydrochloride salt and a mono hydrate. Food administered together with the 
respective formulation might have an influence on the rate and extent of absorption in the target 
population. 
The trial design is based on the regulatory guidelines of the Food and Drug Administration (FDA)
[1, 2] and the European Medicines Agency (EMA) [3].
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This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP [7], 
and any additional applicable regulatory requirements.
Based on the available nonclinical and clinical data to date, the conduct of the trial specified in 
this protocol is considered justifiable.
4
Trial Objectives
4.1
Primary Objectives
Part A: To demonstrate bioequivalence between the new tablet formulation (TF3, test treatment) 
and the tablet formulation used in clinical studies (TF2, reference treatment) after single dose 
administration in healthy subjects under fasting conditions
Parts B and C: To investigate the food effect, ie the difference in PK between administration 
after a high-calorie, high-fat breakfast and administration under fasting conditions in healthy 
subjects, for both TF3 and TF2.
4.2
Secondary Objectives
To further investigate the PK of tepotinib
To assess the safety and tolerability of tepotinib (TF3 and TF2) under fasting and non-fasting 
conditions.
4.3
Exploratory Objectives
Part A: To investigate the PK of metabolites after administration of both tablet formulations 
(TF3 and TF2) of tepotinib
Parts B and C: To investigate the effect of food on the PK of metabolites of tepotinib
To explore the effect of pharmacogenetics (PGx) and variations of associated genes on the PK 
profile of tepotinib (if applicable).
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase 1, single-dose, open-label, 3 parts trial (Parts A, B and C; see Figure 1). In each of 
the parts, a 2-way, 2-period, 2-sequence cross-over design will be conducted. Part A has 2 stages. 
The procedure will follow the method C described by Montague [4] and Potvin [5]. All 3 study 
parts are planned to be conducted concurrently.
Part A has a two-stage adaptive design (see section 8.2.1). This design is chosen due to the residual 
risk with respect to the PK-variability of tepotinib in the fasted state.
Stage 1 will be sufficiently powered to show the bioequivalence of the new tablet formulation 
(TF3) and the tablet formulation used in clinical studies (TF2), based on an assumption for PK-
variability in the fasted state as data is not available. The Stage 2 will be performed only, if after 
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Stage 1, the PK-variability turns out larger than initially assumed. For Stage 2, additional subjects 
will be randomized based on the newly estimated PK-variability.
More details are given in Section 8.2.1. 
Parts B and C will investigate the effect of food on the PK of tepotinib using a 2-way, 2-period, 
2-sequence cross-over design following administration of the previous tablet formulation (TF2, 
Part B) and administration of the new tablet formulation (TF3, Part C), in 12 healthy subjects each. 
Each subject will receive the tablet under fasted and fed conditions.
Common Visit Schedule
Trial procedures are the same for all periods in all parts except for the food intake on Day 1. 
The washout period will be at least 21 days between Day 1 of each period (see Figure 2).
A screening period is implemented from Day -21 to Day -2.
Subjects will be admitted to the study site on Day -1 of each period and will be resident at the 
study site under medical supervision from Days -1 to 4. They must visit the site on the morning of 
Days 5 to 8 for further blood sampling. 
Blood and urine samples will be collected for laboratory assessments (hematology, biochemistry, 
urinalysis), which will be performed at Screening, throughout the in-patient period of each 
treatment period and for the End of Trial Visit. 
Serial blood samples for PK assessments will be collected for 168 h after tepotinib administration 
in all periods. 
The End of Trial Visit is planned 21 days (± 1 day) after tepotinib administration in the second 
period. An Early Termination Visit will be conducted for subjects who withdraw prematurely. The 
same assessments as for the End of Trial Visit will be conducted at the Early Termination Visit.
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Figure 1
Overall Trial Design
Each rounded rectangle represents a crossover.
TF2 = tablet formulation 2; TF3 = tablet formulation 3
Figure 2
Design of the Trial Parts
AE = adverse event, PK = pharmacokinetics
The washout period will be at least 21 days between Day 1 of each period.
a Safety assessments: Vital signs, 12-lead electrocardiogram, clinical laboratory during hospitalization.
A detailed schedule of study procedures and assessments is provided in Table 1.
5.2
Discussion of Trial Design
The trial design is based on the regulatory guidelines of the FDA [1, 2] and the EMA [3]. The 
primary objectives are to demonstrate the bioequivalence under fasting conditions of the new 
formulation TF3 versus the current formulation TF2 (Part A), and to investigate the food effect for 
Seq. 1:
TF2 – TF3
Seq. 2:
TF3 – TF2
TF3 vs. TF2, fasted
Bioequivalence
Part A
Part A
Seq. 1:
fasted – fed
Seq. 2:
fed - fasted
TF2 fasted vs. fed
Seq. 1:
fasted - fed
Seq. 2:
fed - fasted
TF3 fasted vs. fed
Food effect
Parts B and C
Part B
Part C
Stage 1
Seq. 1:
TF2 – TF3
Seq. 2:
TF3 – TF2
TF3 vs. TF2, fasted
Optional stage 2
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both TF2 (Part B) and TF3 formulations (Part C). The new formulation TF3 has been developed 
aiming for a robust and reliable manufacturing process. While TF2 is administered under fed 
conditions in the Phase 2 studies due to its higher bioavailability under fed state conditions, the 
bioequivalence of TF3 versus TF2 will be investigated in this study Part A under fasted conditions, 
in line with the regulatory recommendations for bioequivalence studies with immediate-release 
formulations (see [1, 2, 3]). Hence, demonstration of bioequivalence of TF3 versus TF2, and 
knowledge of the extent of any food effect on both formulations are essential information for 
further clinical development of TF3.
5.2.1
Inclusion of Special Populations
Not applicable.
5.2.2
Scientific Rationale for Trial Design
The trial design and endpoints are typical for bioequivalence or food interaction studies of this 
type. The single dose design is more sensitive in showing changes in the PK as compared to 
multiple dose designs. 
As illustrated in Figure 1, the study consists of 3 parts (Parts A, B, and C), and will utilize a 
randomized open-label, 2-period, 2-sequence crossover design in each part to minimize the 
influence of covariates. Part A will investigate the bioequivalence of TF3 (test) vs TF2 (reference) 
administered under fasted condition (Part A: TF3 fasted vs TF2 fasted). Part B will investigate the 
food effect on TF2 (Part B: TF2 fasted vs fed), and Part C will investigate the food effect on TF3 
(Part C: TF3 fasted vs fed). The washout period will be at least 21 days between Day 1 of each 
treatment period. Despite the elimination terminal half-life (t1/2) of about 30 h for the parent 
compound and about 45 h for the main metabolites MSC2571109A and MSC2571107A (Study 
MS200095-0012), very low concentrations (< 5% of the maximum plasma concentration [Cmax]) 
were observed after 14 days in study MS200095-0012. Thus, no (or very low) concentrations 
above the detection limit are expected after a 21 days washout period as implemented in this study. 
This trial will be performed in healthy volunteers to standardize the trial population and minimize 
inter-subject variability. 
Since relevant data on the variability of the tepotinib PK for TF2 at the relevant dose under fasted 
conditions are currently not available, Part A will utilize a 2-stage design with bioequivalence
testing after Stage 1 and potential extension to Stage 2 with adjusted sample size if the PK 
variability is larger than expected (see Section 8.2.1 for details).
5.2.3
Justification for Dose
The 500 mg single oral dose has been studied in previous studies in healthy subjects and was found 
to be safe and well tolerated. The tepotinib dose of 500 mg is the Phase 2 dose for the treatment of 
human malignant tumors.
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5.2.4
Rationale for Endpoints
The peak (Cmax) and extent (area under the plasma concentration-time curve [AUC]) of exposure 
after single dose administration are considered adequate endpoints to evaluate the bioequivalence 
(Part A) and the effect of food (Parts B and C). These endpoints are in line with the regulatory 
guidance of the FDA and the EMA (see Section 3.1). In a previous clinical study with single-dose 
administrations in 23 subjects of 500 mg tepotinib as the TF2 formulation (EMR200095-0012), 
the median time to reach the maximum plasma concentration (tmax) was 8 h (ranging from 4 h to 
24 h), and the mean apparent half-life was 35 h (ranging from 28.3 h to 58.8 h). The PK sampling 
scheme (see Table 1) with sampling up to 168 h after administration is expected to adequately 
cover the absorption, distribution and elimination phases up to > 80% of the AUC from time zero 
(dosing time) extrapolated to infinity (AUC0-∞).
5.3
Selection of Trial Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Prior to performing any trial assessments not part of the subject’s routine medical care, 
the Investigator will ensure that the subject has provided written informed consent following the 
procedure described in Section 9.2.
5.3.1
Inclusion Criteria
To be eligible, the subject must fulfill all the following criteria:
1.
Male or female, aged 18 to 55 years inclusive (at Screening)
2.
Body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 and body weight between 50 to 100 kg, 
inclusive (at Screening)
3.
A female participant is eligible to participate if she is not pregnant, not breastfeeding and of 
non-childbearing potential, confirmed at Screening, by fulfilling at least 1 of the following 
criteria: 
Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL)
Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy
4.
A male participant must agree to use and to have his female partner of childbearing potential 
to use highly effective methods of contraception (ie methods with a failure rate of less than 
1% per year) as detailed in the Clinical Trial Facilitation Group (CTFG) recommendations
[6] during the period of participation in the study and for at least 3 months after the last IMP
administration (see Appendix III). Males must also refrain from donating sperm during this 
period and should always use a barrier method such as condom concomitantly. The male 
participants will be asked to report pregnancies in their female partners up to 3 months after 
the last IMP intake.
5.
Subject must be healthy, as assessed by the Investigator, with no clinically significant 
abnormality identified on physical examination and no active clinically significant disorder, 
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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, coagulation, and biochemistry tests of blood and urinalysis within 
the normal range (at Screening). Minor (solitary) non-clinically relevant deviation(s) are 
allowed as judged by the Investigator, however amylase and lipase should not exceed the 
upper limit of normal range (ULN); alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) should not exceed the ULN x 1.1.
5.3.2
Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:
1.
Participation in the treatment phase of a clinical study within 60 days or 5 half-lives after last 
dosing of the previous study drug, whatever is longer, before administration of study drug
2.
Whole blood donation or loss of > 450 mL within 60 days before administration of study drug
3.
Any surgical or medical condition, including findings in the medical history or in the pre-
study assessments, or any other significant disease, that in the opinion of the Investigator, 
constitutes a risk or a contraindication for the participation of the subject in the study or that 
could interfere with the study objectives, conduct, or evaluation
4.
Supine systolic blood pressure > 140 or < 90 mmHg, diastolic blood pressure > 90 or 
< 50 mmHg, and pulse rate > 90 or < 50 beats per minute (min) at Screening and at Admission 
on Day -1 (Any abnormal blood pressure results may be repeated once and if the repeat result 
is within the normal range, it is not considered to have met the exclusion criterion)
5.
12-Lead ECG showing a QTcF > 450 ms, PR > 215 ms, or QRS > 120 ms 
6.
Creatinine clearance estimated glomerular filtration rate (eGFR) < 90 mL/min as assessed by 
using the estimated measure with the Cockcroft-Gault equation (at Screening). In case of a 
borderline result between ≥80 and 90 mL/min, Cystatin C will be determined in addition, and 
the subject will only be included if the Cystatin C value is below the ULN. 
7.
Subjects with gall bladder removal or other relevant surgery of gastrointestinal tract.
(Appendectomy is not considered as relevant)
8.
History of any malignancy except for adequately treated superficial basal cell carcinoma 
9.
History of epilepsy
10. Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or 
excipients; history of anaphylaxis to drugs or serious allergic reactions leading to 
hospitalization or any other allergy reaction in general, which the Investigator considers may 
affect the safety of the subject and/or outcome of the study
11. Positive screen for alcohol and drugs of abuse (at Screening and Day -1 of Period 1) 
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12. Positive screen for hepatitis B surface antigen, hepatitis B core antibody, hepatitis C virus 
antibody, 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 for less 
than 6 months before the time of the Screening Visit
16. Intake of grapefruit, Seville orange, cranberry or juices of these fruits, or St John’s Wort, from 
14 days prior to Day -1 of Period 1
17. Inability to communicate or cooperate with the Investigator (eg, language problem, illiteracy, 
poor mental status) or to comply with the requirements of the entire study, including dietary 
restrictions 
18. Other factors, which in the opinion of the Investigator may interfere with study conduct (at 
Screening and Day -1 of Period 1 only)
19. Legal incapacity or limited legal capacity
20. Subjects kept in detention
21. Subjects of Part B and Part C who are not able or willing to eat the entire high fat, high calorie 
breakfast.
5.4
Criteria for Initiation of Trial Treatment
Inclusion and exclusion criteria will be checked within the screening period and again on Day -1 
of Period 1. Subjects meeting all the inclusion and none of the exclusion criteria will be 
randomized to a treatment sequence on Day 1 of the first treatment period.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Therapy 
A subject must be withdrawn from IMP administration if any of the following occur:
The subject requires treatment with any medication suspected or known to interfere with the 
IMP 
The subject is suspected or known not to comply with the protocol directives (use of prohibited 
medication, noncompliance with the sampling schedule, nonadherence to dietary rules, and 
nonattendance at study assessments).
Withdrawal of a subject from study drug due to any of the above reasons means that this subject 
prematurely discontinues the study, ie before completion of the full profiling and all safety 
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investigations. Subjects who dropped out, must be encouraged to attend the End of Trial 
examination for safety reasons (see Table 1).
Part A: Subjects who dropped out will not be replaced as per design specificity. A drop-out 
compensation of 4 subjects will be added for Stage 1. A drop-out compensation for Stage 2 will 
be considered, if appropriate.
Parts B and C: Subjects who dropped out will be replaced as needed to have at least 12 evaluable 
subjects as recommended by the guideline.
5.5.2
Withdrawal from the Trial
Subjects must be withdrawn from the trial by the Investigator at any time for any of the following 
reasons:
Subject withdrew consent
Subject lost to Follow-up
Participation in another clinical study 
Relevant adverse events (AEs), especially SAEs, occur that do not justify the subject’s 
continuation in the study
Pregnancy
Protocol noncompliance judged as significant by the Investigator and/or Sponsor
Use of a non-permitted concomitant drug as defined in Section 6.5.2. However, any medications 
that are considered necessary for the subject’s well-being (eg paracetamol up to 1500 mg per 
day) may be given at the discretion of the Investigator
Subject is no longer able to participate for other medical reasons (eg surgery, intercurrent 
illness)
Any other condition which to the opinion of the Investigator no longer justifies or permits a 
safe participation of the subject
Any of the following individual stopping criteria is met unless deemed unrelated to the IMP by 
the Investigator with alternate etiology identified:
o Abnormal clinically relevant vital signs confirmed on 2 or more measurements 
(minimum 5 min intervals), including abnormal blood pressure 
-
hypotension defined as systolic < 80 mmHg and/or diastolic < 40 mmHg, or
-
hypertension defined as systolic > 160 mmHg and/or diastolic > 100 mmHg 
o Abnormal clinically relevant ECG findings, including a corrected QT-interval (ad modus 
Fridericia; QTcF) > 500 ms or an increase in QTcF > 60 ms compared to baseline, confirmed 
on ≥2 repeat measurements
