The Effect of Multiple Doses of Zongertinib on the Single-dose Pharmacokinetics of Midazolam, Omeprazole and Repaglinide in Healthy Male Subjects (an Open-label, 2-period, Fixed-sequence Trial)
Phase: PHASE1
Conditions: Healthy
Sponsor: Boehringer Ingelheim

BI-VQD-11906_40-106_AD-13 (8.0)
TITLE PAGE
Document Number:
c42988075-04
EU Trial No.
2023-510263-35-00
UTN
U1111-1301-9035
BI Trial No.
1479-0014
BI Investigational
Medicinal Product
Zongertinib (BI 1810631)
Title
The effect of multiple doses of zongertinib on the single-dose 
pharmacokinetics of midazolam, omeprazole and repaglinide in 
healthy male subjects (an open-label, 2-period, fixed-sequence 
trial)
Lay Title
A study in healthy men to test whether zongertinib affects how
3 other medicines (midazolam, omeprazole, and repaglinide) are 
taken up and processed in the body
Clinical Phase
I
Clinical Trial Leader
Phone:
, Fax: 
 Investigator
Phone: 
, Fax: 
Current Version, Date
Version 4.0, 12 Jul 2024
Original Protocol Date
06 Mar 2024
Page 1 of 88
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
Clinical Trial Protocol
Boehringer 
\11lll1v lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Original protocol date
06 Mar 2024
Revision date
12 Jul 2024
BI trial number
1479-0014
Title of trial
The effect of multiple doses of zongertinib on the single-dose pharmacokinetics of 
midazolam, omeprazole and repaglinide in healthy male subjects (an open-label, 2-
period, fixed-sequence trial)
 Investigator
Trial site
Clinical phase
I
Trial rationale
Based on in-vitro data zongertinib is a potential
as well as a time-dependent inhibitor of CYP3A4. Additionally, 
zongertinib may exhibit inductive effects on the three enzymes as well. This trial 
aims to investigate the in-vivo effect of zongertinib on the activity of CYP3A4, 
CYP2C8 and CYP2C19 using the recommended in-vivo probes midazolam (for 
CYP3A4), repaglinide (for CYP2C8) and omeprazole (for CYP2C19).
Trial objective
To assess the effect of multiple oral doses of zongertinib on the pharmacokinetics of 
midazolam, omeprazole and repaglinide.
Trial endpoints
Primary endpoints: AUC0-and Cmax of midazolam, omeprazole and repaglinide
Secondary endpoints: AUC0-tz of midazolam, omeprazole and repaglinide
Trial design
Non-randomised, open-label, 2-period, fixed-sequence trial 
Number of subjects 
total entered
16
on each treatment
16
Diagnosis
Not applicable
Main inclusion criteria
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)
Trial product 1
zongertinib, 60 mg film-coated tablets
dose
1 x 2 tablets (=120 mg zongertinib) qd for 15 days (in period 2 only)
mode of 
admin.
Oral with 240 mL of water 

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Trial product 2
NovoNorm® 0.5 mg Tabletten 
dose
1 x 1 tablet (= 0.5 mg repaglinide), 1 single dose in period 1 and 2 single doses in 
period 2
mode of admin.
Oral with 240 mL of water 
Trial product 3
Omeprazol STADA® protect 20 mg magensaftresistente Tabletten
dose
1 x 1 tablet (=20 mg omeprazole), 1 single dose in period 1 and 2 single doses in 
period 2
mode of admin.
Oral with 240 mL of water
Trial product 4
Midazolam ratiopharm® 2 mg/ml orale Lösung
dose
1 x 0.5 ml (= 1 mg midazolam), 1 single dose in period 1 and 2 single doses in
period 2
mode of admin.
Oral with 240 mL of water 
Duration of treatment
Treatment Reference 1 (R1):
1 x 1 tablet repaglinide on Day 1 of period 1
Treatment Reference 2 (R2):
1 x 0.5 mL midazolam solution together with 1 x 1 tablet omeprazole on Day 2 of 
period 1
Treatment Test 1 (T1 – investigation of CYP2C8 inhibition):
1 x 1 tablet repaglinide together with 1 x 2 tablets zongertinib on Day 1 of period 2
Treatment Test 2 (T2 – investigation of CYP3A4 & CYP2C19 inhibition):
1 x 0.5 mL midazolam solution together with 1 x 1 tablet of omeprazole and 1 x 2 
tablets zongertinib on Day 2 of period 2 (following predosing with zongertinib on 
Day 1 of period 2) 
Treatment Test 3 (T3 – investigation of CYP2C8 induction):
1 x 1 tablet of repaglinide together with 1 x 2 tablets zongertinib on Day 14 of 
period 2 (following predosing with zongertinib over 13 days)
Treatment Test 4 (T4 – investigation of CYP3A4 and CYP2C19 induction):
1 x 
 midazolam solution together with 1 x 1 tablet of omeprazole and 1 x 2 
tablets zongertinib on Day 15 of period 2 (following predosing with zongertinib 
over 14 days)

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Statistical methods
Relative bioavailability of midazolam, omeprazole and repaglinide will be 
estimated by the ratios of the geometric means (test/reference) for the primary and 
secondary endpoints. Additionally, their two-sided 90% confidence intervals (CIs) 
will be provided. This method corresponds to the two one-sided t-test procedure, 
each at a 5% significance level. Since the main focus is on estimation and not 
testing, a formal hypothesis test and associated acceptance range is not specified. 
The statistical model will be an analysis of variance (ANOVA) on the logarithmic 
scale including effects for ‘subject’ and ‘treatment’. CIs will be calculated based on 
the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.

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FLOW CHART – PERIOD 1 (R1, R2)
Period
Visit
Day
Planned time (relative 
to the first drug intake 
[h:min])
Approximate clock time 
of actual day [h:min]
Event and comment
Safety laboratory11
PK blood
midazolam/omeprazole
PK blood repaglinide
ECG
Vital signs (BP, PR)
Questioning for AEs 
and concomitant 
therapy 6
SCR
1
-21 to -2
Screening (SCR)1
A
x
x
Period 1 
2
-1
-12:00
20:00
Admission to trial site7
x5,7
x7
1
-1:00
07:00
Allocation to subject number2
x2
x2
x2
0:00
08:00
Repaglinide dosing
0:15
08:15
x
0:30
08:30
x10
x
0:45
08:45
x
1:00
09:00
x10
x
1:30
09:30
x10
x
2:00
10:00
240 mL fluid intake + snack3
x
x
2:30
10:30
x
3:00
11:00
x
4:00
12:00
240 mL fluid intake, lunch3
x
x
6:00
14:00
x
8:00
16:00
Snack (voluntary)3, all subjects 
together
11:00
19:00
Dinner3, all subjects together
2
24:00
08:00
Midazolam & Omeprazole dosing
x8
x8
x2
x2
24:15
08:15
x
24:30
08:30
x
24:45
08:45
x
25:00
09:00
x
25:30
09:30
x
26:00
10:00
240 mL fluid intake + snack3
x
x
28:00
12:00
240 mL fluid intake, lunch3
x
x
30:00
14:00
x
32:00
16:00
Snack (voluntary)3
x
34:00
18:00
x
35:00
19:00
Dinner3, all subjects together
36:00
20:00
x
x
3
48:00
08:00
Breakfast (voluntary), discharge 
from trial site
x
Wash-out of at least 3 days (following last medication)

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FLOW CHART – PERIOD 2 (T1, T2, T3, T4)
Period
Visit
Day
Planned time (relative to the 
first drug intake [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory11
PK blood
midazolam/omeprazole
PK blood repaglinide
PK blood zongertinib
Liquid biopsy
ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
Period 2 
3
-1
-12:00
20:00
Admission to trial site7
x5,7
x7
1
-01:00
07:00
B2
x2
x2
x2
x2
x2
x2
x2
0:00
08:00
Zongertinib + Repaglinide 
dosing
0:15
08:15
x
0:30
08:30
x10
x
x
0:45
08:45
x
1:00
09:00
x10
x
x
1:30
09:30
x10
x
x
2:00
10:00
240 mL fluid intake + snack3
x
x
x
x
x
2:30
10:30
x
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake, Lunch3
x
x
x
x
x
6:00
14:00
x
x
8:00
16:00
Snack (voluntary)3
x
10:00
18:00
x
11:00
19:00
Dinner3, all subjects together
12:00
20:00
x
x
2
24:00
08:00
Zongertinib + Midazolam + 
Omeprazole dosing
x8
x8
x8
x2
x2
x2
24:15
08:15
x
24:30
08:30
x
24:45
08:45
x
25:00
09:00
x
25:30
09:30
x
26:00
10:00
240 mL fluid intake + snack3
x
x
x
x
28:00
12:00
240 mL fluid intake, Lunch3
x
x
x
x
30:00
14:00
x
32:00
16:00
Snack (voluntary)3
x
34:00
18:00
x
35:00
19:00
Dinner3, all subjects together
36:00
20:00
x
x
3
48:00
08:00
Zongertinib dosing12, 
followed by discharge from 
trial site
x12
x12
x2
x2
4
72:00
08:00
Zongertinib dosing9
B8
x2
5
96:00
08:00
Zongertinib dosing9
x8
x2
x2
x2
6
120:00
08:00
Zongertinib dosing9
x2
7
144:00
08:00
Zongertinib dosing9
B8
x8
x2
8
168:00
08:00
Zongertinib dosing9
x2
9
192:00
08:00
Zongertinib dosing9
x8
x2
10
216:00
08:00
Zongertinib dosing9
B8
x8
x2
x2
x2
11
240:00
08:00
Zongertinib dosing9
x8
x2
12
264:00
08:00
Zongertinib dosing9
x2
13
288:00
08:00
Zongertinib dosing9
B8
x8
x2
300:00
20:00
Admission to trial site7
x5,7
x7

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Period
Visit
Day
Planned time (relative to the 
first drug intake [h:min])
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory11
PK blood
midazolam/omeprazole
PK blood repaglinide
PK blood zongertinib
Liquid biopsy
ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
14
312:00
08:00
Zongertinib + Repaglinide 
dosing
x8
x8
x2
x2
x2
312:15
08:15
x
312:30
08:30
x10
x
x
312:45
08:45
x
313:00
09:00
x10
x
x
313:30
09:30
x10
x
x
314:00
10:00
240 mL fluid intake + snack3
x
x
x
x
x
314:30
10:30
x
x
315:00
11:00
x
x
316:00
12:00
240 mL fluid intake, Lunch3
x
x
x
x
x
318:00
14:00
x
x
320:00
16:00
Snack (voluntary)3
x
322:00
18:00
x
323:00
19:00
Dinner3, all subjects together
324:00
20:00
x
x
15
336:00
08:00
Zongertinib + Midazolam + 
Omeprazole dosing
B2
x8
x8
x8
x2
x2
x2
x2
x2
336:15
08:15
x
336:30
08:30
x
336:45
08:45
x
337:00
09:00
x
337:30
09:30
x
338:00
10:00
240 mL fluid intake + snack3
x
x
x
x
340:00
12:00
240 mL fluid intake, Lunch3
x
x
x
x
342:00
14:00
x
344:00
16:00
Snack (voluntary)3
x
346:00
18:00
x
347:00
19:00
Dinner3, all subjects together
348:00
20:00
x
x
16
360:00
08:00
Breakfast (voluntary), 
discharge from trial site
x
FU
4
29 
-
50
End of study (EoS) 
Examination4
C
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening), 
demographics (including determination of body height and weight, smoking status and alcohol history), relevant 
medical history, concomitant therapy and review of inclusion/exclusion criteria. Pharmacogenetic samples will be 
collected if needed.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of study (synonym for end of trial), the EoS examination includes physical examination, vital signs, ECG, 
safety laboratory, recording of AEs and concomitant therapies. 
5.
Only urine drug screening and alcohol breath test will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
The time is an approximate. The procedure is to be completed not later than 10 hours prior to drug administration.
8. 
To be performed within 15 min prior to drug dosing