o Marked increases in liver or renal parameters (ALT/AST ≥3 x ULN, total bilirubin ≥2 x 
ULN, creatinine ˃ 1.5 x ULN confirmed by ≥2 repeat measurements
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o Any clinically relevant symptom or sign which in the opinion of the investigator and/or 
sponsor warrants subject withdrawal.
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
In case a subject should be withdrawn from the trial, the medical monitor and clinical trial leader 
at the Sponsor will be informed immediately. If there is a medical reason for the withdrawal, 
appropriate medical care will be provided.
In case of premature withdrawal from the trial, the assessments scheduled for the last End of Trial 
Visit should be performed, as Early Termination Visit, if possible with focus on the most relevant 
assessments (see Table 1). In any case, the appropriate electronic case report form (eCRF) section 
must be completed.
Subjects who withdraw from the trial prior to the first administration of IMPs, or for any reason 
do not have a full PK dataset may be replaced. A discussion should occur between the Investigator 
and the Sponsor regarding whether a replacement may be considered.
5.6
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for any IMP. 
The Sponsor may discontinue the trial if it becomes unjustifiable for medical or ethical reasons, 
for poor enrolment, or because of discontinuation of clinical development of an IMP or withdrawal 
of an IMP or comparator from the market for safety reasons.
Health Authorities and IECs will be informed about the discontinuation of the trial in accordance 
with applicable regulations.
5.7
Definition of End of Trial
The End of Trial is defined as the last contact (related to this trial) with the last subject who 
participates in this study (last subject’s End of Trial Visit, independent of whether the subject is in 
End of Trial Visit or discontinued from the study).
A clinical trial protocol may not be considered closed as long as:
Any subject is still receiving any IMP
Visits specified by the protocol are still taking place
Procedures or interventions according to the protocol are still being undertaken in any subject 
The post-treatment follow up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject.
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6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
6.1
Description of the Investigational Medicinal Products
Investigational Medicinal Products: 
Tepotinib 
(MSC2156119J), 
3-(1-{3-[5-(1-Methyl-piperidin-4-ylmethoxy)-pyrimidin-2-yl]-
benzyl}-1,6-dihydro-6-oxo-pyridazin-3-yl)-benzonitrile hydrochloride hydrate (HCl), is supplied 
as
250 mg (oblong, light pink) film-coated TF3 for oral administration (test formulation)
Tepotinib 250 mg film-coated tablets TF3 have a drug load of approximately 30% and contain 
the excipients D-mannitol, microcrystalline cellulose, crospovidone, magnesium stearate, silica 
colloidal anhydrous, and Opadry® II pink.
500 mg (oblong, light yellow) film-coated TF2 for oral administration (reference formulation). 
Tepotinib 500 mg film-coated tablets (TF2) 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 formulations are of compendial grade. Supplier’s certificates show 
that there is no transmissible spongiform encephalopathy risk. Tepotinib is provided in aluminum 
(ALU)/ALU blisters and storage is at or below 25°C.
For dosage and administration see Section 6.2.
Reference product: Not applicable.
Specific rules for treatment modifications: Not applicable.
6.2
Dosage and Administration
Subjects will receive the following treatments: 
Part A - Bioequivalence
Subjects will receive the following single doses of tepotinib in randomized order:
1 film-coated tablet TF2 containing 500 mg tepotinib 
2 film-coated tablets TF3 containing 250 mg tepotinib each, total dose 500 mg tepotinib.
TF2 and TF3 will be administered in the fasted state (at least 10 h fasting) together with 240 mL 
of water.
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Parts B and C - Food Effect 
Part B (Tepotinib TF2):
Subjects of Part B will receive the following single doses of tepotinib in randomized order:
1 film-coated tablet TF2 containing 500 mg tepotinib, administered in the fasted state (at least 
10 h fasting) together with 240 mL of water
1 film-coated tablet TF2 containing 500 mg tepotinib, administered 30 min after start of a high-
fat, high-calorie breakfast which must be consumed completely within 25 min. The tablet will 
be administered together with 240 mL of water.
Part C (Tepotinib TF3):
Subjects of Part C will receive the following single doses of tepotinib in randomized order:
2 film-coated tablets TF3 containing 250 mg tepotinib each, total dose 500 mg tepotinib, 
administered in the fasted state (at least 10 h fasting) together with 240 mL of water
2 film-coated tablets TF3 containing 250 mg tepotinib each, total dose 500 mg tepotinib, 
administered 30 min after start of a high-fat, high-calorie breakfast which must be consumed 
completely within 25 min. The tablets will be administered together with 240 mL of water.
The high-fat (approximately 50% of total caloric content of the meal), high-calorie (approximately 
800 to 1000 calories) breakfast consists of: 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast 
with butter, 4 ounces (1 ounces = 28.35 g) of hash brown potatoes (approximately 120 g) and 
8 ounces of whole milk (approximately 240 mL).
For all Parts (A, B and C):
The minimum washout period will be at least 21 days between Day 1 of each period to prevent 
any significant PK carryover effects between periods.
Subjects will be administered the tablet formulations in upright position. 
In all periods subjects will stay in a semi-recumbent position for 4 h post-dose, except for use of 
the toilet, when the subjects will be allowed to leave the bed without undue physical stress/activity.
Food intake is not allowed for 4 h after IMP administration. Further drinking is not allowed from 
1 h before to 1 h after IMP administration.
Standardized meals will be served 4 h (lunch), 8 h (snack) and 10 h (dinner) after administration 
of tepotinib; thereafter, meals will be served at customary times during the in-patient period.
6.3
Assignment to Treatment Groups
Only subjects who comply with all selection criteria will be included into the trial. The subjects 
will be enrolled into either Part A, B or C, and will be recruited separately for each of the study 
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce ( T F 3/ T F 2) a n d Effect of F o o d o n t he P K of Te p oti ni b
M S 2 0 0 0 9 5- 0 0 4 4
C O N F I D E N T I A L
I N F O R M A T I O N
2 9 /6 8
parts. Pri or t o t he first a d mi nistrati o n , t he s u bjects e nr olle d i nt o t he res pecti ve Part A, B, or C will 
be ra n d o mly a ssi g ne d t o 1 of 2 treat me nt se q ue nces, via t he ra n d o m n u m ber o n Da y  1 (see Secti o n 
8. 3) .
Acc or di n g t o C R O sta n dar d o perati o nal pr oce d ures ( S O Ps), t he s u bjects will be assi g ne d t o t he 
ra n d o m n u m ber i n t he or der of t heir re gistrati o n t o t he st u d y (first re gistrati o n res ults i n t he l o west 
a vaila ble ra n d o m n u m ber, sec o n d re gistrati o n res ults i n t he sec o n d l o west a vaila ble ra n d o m 
n u m ber, a n d s o o n). H o w e ver, prece de nce will be gi ve n t o s u bjects w h o partici pate i n a trial at 
 f or t he first ti me a n d f or s u bjects w h o ser ve d as “sta n d -b y ” d uri n g a prece di n g 
trial. 
T he I n vesti gat or will kee p a rec or d relati n g t he s u bjects’ ra n d o m n u m bers a n d t he na mes of all 
s u bjects (i ncl u di n g scree ni n g n u m ber a n d t he N u visa n G m b H I D n u m ber) w h o ha ve gi ve n t heir 
i nf or me d c o nse nt, t o all o w eas y chec ki n g of data i n s u bject files, w he n re q uire d. T his rec or d will 
als o i ncl u de t he date of s u bject’s e nr ol me nt a n d c o m pl eti o n, as well as s u bjects w h o c o ul d n ot be 
ra n d o mize d f or w hate ver reas o n.
6. 4
N o n- i n vesti g ati o n al Me dici n al Pr o d ucts t o be Use d
N ot a p plica ble .
6. 5
C o nc o mit a nt Me dic ati o ns a n d T her a pies
All c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m t he date of si g nat ure of 
i nf or me d c o nse nt are t o be rec or de d i n t he a p pr o priate secti o n of t he eC R F , n oti n g t he na me, d ose, 
r o ute, d urati o n , re gi me n, stat us a n d i n dicati o n of eac h dr u g. N o n dr u g i nter ve nti o ns a n d a n y 
c ha n ges t o a c o nc o mita nt me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or de d i n t he e C R F .
6. 5. 1
Per mitte d Me dici nes
Paraceta m ol is t he o nl y per mitte d me dicati o n. Paraceta m ol will be per mitte d u p t o a ma xi m u m 
dail y  d osa ge of 1 5 0 0 m g . 
A n y  me dicati o ns t hat are c o nsi dere d necessar y  to pr otect s u bject we lfare a n d t hat will n ot i nterfere 
wit h t he I MP ma y  be gi ve n at t he I nvesti gat or’s discreti o n. T he p ote ntial dr u g -dr u g i nteracti o ns 
wit h te p oti ni b are still u n der e val uati o n. T heref ore, me dicall y  re q uire d c o nc o mita nt me dicati o n 
mi g ht ha ve t o be a dj uste d bas e d o n t olera bilit y a n d t he cli nical res p o nse.
T he I nvesti gat or will rec or d, i n t he a p pr o priate secti o n of t he eC R F , all pre vi o us/c o nc o mita nt 
me dicati o ns ta ke n b y t he s u bject d uri n g t he st u d y fr o m t he date of si g nat ure of i nf or me d c o nse nt.
6. 5. 2
Pr o hi bite d Me dici nes
T he s u bjects are pr o hi bite d fr o m usi n g prescri pti o n or o ver -t he-c o u nter me dicati o ns (a part fr o m 
paraceta m ol u p t o 1 5 0 0 m g per d a y , as j u d ge d a p pr o priate b y  the I n vesti gat or) wit hi n 1 4 d a y s or 
5 half -li ves, w hic he ver is l o n ger, pri or t o t he first I M Ps ad mi nistrati o n d uri n g t he trial, a n d u ntil 
after t he E n d of Trial Visit.
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0e d 6c 2 2 v 1. 0
0 9 0 0 ba be 8 0fc b 4 1f
Pa ge 3 0 of 6 9
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6.5.3
Permitted / Prohibited Procedures
Subjects should drink about 2 L fluids per day during the hospitalization phase (as provided by the 
site) and will be reminded regularly.
Throughout the PK profiling day, the following restrictions must be met:
Subjects will be in the fasted state for at least 10 h before administration of tepotinib (except 
for the breakfast)
Drinking is not allowed 1 h before and after administration of tepotinib (except for the breakfast 
and administration)
Chewing gum is not allowed during the PK profile days.
Throughout the study, the following restrictions must be met:
No smoking or use of tobacco products
No alcohol intake
No intake of food or beverages other than that provided to the subjects by the trial site during 
the in-patient period
No intake of caffeine- and xanthine-containing food and beverages (eg coffee, black or green 
tea, cola, cocoa, chocolate or chocolate-containing food or beverages) from 48 h before 
administration of tepotinib in each period until collection of last PK blood sampling of each 
period
No intake of herbs or fruits that can have an influence on the PK (eg St. John’s wort, Seville 
oranges, grapefruits, cranberry or the juice of these fruits), from 14 days prior to Day -1 of 
Period 1 until final examination
No intake of poppy seeds (eg poppy seed rolls, poppy seed cake, yoghurt containing poppy seed 
etc.) from 72 h before first administration of study drug until completion of final examination
No intake of concomitant medication within 14 days or 5 half-lives, whatever is longer, before 
first administration of study drug until final examination (except for paracetamol up to 1500 mg 
per day, may be given at the discretion of the Investigator) 
No intake of recreational drugs within 14 days or 5 half-lives, whatever is longer, before first 
administration of study drug until final examination
No exhausting physical activities (body building, sports) from at least 72 h before the first 
administration of study drug until the final examination 
No sun baths, solarium, or sauna at least 12 h before first administration of study drug until 
final examination.
6.5.4
Other Interventions
Not applicable.
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6.5.5
Special Precautions
Not applicable.
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions
No specific measures are proposed at this stage. Standard medical care will be provided at the 
study site for all AEs occurring during the study.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
The investigational product tepotinib will be provided by the Sponsor packed in ALU/ALU blister.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
The pharmacy or designee will receive the IMPs labeled and packaged according to the local 
regulatory requirements and the storage requirements. Tepotinib will be supplied in ready to use 
oral formulations. The responsible pharmacist will dispense the necessary amount of the IMPs. 
Detailed guidance will be provided in an IMP handling manual.
The IMP supplies will be recorded in an IMP inventory.
Tepotinib must be carefully stored at the trial site in a closed room or cabinet with restricted access, 
safely and separately from other drugs and protected from environmental extremes until used in 
the trial. Tepotinib should be stored at or below 25°C. Any deviations from the recommended 
storage conditions should be immediately reported to the Sponsor, and the IMP should not be used 
until authorization has been received from the Sponsor. The preparation, handling and storage of 
the IMP will be documented.
The IMPs must not be used for any purpose other than the trial in question.
It must be ensured at the trial site that the IMPs are not used after the use-by date. This is to be 
closely monitored by the responsible monitor.
6.8
Investigational Medicinal Product Accountability
The Clinical Trial Supply Department of Nuvisan GmbH is responsible for ensuring IMP 
accountability, including reconciliation of drugs and maintenance of records. Drug accountability 
will also be confirmed by the Trial Monitor.
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Upon receipt of IMPs, the responsible person will check for accurate delivery and acknowledge 
receipt by signing or initialing and dating the appropriate documentation and returning it to the 
location specified. A copy will be archived for the Investigator Site File
IMP dispensing will be recorded on the appropriate drug accountability forms so that accurate 
records will be available for verification at each monitoring visit.
Trial site IMP accountability records will include the following:
-
Confirmation of IMP receipt, in good condition and in the defined temperature range
-
The inventory of IMPs provided for the clinical trial and prepared at the site
-
The use of each dose by each subject
-
The disposition (including return, if applicable) of any unused IMP
-
Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP prepared 
at the site), and the individual subject trial numbers.
The Investigator site should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. No IMP 
that is dispensed to a subject may be redispensed to a different subject.
A Trial Monitor will periodically collect the IMP accountability forms. 
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. 
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6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol or planned for an individual subject enrolled in the trial. Even if it does not meet other 
criteria for an SAE, any overdose must be recorded in the trial medication section of the eCRF and
reported to Drug Safety in an expedited manner using the SAE Report Form, and following the 
procedure in Section 7.4.
The effects of an overdose of tepotinib are unknown, and therefore no standard treatment is 
currently established. In the event of an overdose, the Investigator or treating physician should use 
appropriate clinical judgment for the management of any clinical symptoms or evaluation results.
6.13
Medical Care of Subjects after End of Trial
Not applicable in a trial with healthy subjects.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
Study procedures are the same for all periods in all parts except for the food intake on Day 1. A 
detailed schedule of trial procedures/assessments is provided in Table 1.
Prior to performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2.
7.1.1
Screening Examination
All subjects will undergo an entry examination to evaluate their health status and their eligibility 
for inclusion in the study. The Screening examination will be conducted not more than 21 days 
prior to the planned first drug administration, ie between Day -21 to Day -2 before commencing 
to first study period. Only subjects who meet the inclusion criteria and none of the exclusion 
criteria will be admitted to the trial. 
Prior to Screening examination, the subjects will receive a screening number for identification. 
Eligible subjects will receive a random number upon enrolment into the study. 
There is a notification on the subject’s card as well as in the electronic subjects’ data base on the 
last participation in a trial. In addition, all subjects are reported to a central checking organization 
(VIP Check) before inclusion into the trial.
Prior to any Screening examinations the subjects must sign the Informed Consent Form (ICF). 
At Screening (Days -21 to -2), the following assessments will be performed (Table 1):

Recording of demographic information including body height, body weight and BMI

Recording of medical history
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
Physical examination

Measurement of vital signs

12-lead safety ECG recording (as triplicate)

Blood and urine sampling for safety laboratory assessments 

Serological tests for hepatitis B, C, and HIV1/HIV2

Serum Pregnancy test (for females)

Urine drug screen (including test for cotinine)

Alcohol breath test

Assessments of AEs

Documentation of prior and concomitant medication

Preliminary evaluation of inclusion and exclusion criteria.
7.1.2
Treatment Periods
The subjects willing to participate in the trial will only be included when all Screening examination 
procedures have demonstrated that all inclusion criteria and none of the exclusion criteria apply. 
Subjects will be assigned to a random number within the trial prior to the first administration. 
For time points and assessments please refer to Table 1 (Parts A, B and C).
Day -1 (Admission)
Subjects will be admitted to the clinic in the morning of Day -1 until completion of the 72 h 
assessments in the morning of Day 4 of each period.
In each period, the following assessments will be performed:

Physical examination

Measurement of vital signs 

12-lead safety ECG recording

Blood and urine sampling for safety laboratory assessments 

Pregnancy test (in urine)

Urine drug screen (including test for cotinine) 

Alcohol breath test

Assessment of AEs

Documentation of concomitant medication

Evaluation of inclusion and exclusion criteria (Period 1 only)
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
Blood sampling for PGx (Period 1 only).
Days 1 to 4 (inpatient)
Prior to dosing on Day 1 the following assessments will be done:

Measurement of vital signs 

12-lead safety ECG recording

Blood and urine sampling for safety laboratory assessments 

Pre-dose PK blood sample for determination of tepotinib and its metabolites.
After completion of pre-dose assessments study drug will be administered in the morning of Day 1
of each period as the following:
Part A: Study drug will be administered in both periods in the fasted state together with 240 mL 
of water.
Parts B and C: Study drug will be administered in one period in a fasted state and in the other 
period 30 min after start of a standardized high fat, high calorie breakfast, which must be consumed 
completely within 25 min. The study drug will be administered together with 240 mL of water.
A detailed guidance on dosage and administration is provided in Section 6.2.
After dosing the following assessments will be performed at the time points given in the Schedule 
of Assessments (Table 1):

PK blood samples for determination of tepotinib and its metabolites will be taken regularly 
until 72 h (Day 4) post-dose before discharge (for time points please refer to Table 1)

Measurement of vital signs and 12-lead safety ECG recordings on Day 1 (2 h and 8 h post-
dose), Day 2 and Day 4 before discharge

Blood and urine sampling for safety laboratory assessments on Day 2 and Day 4 before 
discharge

Physical examination (only on Day 2 and Day 4 before discharge)

Regular assessment of AEs and concomitant medication.
After completion of the Day 4 assessments (72 h measurements) subjects will be discharged.
Days 5 to 8 (ambulatory)
Subjects will return to the clinic for daily blood sampling to determine the PK of tepotinib.
Additionally, AEs will be monitored and concomitant medications will be recorded.
The washout period will be at least 21 days between Day 1 of each period (see Figure 2).
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Restrictions:
A detailed listing of restrictions during the trial is provided in Section 6.5.
7.1.3
End of Trial Visit
The End of Trial examination has to verify that all values tested in the Screening have remained 
within a clinically acceptable range. The assessments will be performed 21 days (± 1 day) after 
tepotinib administration in the second period. Unacceptable values and AEs will be followed up 
until they return to the reference ranges/resolved or there is an adequate explanation which is not 
related to the trial.
The following assessments will be performed:

Physical examination

Measurement of vital signs 

12-lead ECG recording

Blood and urine sampling for safety laboratory assessments 

Serum Pregnancy test (for females)