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9.
Subjects are required to be fasted for at least 10 hours prior and 1 hour post planned ambulatory drug administration. In 
addition, the tolerance time for ambulatory dosing in period 2 from Day 4 to Day 13 in Period 2 is ± 2 hours.
10. Bedside glucose test only
11. Letters A, B and C describe different sets of safety laboratory examinations. For details see Section 5.2.3
12. PK samples to be taken on time and zongertinib to be given within 15 minutes afterwards

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART – PERIOD 1 (R1, R2).............................................................5
FLOW CHART – PERIOD 2 (T1, T2, T3, T4)................................................6
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS AND DEFINITIONS..................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................18
1.2.1
Zongertinib............................................................................................18
1.2.1.1
Mode of action.........................................................................18
1.2.1.2
Data from non-clinical studies.................................................18
1.2.1.3
Data from studies in humans....................................................19
1.2.1.4
Data from studies in patients....................................................19
1.2.1.5
Data from studies in healthy volunteers...................................21
1.2.1.6
Clinical Pharmacology.............................................................23
1.2.2
Repaglinide............................................................................................24
1.2.3
Midazolam .............................................................................................25
1.2.4
Omeprazole............................................................................................26
1.2.5
Residual Effect Period..........................................................................26
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................26
1.4
BENEFIT - RISK ASSESSMENT ...................................................................27
1.4.1
Benefits...................................................................................................27
1.4.2
Risks .......................................................................................................27
1.4.3
Discussion...............................................................................................32
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 33
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......33
2.1.1
Main objectives......................................................................................33
2.1.2
Primary endpoint(s)..............................................................................33
2.1.3
Secondary endpoint ..............................................................................33
2.2.2.3
Safety and tolerability..............................................................36
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 37
3.1
OVERALL TRIAL DESIGN............................................................................37

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................38
3.3
SELECTION OF TRIAL POPULATION ......................................................39
3.3.1
Main diagnosis for trial entry..............................................................39
3.3.2
Inclusion criteria...................................................................................39
3.3.3
Exclusion criteria ..................................................................................39
3.3.4
Withdrawal of subjects from treatment or assessments ...................41
3.3.4.1
Withdrawal from trial treatment ..............................................41
3.3.4.2
Withdrawal of consent to trial participation ............................42
3.3.4.3
Discontinuation of the trial by the sponsor..............................42
3.3.5
Replacement of subjects .......................................................................43
4.
TREATMENTS........................................................................................ 44
4.1
INVESTIGATIONAL TREATMENTS ..........................................................44
4.1.1
Identity of the Investigational Medicinal Products ...........................44
4.1.2
Selection of doses in the trial................................................................45
4.1.3
Method of assigning subjects to treatment groups ............................46
4.1.4
Drug assignment and administration of doses for each subject .......46
4.1.5
Blinding and procedures for unblinding ............................................47
4.1.6
Packaging, labelling, and re-supply ....................................................47
4.1.7
Storage conditions.................................................................................48
4.1.8
Drug accountability ..............................................................................48
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................49
4.2.1
Other treatments and emergency procedures....................................49
4.2.2
Restrictions............................................................................................49
4.2.2.1
Restrictions regarding concomitant treatment .........................49
4.2.2.2
Restrictions on diet and life style.............................................49
4.2.2.3
Contraception requirements.....................................................50
4.3
TREATMENT COMPLIANCE.......................................................................50
5.
ASSESSMENTS....................................................................................... 51
5.1
ASSESSMENT OF EFFICACY.......................................................................51
5.2
ASSESSMENT OF SAFETY............................................................................51
5.2.1
Physical examination ............................................................................51
5.2.2
Vital signs...............................................................................................51
5.2.3
Safety laboratory parameters..............................................................51
5.2.4
Electrocardiogram................................................................................54
5.2.5
Other safety parameters.......................................................................54
5.2.5.1
Suicidality assessment .............................................................54
5.2.6
Assessment of adverse events...............................................................54
5.2.6.1
Definitions of adverse events...................................................54

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5.2.6.1.1 Adverse event ............................................................54
5.2.6.1.2 Serious adverse event ................................................55
5.2.6.1.3 AEs considered ‘Always Serious’.............................55
5.2.6.1.4 Adverse events of special interest .............................56
5.2.6.1.5 Intensity (severity) of AEs.........................................56
5.2.6.1.6 Causal relationship of AEs ........................................56
5.2.6.2
Adverse event collection and reporting ...................................57
5.2.6.2.1 AE collection.............................................................57
5.2.6.2.2 AE reporting to the sponsor and timelines ................58
5.2.6.2.3 Pregnancy ..................................................................58
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................59
5.3.1
Assessment of pharmacokinetics .........................................................59
5.3.2
Methods of sample collection...............................................................59
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................59
5.5
BIOBANKING ...................................................................................................62
5.6
OTHER ASSESSMENTS .................................................................................62
5.6.1
Pharmacogenomic evaluation..............................................................62
5.6.2
Liquid Biopsy ........................................................................................62
5.7
APPROPRIATENESS OF MEASUREMENTS.............................................63
6.
INVESTIGATIONAL PLAN.................................................................. 64
6.1
VISIT SCHEDULE............................................................................................64
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................64
6.2.1
Screening period....................................................................................64
6.2.2
Treatment period(s)..............................................................................64
6.2.3
Follow-up period and trial completion ...............................................65
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 66

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7.1
NULL AND ALTERNATIVE HYPOTHESES ..............................................66
7.2
PLANNED ANALYSES....................................................................................66
7.2.1
General considerations.........................................................................66
7.2.1.1
Analysis sets.............................................................................66
7.2.1.2
Pharmacokinetics.....................................................................66
7.2.1.3
Biomarkers...............................................................................67
7.2.2
Primary endpoint analyses...................................................................68
7.2.3
Secondary endpoint analyses ...............................................................68
7.2.5
Safety analyses.......................................................................................69
7.2.6
Interim analyses ....................................................................................70
7.3
HANDLING OF MISSING DATA ..................................................................70
7.3.1
Safety......................................................................................................70
7.3.2
Pharmacokinetics..................................................................................70
7.4
RANDOMISATION ..........................................................................................70
7.5
DETERMINATION OF SAMPLE SIZE ........................................................71
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 73
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................73
8.2
DATA QUALITY ASSURANCE .....................................................................74
8.3
RECORDS..........................................................................................................74
8.3.1
Source documents .................................................................................74
8.3.2
Direct access to source data and documents.......................................75
8.3.3
Storage period of records.....................................................................76
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................76
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......76
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................76
8.6
TRIAL MILESTONES .....................................................................................77
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................77
9.
REFERENCES......................................................................................... 79
9.1
PUBLISHED REFERENCES...........................................................................79
9.2
UNPUBLISHED REFERENCES.....................................................................82
10. APPENDICES .......................................................................................... 83

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11. DESCRIPTION OF GLOBAL AMENDMENT................................... 84
11.1
GLOBAL AMENDMENT 1 .............................................................................84
11.2
GLOBAL AMENDMENT 2 .............................................................................86
11.3
GLOBAL AMENDMENT 3 .............................................................................88

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ABBREVIATIONS AND DEFINITIONS
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AESI
Adverse events of special interest
AMP
Auxiliary Medicinal Product
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
%AUCtz-∞
Percentage of AUC0-∞obtained by extrapolation
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at 
steady state over a uniform dosing interval τ
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EoS
End of Study (synonym for End of Trial)

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EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FAS
Full Analysis Set
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastro-intestinal
gMean
Geometric mean
HPC
Human Pharmacology Centre
HR
Heart rate
IB
Investigator’s brochure
IEC
Independent Ethics Committee
iPD
Important protocol deviation
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRT,po
Mean residence time of the analyte in the body after oral administration
MRT,po,ss
Mean residence time of the analyte at steady state in the body after oral 
administration
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
PTF
Peak-trough fluctuation
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
QT interval corrected for heart rate, e.g. using the method of Fridericia 
(QTcF) or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics

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SOP
Standard operating procedure
ss
(at) steady state
T
Test product or treatment
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma
TS
Treated set
tz
Time of last measurable concentration of the analyte in plasma
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
Vss
Apparent volume of distribution at steady state after intravascular 
administration
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration

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1.
INTRODUCTION
This trial investigates the in-vivo effect of  zongertinib on the activity of CYP3A4, CYP2C8
and CYP2C19 using the recommended in-vivo probes midazolam (for CYP3A4), repaglinide 
(for CYP2C8) and omeprazole (for CYP2C19).
1.1
MEDICAL BACKGROUND
Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor 
receptor (EGFR) family of homologous transmembrane receptor tyrosine kinases. The family 
of ErbB transmembrane receptor tyrosine kinases (RTKs) consists of the four members EGFR 
(ErbB1), HER2 (Neu, ErbB2), HER3 (ErbB3) and HER4 (ErbB4), which fulfil essential 
functions during development [R20-1872, R09-6185, R20-1990]. ErbB signalling is initiated 
upon binding of the extracellular domains of EGFR, HER3 or HER4 to their respective ligands 
and subsequent homo- or heterodimerization of ErbB family members. HER2, for which no 
ligand has been identified, is the preferred dimerization partner for the other ErbB members. 
Once an active ligand-receptor complex has been formed, the intracellular tyrosine kinase 
domains of EGFR, HER2 or HER4 are activated by auto- or transphosphorylation and 
subsequently elicit a signal transduction cascade most notably engaging the mitogen-activated 
protein kinase and/or the phosphoinositide 3-kinase pathways [R20-1872, R09-6185, R20-
1990].
Aberrant ErbB signalling is implicated in several pathophysiological conditions including 
cancer or neurological diseases. In cancer, ErbB signalling is hyper-activated through 
mutations that render the RTK constitutively active by promoting dimerization or shifting the 
equilibrium towards the active conformer of the kinase and/or through amplification and 
consequent over-expression of the RTK. Both oncogenic mechanisms increase the net output 
of ErbB signalling and thereby promote cell survival, cell growth and proliferation [ P15-
01211].
More recently, increasing attention has been given to the emerging impact of oncogenic HER2 
activation through somatic gene mutation. The majority of these HER2 mutant cancers have 
not been associated with concurrent HER2 gene amplification. Mutations are found across all 
exons of the HER2 gene including exon 20, with significant heterogeneity both between and 
within human cancer types. The highest prevalence of HER2 mutations is observed in prostate 
neuroendocrine cancer, metastatic cutaneous squamous cell carcinoma, and bladder cancer (all 
>10% of cases). A significant HER2 mutation prevalence is also found in more common 
cancers, including lung, colorectal and breast cancers, indicating a large additional patient base 
that could potentially be targeted with HER2-directed therapies [P19-10412].
Mutations in HER2 have been identified as oncogenic drivers and occur in 2 to 3% of non-
small cell lung cancer (NSCLC). HER2 mutations most commonly consist of a 12 base pair in-
frame insertion YVMA (p.A775_G776insYVMA) in exon 20 [ P19-00456, P20-09250].There 
is no standard targeted treatment for NSCLC with HER2 aberrations including HER2 exon 20 
insertion mutations. Clinically approved tyrosine kinase inhibitors have not been shown to be 
efficacious in these patients, as they are limited by EGFR wild type mediated dose limiting 