Assessment of AEs

Documentation of concomitant medication.
No medical treatment is planned after the End of Trial.
The End of Trial is defined as the last contact (related to this trial) of the last subject undergoing 
the trial.
7.2
Demographic and Other Baseline Characteristics
At Screening, the following demographic data will be collected: date of birth, sex (gender), race, 
ethnicity, height, weight, and BMI.
Furthermore, the following will be documented:
Clinically relevant findings in the medical history are recorded
Prior medication within 14 days of Screening and concomitant medication at Screening (any 
prescribed medicine or over-the-counter drug or dietary supplement including herbal remedies, 
vitamins, and minerals)
Smoking status, alcohol intake
Female status (postmenopausal, sterilization).
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7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. The investigator will report any 
AEs, whether observed by the Investigator or reported by the subject (see Section 7.4.1.2). The 
reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE. Investigators will 
reference the National Cancer Institute (NCI) - Common Terminology Criteria for AEs 
(CTCAE), version 5.0 (publication date: 27 Nov 2017), a descriptive terminology that can be used 
for AE reporting. A general grading (severity/intensity; hereafter referred to as severity) scale is 
provided at the beginning of the above referenced document, and specific event grades are also 
provided. If the severity of a particular AE is not specifically graded by the guidance document, 
the Investigator is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 
following his or her best medical judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe 
Grade 4 or Life-threatening
Grade 5 or Death.
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According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as hemoglobin decreased 
or neutrophils count decreased, is considered serious only if the condition meets one of the serious 
criteria described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (eg, sudden death, 
unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to the IMP (including 
any other non-IMPs, or medical procedures, as applicable, etc.) using the following definitions. 
Decisive factors for the assessment of causal relationship of an AE to the IMP include, but may 
not be limited to, temporal relationship between the AE and the IMP, known side effects of the 
IMP, medical history, concomitant medication, course of the underlying disease, trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMP. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under trial in 
this clinical trial protocol. A reasonable alternative explanation must be available
Related:
Reasonably related to the IMP. AE could medically (pharmacologically/clinically) 
be attributed to the IMP/study treatment under trial in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(for example, anemia, increased ALT) must be reported as the AE rather than the abnormal value 
itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
Results in death
Is life-threatening (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused death 
if it was more severe.)
Requires inpatient hospitalization or prolongs an existing hospitalization
Results in persistent or significant disability or incapacity
Is a congenital anomaly or birth defect
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Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.)
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE, as described in Section 7.4.1.4
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy and related hydration therapy application) 
are not considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (for example, undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs and all non-serious AEs of special interest must be additionally documented and reported 
using the appropriate Report Form as described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and
resolution dates and times when it is important to assess the time of AE onset relative to the 
recorded treatment administration time), its severity, its causal relationship with the trial treatment, 
any other potential causal factors, any treatment given or other action taken, including dose 
modification or discontinuation of the IMP, and its outcome. In addition, serious cases should be 
identified and the appropriate seriousness criteria documented.
Specific guidance can be found in the eCRF Completion and Monitoring Conventions.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent) and continues until the End of Trial Visit. 
Any SAE assessed as related to the IMP must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of the IMP. 
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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 h after becoming aware of the event) inform the Sponsor 
or its designee in writing. All written reports should be transmitted using the SAE Report Form, 
which must be completed by the Investigator following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the trial-specific 
SAE Report Form.
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, autopsy report). In all cases, the information provided 
on the SAE Report Form must be consistent with the data about the event recorded in the eCRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
Adverse Events of Special Interest
Healthy subjects might experience asymptomatic elevations in serum lipase and amylase. Any 
elevation in serum lipase and amylase of Grade ≥3 will lead to the recording of an AE of special 
interest (AESI). The severity of these AEs should be defined based on clinical judgment of the 
Investigator and defined according to NCI-CTCAE Severity Scale.
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.
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In accordance with ICH GCP [7], the Sponsor/designee will inform the Investigator of “findings 
that could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s
approval/favorable opinion to continue the trial. In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and are considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” [SUSARs]). The Investigator should place copies of Safety Reports in 
the Investigator Site File. National regulations with regard to Safety Report notifications to 
Investigators will be taken into account.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications. When direct reporting is not clearly defined by national or site-specific regulations, 
the Investigator will be responsible for promptly notifying the concerned IEC of any Safety 
Reports provided by the Sponsor/designee and of filing copies of all related correspondence in the 
Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities regarding 
the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that Directive 
and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
AEs are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) and are 
assessed for final outcome at the End of Trial Visit. All SAEs ongoing at the End of Trial Visit
must be monitored and followed up by the Investigator until stabilization or until the outcome is 
known, unless the subject is documented as “lost to follow-up”. Reasonable attempts to obtain this 
information must be made and documented. It is also the responsibility of the Investigator to ensure 
that any necessary additional therapeutic measures and follow-up procedures are performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example,
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
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.
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Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Fasted blood and urine samples will be collected for the clinical laboratory tests (hematology, 
biochemistry, virology, drugs of abuse, hormones, and urinalysis) following the timing noted in 
the Schedule of Assessments (Table 1). Additional laboratory safety examinations during the 
course of the trial are at the discretion of the Investigator.
All blood and urine samples must be clearly identified and will be worked up and analyzed in 
Nuvisan's clinical laboratory. Any abnormalities in any of the laboratory parameters will be judged 
by a physician individually in relation to the reference ranges from the laboratory.
The Sponsor should receive a list of laboratory normal ranges before shipment of the IMP. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor, including 
laboratory certificates.
All safety laboratory examinations will be carried out under fasting conditions. Some additional 
parameters may be routinely analyzed by the laboratory after abnormal findings, or requested by 
the Investigator, including but not limited to eg microscopic differential blood count, direct 
bilirubin and creatine phosphokinase myocardium/brain type.
In case of positive findings of blood, protein, nitrite or leucocytes in the urinalysis, a subsidiary 
microscopic examination of the sediment will be performed.
For all findings with major deviation and/or possible pathological relevance, follow-up 
examinations will be carried out until the deviation returns to normal or the absence of pathological 
relevance can be confirmed. If a deviation considered clinically relevant has not returned to a 
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 2.
The amount of blood sampled in this trial is specified in Appendix II.
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Table 2
Clinical Laboratory Evaluations
Biochemistry
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyl-transferase
Lactate dehydrogenase
Creatine phosphokinase b
Amylase
Lipase
Bilirubin (total) a
Cholesterol
Triglycerides
Uric acid
Sodium
Potassium
Creatinine
Urea
Glucose
Cystatin C (if applicable)
Hematology 
Hematocrit
Hemoglobin
Red blood cell count
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration
Platelet count 
White blood cell 
count
White blood cell differentials and 
absolute counts c:
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils 
Urinalysis 
pH
Nitrite
Protein 
Glucose
Ketone bodies
Urobilinogen 
Bilirubin
Urine pregnancy 
test, females only
Leucocytes
Blood
Microscopic examination d
Urine drug screen
Cocaine
Amphetamines
Methamphetamines
Opiates
Barbiturates
Benzodiazepine
Methadone
Cannabinoids
Tricyclic antidepressants
Cotinine
Ecstasy
Other tests
Hepatitis B surface antigen
Hepatitis B core antibody
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
eGFR = estimated glomerular filtration rate, HIV = human immunodeficiency virus, beta-HCG = beta-human chorionic 
gonadotropine
a
In case of an increased bilirubin (total) the direct bilirubin will be determined. 
b
In case of an increased creatine phosphokinase (CK), myocardium/brain type (CK-MB) will be determined; if 
the ratio of CK/CK-MB is above 6, troponin will be determined as well.
c
In case of abnormal findings, manual differential blood count can be requested by the Investigator.
d
Only if blood, protein, nitrite, or leukocytes are positive on the dipstick.
e
Estimated glomerular filtration rate calculated using the Cockcroft-Gault equation.
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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 per the oscillometric method using an automated device, which also indicates the 
corresponding pulse rate. Blood pressure and pulse rate will be measured after at least 5 min in a 
supine position, according to the Schedule of Assessments (see Table 1).
Body temperature will be measured auricular.
Further vital sign measurements during the trial are at the discretion of the Investigator.
7.4.4.2
Physical Examination
A standard examination will be performed including general appearance, skin, head, neck 
(including thyroid), eyes, ears, nose, throat, abdomen, as well as neurological, peripheral vascular, 
musculoskeletal, cardiovascular and pulmonary system. 
Physical examination will be scheduled according to the Schedule of Assessments (see Table 1). 
Further physical examinations during the trial are at the discretion of the Investigator. Any relevant 
findings are to be recorded on the Medical History form in the eCRF (for findings from the past 
that occurred prior to ICF signature) or on the AE form in the eCRF (for findings presently 
occurring; events existing but unresolved prior to drug administration).
7.4.4.3
Electrocardiogram 
12-lead ECGs will be recorded according to the Schedule of Assessments (see Table 1) using the 
ECG system Cardio Perfect®, Welch Allyn. The ECGs will be recorded in a supine position after 
at least 5 min rest. 
Per time-point, the ECG will be stored electronically, printed and reviewed in a timely manner by 
the Investigator. The original printout will be stored with the subject’s source data. Electronic data 
may be transferred to a central ECG laboratory for central reading and further analysis; these 
results would be reported separately.
ECG printouts will be signed and dated electronically by the person evaluating the ECG. The ECG 
will be interpreted by the Investigator (normal/abnormal). For abnormal ECGs, the clinical 
significance (yes/no) must be judged by the Investigator and the abnormality is to be specified.
Additional ECGs during the trial are at the discretion of the Investigator.
7.4.4.4
Alcohol Breath Test
A commercially available breath analyzer (Alcotest 6510, Draeger Safety GmbH) will be used to 
determine the concentration of alcohol in the subject’s breath according to the Schedule of 
Assessments (see Table 1). 
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Additional alcohol breath tests during the trial are at the discretion of the Investigator.
7.5
Pharmacokinetics
7.5.1
Blood Sampling
On the PK profiling day, an indwelling venous catheter will be positioned in a suitable forearm 
vein for blood sampling and should be kept, if possible, until at least 24 h after dosing. After 
removing the indwelling venous cannula, samples will be taken by venipuncture.
At visits where assessment time points coincide with each other, the vital signs and ECG 
assessments should be performed slightly before the specific time point and the PK blood sampling 
should be performed on time.
Plasma concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A will 
be determined in each period according to the sampling schedule outlined in the Schedule of 
Assessments (see Table 1). The exact date and time of sample collection must be recorded in the 
eCRF and will be used in the calculation of PK parameters. Blood samples should be taken as 
close as possible to the scheduled time points. Samples taken outside of the time periods shown in 
Table 3 need an explanation and will be considered as protocol violation.
Table 3
Time Windows
Planned Blood Sampling
Time Windows (min)
Pre-dose
- 60
0.25 - 1 h post-dose
± 2
> 1 h - 12 h post-dose
± 5
> 12 h - 48 h post-dose
± 15
> 48 h - 168 h post-dose
± 30
Concentrations of tepotinib and its metabolites MSC2571109A and MSC2571107A will be 
measured using validated liquid chromatography-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 trial. Full details of the bioanalytical method used will be described in a 
separate bioanalytical report.
7.5.2
Calculation of Pharmacokinetic Variables
Noncompartmental computation of PK parameters will be performed using the software Phoenix®
WinNonlin® 6.4 or higher (Certara, L.P., Princeton, New Jersey). For definitions of PK 
parameters, see Table 4.
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Table 4
Definition of PK Parameters for Tepotinib and its Metabolites After 
Single Dose Administration
Symbol
Definition
AUC0-t
Area under the plasma concentration-time curve (AUC) from time zero (= dosing time) to 
the last sampling time (tlast) at which the concentration is at or above the lower limit of 
quantification (LLOQ), calculated per the mixed log linear trapezoidal rule (ie linear up/log 
down)
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing time) 
extrapolated to infinity, calculated as AUC0-t + AUCextra. AUCextra represents the 
extrapolated part of AUC0-∞ calculated by Clastpred/λz, where Clastpred is the predicted plasma 
concentration at the last sampling time point, calculated from the log-linear regression line 
for λz determination at which the measured plasma concentration is at or above LLOQ
Cmax
Maximum plasma concentration observed
tlast
The last sampling time at which the concentration is at or above the lower limit of 
quantification
tmax
Time to reach the maximum plasma concentration
t1/2
Terminal half-life, calculated as ln2/λz
λz
Terminal rate constant determined from the terminal slope of the log-transformed plasma 
concentration curve using linear regression on terminal data points of the curve
CL/f 
Apparent total body clearance of drug from plasma following oral/extravascular 
administration, calculated as dose/AUC0-∞, only parent drug, will not be calculated for the 
metabolites
Vz/f 
Apparent volume of distribution during the terminal phase following oral/extravascular 
administration, will not be calculated for the metabolites
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra% = (AUCextra / AUC0-∞) x 100
Individual PK parameters will be calculated using actual sampling times. The pre-dose sample will 
be considered as if it had been taken simultaneously with the administration of study drug. PK 
variables will be evaluated and listed for all subjects who provide sufficient concentration-time 
data.
Concentrations below the lower limit of quantification (< LLOQ), which are before the last 
quantifiable data point, will be taken as zero for calculating the AUC.
7.6
Biomarkers
Biomarkers are not determined in this trial.
7.7
Pharmacogenetics
Pharmacogenetic sampling is mandatory for trial participation. An additional separate ICF will be 
used. One blood sample should be collected in duplicate on Day -1 of the first treatment period 
prior to administration. The pharmacogenetic samples will be analyzed conditionally in case of 
unexpected PK profiles. The results of the PGx analysis, as applicable, will be described in a 
separate report.
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Storage and analyses of samples will be handled according to the specifications described in the 
ICF.
7.8
Other Assessments
Not applicable.
8
Statistics
8.1
Statistical Hypotheses
Part A
The following null hypothesis for the ratio of the geometric means (GeoMean) will be used to 
assess bioequivalence
H0:
µT/µR ≤
or 1.2500 ≤µT/µR for at least one parameter (AUC0-t
or 
AUC0-∞or Cmax)
H1:
00 < µT/µR < 1.2500 for all parameters (AUC0-t and AUC0-∞and Cmax)
where µT and µR are the geometric means for the test and reference treatment respectively.
The test treatment is the new tablet formulation (TF3) and reference is the tablet formulation used 
in clinical studies (TF2) both under fasting condition. 
The null hypothesis will be tested using a two-stage adaptive design. 
Parts B and C
The statistical analysis of study data will be descriptive; no hypothesis tests will be performed.
8.2
Sample Size
8.2.1
Part A (Bioequivalence)
Part A of the study is planned as a two-stage adaptive design (see Figure 3) due to the residual risk 
with respect to the unknown PK-variability of tepotinib in the fasted state. The procedure will 
follow the method C described by Montague [4] and Potvin [5]. For the first stage, the trial will be 
sufficiently powered to show bioequivalence based on an assumption for PK-variability in the 
fasted state (reliable data not available).
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Figure 3
Diagram of Two-Stage Adaptive Design
Source: (Montague et al [4]) Figure 2; BE: Bioequivalence
The total and mixed intrasubject variabilities CVs (%) observed most recently for AUC0-t and Cmax
of tepotinib are summarized in Table 5.
Table 5
Overview of the PK-Variability Observed in the Previous Tepotinib 
Studies
Study
Formulation
Dose (Condition)
Arm
AUC0-t
Cmax
Total 
Geometric 
CV%
Mixed intra-
individual 
CV%
Total 
Geometric 
CV%
Mixed intra-
individual 
CV%
EMR200095-002 
TF1 - 30 mg 
(fed vs. fasted)
TF1 Fed
TF1 Fasted
12.9%
18.3%
11.1%
14.8%
28.2%
23.7%
CF2 vs. TF1 
30 mg (fed)
CF2
TF1
28.7%
21.4%
12.2%
30.4%
26.3%
12.8%
EMR200095-007
TF1 vs. TF1*
100 mg (fed)
TF1
TF1*
20.4%
24.8%
10.0%
22.8%
29.5%
12.7%
EMR200095-0012 TF1 vs. TF2 
500 mg (fed)
TF1
TF2
24.0%
27.0%
10.1%
19.8%
26.2%
12.6%
AUC0-t = area under the plasma concentration-time curve from time zero to the last sampling time at which the 
concentration is at or above the lower limit of quantification, CF2 = Capsule Formulation 2; Cmax = maximum plasma 
concentration, CV = coefficient of variation, PK = pharmacokinetics, TF1 = Tablet Formulation 1; TF1* = Tablet 
Formulation 1 with finely micronized active pharmaceutical ingredient; TF2 = Tablet Formulation 2.
Overall, the total variability in AUC and Cmax in the fed state was between 12.9% and 26.3% for 
the formulation TF1. The mixed intrasubject variabilities of AUC and Cmax were largely dose-
independent ranged between 10.0% and 12.8% in the fed state across all the investigated doses.
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AUC total variability was similar between TF1 and TF2 at the dose of 500 mg but Cmax variability 
was somewhat higher for TF2. 
Only one study (EMR200095-002) investigated tepotinib under fasted condition. The maximum 
value for the mixed intrasubject variability was observed for Cmax (CV of 23.7%). As no data is
available for the 500 mg dose level under fasted conditions, the CV value is assumed to be around 
24% for Cmax and slightly lower for AUC in this study.
With these assumptions, an assumed geometric mean ratio Test/Reference (GMR T/R) of 0.95, a 
one-sided alpha level of 0.05, 36 evaluable subjects will be needed to provide approximatively 
90% power to show bioequivalence already in the first stage. A drop-out compensation of 4 
subjects will be added. 
With a CV of 29%, the sample size of 36 evaluable subjects would still result in approximately 
80% power to show bioequivalence in the first stage.
The second stage will be performed only, if after Stage 1 the PK-variability turns out to be larger 
than initially assumed as specified in Figure 3 (if power is less than 80% and bioequivalence
criteria are not met in Stage 1 with an alpha of 0.0294). For Stage 2, the sample size will be adjusted 
based on the newly estimated PK-variability (maximum CV (%) value of the 3 PK primary 
endpoints), a targeted power of 80% and an adjusted alpha of 0.0294. The GMR T/R will be 
assumed to be 0.95 and will not be adjusted for the second stage.
As reported in Potvin [5] Table I and Table II for method C, with a first stage sample size of 36 
subjects under the assumptions of a CV value of 20% (lower than the assumed CV of 24%), and a 
GMR of 0.95, the power to show bioequivalence will be approximately 98% and the probability 
of proceeding to Stage 2 will be 0.0%. With a first stage sample size of 36 subjects under the 
assumptions of a CV value of 30% (higher than the assumed CV of 24%), and a GMR of 0.95, the 
power to show bioequivalence will be less than 90% and the probability of proceeding to Stage 2 
will be 22.7%. Table 6 summarizes the probability, mean total sample size (n) to proceed to Stage 
2 for CV values up to 50% and the estimated overall power for both stages when considering a 
first stage sample size of 36 subjects.
Table 6
Power and Mean n for Declaring Bioequivalence for Individual PK 
Parameters
Sample size 
Stage 1 (n1)
CV (%)
% Studies in Stage 2
Mean n
Power (%)
36
20
0.0
36.0
98
36
30
22.7
40.5
85
36
40
65.9
67.3
82
36
50
90.8
112.6
81
CV = coefficient of variation, n = total number of subjects, PK = pharmacokinetics
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8.2.2
Parts B and C (Food Effect)
A total of 12 subjects will be randomized into Part B and Part C each. To obtain at least 12 
evaluable subjects per group for the primary endpoint analysis, every drop-out with incomplete 
data must be replaced.
The half-width of the 90% confidence interval (CI) will be taken as a measure of precision. 
The precision for the T/R ratios to be estimated for AUC and Cmax for a series of CVs and a fixed 
sample size of 12 subjects per group is shown in Table 7. 
A 2-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.
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 
per Group
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
SAS software version 9.4 was used to perform the calculations.
CI = Confidence Interval, CV = Coefficient of variation, LCL = Lower Confidence Limit, R = reference, T = test, 
UCL = Upper Confidence Limit
8.3
Randomization
Refer to Section 6.3 for the technical and logistical aspects of treatment allocation.
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A total of 40 subjects will be randomized to Part A and 12 subjects each will be randomized to 
Parts B and C. In each study part, the subjects will be randomized to 1 of 2 sequences at a ratio of 
1:1:
Part A:
Sequence 1: TF3 - TF2
Sequence 2: TF2 - TF3
Part B:
Sequence 1: TF2 fasted - TF2 fed
Sequence 2: TF2 fed - TF2 fasted
Part C:
Sequence 1: TF3 fasted - TF3 fed
Sequence 2: TF3 fed - TF3 fasted.
If the PK-variability in Stage 1 of Part A is larger than assumed, additional subjects will be 
randomized to Part A as required.
A computer-generated randomization scheme will be provided by Nuvisan GmbH CTS 
Department.
8.4
Endpoints
8.4.1
Primary Endpoints
Part A: AUC0-t, AUC0-∞and Cmax of tepotinib observed from time zero to 168 h post-dose of 
each period
Parts B and C: AUC0-t, AUC0-∞and Cmax of tepotinib observed from time zero to 168 h post-
dose of each period.
8.4.2
Secondary Endpoints
tmax, t1/2, apparent total body clearance considering the fraction of dose absorbed (CL/f), and 
apparent volume of distribution during terminal phase (Vz/f) of tepotinib observed from time 
zero to 168 h post-dose of each period
Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of changes in 
safety laboratory assessments, 12-lead ECGs and vital signs.
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8.4.3
Exploratory Endpoints
PK profiles of tepotinib metabolites: 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time zero to 168 h post-
dose of each period
Genetic variants and mutations in genes that potentially influence PK of tepotinib.
8.5
Analysis Sets
8.5.1
Safety Analysis Set
The Safety analysis set will be defined for each part and will include all subjects who have received 
at least 1 dose of planned IMP and have had 1 subsequent safety assessment. 
8.5.2
Definition of Pharmacokinetic Analysis Set 
Part A (Bioequivalence)
The PK Analysis Set for Part A will include all subjects without any relevant protocol deviations 
with respect to PK and absence of factors likely to affect the comparability of PK results, with 
adequate trial medication compliance, and who have valid primary endpoints for both treatments. 
All PK analyses for Part A will be based on this analysis set.
Parts B and C (Food Effect)
The PK Analysis Set for each Part B and C, will include all subjects without any relevant protocol 
deviations with respect to PK and absence of factors likely to affect the comparability of PK 
results, with adequate trial medication compliance, and who have at least 3 post-dose concentration 
measurements. 
All PK analyses for Parts B and C will be based on the respective PK analysis set.
For all Parts (A, B and C)
Subjects in a particular period may be excluded after vomiting or with diarrhea 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. 
Relevant decisions will be made before database lock.
8.6
Description of Statistical Analyses
8.6.1
General Considerations
Statistical analyses will be performed using the computer program package SAS® System for 
Windows™ (Version 9.4 or later; SAS Institute, Cary, North Carolina, USA).
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The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment and/or scheduled time point, as appropriate.
For demographic, baseline and safety assessments, continuous measurements will be summarized 
by means of descriptive statistics (ie number and percentage of observations, number and 
percentage of missing observations, mean, standard deviation [SD], median, 25th and 75th
percentiles, minimum, and maximum) and categorical data will be summarized by means of 
frequency tables (ie count and percentages), if not stated otherwise.
Concentrations of tepotinib and its metabolites in plasma will be presented in tables and 
descriptively summarized by treatment and nominal time point using n, arithmetic mean, SD, 
standard error of the mean, median, minimum, maximum, and CV%. Values below the LLOQ will 
be taken as zero for descriptive statistics of PK concentrations. Descriptive statistics of PK 
parameters will additionally show the GeoMean, the geometric coefficient of variation (GeoCV%), 
and the 95% CI for the GeoMean.
Graphical displays will be given, where appropriate. PK variables will be evaluated and listed for 
all subjects who provide sufficient concentration-time data. Invalid data will be flagged 
accordingly. 
Missing values will be handled as such and not be replaced by estimates.
Details of the statistical analysis will be described in the statistical analysis plan.
Changes in the conduct of the trial or planned analyses, if any, will be reported in the appropriate 
section of the statistical analysis plan (SAP) and in the clinical trial report.
8.6.2
Analysis of Primary Endpoints
Part A
An analysis of variance (ANOVA) model will be fitted for the log-transformed PK parameters 
Cmax, AUC0-t, AUC0-∞based on the PK analysis set. The model will include treatment, period, 
sequence and subject within sequence as fixed effects. If a Stage 2 is required and the number of 
subjects in Stage 2 is sufficiently large, stage will be included as additional effect in the ANOVA 
model for the analysis of the pooled data of both stages. More details will be given in the SAP.
Treatment differences on the log scale of tepotinib will be estimated for Cmax, AUC0-t, AUC0-∞
together with their CIs with coverage probability according to the planned 2-stage procedure in
Figure 3. Point estimates and CIs will be back-transformed to the original scale for the 
comparisons. The variance estimate from Stage 1 will be used to evaluate the power at Stage 1.
The comparison will be the new tablet formulation (TF3) vs the tablet formulation used in clinical 
studies (TF2) under fasting condition. 
Bioequivalence will be assessed after Stage 1 using Stage 1 data, or after Stage 2 using the pooled 
data of both stages. 
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The null hypothesis will be rejected if the CI corresponding to the α-level in the Figure 3 (either 
90% or 94.12%) for the ratio of the GeoMean lies within the interval 0.8000 to 1.2500. 
Parts B and C
A mixed model with treatment, period and sequence as fixed effects and a random effect for subject 
within sequence will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞
based on the PK analysis set. Treatment differences on the log scale of tepotinib 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 for the comparisons:
Part B: Tepotinib PK parameters after administration of the tablet formulation TF2 under fasting 
administration vs tepotinib TF2 after a high fat, high calorie breakfast
Part C: Tepotinib PK parameters after administration of the tablet formulation TF3 under fasting 
administration vs tepotinib TF3 after a high fat, high calorie breakfast.
Individual estimates of relative bioavailability will be calculated for each subject.
8.6.3
Analysis of Secondary Endpoints
Summary statistics will be provided for all secondary PK parameters in plasma by time point. 
Graphical displays will be given, where appropriate. Details of the statistical analysis will be 
described in the SAP.
8.6.4
Analysis of Safety and Exploratory Endpoints
Safety data analysis will be conducted on the Safety Analysis Set of each part. The number and 
percentage of subjects experiencing at least 1 TEAE will be summarized by treatment as will the 
number of events. Tables by relationship to study drug and by severity will be generated. AEs will 
be coded using Medical Dictionary for Regulatory Activities terminology. All laboratory data will 
be reported with SI units. 
Laboratory parameters will be summarized using descriptive statistics for absolute values and 
change from baseline over time, by post-dose shifts relative to baseline, and data listings of 
clinically significant abnormalities/out of the normal range. 
Vital signs and ECG data will be summarized by changes from baseline values by treatment using 
descriptive statistics. Clinically significant ECG findings for individual subjects will be listed and 
summarized as appropriate.
PK concentrations will be descriptively summarized. Individual and mean concentration-timeplots 
will be produced in linear and log-linear scale.
Exploratory endpoints will be analyzed with descriptive statistics.
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8.7
Interim and Additional Planned Analyses
A two-stage design is used in Part A. Based on the measured variability, the corresponding power 
for the number of subjects in Stage 1 will be estimated. If the power is < 80%, an interim analysis 
will be performed. The significance level for both the interim analysis and the final analysis will 
then be set to 0.0294. For details refer to section 8.6.2.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP [7], and any other applicable regulations. The Investigator must ensure that
only subjects who have given informed consent are included in the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written informed 
consent, which must be given before any trial-related activities are carried out. Adequate 
information must therefore be given to the subject by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained. 
A subject information sheet must be prepared in the local language in accordance with ICH GCP
[7] and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or a designate will 
inform the subject verbally of all pertinent aspects of the trial, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given sufficient 
time to read the information and the opportunity to ask questions and to request additional 
information and clarification.
After the information is provided by the Investigator, the ICF must be signed and dated by the 
subject and the Investigator. The signed and dated declaration of informed consent will remain at 
the Investigator’s site, and must be safely archived so that the forms can be retrieved at any time 
for monitoring, auditing and inspection purposes. A copy of the signed and dated information and
ICF should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be
provided to the subjects and submit them to the IEC for review and opinion. Using the approved 
revised subject information sheet and other written information, The Investigator will explain the 
changes to the previous version to each trial subject and obtain new written consent for continued 
participation in the trial. The subject will be given sufficient time to read the information and the 
opportunity to ask questions and to request additional information and clarification about the 
changes.
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A separate subject information sheet will be prepared for the PGx testing. The subjects will be 
informed in the written form and verbally about pertinent aspects of the planned PGx testing 
including an explanation that this additional examination is mandatory for subjects’ participation 
in this clinical trial. Only subjects who have signed and dated the ICF for PGx testing will be 
included in this clinical trial.
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial data to an individual subject via an identification list 
kept at the site. For each subject, original medical data will be accessible for the purposes of source 
data verification by the Monitor, audits and regulatory inspections, but patient confidentiality will 
be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by Nuvisan GmbH for 
use during trial participation in order to provide clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial and to give health care providers access to any
information about this participation that may be needed to determine the course of medical 
treatment for the subject. The information provided on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, he/she will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators.
In cases where the Investigator is not available, the Phase 1 facility will provide the appropriate 
means to contact a physician. This includes the provision of a 24-hour contact number at the 
facility, whereby the health care providers will be given access to an appropriate physician to assist 
with the medical emergency.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for this trial. Insurance conditions will meet good local 
standards, as applicable.
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9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents (including but not limited to Subject Information and ICF, 
insurance certificate, Investigator’s Brochure) to the responsible IEC for its favorable opinion or 
approval, which will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial 
Master File.
The IEC will be asked to document the date of the meeting at which the favorable opinion or 
approval was given and the members and voting members present. Written evidence of favorable 
opinion or approval that clearly identifies the trial, the clinical trial protocol version and the Subject 
Information and ICF version reviewed should be provided. Where possible, copies of the meeting 
minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC, before 
implementation of substantial changes (see Section 10.5). Relevant safety information will be 
submitted to the IEC during the course of the trial in accordance with national regulations and 
requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, IMP Dossier, Subject 
Information and ICF) will be submitted or notified to the Health Authorities in accordance with 
all local and national regulations for each site.
10
Trial Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for eCRF handling guidelines.
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible and timely manner. The data in the eCRF should be consistent with the relevant 
source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of this 
trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure that the eCRFs and any other associated documents 
forwarded to Sponsor or its designated organization contain no mention of any subject names.
The data will be entered into a validated database. Nuvisan GmbH will be responsible for data 
processing, in accordance with the Sponsor’s data management procedures. Database lock will 
occur once quality control and quality assurance procedures have been completed. PDF files of the 
eCRFs will be provided to the Investigators at the completion of the trial.
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10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial. It must be possible to identify each subject by using this subject file. 
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible. 
Subject’s full name, date of birth, sex, height, weight
Medical history and concomitant diseases
Prior and concomitant therapies (including changes during the trial)
Trial identification, that is, the Sponsor trial number for this clinical trial, and subject number
Dates for entry into the trial (informed consent) and visits to the site
Any medical examinations and clinical findings predefined in this clinical trial protocol
All AEs
Date that the subject left the trial including any reason for early withdrawal from the trial or 
IMP (if applicable).
All documents containing source data must be filed, including, but not limited to ECG recordings, 
and laboratory results. Such documents must bear the subject number and the date of the procedure. 
If possible, this information should be printed by the instrument used to perform the assessment or 
measurement. As necessary, medical evaluation of such records should be performed; all 
evaluations should be documented, signed, and dated by the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the Monitor, during Sponsor audits and for 
inspection by Health Authorities during and after the trial, and must be safely archived for at least 
15 years after the end of the trial. The documents to be archived include the Subject Identification 
List and the signed subject ICFs. If archiving of the Investigator Site File is no longer possible at 
the site, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per ICH 
GCP guidelines [7], whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP [7] and any other applicable 
regulations. The site Monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, including the Investigator Site File, the completed eCRFs, all IMP and
IMP accountability records, and the original medical records or files for each subject.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantial amendments will 
usually require submission to the Health Authorities and to the relevant IEC for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by Nuvisan GmbH following the 
guidance in ICH Topic E3 [8].
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints. The results 
of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This 
allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results.
Posting of data on ClinicalTrials.gov and EudraCT is planned and will occur 12 months after the 
last clinic visit of the final trial subject or another appropriate date to meet applicable requirements.
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11
References Cited in the Text
1. Guidance for Industry; Bioavailability and Bioequivalence Studies submitted for NDAs or 
INDs – General Considerations. FDA CDER Office of Clinical Pharmacology, Mar 2014.
2. Guideline for Industry: Food-Effect Bioavailability Fed Bioequivalence Studies. FDA 
CDER. Dec 2002.
3. EMA 
GUIDELINE 
ON 
THE 
INVESTIGATION 
OF 
BIOEQUIVALENCE. 
CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** London, 20 January 2010.
4. Montague TH, Potvin D, DiLiberti CE, et al. Additional results for ‘Sequential design 
approaches for bioequivalence studies with crossover designs. Pharmaceut Statist.
2012;11(1):8-13.
5. Potvin D, DiLiberti CE, Hauck WW, et al. Sequential design approaches for 
bioequivalence studies with crossover designs. Pharm Stat 2008 Oct-Dec;7(4):245-62.
6. Recommendations related to contraception and pregnancy testing clinical trials. Clinical 
Trial Facilitation Group (CTFG), Heads of Medicines Agencies. 15 September 2014. 
Downloaded from ‘www.hma.eu’ on 07 November 2017.
7. ICH 
Topic 
E6(R2)
Guideline 
for 
good 
clinical 
practice 
E6(R2). 
EMA/CHMP/ICH/135/1995. London, 1 December 2016. 1-70.
8. ICH Topic E3. Structure and Content of Clinical Study Reports. CPMP/ICH/137/95, 
London July 1996. 1-47.
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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 e p oti ni b ( M S C 2 1 5 6 1 1 9. J) 
Bi o e q ui v al e n c e ( T F 3/ T F 2) a n d Eff e ct of F o o d o n t he P K of T e p oti ni b 
M S 2 0 0 0 9 5- 0 0 4 4 
Si g n at u r e P a g e - P r ot o c ol L e a d 
T ri al Title: 
P hase l , O p e n-l a b el , 3- P arts St u d y wit h Cr oss o v er 
D esi g n i n e a c h p art t o I n v esti g at e t h e Bi o e q ui v al e n c e 
of t he T a bl et F or m ul ati o n of T e p oti ni b T F 3 c o m p ar e d 
t o T F 2 ( P art A), a n d t o I n v esti g at e t h e I nfl u e n c e of 
F o o d 
o n 
t he P h ar m a c o ki n eti cs 
of e a c h T a bl et 
F or m ul ati o n T F 2 
( P art B) 
a n d T F 3 
( P art C) 
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 ber: 
2 0 1 7- 0 0 5 0 5 6- 2 9 
Cli ni c al 
T ri al 
P r ot o c ol 
D at e 
/ 2 9 M a y 2 0 1 8 / V ersi o n 1. 0 
Versi o n: 
P r ot o c ol Le a d: 
I a p pr o v e t h e desi ~ n of t he cli ni c al trial:  
Si g n at ur e 
D at e of Si g n at ur e 
N a m e , a c a d e mi c d e gr e e: 
, 
 