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toxicity. Therefore there is a clear unmet medical need for new treatment options for NSCLC 
patients with HER2 insertion mutations.
1.2
DRUG PROFILE
For a more detailed description of the zongertinib profile, please refer to the current version of 
the Investigator’s Brochure (IB) [c32836122] and for midazolam, repaglinide and omeprazole 
to the respective SmPCs [R20-1699 + R24-2815 + R24-0703]
1.2.1
Zongertinib
1.2.1.1
Mode of action
Zongertinib is an EGFR wild type sparing, selective HER2 inhibitor with potent inhibitory 
activity on all major HER2 mutations including the HER2 YVMA insertion allele. It is intended 
to treat patients with advanced solid tumors with HER2 aberrations.
1.2.1.2
Data from non-clinical studies

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1.2.1.3
Data from studies in humans
Prior to the current trial, zongertinib was administered in the ongoing first-in-man trial in 
patients with cancer 1479-0001 and in five PK studies in healthy volunteers (trial 1479-0003,
1479-0004, 1479-0006, 1479-0010, 1479-0011). A short summary of the trials and drug-related 
adverse events in these trials is provided here. For details on PK, safety, and efficacy refer to 
the current version of the IB [c32836122].
1.2.1.4
Data from studies in patients 
Short description of patient first-in-man trial 1479-0001
1479-0001 is an open-label, Phase I dose escalation trial, with dose confirmation and 
expansion, of zongertinib as monotherapy in patients with advanced or metastatic solid tumors 
with HER2 aberrations. Patients are continuously treated in different dose groups with 
 
 PK, safety, and efficacy data are collected. Patients were treated in the 
dose escalation phase with escalating doses of zongertinib
 administered using 
either 
 
 as well as in the dose expansion phase with 
 
 Overall, the median treatment duration was 147 days and the exposure ranged 
from 1 to 568 days during the dose escalation at data cut-off; during the dose expansion, the 
median treatment duration was 
 and the exposure 
. Data cut 
time point for the data described 
. For further information also refer to the 
current version of the IB [c32836122].

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Preliminary safety and tolerability data of patient first-in-man trial 1479-0001
Overall, zongertinib was well tolerated in patients in trial 1479-0001 and the majority of drug-
related AEs was manageable. The MTD has not been reached in both treatment schedules. AEs 
leading to dose reductions, treatment interruptions, and treatment discontinuations were 
infrequent. During dose escalation, the most frequent AEs were diarrhoea (24 patients, 39.3%), 
followed by anaemia (13 patients, 21.3%), ALT increased (11 patients, 18.0%), AST increased 
(11 patients, 18.0%), blood alkaline phosphatase increased (10 patients, 16.4%), blood 
creatinine increased (10 patients, 16.4%) and COVID-19 (7 patients, 11.5%). Dose limiting 
toxicities during the MTD evaluation period were diarrhoea Grade 3 (
 and 
platelet count decreased Grade 3 
). In total, 25 (41%) patients had an SAE, with 
1 patient (1.6%) having SAEs that were considered drug-related by the investigator (Grade 3 
ALT increased and Grade 3 AST increased). Reported fatal AEs were not drug-related.
During dose expansion, most frequent AEs were diarrhoea (28 patients, 35.4%), anaemia (15 
patients, 19%), ALT increased (10 patients, 12.7%), AST increased (10 patients, 12.7%), 
decreased appetite (9 patients, 11.4%), lymphocyte count decreased (9 patients, 11.4%) and 
dysgeusia (8 patients, 10, 1%). Dose limiting toxicities during the MTD evaluation period were 
diarrhoea Grade 3, febrile neutropenia Grade 3 and immune thrombocytopenia Grade 4 (
 
 SAEs were reported in 9 (11.4%) of patients. SAEs assessed as drug-related by 
the investigator occurred in 5 patients (6.3%). These were ALT increased and AST increased 
(in 2 patients each, 2.5%), as well as hepatic failure, immune thrombocytopenia, intestinal 
obstruction and neutrophil count decreased (in 1patient each, 1.3%). Reported fatal AEs were 
not drug-related. For further information also refer to the current version of the IB [c32836122].
Hepatotoxicity
Elevations of liver enzymes and bilirubin have been reported during treatment with zongertinib 
in trial 1479-0001. AEs in the SMQ liver related investigations, signs and symptoms occurred 
in 20 patients (32.8%) during dose escalation and in 19 patients (24.1%) during dose expansion. 
During dose escalation, liver related investigations were Grade 3 in 6 patients (9.8%) and 
during dose expansion, Grade 3 or 4 in 2 patients (2.5%) each. First onset of the liver related 
investigations was within 30 days in 13 patients (21.3%) during dose escalation and in 16 
patients (20.3%) during dose expansion. During dose escalation, liver related investigations led 
to interruption of trial medication in 5 patients (8.2%) and to permanent treatment 
discontinuation or dose reduction in 1 patient each (1.6%). During dose expansion, liver related 
investigations led to dose reduction or treatment interruption in 2 patients (2.8%) each. Two 
cases of severe hepatic AEs have been reported.
A patient had occasional right hypochondrium pain, choluria, progressive jaundice, and 
diarrhoea starting on Day 36 of treatment with 240 mg zongertinib QD. One week later the 
patient was admitted to the hospital with hepatic failure and prolonged prothrombin time. 
During hospitalisation, study medication was interrupted, and the patient was treated with N-
acetylcysteine and methylprednisolone over 7 days. After discharge from the hospital treatment 
continued with 50 mg prednisolone. The patient was recovering and restarted study drug on 
Day 63 at reduced dose of 180 mg QD. Liver enzymes and bilirubin were further normalising. 
The patient had COVID-19 infection and was treated with Remdisivir starting on Day 25 of 
study treatment as possible confounding factors.

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A second patient who was treated with 240 mg zongertinib QD over 42 days developed, despite 
interruption of study drug due to ALT, AST Grade 2 and total bilirubin Grade 1, further 
increases of ALT and AST up to Grade 4 (>20.0x ULN), increased total bilirubin up to Grade 
3 (>3x ULN), and coagulopathy Grade 3 on Day 55. On Day 57, the patient had developed 
subacute hepatic failure Grade 4, cholestasis Grade 4 and hypoalbuminaemia Grade 2. 
Treatment of the AEs included hepatoprotective and anticholestatic agents as well as 
dexamethasone. Liver enzymes and total bilirubin were improving between Days 66 and 76. 
During the further course the patient developed infection (on Day 81) and subsequent sepsis 
(on Day 86) with fatal outcome 7 days later. Further evaluations are ongoing. For further 
information also refer to the current version of the IB [c32836122].
Diarrhoea
Diarrhoea was reported during treatment with zongertinib and was of mainly of Grade 1 and 2. 
Diarrhoea occurred in 24 patients (39.3%) during dose escalation and in 28 patients (35.4%) 
during dose expansion. Diarrhoea was Grade 3, in 3 patients (4.9%) during dose escalation, 
and in 2 patients (2.5%) during dose expansion. Due to observed long-lasting periods in some 
patients, a proactive management of diarrhoea including adequate hydration combined with 
anti-diarrhoeal agents should start at first signs of diarrhoea. For further information also refer 
to the current version of the IB [c32836122].
1.2.1.5
Data from studies in healthy volunteers 
Safety and tolerability data of healthy volunteer trial 1479-0003
Trial 1479-0003 was an open-label, randomized, 4-way crossover Phase I trial. The trial 
investigated relative bioavailability of zongertinib after administration as two different 
formulations (trial formulation 1 [TF1] and new formulation [NF]). Additionally, the trial
investigated the food effect on the pharmacokinetics of a single dose of zongertinib in plasma
and investigated the effect of multiple-dose treatment with rabeprazole on the 
pharmacokinetics of a single dose of zongertinib. Thirteen healthy male volunteers were dosed 
with single doses of 30 mg zongertinib in 4 treatment periods in randomized order.
In trial 1479-0003 there were no SAEs, no adverse events of special interest (AESI), and no 
other significant AEs. All AEs were of CTCAE Grade 1 or 2 severity, and none of the AEs 
were assessed as drug-related. Available safety data including AEs, Electrocardiogram 
(ECGs), VS, and safety laboratory indicate that single doses of 30 mg zongertinib were safe 
and well tolerated in trial 1479-0003. For more details refer to the current version of the IB 
[c32836122].
Safety and tolerability data of healthy volunteer trial 1479-0004
In trial 1479-0004, the effect of multiple doses of itraconazole on the pharmacokinetics of a 
single oral dose of zongertinib in 16 healthy male subjects (an open-label, two-period, fixed-
sequence trial) was tested.
There were no deaths, no serious AEs, no CTCAE grade 3, 4, or 5 AEs, and no protocol-
specified AEs of special interest reported. A grade 1 AE of diplopia led to the premature 
discontinuation of itraconazole in 1 subject (6.3%) and was the only significant AE in the trial, 

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according to ICH E3. The event was considered related to trial drug and resolved without 
therapy. Overall, 7 out of 16 subjects (43.8%) while on treatment with zongertinib (with and 
without itraconazole) had drug-related AEs, the most frequent events being diarrhoea (5 
subjects, 31.3%) and headache (2 subjects, 12.5%). All AEs were reported as resolved by the 
end of the trial, except an AE of hand fracture which was not considered related to trial drug. 
No relevant changes in laboratory values, vital signs, or ECGs were reported as AEs. For 
further information also refer to the current version of the IB [c32836122].
Preliminary Safety and tolerability data of healthy volunteer trial 1479-0006
In trial 1479-0006, a phase I, open-label trial in two parallel parts investigated mass balance, 
metabolism, and basic pharmacokinetics of zongertinib (C-14) administered as oral solution 
(part A) and investigated absolute bioavailability of zongertinib administered as film-coated 
tablet together with an intravenous microtracer dose of zongertinib (C-14) (part B) in 15 
healthy male volunteers.
There were no SAEs, no AESIs, and no other significant AEs. All AEs were of CTCAE Grade 
1 severity. In part A and B, only diarrhoea (in 2 HVs) and abdominal pain (all Grade 1) were 
assessed as drug-related. Available safety data including AEs, ECGs, VS, and safety laboratory 
indicate that single doses of 60 mg zongertinib were safe and well tolerated in trial 1479-0006.
For further information also refer to the current version of the IB [c32836122].
Preliminary Safety and tolerability data of healthy volunteer trial 1479-0010
In trial 1479-0010, the relative bioavailability of 240 mg zongertinib following oral 
administration under fed and fasted conditions in 16 healthy male subjects (an open-label, 
randomised, single-dose, two-way crossover trial) was investigated.
There were no SAEs, no AESIs, and no CTCAE grade 3, 4 and 5 AEs. Based on the preliminary 
safety data, 7 drug-related adverse events were reported in this trial (4x headache, 1x nausea, 
1x cough, 1x tiredness). Thus, available safety data including AEs, ECGs, VS, and safety 
laboratory indicate that single doses of 240 mg zongertinib were safe and well tolerated in trial 
1479-0010. For further information also refer to the current version of the IB [c32836122].
Preliminary Safety and tolerability data of healthy volunteer trial 1479-0011
In trial 1479-0011, the effect of multiple doses of carbamazepine on the pharmacokinetics of a 
single oral dose of 60 mg zongertinib was tested in 16 healthy male subjects (an open-label, 
two-period, fixed-sequence trial).
There were no SAEs, no AESIs, and no other significant AEs. All AEs were of CTCAE Grade 
1 severity. During the treatment period with zongertinib alone a case of grade I fatigue was 
reported as the sole drug-related AE (as assessed by the investigator). Available safety data 
including AEs, ECGs, VS, and safety laboratory indicate that single doses of 60 mg zongertinib
were safe and well tolerated in trial 1479-0011. For further information also refer to the current 
version of the IB [c32836122].

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1.2.1.6
Clinical Pharmacology
Preliminary, exploratory PK analysis in trial 1479-0001 indicated 
 
 
(see Table 1.2.1.6: 1). PK analysis of the Phase Ib extension by and large confirmed the data 
obtained in the previous analysis 
 (see Table 1.2.1.6.: 2). 
The observed PK profile of zongertinib appears to 
 to achieve 
efficacious plasma exposure, which is also suggested by the 
 
Table 1.2.1.6: 1
gMean (gCV%) PK parameters of zongertinib after 
 
 in trial 1479-0001 Phase 1a
Treatment (N)
tmax,ss 1
(h)
Cmax,ss
(nM)
AUC,ss
(nM*h)
1
Median (min -max)

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Table 1.2.1.6: 2
gMean (gCV%) PK parameters of 
 
zongertinib dose cohorts after 
 in trial 1479-
0001 Phase Ib 
Treatment (N)
tmax,ss1
(h)
Cmax,ss
(nM)
AUC0-6,ss
(nM*h)
1 Median (min -max)
1.2.2
Repaglinide
Potential inducing and inhibitory effects of zongertinib on CYP2C8 will be investigated using 
the probe substrate repaglinide.
Repaglinide is indicated for therapy of type-2 diabetes mellitus alone or in combination with 
metformin. It is a short-acting stimulator of pancreatic insulin secretion. It causes 
depolarisation of pancreatic beta-cells which, in turn, enhances calcium influx, followed by 
insulin release.
After oral administration, repaglinide is rapidly absorbed with plasma tmax values within one 
hour and an absolute bioavailability of 63%. Volume of distribution is low (30 L), and plasma 
protein binding is high (>98%). Repaglinide is eliminated within 4-6 hours; plasma t1/2 is 
around one hour. Elimination is principally via metabolism, mainly by CYP2C8 and to a lesser 
extent by CYP3A4 [R20-1699]. The drug transporter OATP1B1 has been shown to contribute 
to hepatocellular uptake of repaglinide [P13-07476]. Both the U.S. Food and Drug 
Administration (FDA) and the European Medicines Agency (EMA) recommend the use of 
repaglinide as in vivo probe drug for CYP2C8 in DDI trials (FDA guidance [R20-2271] and 
EMA guideline [P12-10638]).
Repaglinide should be taken within 30 min before a meal. The recommended initial dose of 
repaglinide is 0.5 mg, the recommended maximal single dose is 4 mg, and the recommended 
maximal daily dose is 16 mg [ R20-1699].
The most frequent side effect of repaglinide is hypoglycaemia. Niemi et al. reported a clinical 
trial in 12 healthy volunteers that were dosed with repaglinide (0.25 mg single dose followed 
by breakfast, snacks and a meal within 3 h after repaglinide dosing) with or without 
concomitant treatment with gemfibrozil, itraconazole, or both. Concomitant treatment with 
both gemfibrozil and itraconazole increased repaglinide AUC and Cmax by 19.4- and 2.8-fold 
and prolonged repaglinide t1/2 from 1.3 to 6.1 h [R14-3624]. In this trial, gemfibrozil and 
itraconazole enhanced and prolonged the effects of repaglinide on blood glucose 
concentrations, and two subjects required carbohydrate supplementation because of 
symptomatic hypoglycemia. In another trial in 24 healthy volunteers, 4 mg repaglinide was 
given with or without concomitant administration of flucloxacillin in the morning as oral single 
dose in fasted state followed by fasting for another 3 h [R14-3583]. Administration of 
repaglinide was followed by a decrease in plasma glucose concentrations (with plasma glucose 
concentrations in the range of 3.26-5.61 mM), but no symptoms of hypoglycemia were 
reported. In another trial in 29 healthy volunteers, oral single doses of 2 mg repaglinide were 

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administered after a 9 h fasting period and followed by a 6 h fasting period after repaglinide 
dosing [R14-3626]. In this trial, transient symptoms of hypoglycaemia such as dizziness, 
sweating, and tremor were observed but quickly disappeared after administration of apple juice. 
Otherwise repaglinide was well tolerated.
Repaglinide may be given to healthy subjects at fasted state, before a breakfast, or with sugar-
containing drinks (e.g., apple juice or glucose-water solution). However, intake of
carbohydrate-containing solution may relevantly slow gastric emptying and could therefore
affect repaglinide oral absorption. Therefore repaglinide will be administered at fasted state in 
this trial. In order to prevent hypoglycemic episodes, carbohydrate-containing snacks will be
handed out two hours after repaglinide intake. Moreover, to allow for timely detection of
hypoglycaemic episodes and in order to ensure subject safety, blood glucose will be determined 
in 30 minute intervals until the subjects receive a carbohydrate-containing snack 2 hours after 
dosing (see Flow Chart). Additionally, subjects are hospitalized at the trial site and are under 
close medical surveillance for at least 12 hours after dosing with repaglinide. In addition, 
subjects are frequently asked for AEs after repaglinide. In case of clinical signs of 
hypoglycemia or blood glucose concentrations below 45 mg/dL (<2.5 mmol/L), oral glucose 
will be administered (see Section 4.2.1).
For further details see the current version of SmPC for repaglinide (R20-1699).
1.2.3
Midazolam
Potential inducing and inhibitory effects of zongertinib on CYP3A4 will be investigated using 
the probe substrate midazolam.
Midazolam is a short acting benzodiazepine which is used for the treatment of insomnia and as 
sedative premedication before surgical or diagnostic procedures. It has a volume of distribution 
of 0.7 to 1.2 L/kg at steady state. Its elimination half-life in young healthy volunteers ranges 
from 1.5 to 2.5 hours. The plasma clearance was determined to be 300 to 500 mL/min. 
Midazolam is almost completely eliminated by biotransformation to 1-hydroxymidazolam, and 
this process is mediated by CYP3A enzymes [R19-1961, R06-0294]. In contrast to testosterone 
or erythromycin, which have also been proposed as probes to monitor CYP3A activity, 
midazolam is metabolised specifically by CYP3A, and does not serve as a substrate for other 
CYP450 isoenzymes or the drug transporter P-glycoprotein (P-gp). Intravenous midazolam is 
a sensitive in vivo probe of hepatic CYP3A activity, whereas orally-administered midazolam 
is metabolised by both intestinal and hepatic CYP3A.
The administration of an oral dose of 1 mg midazolam is without a major sedative effect [ P10-
00100]. The therapeutic dose of midazolam is 7.5 mg to 15 mg. Thus, the chosen dose of 1 mg
provides a sufficient safety margin. The subjects will be kept in-house at the trial site for 24
hours after dosing, covering the tmax and more than 5 half-lives of midazolam.
For further details see the current version of SmPC for midazolam (R24-0703).

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1.2.4
Omeprazole
Potential inducing and inhibitory effects of zongertinib on CYP2C19 activity will be 
investigated using the probe substrate omeprazole.
Omeprazole is a proton pump inhibitor applied to treat ulcers, heartburn, gastroesophageal
reflux, and Zollinger-Ellison syndrome [R24-0704, R24-2815]. The formation of 5-
hydroxyomeprazole, the major primary metabolite of omeprazole, is dependent on CYP2C19 
activity. In addition, omeprazole is metabolised by CYP3A to omeprazole sulphone. Since the 
affinity of omeprazole to CYP2C19 is 10 times higher than to CYP3A, omeprazole interferes 
with the metabolism of substrates for CYP2C19 but not of substrates for CYP3A [P96-3991].
Omeprazole has a small volume of distribution (0.3 L/kg). The plasma half-life is 
approximately 40 min. Plasma clearance was determined to be 0.3 to 0.6 L/min.
The therapeutic standard dose of omeprazole is 20 mg to 40 mg daily. In the treatment of 
Zollinger-Ellison syndrome, daily doses of up to 80 mg may be required. Omeprazole has a 
large therapeutic window. Fluvoxamin, a potent inhibitor of CYP2C19, caused a 4.5 fold 
increase of omeprazole exposure in healthy subjects (P14-11944). No side effects attributed to 
the intake of omeprazole have been reported by the authors. Similar to the trial described 
herein, a dose of 20 mg omeprazole was utilized.
For further details see the current version of SmPC for omeprazole (R24-2815).
1.2.5
Residual Effect Period
The Residual Effect Period (REP) of zongertinib is conservatively estimated as 14 days. This 
is the period after the last dose during which measurable drug levels and/or pharmacodynamic 
effects are still likely to be present.
The REP for omeprazole is 48 hours, the REP for repaglinide is 12 hours, the REP for 
midazolam is 24 hours.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Drug-drug interactions (DDI) are complex and have proven to be a major challenge for health 
care providers. One of the questions that must be addressed before new drugs can be safely 
administered is whether there is a drug interaction with other medications taken by the patient 
for the treatment of co-morbidities. Therefore, the interaction potential of a new compound is 
regularly evaluated during clinical drug development. 
 
 
 
Therefore, this trial is aimed to investigate the in-vivo effect of zongertinib on the activity of 
CYP3A4, CYP2C8 and CYP2C19 using the in-vivo probe drugs midazolam (for CYP3A4), 
repaglinide (for CYP2C8) and omeprazole (for CYP2C19) recommended by both the FDA and 
EMA as sensitive substrates for the respective CYP enzymes.