F u n cti o n I Title: 
M e di c al R es p o nsi bl e / 
 
I nstit uti o n: 
M 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 mst a dt, G er m a n y 
T el e p h o n e n u m b er: 
 
E- m ail a d dress: 
 
D o c u m e nt N o. 0 9 0 0 b a h e 8 0 e d 6 c 2 2 v 1. 0 
O bj e ct N o. 0 9 0 0 h a b e 8 0f c b 4 l f 
C O N
F 1 D E N T 1
A L 
l N F O R M A Tl O N 
6 3 / 6 8 
Pa ge 6 4 of 6 9
PI
PI
PI
PI
PI
PI
PI


T e p oti ni b ( M S C 2 J 5 6 1 1 9 J) 
Bi o e q ui v al e n c e ( T F 3/ T F 2) a n d Eff e ct of F o o d o n t h e P K of T e p oti ni b 
M S 2 0 0 0 9 5- 0 0 4 4 
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 Titl e 
P h as e I, O p e n-l a b el, 3- P arts St u d y wit h Cr oss o v er 
D esi g n i n e a c h p art t o I n v esti g at e t h e Bi o e q ui v a len c e 
of t h e T a bl et F or m ul ati o n of T e p oti ni b T F 3 c o m p ar e d 
t o T F 2 ( P art A) , a n d t o I n v esti g at e t h e I nfl u e n c e of 
F o o d 
o n 
t h e P h ar m a c o ki n eti c s of e a c h 
T a bl e t 
F or m ul ati o n T F 2 
(P art B) 
a n d T F 3 
( P art C) 
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 
Cli ni c al T ri al P r ot o c ol D at e / 
V e rsi o n 
C e nt e r N u m b e r 
P ri n ci p al I n v esti g at o r 
2 0 1 7- 0 0 5 0 5 6- 2 9 
2 9 M a y 2 0 1 8 / V ersi o n 1 . 0 
 
I, t h e u n d ersi g n e d , a p pr o v e t h e d esi g n of t h e cli ni c al tri al a n d I u n d er st a n d a n d will c o n d u ct t h e 
tri al a c c or di n g t o t h e cli ni c al tri al pr ot o c ol , a n y a p pr o v e d pr ot o c o l a m e n d m e nts , I nt er n ati o n al 
C o u n cil f or H ar m o ni sati o n G o o d C li ni c al Pr a cti c e ( T o pi c E 6) a n d a ll a p pli c a bl e H e alt h A ut h o rity 
r e q uir e m e nts a1) <l n ati o n al la ws. 
Si g n at ur e 
D at e of Si g n at ur e 
N a m e , a c a d e mi c d e gr e e: 
, 
 
F u n cti o n / Titl e: 
Pri n ci p al I n v esti gat or 
I nstit uti o n: 
 
A d dr e ss: 
, G er m a n y 
T el e p h o n e n u m b er: 
 
F a x n u m b er: 
 
E- m ail a d dr ess: 
 
D o c u m e nt N o. 0 9 0 0 b a b e 8 0 e d 6 c 2 2 v l.0 
O bj e c t No. 0 9 0 0 b a b e 8 0f c b 4 If 
C O N F
I  D E N T I A L 
I N F O R M A TI O N 
6 4 /6 8 
Pa ge 6 5 of 6 9
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Bi oe q ui v ale nce ( T F 3/ T F 2) a n d Effect of F o o d o n t he P K of Te p oti ni b
M S 2 0 0 0 9 5- 0 0 4 4
C O N F I D E N T I A L
I N F O R M A T I O N
6 5 /6 8
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:
o n be half of 
I nstit uti o n:
C y tel Fra nce Sarl
A d dress:
6 3 A ve n ue des C ha m ps El y sées, 7 5 0 0 8 Paris, Fra nce
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:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
E- mail a d dress:
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0e d 6c 2 2 v 1. 0
0 9 0 0 ba be 8 0fc b 4 1f
Pa ge 6 6 of 6 9
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PI
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Appendix II
Blood Volume Sampled in the Clinical Trial
Blood sample for
Amount 
per 
sample 
(mL)
Number of Scheduled Blood Samples per Subject
Total 
amount 
per 
Subject
(mL)
Screening Per Period
No. of 
Periods 
per Part
End of Trial
Visit
Total
Clinical laboratory tests 
Biochemistry (incl. viral 
serology, TSH and FSH 
levels, if applicable)
4.7
1
4 a
2
1
10
47.0
Hematology
2.7
1
4 a
2
1
10
27.0
PK
2.0
22 b
2
44
88.0
PGx
2.0
2 c
2
4.0
Total
2
32
2
66
166.0
Note: the number of blood samples may increase above the scheduled number. Blood samples for 
clinical laboratory follow-up determinations may become necessary. Technical failure of PK/PGx blood 
drawing may lead the Investigator to decide immediately to repeat a single blood drawing to have a 
sample. 
Maximal blood volume drawn: Estimate per Subject in this Study 
that will not be exceeded in this planned trial as by experience of the Investigating Institution: 
200
FSH = follicle stimulating hormone, PGx = pharmacogenetics, PK = pharmacokinetics, TSH = thyroid stimulating 
hormone.
Clinical laboratory (biochemistry and hematology) blood samples:
a
Each period: on Day -1, pre-dose on Day 1, on Day 2 and before discharge on Day 4 = 4 samples;
PK blood samples for determination of tepotinib and its metabolites:
b
Each period: pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 
168 h post-dose = 22 samples;
PGx blood samples:
c
PGx blood samples of 2 x 2 mL to be drawn on Day 1 of Period 1 at pre-dose = 2 samples.
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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. 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. However, they must 
discontinue HRT to allow confirmation of postmenopausal status before study enrolment.
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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 a. 