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1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. Their 
participation, however, is of major importance for the development of zongertinib for treatment 
of patients with advanced solid tumours with HER2 aberrations.
1.4.2
Risks
Subjects are exposed to risks of trial procedures and risks related to the exposure to the trial 
medications. An overview of trial-related risks is given in Table 1.4.2: 1.
Table 1.4.2: 1
Overview of trial-related risks for this trial
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: zongertinib (BI 1810631)
Drug-induced liver injury 
(DILI)
Rare but can be a potentially 
severe event, thus under 
constant surveillance by 
sponsors and regulators for 
all drugs in development.
Elevations of liver enzymes 
and bilirubin and other 
hepatic AEs have been 
reported during treatment 
with zongertinib in trial 1479-
0001. AEs in the SMQ liver 
related investigations, signs 
and symptoms occurred in 20 
patients (32.8%) during dose 
escalation and in 19 patients
(24.1%) during dose 
expansion. This included AEs 
≥ Grade 3, treatment 
interruptions, dose reductions 
and permanent 
discontinuations of trial 
medication. First onset of the 
liver related investigations 
was within 30 days in around 
20% of patients. For further 
details see Section 1.2.
Short treatment duration (15 days) 
makes the occurrence of liver injury 
unlikely. In addition, timely 
detection, evaluation, and follow-up 
of liver function tests (laboratory 
parameters) are in place to ensure 
subjects´ safety.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Intestinal toxicity
Reversible intestinal effects 
in dogs after multiple dosing 
(fecal alterations, Goblet cell 
hyperplasia) [c32836122].
Reported diarrhoea during 
treatment with zongertinib in 
trial 1479-0001, was mainly 
of Grade 1 and 2. Grade 3
diarrhoea occurred in few 
patients (see Section 1.2).
AE questioning (see Flow Chart)
Instruction of subjects to report
AEs spontaneously
Discontinuation of subject if 
diarrhoea CTCAE Grade 3 or 
higher.
Implementation of a sentinel 
cohort of max. 4 subjects to 
undergo treatment with
zongertinib prior to main cohort.
QT prolongation
Preclinical data indicate a low
proarrhythmic potential of 
zongertinib. In trial 
1479.0001, ECG QT 
prolongation was reported as 
AE in 3 patients (4.9%) 
during dose escalation and in 
no patient during dose 
expansion. The reported AEs 
were of Grade 1 and 2 [
c40238724].
Subjects with a marked QTc 
prolongation at baseline are 
excluded from participation in this 
trial (see exclusion criterion 21).
Subjects with a history of risk 
factors for Torsade de Pointes are 
excluded from participation in this 
trial (see exclusion criterion 22).
ECGs will be performed as 
defined in the Flow Chart.
Mucositis
Lesions of oral mucosa 
observed in dog toxicology 
and general pharmacology 
studies [c32836122].
Stomatitis/mouth ulceration 
cases of Grade 1 and 2 were 
observed in patients in trial 
1479-0001.
AE questioning (see Flow Chart)
Instruction of subjects to report
AEs spontaneously
Dysgeusia
Reported dysgeusia during 
treatment with zongertinib in 
trial 1479-0001, was mainly 
of Grade 1 and 2. Dysgeusia 
was reported as AE in 11 
patients (7.9%) during dose 
escalation and dose expansion
(c42938800).
AE questioning (see Flow Chart)
Instruction of subjects to report
AEs spontaneously
Implementation of a sentinel 
cohort of max. 4 subjects to 
undergo treatment with 
zongertinib prior to main cohort.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Reproductive and 
developmental toxicity
Embryo-fetal toxicity was 
observed in dose-range 
finding study in rats
[c32836122]. Through the 
ejaculate, zongertinib could 
potentially be transferred to a 
female partner of the male 
patient, be vaginally absorbed 
and could thus potentially 
harm the fetus.
Volunteers will, together with
their WOCBP (woman of 
childbearing potential) partner, 
use highly effective contraception 
from first dosing of zongertinib
until 30 days after the last dosing 
with zongertinib (see also 
exclusion criteria in Section 3.3.3)
Toxicity to adrenal glands
Reversible changes to adrenal 
glands in rats after multiple 
dosing (increased organ 
weights, vacuolation, 
minimal single cell necrosis, 
hypertrophy of zona 
fasciculata/ reticularis)
[c32836122]. Reversible
changes to adrenal glands in 
dogs after multiple dosing
(hyperplasia of zona 
glomerulosa) [c32836122].
Thus far, no adrenal glands 
disorder cases were reported 
in trial 1479-0001.
Safety laboratory (see Section
5.2.3) includes serum electrolytes
Implementation of a sentinel 
cohort of max. 4 subjects to 
undergo treatment with 
zongertinib prior to main cohort.
Hair discoloration
Yellow hair discoloration 
with indication for 
reversibility in rats and dogs 
[c32836122].
Thus far, no cases of hair
discoloration reported in trial 
1479-0001.
AE questioning (see Flow Chart)
Instruction of subjects to report 
AEs spontaneously
Physical examination of subjects 
at end-of-study visit
Implementation of a sentinel 
cohort of max. 4 subjects to 
undergo treatment with 
zongertinib prior to main cohort.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
LVEF decrease
Risk is due to limited clinical 
experience with this drug and 
considering the potential 
effect of the other HER2 
targeted agents on heart 
function.
In trial 1479-0001, ejection 
fraction decreased was 
reported in one patient each 
during dose escalation (1.6%) 
and dose expansion (1.3%). 
The AEs were Grade 2 and 
occurred at dose levels 240 
mg qd and 300 mg qd) [
c40238724].
Only healthy volunteers will be
included in the trial.
ECGs will be performed as 
defined in the Flow Chart
Implementation of a sentinel 
cohort of max. 4 subjects to 
undergo treatment with 
zongertinib prior to main cohort.
Interstitial Lung Disease 
(ILD) and Pneumonitis
Thus far no ILD cases were 
observed in trial 1479-0001; 
however, ILD has been 
reported with other TKIs
inhibiting Her2 or EGFR
AE questioning (see Flow Chart)
Instruction of subjects to report
AEs spontaneously
Implementation of a sentinel 
cohort of max. 4 subjects to 
undergo treatment with 
zongertinib prior to main cohort.
Uncertainties due to the 
early stage of development
Comparatively very high
plasma exposures were 
explored in humans (see 
current version of the IB 
[c32836122]) and showed a 
well tolerable and
manageable safety profile so
far (see Section 1.2.2 and 
current versoion of the IB 
[c32836122]). However,
zongertinib is currently in 
early development and there 
may be unknown risks of 
treatment with zongertinib.
AE questioning (see Flow Chart)
Instruction of subjects to report
AEs spontaneously
Monitoring of safety laboratories, 
vital signs and ECGs during 
dosing (see Flow Chart)
Implementation of a sentinel 
cohort of max. 4 subjects to 
undergo treatment with 
zongertinib prior to main cohort.

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Table 1.4.2: 1
Overview of trial-related risks for this trial (cont.)
Possible or known risks of 
clinical relevance 
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product: repaglinide
Hypoglycemia
Increased insulin release from 
pancreatic β-cells and 
subsequent decrease in blood 
glucose concentrations
(pharmacodynamic effect).
AE questioning (see Flow Chart)
Instruction of subjects to report
AEs spontaneously
Glucose testing 30, 60 and 90 
minutes post repaglinide dosing
Mandatory snack 120 minutes 
post repaglinide dosing
Investigational Medicinal Product: midazolam
Sedation
Enhanced effect of the 
neurotransmitter GABA on
GABAA receptors resulting in 
neural inhibition and 
subsequent sedation 
(pharmacodynamic effect)
AE questioning (see Flow Chart)
Instruction of subjects to report
AEs spontaneously
Subjects are confined to in-house 
stay at trial site and remain under 
close observation for at least 24
hours following midazolam 
administration.
Low dose of midazolam of 1mg 
(recommended dose for clinical 
use: 7.5 – 15mg)
Investigational Medicinal Product: omeprazole
None
Trial procedures
Bruising and, in rare 
cases, phlebitis, or nerve 
injury, potentially 
resulting in paraesthesia, 
reduced sensibility, and/or 
pain 
General risk by venipuncture
for blood sampling,
acceptable in the framework 
of trial participation.
Medical expertise of the trial site 
The total volume of blood withdrawn per subject during the entire trial will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.

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1.4.3
Discussion
There is significant unmet medical need in cancer patients harbouring HER2 mutations for 
effective, safe and well-tolerated therapies. zongertinib is an EGFR wild-type sparing selective 
HER2 inhibitor with potent inhibitory activity on all major HER2 mutations. It provides a 
unique opportunity for the treatment of NSCLC patients harbouring HER2 mutations, and data 
further suggest that zongertinib could be efficacious in all HER2-dependent cancers.
Zongertinib has been adequately characterized in preclinical studies and identified toxicities 
are addressed by appropriate mitigation (see section 1.4.2.). Moreover, data from 6 clinical 
trials are available (see section 1.2.1) that support multiple dosing of zongertinib as planned 
for the current trial. In particular, zongertinib has been administered at multiple doses of up to 
360 mg q.d. and of up to 150 mg b.i.d. to patients in first-in-man trial 1479-0001. Furthermore, 
zongertinib has been administered to 66 healthy volunteers thus far with an acceptable safety 
profile. Specifically, 16 healthy volunteers received a single dose of 240 mg as part of the food-
effect trial 1479-0010 (see section 1.2.1). Based on the preliminary safety data, 7 drug-related 
adverse events were reported in this trial (4x headache, 1x nausea, 1x cough, 1x tiredness) and 
all reported adverse events were of CTCAE grade 1 and 2.
Overall, in both patients and healthy volunteers, zongertinib showed acceptable safety and 
tolerability and reported AEs were manageable in the context of the respective trial.
The current study is necessary to support the development of zongertinib: The trial investigates 
the effect of zongertinib on the activity of CYP3A4, CYP2C8 and CYP2C19 in vivo. The data 
of this trial are required for an in-depth understanding of the pharmacokinetics of zongertinib. 
Considering the unmet medical need for an effective and safe treatment of solid tumours with 
HER2 mutations, the benefit of this trial is assessed to outweigh the potential risks.

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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to assess the influence of multiple doses of zongertinib on 
single dose kinetics of cytochrome P450 (CYP) probe substrates, as a means of predicting drug-
drug interactions. These probe drug substrates are midazolam (for CYP3A4), repaglinide (for 
CYP2C8) and omeprazole (for CYP2C19).
2.1.2
Primary endpoint(s)
The following pharmacokinetic parameters will be determined for the probe drugs
midazolam, repaglinide and omeprazole:

AUC0-(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for the probe drugs midazolam, 
repaglinide and omeprazole:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 to the last quantifiable data point)

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2.2.2.3
Safety and tolerability
Safety and tolerability of zongertinib and probe drugs will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN
This trial is designed to assess the effects of zongertinib on the activity of CYP3A4, CYP2C8 
and CYP2C19 by utilizing specific probe drugs for the three CYP enzymes. The trial will assess 
the immediate inhibitory effects of zongertinib on CYP3A4 (probe drug: midazolam), CYP2C8 
(probe drug: repaglinide) and CYP2C19 (probe drug: omeprazole) as well as the long-term 
inducing effects of zongertinib on the three CYP enzymes after achievement of steady-state 
levels of zongertinib and adaptation of CYP enzyme levels. Of note, the effects of zongertinib 
on CYP3A4 and CYP2C19 will be examined in a cocktail approach, i.e. midazolam (as a probe 
substrate for CYP3A4) and omeprazole (as a probe substrate for CYP2C19) will be 
administered simultaneously. Both drugs are part of the well-established 
 probe 
cocktail (P10-00100). The cocktail approach is especially valuable for drugs that may affect 
more than one metabolic pathway as it reduces the number of subjects required to attain 
valuable information on drug-drug-interactions [P04-02212]. In these cases the performance 
of cocktail studies is accepted by regulatory authorities (R20-2271 ; P12-10638).
Since the interaction potential of the components of the CYP cocktail and repaglinide has not 
yet been established, the administration of repaglinide is scheduled 24 hours prior to dosing of 
the two cocktail drugs (midazolam and omeprazole). Due to the short half-life of repaglinide 
(t1/2 = approx. 1 hour), no specific wash-out period above and beyond 24 hours is required.
The trial will be performed as an open-label, two-period fixed sequence design trial in healthy 
male subjects enrolled at a single site. Sixteen subjects will receive the following oral 
treatments (for details, refer to Section 4.1.).
Reference Treatments

R1: 0.5 mg of repaglinide in the morning of Day 1 of Visit 2

R2: 1 mg of midazolam and 20 mg of omeprazole in the morning of Day 2 of Visit 2
Test Treatments

T1 120 mg of zongertinib, 0.5 mg of repaglinide in the morning of Day 1 of Visit 3

T2: 120 mg of zongertinib, 1 mg of midazolam and 20 mg of omeprazole in the morning 
of Day 2 of Visit 3 (following predosing with zongertinib on Day 1 of period 2)

T3: 120 mg of zongertinib, 0.5 mg of repaglinide in the morning of Day 14 of Visit 3
(following predosing with zongertinib over 13 days)

T4: 120 mg of zongertinib, 1 mg of midazolam and 20 mg of omeprazole in the morning 
of Day 15 of Visit 3 (following predosing of zongertinib over 14 days)
A schematic diagram of the trial design is displayed in Figure 3.1: 1 below.