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 
(Bilateral vasectomy of the partner is a highly effective contraceptive 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 
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SAP_001.pdf: 
Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)  
Bi oe q ui v ale nce ( T F 3/ T F 2) a n d Effect of F o o d o n t he P K of Te p oti ni b 
M S 2 0 0 0 9 5- 0 0 4 4   
Fi n al v 1. 0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
1/ 2 7  
 
 
 
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 4 4 
Title 
P hase  1,  O pe n-l a bel,  3- Parts  St u d y  wit h  Cr oss o ver  Desi g n  i n 
eac h  part  t o  I n vesti gat e  t he  Bi oe q ui val e nce  of  t he  T a blet 
F or m ulati o n of  Te p oti ni b  T F 3  c o m pare d t o  T F 2 ( Part  A), a n d 
t o I n vesti gate t h e I nfl ue n ce of F o o d o n t h e P har m ac o ki netics of 
eac h  Ta blet  F or m ulati o n  T F 2  ( Part  B)  a n d  T F 3  ( Part  C)  of 
Te p oti ni b i n Healt h y S u bjects 
Tri al P h ase 
1  
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 
Versi o n 
2 9 Ma y 2 0 1 8 / V ersi 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 
 
O n b e h alf of 
, 
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 
, N u vis a n 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n 
 0 5 Dece m b er 2 0 1 8 / Fi n al Versi o n 1. 0  
I nte gr ate d A n al ysis Pl a n 
Re vie wers  
F u n cti o n 
N a m e 
 
 
M e di c al R e s p o n si bl e, M er c k 
  
 
 
 M er ck 
 
 
, M er c k 
 
, M er c k 
 
, M er c k 
 
 
 
C o nfi de nti al  
T his d oc u me nt is t h e pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies. 
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yri 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 affili ate. All ri g hts reser ve d. 
Pa ge 1 of 2 8
PI
PI
PI
PI
PI
PI
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PI
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PI
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T e p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
M S 2 0 0 0 9 5- 0 0 4 4 
Bi o e q ui v al e n c e ( T F 3/ T F 2) a n d Eff e ct of F o o d o n t h e P K of T e p oti ni b 
Fi n al vl. O 
Si g n at u r e P a g e 
I nt e g r at e d A n al ysis Pl a n: M S 2 0 0 0 9 5- 0 0 4 4 
P ha s e I, O p e n-l a b el , 3- Par 1s St u d y wit h Cr oss o v er D esi g n i n e a c h p art t o I nv es tigate t h e 
Bi o e q ui v al e n c e of t h e T a bl et F or m ul ati o n of T e p oti ni b T F 3 c o m p ar e d t o T F 2 ( P art A) , a n d t o 
I n v esti g at e t he I nfl u e n c e of F o o d o n t h e P h ar m a c o ki n eti cs of e a c h T a bl et F o n n ul ati o n T F 2 
( P m 1 B) a n d T F 3 ( P art C) of T e p oti ni b i n H e alt h y S u bj e cts 
, 
, 
 
N U VI S A N G m b H , 
W e g e n erstr ass e 1 3, 
8 9 2 3 1 N e u- Ul m, G er m a n y 
, 
, 
C ytel Fr a n c e Sarli 
6 3 A v e n u e d es C h a m ps El ys e es , 
7 5 0 0 8 P ari s, Fr a n c e 
D at e 
C  O  N FI D E N T I A L 
I  N F O R M A TI O N 
Si g n at u r e 
2 1 2 7 
Pa ge 2 of 2 8
PI
PI
PI
PI
PI
PI
PI


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Bi oe q ui v ale nce ( T F 3/ T F 2) a n d Effect of F o o d o n t he P K of T e p oti ni b 
l\I S 2 0 0 0 9 5- 0 0 4 4 
Fi n al vl. O 
Si g n at u r e P a g e 
I nt e g r at e d A n al ysis Pl a n: M S 2 0 0 0 9 5- 0 0 4 4 
P h as e 1, O p e n-l a b el, 3- P arts St u d y wit h Cr oss o v er D esi g n i n e a c h p art t o I n v esti g at e t h e 
Bi o e q ui v al e n c e of t h e T a bl et F or m ul ati o n of T e p oti ni b T F 3 c o m p ar e d t o T F 2 ( P art A), a n d t o 
I n v esti g at e t h e I nfl u e n c e of F o o d o n t h e P h ar m a c o ki n eti cs of e a c h T a bl et F or m ul ati o n T F 2 
( P art B) a n d T F 3 ( P art C) of T e p oti ni b i n H e alt h y S u bjects 
, 
, 
 
N U VI S A N G m b H, 
W e g e n erstr ass e 1 3, 
8 9 2 3 1 N e u- Ul m, G er m a n y 
, 
 
, 
C yt el Fr a n c e Sarli 
6 3 A v e n u e des C h a m ps El ys e es, 
7 5 0 0 8 P aris, Fr a n c e 
D at e 
C O N FI D E N TI A L 
I N F O R M A TI O N 
Si g n at u r e 
2/ 2 7 
Pa ge 3 of 2 8
PI
PI
PI
PI
PI
PI
PI
PI
PI


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/27 
 
 
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 .....................................................................6 
6 
Overview of Planned Analyses .............................................................7 
6.1 
Interim Analysis ....................................................................................7 
6.2 
Final Analysis .......................................................................................7 
7 
Changes to the Planned Analyses in the Clinical Trial Protocol ..........8 
8 
Protocol Deviations and Analysis Sets .................................................8 
8.1 
Definition of Protocol Deviations and Analysis Sets ...........................8 
8.2 
Definition of Analysis Sets ...................................................................9 
9 
General Specifications for Data Analyses ............................................9 
10 
Trial Subjects ......................................................................................11 
10.1 
Disposition of Subjects and Discontinuations ....................................11 
10.2 
Protocol Deviations ............................................................................12 
10.2.1 
Important Protocol Deviations ............................................................12 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................12 
11 
Demographics and Other Baseline Characteristics .............................12 
11.1 
Demographics .....................................................................................12 
11.2 
Medical History ..................................................................................13 
11.3 
Other Baseline Characteristics ............................................................13 
12 
Previous or Concomitant Medications/Procedures .............................13 
13 
Treatment Compliance and Exposure .................................................14 
14 
Efficacy Analyses ...............................................................................14 
15 
Safety Analyses ..................................................................................14 
15.1 
Adverse Events ...................................................................................14 
15.1.1 
All Adverse Events .............................................................................15 
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Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
4/27 
 
 
15.1.2 
Adverse Events Leading to Treatment Discontinuation .....................16 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................16 
15.2.1 
Deaths .................................................................................................16 
15.2.2 
Serious Adverse Events ......................................................................17 
15.2.3 
Other Significant Adverse Event ........................................................17 
15.2.3.1 
Adverse Events of Special Interest .....................................................17 
15.3 
Clinical Laboratory Evaluation ...........................................................17 
15.4 
Vital Signs ..........................................................................................18 
15.5 
ECG Evaluation ..................................................................................18 
16 
Analyses of Other Endpoints ..............................................................19 
16.1 
Pharmacokinetics ................................................................................19 
General Specifications for Plasma Concentration Data .....................................................19 
General Specifications for PK Parameter Data ..................................................................19 
16.1.1 
Primary Endpoints ..............................................................................20 
16.1.1.1 
Primary Endpoints in Part A ...............................................................20 
16.1.1.2 
Primary Endpoints in Parts B and C ...................................................22 
16.1.2 
Secondary Endpoints ..........................................................................23 
16.1.3 
Exploratory Endpoints ........................................................................23 
16.1.4 
Plasma Concentration Data .................................................................24 
16.1.5 
Estimation of Individual Pharmacokinetic Parameters .......................24 
16.2 
Pharmacogenetics ...............................................................................26 
17 
References ...........................................................................................26 
18 
Appendices .........................................................................................27 
 
Page 5 of 28


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
5/27 
 
 
2 
List of Abbreviations and Definition of Terms 
 
AE 
Adverse Event 
ANOVA 
Analysis of VARIANCE 
BMI 
Body Mass Index 
eCRF 
Electronic Case Report Form 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
GeoCV% 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
GMR 
Geometric Mean Ratio 
IAP 
Integrated Analysis Plan 
ICH 
International Conference on Harmonization 
LCI 
Lower Confidence Interval Bound 
LLOQ 
Lower Limit of Quantification 
MCAR 
Missing Completely at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
Max 
Maximum 
Min 
Minimum 
PT 
Preferred Term 
PD 
Pharmacodynamics 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetics 
Q1 
First Quartile 
Q3 
Third Quartile 
QTcF 
Corrected QT interval per Fridericia‟s formula 
SAE 
Serious Adverse Event 
SEM 
Standard Error of the Mean 
Page 6 of 28


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)  
Bi oe q ui v ale nce ( T F 3/ T F 2) a n d Effect of F o o d o n t he P K of Te p oti ni b 
M S 2 0 0 0 9 5- 0 0 4 4   
Fi n al v 1. 0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
6/ 2 7  
 
 
S O C 
S yste m Or ga n Class 
T E A E 
Treat me nt E mer ge nt A d v erse E ve nt 
T F 2 
Ta blet F or m ulati o n 2 
T F 3 
Ta blet F or m ulati o n 3 
U CI 
U p per C o nfi de n ce I nter val B o u n d 
U L O Q 
U p per Li mit of Q ua ntificati o n 
 
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 
1 4 - N O V-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 4 4. Res ults of t he a nal ys es des cri be d i n t his I A P will 
be 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 res 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 cl earl 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 wit h I C H E 9.  
5  
O bjecti ves a n d E n d p oi nts 
 
 
O bj e cti v e 
E n d p oi nt 
I A P 
s e cti o n 
Pri m ar y 
O bj e cti v e s 
  
P art A: T o d e m o n str at e 
bi o e q ui v al e n c e b et w e e n t h e n e w 
t a bl et f or m ul ati o n ( T F 3, t e st 
tr e at m e nt) a n d t h e t a bl et f or m ul ati o n 
u s e d i n cli ni c al st u di e s ( T F 2, 
r ef er e n c e tr e at m e nt) aft er si n gl e d o s e 
a d mi ni str ati o n i n h e alt h y s u bj e ct s 
u n d er f a sti n g c o n diti o n s 
Pri m ar y E n d p oi nt s: 
P art A:  
  Ar e a u n d er t h e pl a s m a c o n c e ntr ati o n-
ti m e c ur v e ( A U C) fr o m ti m e z er o 
( =d o si n g ti m e) t o t h e l a st s a m pli n g ti m e 
at w hi c h t h e c o n c e ntr ati o n i s at or a b o v e 
t h e l o w er li mit of q u a ntifi c ati o n ( A U C0-t ) 
   A U C fr o m ti m e z er o e xtr a p ol at e d t o 
i nfi nit y ( A U C0- ∞)  
  
m a xi m u m pl a s m a c o n c e ntr ati o n ( Cm a x ) 
of t e p oti ni b o b s er v e d fr o m ti m e z er o t o 
1 6. 1. 1. 1  
Pa ge 7 of 2 8
PI


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/27 
 
 
168 h postdose of each period 
 
Parts B and C: To investigate the 
food effect, ie the difference in PK 
between administration after a high-
calorie, high-fat breakfast and 
administration under fasting 
conditions in healthy subjects, for 
both TF3 and TF2. 
Parts B and C: 
 
 AUC0-t, AUC0-∞ and Cmax of tepotinib 
observed from time zero to 168 h 
postdose of each period. 
16.1.1.2 
Secondary 
Objectives 
 
To further investigate the PK of 
tepotinib 
Secondary endpoints: 
 
Time to reach Cmax (tmax), terminal half-
life (t1/2), apparent total body clearance 
considering the fraction of dose 
absorbed (CL/f) and apparent volume 
of distribution during terminal phase 
(Vz/f) of tepotinib observed from time 
zero to 168 h post-dose of each period. 
16.1.2 
 
To assess the safety and tolerability 
of tepotinib (TF3 and TF2) under 
fasting and non-fasting conditions. 
 
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. 
15 
Exploratory 
Objectives 
 
Part A: To investigate the PK of 
metabolites after administration of 
both tablet formulations (TF3 and 
TF2) of tepotinib 
Exploratory Endpoints: 
 
PK profiles of tepotinib metabolites: 
 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of 
tepotinib metabolites observed from 
time zero to 168 h post-dose of each 
period 
16.1.3 
 
Parts B and C: To investigate the 
effect of food on the PK of 
metabolites of tepotinib 
 
AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of 
tepotinib metabolites observed from 
time zero to 168 h post-dose of each 
period 
16.1.3 
 
To explore the effect of 
pharmacogenetics (PGx) and 
variations of associated genes on the 
PK profile of tepotinib (if applicable). 
 
Genetic variants and mutations in 
genes that potentially influence PK of 
tepotinib. 
16.2 
6 
Overview of Planned Analyses 
6.1 
Interim Analysis 
A two-stage design is used in Part A. Based on the measured variability, the corresponding 
power for the number of subjects in Stage 1 will be estimated. The final bioequivalence analysis 
for Part A will be performed after Stage 1 or Stage 2, depending on the result of the interim. 
6.2 
Final Analysis 
The final, planned analyses identified in the Clinical Trial Protocol and in this IAP will be 
performed 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.  
Page 8 of 28


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
8/27 
 
 
A data review meeting will be held prior to database lock for both the interim and final analysis. 
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.  
 
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 
Page 9 of 28


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
9/27 
 
 
All important protocol deviations will be documented in CDISC datasets whether identified 
through sites monitoring or medical review.  
8.2 
Definition of Analysis Sets 
Part A (Bioequivalence) 
The PK Analysis Set for Part A will include all subjects without any relevant protocol deviations 
with respect to PK and absence of factors likely to affect the comparability of PK results, with 
adequate trial medication compliance, and who have valid primary endpoints for both treatments. 
All PK analyses for Part A will be based on this analysis set. 
Parts B and C (Food Effect) 
The PK Analysis Set for each Part B and C, will include all subjects without any relevant 
protocol deviations with respect to PK and absence of factors likely to affect the comparability of 
PK results, with adequate trial medication compliance, and who have at least 3 post-dose 
concentration measurements. 
All PK analyses for Parts B and C will be based on the respective PK analysis set. 
All Parts (Safety) 
The Safety Analysis Set will include all subjects who have received at least 1 dose of planned 
IMP in the respective Parts. Subjects will be analyzed according to the actual treatment they 
receive.  
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.  
For all Parts (A, B and C) 
Subjects in a particular period may be excluded after vomiting or with diarrhea 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. 
Relevant decisions will be made before database lock. 
 