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Figure 3.1: 1
Trial design
Considering the flexible time frame for screening and follow-up examination the expected total 
trial duration for a single subject is about 10 weeks. The trial population will be divided into at 
least 2 cohorts. The first cohort should not contain more than 4 subjects. The dosing of the 2nd
cohort with zongertinib will start at the earliest when the 1st cohort has completed Visit 3 (i.e.
Period 2). Of note, in Visit 2 (Period 1), all cohorts may be treated together.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule and 
details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For drug-drug interaction trials with pharmacokinetic outcome parameters, the crossover 
design is preferred because of its efficiency: since each subject serves as his own control, the 
comparison between treatments is based on an intra-subject comparison, thus removing inter-
subject variability from the comparison between treatments [R94-1529].
Because of the long half-life of zongertinib, a fixed-sequence design was selected, in which
zongertinib is administered in the second trial period only. The fixed-sequence design is not 
expected to lead to systematic errors in the estimation of the treatment effects since non-
specific time-effects are unlikely due to the short trial duration.
The open-label treatment is not expected to bias results, since the trial endpoints are derived 
from measurement of plasma concentrations of the analytes (PK endpoints).
The dosing duration for zongertinib is
 
Due to the short half-lives of the three probe drugs (t1/2 repaglinide: approx. 1 hour; 

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t1/2 midazolam: 1.5 – 2.5 hours; t1/2 omeprazole: < 1 hour) dosing of zongertinib past Day 15 of 
Period 2 is not considered necessary.
All three probe drugs used in this trial are listed as sensitive in vivo probes for drug-drug 
interaction trials by both the FDA [R20-2271] and EMA [P12-10638].
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 healthy male subjects will enter the trial. They will be recruited from the 
volunteers' pool of the trial site.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF, irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as based on a 
complete medical history including a physical examination, vital signs (BP, PR), 12-lead 
ECG, and clinical laboratory tests
2. Age of 18 to 55 years (inclusive)
3. BMI of 18.5 to 29.9 kg/m2 (inclusive)
4. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) deviating from normal 
and assessed as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range 
of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator

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5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures or 
stroke), and other relevant neurological or psychiatric disorders 
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Relevant chronic or acute infections
10. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
12. Use of drugs (including vaccinations) within 30 days of planned administration of trial 
medication that might reasonably influence the results of the trial (including drugs that 
cause QT/QTc interval prolongation)
13. Intake of an investigational drug in another clinical trial within 60 days of planned 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
14. Use of nelfinavir, gemfibrozil, amprenavir, indinavir, ritonavir, itraconazole or 
ketoconazole within 30 days of planned administration of trial medication.
15. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
16. Inability to refrain from smoking on specified trial days
17. Alcohol abuse (consumption of more 24 g per day)
18. Drug abuse or positive drug screening
19. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
20. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
21. Inability to comply with the dietary regimen of the trial site
22. A marked prolongation of QT/QTc interval (such as QTc intervals that are repeatedly 
greater than 450 ms in males) or any other relevant ECG finding at screening
23. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
24. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the 
subject is not considered able to understand and comply with study requirements, or has a 
condition that would not allow safe participation in the study 

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25. Subjects with WOCBP partner who are unwilling to use highly effective contraception 
from time point of first administration of zongertinib until 30 days after the last 
administration of zongertinib. Highly effective methods of contraception are:
- Subject is sexually abstinent
- Subject is vasectomized (with appropriate post-vasectomy documentation of the absence 
of sperm in the ejaculate) and uses condom
- Use of intrauterine device or intrauterine hormone-releasing system by female partner 
plus use of condom
- Use of progestogen-only hormonal contraception by female partner that inhibits ovulation 
(injectables or implants) plus use of condom
- Use of combined (estrogen and progestogen containing) hormonal contraception by
female partner that prevents ovulation (oral, intravaginal, or transdermal) plus use of
condom
- Bilateral tubal occlusion in the female partner plus use of condom
Sperm donation is not allowed from the time point of first administration of zongertinib 
until 30 days after the last administration of zongertinib
26. ALT (alanine transaminase), AST (aspartate transaminase), or serum creatinine above 
upper limit of normal range at screening examination, confirmed by a repeat test; 
 
 
confirmed by a repeat test
For restrictions of the trial, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may withdraw or may be removed from trial treatment or may withdraw consent to 
trial participation as a whole (‘withdrawal of consent’) with very different implications; please 
see Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) and will 
not be reported in the clinical trial report (CTR).
If a subject is removed from or withdraws from the trial after the first administration of trial 
medication, this will be documented and the reason for discontinuation must be recorded in the 
CRF; in addition, trial data will be included in the CRF and will be reported in the CTR. 
Following removal or withdrawal, a complete end-of-trial examination should be performed.
If the discontinuation or withdrawal occurs before the end of the REP (see Section 1.2.4) the 
discontinued subject should, if possible, be questioned for AEs and concomitant therapies at or 
after the end of the REP, in order to ensure collection of AEs and concomitant therapies 
throughout the REP, if not contrary to any consent withdrawal of the subject.
3.3.4.1
Withdrawal from trial treatment
An individual subject will be withdrawn from trial treatment if:

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1. The subject wants to withdraw from trial treatment. The subject will be asked to explain 
the reasons but has the right to refuse to answer.
2. The subject has repeatedly shown to be non-compliant with important trial procedures and, 
in the opinion of both, the investigator and sponsor representative, the safety of the subject 
cannot be guaranteed as he is not willing or able to adhere to the trial requirements in the 
future.
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events (AEs), or diseases)
5. The subject exhibits an AE of CTCAE grade 3 or a serious AE (SAE)
6. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF.
In addition to these criteria, the investigator may discontinue subjects at any time based on his 
or her clinical judgment.
If new efficacy or safety information becomes available, Boehringer Ingelheim will review the 
benefit-risk-assessment and, if needed, pause or discontinue the trial treatment for all subjects
or take any other appropriate action to guarantee the safety of the trial subjects.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to justify 
the decision. If a subject wants to withdraw consent, the investigator should be involved in the 
discussion with the subject and explain the difference between trial treatment discontinuation 
and withdrawal of consent to trial participation, as well as explain the options for continued 
follow-up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons (if reasons 4 and/or 5 are met, the trial should be discontinued immediately):
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. The sponsor decides to discontinue the further development of the investigational products
3. Deviation from GCP, or the CTP impairing the appropriate conduct of the trial
4. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment (see Section 3.3.4.1)
5. More than 50% of the subjects show drug-related and clinically relevant adverse events of 
CTCAE grade 2 or grade 3 severity (except for grade 2 headache and grade 2 diarrhoea), 
or if at least one drug-related serious adverse event is reported

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3.3.5
Replacement of subjects
In case more than 4 subjects do not complete the trial (including subjects non-evaluable for 
PK), subjects may be replaced if considered necessary to reach the objective of the trial.
Subjects who withdraw or are withdrawn from treatment or assessments because of a drug-
related adverse event will not be replaced. The Clinical Trial Leader together with the Trial 
Pharmacologist and the Trial Statistician are to decide, if and how many subjects will be 
replaced. The total number of replacements may not exceed 4. A replacement subject will be 
assigned a unique randomization number, and will be assigned to the same treatment sequence
as the subject he replaces.

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Trial product 1
Substance:
zongertinib
Pharmaceutical formulation: Film-coated tablet (SDD-iCF)
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
60 mg
Posology:
2-0-0
Mode of administration:
Oral
Duration of use:
q.d. for 15 consecutive days in Period 2
Trial product 2
Name:
NovoNorm® 0.5 mg Tabletten
Substance:
Repaglinide
Pharmaceutical formulation: Tablet
Source:
Public pharmacy
Unit strength:
0.5 mg
Posology:
1 – 0 – 0
Mode of administration:
Oral
Duration of use:
1 single dose treatment in period 1 & 2 single dose treatments in 
period 2

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Trial product 3
Name:
Omeprazol STADA® protect 20 mg magensaftresistente 
Tabletten
Substance:
Omeprazole
Pharmaceutical formulation: Tablet
Source:
Public pharmacy
Unit strength:
20 mg
Posology:
1 – 0 – 0
Mode of administration:
Oral
Duration of use:
1 single dose treatment in period 1 & 2 single dose treatments in 
period 2
Trial product 4
Name:
Midazolam ratiopharm® 2 mg/ml orale Lösung
Substance:
Midazolam
Pharmaceutical formulation: Oral solution
Source:
Public pharmacy
Unit strength:
2 mg/ml
Posology:
0.5 mL – 0 – 0
Mode of administration:
Oral
Duration of use:
1 single dose treatment in period 1 & 2 single dose treatments in 
period 2
Commercially available drug products (i.e. trial products 2, 3 and 4) may be substituted for 
commercially available and approved (in Germany) alternatives containing the same active 
pharmaceutical ingredient (termed “substance” above) via non-substantial amendment. This 
may be necessary e.g. in case of drug supply shortage on the German market. Of note, the dose 
received and duration of use will not be altered.
4.1.2
Selection of doses in the trial
According to DDI-guidelines, the exposure of the offender drug (in this case zongertinib) 
should be similar to the exposure seen under clinical conditions in patients. In the planned 

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Single doses of repaglinide 0.5 mg, midazolam 1 mg and omeprazole 20 mg are standard doses 
used in clinical drug-drug-interaction trials. Generally, the doses were selected based on their 
tolerability and their ability to reliably show PK interactions if indeed present (see Sections 1.2
and 1.4.2). 
4.1.3
Method of assigning subjects to treatment groups
There is only one treatment sequence investigated in this trial, and each subject will be allocated 
to the same treatment sequence. The subjects will be allocated to a trial subject number by 
drawing lots prior to first administration of trial medication. Once a subject number has been 
assigned, it cannot be reassigned to any other subject. Reference and test treatments will be 
administered in the sequence specified in the Flow Chart.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a two-period fixed sequence design trial. All subjects will receive zongertinib and 
probe drugs in a fixed order. The treatments to be evaluated are summarised in Table 4.1.4: 1
below. 
Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength 
(mg)
Dosage
Total daily 
dose (mg)
Study Visit (V), 
Day (D)
Reference
Repaglinide
tablet
V2, D1
Midazolam
oral solution
V2, D2
Omeprazole
tablet
V2, D2
Test
Zongertinib
tablet
V3, D1- D15
Repaglinide
tablet
V3, D1
Midazolam
oral solution
V3, D2
Omeprazole
tablet
V3, D2
Repaglinide
tablet
V3, D14
Midazolam
oral solution
V3, D15
Omeprazole
tablet
V3, D15
Administration of repaglinide, midazolam and omeprazole will be performed after subjects 
have fasted overnight; fasting is to start no later than 10 h before the scheduled dosing. During 
ambulatory dosing of zongertinib from Day 4 to Day 13 in Period 2 subjects are required to 
fast for at least 10 hours prior and 1 hour post planned drug administration. If several drug 
administrations are to take place simultaneously (for example V3 D2: midazolam, omeprazole 
and zongertinib), the drug in liquid form (i.e. midazolam) is to be administered first; 
additionally, zongertinib is to administered last, when scheduled simultaneously with other trial 
medication. The investigator (or authorised designee) will administer all trial medication as an 

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oral dose together with about 240 mL of water to subjects who are in a standing position. For 
drug administration, the so-called four-eye principle (two-person rule) should be applied. For 
this, one authorised employee of the trial site should witness the administration of trial 
medication, and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot 
be ensured otherwise.
Subjects will be kept under close medical surveillance until at least 24 h after administration
of repaglinide, midazolam and omeprazole. During the first 4 h after administration of 
repaglinide, midazolam and omeprazole, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture), except for medical 
reasons or for recording of 12-lead ECG and vital sign measurements.
The last dose of medication in Period 1 and the first dose of medication in Period 2 are to be 
separated by a washout period of at least 3 days.
4.1.5
Blinding and procedures for unblinding
This non-randomised open-label Phase I trial will be handled in an open fashion throughout. 
The treatment assignment will be available to all involved parties. The open-label conduct is 
considered acceptable because the potential for bias is low and does not outweigh practical 
considerations. Emergency envelopes will not be provided, because the dose of trial medication 
is known to investigators and subjects.
4.1.6
Packaging, labelling, and re-supply
Zongertinib
Zongertinib tablets will be provided by BI. They will be packaged and labelled in accordance 
with the principles of Good Manufacturing Practice (GMP). For details of packing and the 
description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EU trial number is indicated on the title 
page of this protocol as well as on the subject information and informed consent forms. 
The label will be prepared according to regulation (EU) No 536/2014, Annex 6, omitting 
certain particulars with the following justification:

The "keep out of reach of children" statement was omitted from the label because the 
product will remain at the clinical site.

The visit number is not relevant for the label because the product will remain at the 
clinical site.

The investigator name was omitted from the label because it is included on the Trial 
Identification Card (TIC), which will be issued to each trial participant
No re-supply is planned.

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Repaglinide, midazolam & omeprazole
Repaglinide, midazolam and omeprazole will be obtained as commercial products by the 
clinical trial site from a public pharmacy. Alternatively, the drug products may be obtained 
from wholesale and sent to the trial site. The drugs will be dispensed out of the original, 
unmodified packages.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area in accordance with the recommended (labelled) storage conditions. If necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. If the storage conditions are found to be outside the specified range, the 
Clinical Trial Manager (as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethics committee

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol  
Midazolam, omeprazole and repaglinid may be obtained by the trial site at any time prior first 
dose.
Only authorised personnel documented in the form 'Trial Staff List' may dispense 
investigational drugs to trial subjects. Investigational drugs are not allowed to be used outside 
of this protocol.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the disposal of unused products. These 
records will include dates, quantities, batch / serial numbers, expiry ('use-by') dates, and the 
unique code numbers assigned to the investigational medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects were 
provided the doses specified by the CTP and reconcile all investigational medicinal products 
received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.
All unused medication will be disposed of locally by the trial site upon written authorisation of 
the Clinical Trial Leader. Receipt, usage and disposal of trial medication must be documented 
on the appropriate forms. Account must be given for any discrepancies.

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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
In case of clinical signs of hypoglycemia or blood glucose concentrations below 45 mg/dL 
(<2.5 mmol/L) in the glucose bedside test, oral glucose will be administered in a stepwise 
manner in defined amounts of about 10 g carbohydrates (e.g., two glucose tablets “Dextro 
Energy classic” (
)).
Otherwise, there are no special emergency procedures to be followed. No additional treatment 
is planned. However, if adverse events require treatment, the investigator may authorise 
symptomatic therapy (e.g. administration of ibuprofen in case of headache). In those cases, 
subjects will be treated as necessary and, if required, kept under supervision at the trial site or 
transferred to a hospital until all results of medical evaluations are acceptable.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
 should not be consumed starting 3 days before the first drug 
administration in each treatment period, in order to avoid false-positive results in the drug 
screen.
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food other than the snack provided at 2 h post-dose is allowed 
for at least 4 h after drug intake during in-house confinement.
On in-house days with dosing of probe drugs (repaglinide or midazolam and omeprazole), from 
1 h before drug intake until lunch, fluid intake is restricted to the water administered with the 
drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all subjects). 
From lunch until 24 h post-dose, total fluid intake is restricted to 3000 mL during in-house 
stays.
On Day 3 of period 2, subjects are required to be fasted for at least 10 h prior as well as 1 h 
post planned drug administration.
During ambulatory dosing of zongertinib from Day 4 to Day 13 of Period 2 subjects are 
required to be fasted for at least 10 h prior as well as 1 h post planned drug administration.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products containing St. John's wort (Hypericum perforatum) are not 

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permitted from 7 days before the first administration of trial medication in the respective trial 
period until after the last PK sample of each trial period is collected.
 
 are not allowed during in-house stays at the trial site.
Smoking is not allowed during in-house confinement.
Excessive physical activity (such as competitive sport) should be avoided from 7 days before 
the first administration of trial medication until the end of trial examination.
 
4.2.2.3
Contraception requirements
Subjects whose sexual partner is a WOCBP must be sexually abstinent or use highly effective 
contraception starting from the first dose of zongertinib and for at least 30 days after the last 
dose of zongertinib. See Section 3.3.3 for required contraceptive measures.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
and of trial medication will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or violate 
trial restrictions) may be removed from the trial and the CRF will be completed accordingly 
(for further procedures, please see Section 3.3.4.1).

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history not mandatory to be entered into CRF or to be 
reported), relevant medical history and concomitant therapy, review of inclusion and exclusion 
criteria, review of vital signs (BP, PR), 12-lead ECG, laboratory tests, and a physical 
examination. At the end of trial examination, it will include review of vital signs, 12-lead ECG, 
laboratory tests, and a physical examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap Pro 100, 
) at the
times indicated in the Flow Chart, after subjects have rested for at least 5 min in a supine 
position. All recordings should be made using the same type of blood pressure recording 
instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart after the subjects have fasted for at least 10 h. 
For retests, at the discretion of the investigator or designee, overnight fasting is not required.
The parameters to be assessed are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges will 
be provided in the ISF. 
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.

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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/Erythrocytes 
White Blood Cells/Leucocytes 
Platelet Count/Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal)
Neut. Poly (segs)/Leukocytes; Neut. Poly (segs), absol.; 
Neutrophils Bands/Leukocytes; Neutrophils Bands, absol.; 
Eosinophils/Leukocytes; Eosinophils, absol.; 
Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/Leukocytes; Monocytes, absol.; 
Lymphocytes/Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time
Prothrombin time – INR (International Normalization Ratio)
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate aminotransferase] /GOT
ALT [Alanine aminotransferase] /GPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
Free T3 - Triiodothyronine
Free T4 – Thyroxine 
X
X
X
--
--
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
GFR/ CKD-EPI
Bilirubin, Total 
Bilirubin, Direct
Albumin
C-Reactive Protein (Quant)
X
X
X
X
X
X
X
X
X
X
X
X
X
--
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium (total)
X
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine HGB (qual)
Urine leukocyte esterase (qual)
Urine pH
X
X
X
X
X
X
X
X
X
--
--
--
--
--
--
--
--
--
X
X
X
X
X
X
X
X
X
Urine sediment1
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
A:
parameters to be determined at Visit 1 (screening examination) 
B:
parameters to be determined at Visit 3 (for time points refer to Flow Chart)
C:
parameters to be determined at Visit 4 (end of trial examination)

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1.
microscopic examination if erythrocytes, leukocytes nitrite or protein are abnormal in urine
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. It is planned to perform these tests during screening only with the exception of drug 
screening, which will be performed at screening and prior to each trial site admission.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Methadone
Methamphetamines/MDMA/Ecstasy
Opiates 
Phencyclidine
Tricyclic antidepressants
Infectious serology (blood)
Hepatitis A antibodies (qualitative)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. AlcoTrue® M, 
) will be performed prior to each trial site admission, and 
may be repeated at any time during the trial at the discretion of an investigator or designee. The 
results will not be included in the CTR.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at 
 
, with the exception of 
drug screening tests. These tests will be performed at the trial site using Surestep™Urine Drug 
Test or comparable test systems. Confirmatory drug screen may be performed at 
 
.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
It is the responsibility of the Investigator to evaluate the laboratory reports. Clinically relevant 
abnormal findings as judged by the Investigator are to be reported as adverse events (please 
refer to Section 5.2.6). 
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.6.1.4).
Glucose bedside test
A glucose bedside test out of venous blood will be performed for safety reasons at predefined 
time points after each repaglinide administration (see Flow Chart). For quantification of blood 
glucose one drop (approximately 50 μL) of blood taken from a vein will be sufficient. The tests 
will be performed at the trial site using an Accu-Chek™Aviva device or comparable test 

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system. The results will not be entered in the CRF/database and will not be reported in the 
CTR.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a computerised 
electrocardiograph (CardioSoft EKG System, 
) at the
times provided in the Flow Chart. 
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment, so that all subjects are at complete 
rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other trial procedures scheduled for 
the same time to avoid compromising ECG quality (except blood drawing from an intravenous 
cannula which is already in place).
All ECGs will be stored electronically on the Muse CV Cardiology System (
 
). Electrode placement will be performed according to the method 
of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and shoulders instead 
of ankles and wrists). 
All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal findings 
will be reported as AEs (during the trial) or baseline conditions (if identified at the screening
visit) if assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG may be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
5.2.5
Other safety parameters
Not applicable.
5.2.5.1
Suicidality assessment
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have to 
have a causal relationship with this treatment.

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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether considered related or not.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the following 
criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe 

Requires inpatient hospitalisation, or prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalisation or development of dependency or abuse
5.2.6.1.3
AEs considered ‘Always Serious’
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which, by their nature, can always be considered 
to be ‘serious’ even though they may not have met the criteria of an SAE as defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. A copy of the latest list of 
‘Always Serious AEs’ will be provided upon request. These events should always be reported 
as SAEs as described in Section 5.2.6.2.
Cancers of new histology must be classified as a serious event regardless of the time since 
discontinuation of the trial medication and must be reported as described in 5.2.6.2, subsections 
‘AE Collection’ and ‘AE reporting to sponsor and timelines’.