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). 
Page 10 of 28


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
10/27 
 
 
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. 
This study has three separate parts (A, B and C). Outputs applicable to more than one part will be 
paged by part with the part indicated in a sub-heading. 
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, the first 
and third quartile [Q1 and Q3], minimum [Min], and maximum [Max]) 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. For 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 collection, the previous non-missing evaluation 
could become the baseline value (e.g. from screening/admission). 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 period of AE = start date of the event – date of First Admin in period + 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 AEs before the 
day of dosing of the study 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). 
Page 11 of 28


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
11/27 
 
 
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: 
 Part A 
o TF2, fasted 
o TF3, fasted 
 Part B 
o TF2, fasted 
o TF2, fed 
 Part C 
o TF3, fasted 
o TF3, fed 
10 
Trial Subjects 
The subjects will be enrolled into either Part A, B or C, and will be recruited separately for each 
of the study parts. Subject disposition will be presented separately for each part. 
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) 
 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 Adverse event 
o Lost to follow-up 
o Death 
o Other  
 Number of treated subjects by treatment and overall 
 Number and percentage of treated subjects who completed study by treatment and overall 
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Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
12/27 
 
 
 Number and percentage of treated subjects who discontinued the study, with the primary 
reason of discontinuation by treatment and overall: 
o Adverse event 
o Lost to follow-up 
o Protocol non-compliance 
o Death 
o Withdrew consent 
o Other 
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.  
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 eCRF pages.  
Demographic characteristics: 
 Sex: male, female  
 Race: Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or Pacific Islander, White, Other 
Page 13 of 28


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
13/27 
 
 
 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: 
 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).  
Page 14 of 28


Tepotinib (MSC2156119J) 
Bioequivalence (TF3/TF2) and Effect of Food on the PK of Tepotinib 
MS200095-0044   
Final v1.0 
 
 
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I N F O R M A T I O N 
14/27 
 
 
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 
CRF), 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.  
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. 
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 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 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, version 5.0 (publication date: 27 Nov 
2017), 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 TEAEs  
 Any trial treatment related TEAEs  
 Any serious TEAEs  
 Any trial treatment related serious TEAEs  
 Any TEAE (grade >=3) 
 Any trial treatment related TEAEs (grade >=3)  
 Any TEAEs leading to death 
 Any trial treatment related TEAEs leading to death 
 
TEAEs will be summarized by treatment and overall in tables with: 
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 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. 
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” CRFs.  
Listing of deaths, if any, will be provided displaying date and cause of death (including TEAE 
leading to death and relatedness to trial treatment, when applicable), and date and time of 
treatment administration. 
 
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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 AE of special 
interest (AESI). The severity of these AEs should be defined based on clinical judgment of the 
Investigator and defined according to NCI-CTCAE Severity Scale. 
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 and by post-dose 
CTCAE grade shift relative to baseline. Shift tables will be based on NCI-CTCAE grades, where 
possible, and on normal ranges otherwise.  
Shift tables will be presented for: 
- 
End of Trial versus Screening 
- 
Discharge Day 4 versus Pre-dose (Tepotinib administration) 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. Any out-of-range values will 
additionally be listed separately including NCI-CTCAE grade.  
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 
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 Urinalysis 
 Other tests 
Tables will be produced for the groups Hematology, and Biochemistry. 
15.4 
Vital Signs 
Vital signs will be listed by subject and time-point and summarized for absolute values and 
changes-from-baseline (period-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 (period-baseline) by treatment group using descriptive statistics. Baseline 
is the pre-dose assessment in each period. See section 9 for a description of how missing baseline 
values are handled. 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
QTcf 
 
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 period baseline into the categories 
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 ≤ 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 and changes from period baseline will be 
listed, with abnormalities (as reported of the investigator on the ECG eCRF page) indicated. 
Investigator reported interpretation results will also be  tabulated by 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 
Concentrations of tepotinib and its metabolites in plasma will be presented in tables and 
descriptively summarized by treatment and nominal time point using number of observations (n), 
Mean, SD, standard error of the mean (SEM), median, Min, Max, and CV%.  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 
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: n, Mean, SEM, SD, 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 
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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 concentration/PK data will be listed. Data of subjects not in 
the PK analysis set or invalid data will be flagged accordingly. 
16.1.1 
Primary Endpoints 
16.1.1.1 
Primary Endpoints in Part A 
Statistical Hypotheses for Part A (Bioequivalence) - Two-stage Adaptive Design 
The following null hypothesis for the ratio of the geometric means will be used to assess 
bioequivalence 
H0: 
µT/µR ≤ 0.8000 or 1.2500 ≤ µT/µR for at least one parameter (AUC0-t or  
AUC0-∞ or Cmax) 
H1: 
0.8000 < µT/µR < 1.2500 for all parameters (AUC0-t and AUC0-∞ and Cmax) 
where µT and µR are the geometric means for the test and reference treatment respectively. 
The test treatment is the new tablet formulation (TF3) and reference is the tablet formulation 
used in clinical studies (TF2) both under fasting condition.  
The null hypothesis will be tested using a two-stage adaptive design Figure 1 . The procedure 
will follow the method C described by Montague [1] and Potvin [2]. 
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Figure 1 
Diagram of Two-Stage Adaptive Design 
 
Source: (Montague et al [1]) Figure 2; BE: Bioequivalence 
The power at stage 1 will be estimated using a geometric mean ratio (GMR) of 0.95 and CV(%) 
as the maximum intra-individual CV(%) for the three PK parameters Cmax, AUC0-t, and AUC0-∞.   
The CV(%) for each parameter will be estimated by analysis of variance (ANOVA) on the log 
transformed parameter. The ANOVA will include TREATMENT, PERIOD, SEQUENCE and 
SUBJECT within SEQUENCE as fixed effects.  
If the power is >= 80% then bioequivalence will be evaluated at an alpha level of 0.05. If the 
power is < 80% and the bioequivalence criteria not met at an alpha level of 0.0294, the study will 
proceed to the second stage with a re-estimated sample size. The re-estimated sample size will be 
the minimum even number of subjects required for the combined data from stages 1 and 2 to 
have at least 80% power (based on the newly estimated CV[%], an assumed GMR of 0.95  and 
an adjusted alpha of 0.0294.).  
The significance level for the second stage analysis will be set to 0.0294. 
The null hypothesis will be rejected if the CI corresponding to the α-level (either 90% or 
94.12%) for the ratio of the geometric mean lies within the interval 0.8000 to 1.2500. 
 
Analyses in Part A 
Primary analysis 
An analysis of variance (ANOVA) model with TREATMENT, PERIOD, SEQUENCE and 
SUBJECT(SEQUENCE) as fixed effects will be fitted  for the log-transformed PK parameters 
Cmax, AUC0-t, and AUC0-∞ based on the PK analysis set. If a Stage 2 is required and the number 
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of subjects in stage 2 is sufficiently large, STAGE will be included as additional effect to the 
ANOVA model for the analysis of both stages. A linear model with STAGE, TREATMENT, 
PERIOD(STAGE), SEQUENCE and SUBJECT(STAGE*SEQUENCE) as fixed effects will be 
applied to the log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞ based on the PK 
analysis set.  
Treatment differences TF3-TF2 under fasting condition on the log scale will be estimated for 
Cmax, AUC0-t, and AUC0-∞ together with their CIs (90% if the power >=80% or 94.12% if the 
power <80% according to the adaptive sample size sequential method in Figure 1). 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 the 
individual PK parameters by treatment group indicating the geometric means within each 
treatment group.      
The PK variables also be listed for all subjects of the PK population. 
Sensitivity analysis 
In order to take into account that the study will be carried out in two or more cohorts (due to the 
logistical reasons, only a limited number of subjects are available at one time), the primary 
statistical model is modified to reflect the multigroup nature of the study. An analysis of variance 
(ANOVA) model with COHORT, TREATMENT, PERIOD(COHORT), SEQUENCE and 
SUBJECT(COHORT*SEQUENCE) as fixed effects will be fitted  for the log-transformed PK 
parameters Cmax, AUC0-t, and AUC0-∞ based on the PK analysis set. 
Treatment differences TF3-TF2 under fasting condition on the log scale will be estimated for 
Cmax, AUC0-t, and AUC0-∞ together with their CIs (90% if the power >=80% or 94.12% if the 
power <80% according to the adaptive sample size sequential method in Figure 1). Point 
estimates and CIs will be back-transformed to the original scale.  
The primary endpoints will be descriptively summarized.  
16.1.1.2 
Primary Endpoints in Parts B and C 
No hypotheses were defined for Parts B or C. 
A mixed model with TREATMENT, PERIOD, SEQUENCE as fixed effects and a random effect 
for SUBJECT(SEQUENCE) will be applied to log-transformed PK parameters Cmax, AUC0-t, and 
AUC0-∞ based on the PK analysis set. Treatment differences Fed-Fasted on the log scale will be 
estimated for Cmax, AUC0-t, and AUC0-∞ together with their 90% CIs for each of the tablet 
formulations TF2 (Part B) and TF3 (Part C) separately. Point estimates and CIs will be 
back-transformed to the original scale.  
Part B: Tepotinib PK parameters after administration of the tablet formulation TF2 under fasting 
administration vs. tepotinib TF2 after a high fat, high calorie breakfast 
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Part C: Tepotinib PK parameters after administration of the tablet formulation TF3 under fasting 
administration vs. tepotinib TF3 after a high fat, high calorie breakfast 
Individual estimates of relative bioavailability will be calculated for each subject and 
descriptively summarized. 
The primary endpoints will be descriptively summarized. Scatter plots will be produced for the 
individual PK parameters by treatment group indicating the geometric means within each 
treatment group. 
The PK variables will also be listed for all subjects of the PK population. 
 
 
16.1.2 
Secondary Endpoints  
The secondary endpoints will be descriptively summarized.  
For tmax, the Hodges-Lehmann shift estimates will be given for, TF2 fed - TF2 fasted, TF3 fed - 
TF3 fasted  together with the 90% confidence intervals according to Tukey.  
The PK variables will also be listed for all subjects of the PK population. 
16.1.3 
Exploratory Endpoints  
Similar analyses will be performed for the parameters based on the metabolites of tepotinib 
(using 90% confidence intervals for all treatment comparisons); 
 Part A:  TF3 - TF2, both under fasting condition  
 Part B: TF2, fed - TF2, fasted 
 Part C: TF3, fed - TF3, fasted 
The ANOVA model will have the same effects as the primary analysis applied to log-
transformed PK parameters Cmax, AUC0-t, and AUC0-∞ in each of the study parts A, B and C: 
 Part A: A linear model with TREATMENT, PERIOD, SEQUENCE and 
SUBJECT(SEQUENCE) as fixed effects  
 Part B and C: A mixed model with TREATMENT, PERIOD, SEQUENCE as fixed 
effects and a random effect for SUBJECT(SEQUENCE)   
The PK endpoints AUC0-t, AUC0-∞, Cmax, tmax, t1/2 of tepotinib metabolites observed from time 
zero to 168 h post-dose of each period for the tepotinib metabolites MSC2571109A and 
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MSC2571107A will be descriptively summarized by treatment and listed for all subjects in the 
PK population.  
16.1.4 
Plasma Concentration Data 
The following figures will be produced for the tepotinib and metabolites plasma concentrations: 
 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 by nominal time by treatment. 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 and metabolites 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 its Metabolites After Single 
Dose Administration 
 
Symbol 
Definition 
AUC0-t 
Area under the plasma concentration-time curve (AUC) from time zero (= dosing 
time) to the last sampling time (tlast) at which the concentration is at or above the 
lower limit of quantification (LLOQ), calculated 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 
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Symbol 
Definition 
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. 
Frel,fed/fasted 
Relative bioavailability (Fasted versus Fed), defined as F = 
(AUC0-∞,fed/AUC0-∞,fasted)*100, where AUC0-∞,fasted is AUC0-∞ under fasting 
administration and AUC0-∞,fed is AUC0-∞ after a high fat, high calorie breakfast, 
calculated in Part B and C. 
Individual PK parameters will be calculated using actual sampling times. The pre-dose sample 
will be considered as if it had been taken simultaneously with the administration of study drug. 
PK variables will be evaluated and listed for all subjects who provide sufficient concentration-
time data. 
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.  
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 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 the 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. 
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 
1. Montague TH, Potvin D, DiLiberti CE, et al. Additional results for „Sequential design 
approaches for bioequivalence studies with crossover designs. Pharmaceut Statist. 
2012;11(1):8-13. 
2. Potvin D, DiLiberti CE, Hauck WW, et al. Sequential design approaches for 
bioequivalence studies with crossover designs. Pharmaceut Statist. 2007.DOI: 
10.1002/pst.294. 
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18 
Appendices 
None. 
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