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5.2.6.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.6.2.2.
The following are considered as AESIs:

Potential severe DILI
A potential severe Drug Induced Liver Injury (DILI) that requires follow-up is defined 
by the following alterations of hepatic laboratory parameters:
o
An elevation of AST (aspartate aminotransferase) and/or ALT (alanine 
aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or in samples drawn within 
30 days of each other, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, etc.) 
without lab results (ALT, AST, total bilirubin) available, the Investigator should make 
sure that these parameters are analysed, if necessary in an unscheduled blood test. 
Should the results meet the criteria of hepatic injury alert, the procedures described in 
the DILI checklist should be followed.
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of AEs should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE)version 5.0 [R18-1357].
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine whether there is a reasonable possibility of a 
causal relationship between the AE and the given trial treatment, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship could 
be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

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
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger

There is an alternative explanation (e.g. situations where other drugs or underlying 
diseases appear to provide a more likely explanation for the observed event than the 
drug concerned

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from baseline 
are noted subsequently. 
Subjects will be required to report spontaneously any AEs. In addition, each subject will be 
regularly assessed by the medical staff throughout the clinical trial and whenever the 
investigator deems necessary. As a minimum, subjects will be questioned for AEs (and 
concomitant therapies) at the time points indicated in the Flow Chart. Assessment will be made 
using non-specific questions such as ‘How do you feel?’. Specific questions will be asked 
wherever necessary in order to more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial
(the End of Study (EoS) visit): 

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o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy volunteers, when subjects discontinue from the trial due 
to screening failures prior to administration of any trial medication. In these 
cases, the subjects’ data must be collected at trial site but will not be entered in 
the CRF and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but 
should only report any occurrence of cancer and trial treatment related SAEs
and trial treatment related AESIs of which the investigator may become aware 
of by any means of communication, e.g. phone call. Those AEs should be 
reported on the BI SAE form (see Section 5.2.6.2.2), but not on the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form to the sponsor’s unique entry point within 24 hours 
of becoming aware of the event, the country specific reporting process will be provided in the 
ISF. The same timeline applies if follow-up information becomes available. On specific 
occasions, the Investigator could inform the sponsor upfront via telephone. This does not 
replace the requirement to complete and send the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after the individual subject’s end of trial, 
must be followed up until they have resolved, have been sufficiently characterized (e.g. as 
‘chronic’ or ‘stable’), or no further information can be obtained.
5.2.6.2.3
Pregnancy
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires written consent of the pregnant partner.
Reporting and consenting must be in line with local regulations. The ISF will contain the trial 
specific information and consent for the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Studies (Part B). The ISF will contain the Pregnancy Monitoring Form for 
Clinical Studies (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Studies and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE form 
must be completed in addition.

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, blood samples will be collected at the time points 
indicated in the Flow Chart. The actual sampling times will be recorded and used for 
determination of pharmacokinetic parameters. 
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
General aspects
Blood samples for PK analyses will be withdrawn by means of either an indwelling venous 
catheter or by venipuncture with a metal needle into blood drawing tubes (as outlined below). 
After completion of the trial, the plasma samples, the left-over, and/or back-up aliquots may 
be used for further investigations related to trial IMPs (e.g., for stability testing or assessment 
of metabolites including, if applicable, re-analysis of parent compound and/or assessments of 
biomarkers). The trial samples will be discarded after completion of the additional 
investigations but not later than 5 years after the CTR is archived. The results of any further 
investigations are not planned to be part of the CTR, but may be included into the CTR if 
necessary.
Sampling and processing for zongertinib, repaglinide, midazolam and omeprazole
For quantification of zongertinib and repaglinide (and its metabolites) concentrations in 
plasma, 
2.7
mL
of 
blood 
will 
be 
drawn 
into
a 
K2-EDTA 
(dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube for each analyte at the times 
indicated in the Flow Chart.
For quantification of midazolam (and its metabolites) and omeprazole (and its metabolites)
concentrations in plasma, 2.7 mL of blood will be drawn into a single K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube for both analytes at the 
times indicated in the Flow Chart.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at
approximately 2000 x g to 4000 x g and 4 to 8 °C. Three plasma aliquots will be obtained and 
stored in polypropylene tubes. All three aliquots should contain at least 0.3 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 120 min , with interim storage of blood samples in ice water or on ice. The 
time each aliquot was placed in the freezer will be documented. Until transfer on dry ice to the 
analytical laboratory, the aliquots will be stored upright at approximately -20°C or below at the 
trial site. The second aliquot will be transferred to the analytical laboratory after the bioanalyst 
has acknowledged safe arrival of the first aliquot. The third aliquot will be transferred to the 
analytical laboratory after the bioanalyst has acknowledged safe arrival of the second aliquot. 
At the analytical laboratory, the plasma samples will be stored at approximately -20°C or below 
until analysis.

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Labelling
At a minimum, the sample tube labels should list BI trial number, barcode, subject number, 
visit, planned sampling time, and the analyte (see table).
Table 5.3.2.1: 1
Labelling of PK sample aliquots
Aliquot
Analyte
zongertinib
repaglinide
midazolam/omeprazole
1
A1 zonger
A1 repa
A1 mid/om
2
A2 zonger
A2 repa
A2 mid/om
3
BU zonger
BU repa
BU mid/om

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5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
5.6.1
Pharmacogenomic evaluation
Pharmacogenomic investigations explore the role of genetic variation in determining an 
individual’s response to drugs. For this purpose, a sample of at most 10 mL of blood will be 
obtained at the screening examination or Visit 2 from each subject whose genotype has not 
been previously determined. Separate informed consent for genotyping will be obtained from 
each volunteer prior to sampling.
DNA will be extracted from the blood sample in order to sequence genes coding for proteins 
that are involved in the absorption, distribution, metabolism, and excretion (ADME) of drugs. 
The gene sequences to be determined include known and likely functional variations of key 
ADME genes and incorporate more than 90% of ADME-related genetic markers identified by 
the PharmaADME group (weblink.pharmaadme.org). It is not intended to include the 
pharmacogenomic data in the CTR. However, the data may be part of the CTR, if necessary.
5.6.2
Liquid Biopsy
For the exploration of individual variability of PK related proteins and activities through small 
extracellular vesicles in plasma by proteomics, RNA profiling and enzyme assay (liquid
biopsy), approximately 15 mL of blood will be collected at the time points indicated in the
Flow Chart. Changes to conditions of sample processing described in the CTP may be
implemented via non-substantial amendement.
Approximately 2 x 7.5 mL of blood (
) will be 
drawn from a vein into a potassium ethylenediaminetetraacetic acid (K2-EDTA)-anticoagulant 
blood drawing tube at the timepoint indicated in the Flow Chart. Blood will be withdrawn by 
means of either an indwelling venous catheter or by venipuncture. The EDTA-anticoagulated 
blood samples will be centrifuged for approximately 15 min at approximately 2500x g at room 
temperature. Plasma will be extracted leaving a 5 mm buffer volume to ensure integrity of the 
buffy coat or clot. Plasma will be transferred from both EDTA collection tubes into two new 5 
mL Eppendorf Protein LoBind tubes. Then, within 60 min minutes of collection, the 5 mL 
Eppendorf Protein LoBind tubes will be centrifuged at 2500 x g for 15 minutes at room 
temperature. Leaving a small buffer volume in the LoBind tubes, plasma samples will be 
aliquoted at a volume of 1 mL into new 5 mL Eppendorf Protein LoBind tubes labelled as ‘Ali 
1’ to ‘Ali 4’ until all available plasma is transferred, any remaining plasma is to be transferred 
in the 5th aliquot labelled ‘Ali 5’. All aliquots are subsequently frozen at approximately -70 °C 
or below until shipment of plasma samples. Until transfer on dry ice to analytical laboratory, 
the aliquots will be stored upright at approximately -70 °C or below at the trial site. At the 
analytical laboratory, the plasma samples will be stored at approximately -70 °C or below until 
analysis. The results of exploratory 
 will be 
described in the report separately from the trial CTR. After analysis the plasma samples may 
be used for further PK and/or biomarker methodological investigations, e.g., for stability 

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testing, enrichment of liver derived exosome, or exploration of shedding factor. The samples 
will be discarded after completion of the additional investigations but no later than 5 years 
upon the final trial report has been signed.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be performed 
in order to monitor subjects’ safety and to determine pharmacokinetic parameters in an 
appropriate way. The scheduled measurements will allow monitoring of changes in vital signs, 
standard laboratory values, and ECG parameters that might occur as a result of administration 
of trial medication. The safety assessments are standard, are accepted for evaluation of safety 
and tolerability of an orally administered drug, and are widely used in clinical trials. The 
pharmacokinetic parameters and measurements outlined in Section 5.3 are generally used 
assessments of drug exposure.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and the end of trial examination are provided in the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 and Day 2 of Visit 2 as well as Day 1, Day 2, Day 3, Day 14 and Day 
15 of Visit 3 are to be performed and completed within a 3 h-period prior to the trial drug 
administration, if not stated otherwise in the Flow Chart.
If not stated otherwise in the Flow Chart, the acceptable deviation from the scheduled time for 
vital signs, safety laboratory tests (excluding blood glucose testing) and ECG will be ± 30 min.
For glucose testing the acceptable deviation from the scheduled time is ± 10 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, and 12-
lead ECG recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned blood sampling times, refer to the Flow Chart. While these nominal times should 
be adhered to as closely as possible, the actual sampling times will be recorded and used for 
the determination of pharmacokinetic parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial.
For information regarding laboratory tests (including drug and virus screening), ECG, vital 
signs, and physical examination, refer to Sections 5.2.1 to 5.2.5.
Genotyping may be performed in those volunteers whose genotypes have not been previously 
determined (for details, see Section 5.6).
6.2.2
Treatment period(s)
Each subject is expected to participate in 2 treatment periods (Period 1: Day -1 to Day 3 and 
Period 2: Day -1 to Day 16). At least 3 days will separate drug administrations in the first and 
second treatment periods.
Trial participants will be admitted to the trial site on Day -1 of Period 1 and will remain under 
close medical surveillance for the entirety of Period 1 (Day -1 to Day 3). In Period 2 trial 

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participants will be admitted to the trial site twice on Day -1 and Day 13 and will remain under 
close medical surveillance for at least 48 h. The subjects will then be allowed to leave the trial 
site after formal assessment and confirmation of their fitness. On all other trial days, subjects 
will be treated in an ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK analysis, 
refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2 of 
this protocol and in the Flow Chart. AEs and concomitant therapy will be assessed continuously 
from obtaining subject’s written informed consent until the end of trial examination.
For details on times of all other trial procedures, refer to the Flow Chart.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Section 5.2.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoS Visit.
If needed in the opinion of the investigator, additional visits may be scheduled after the EoS
Visit for continued safety monitoring.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoS Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can be 
obtained.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of probe drugs, midazolam, omeprazole and repaglinide, 
administered alone compared with co-administered with zongertinib will be estimated by the 
ratios of the geometric means (T1/R1, T2/R2, T3/R1, T4/R2), and their corresponding 2-sided 
90% confidence intervals (CIs) will be provided. This method corresponds to the two one-sided 
t-test procedure, each at the 5% significance level. Since the main focus is on estimation and 
not testing, a formal hypothesis test and associated acceptance range is not specified.
7.2
PLANNED ANALYSES
7.2.1
General considerations
7.2.1.1
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least one 
dose of trial drug. The treated set will be used for safety analyses.
Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation 
of PK or due to PK non-evaluability (as specified in the following subsection 
‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if he contributes 
only one PK parameter value for one period to the statistical assessment. Descriptive 
and model-based analyses of PK parameters will be based on the PKS.

Biomarker parameter analysis set (BMS): This set includes all subjects in the treated 
set (TS) who provide at least one evaluable measure of the 
without protocol deviations relevant to the evaluation of the biomarker 
(as specified in the subsection ‘Biomarkers’). Listing of the biomarker will be based on 
the BMS.
Descriptions of additional analysis sets may be provided in the TSAP.
Adherence to the protocol will be assessed by the trial team. Important protocol deviation (iPD) 
categories will be suggested in the iPD specification file. IPDs will be identified no later than 
in the Report Planning Meeting, and the iPD categories will be updated as needed.
7.2.1.2
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 and 2.2.2 for the probe drugs (and 
metabolites) will be calculated according to the relevant BI internal procedures. 
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol deviation 

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relevant to the evaluation of PK (to be decided no later than in the  Report Planning Meeting) 
or due to PK non-evaluability (as revealed during data analysis, based on the criteria specified 
below). Exclusion of a subject’s data will be documented in the CTR.
Important protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis), 

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which are flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
7.2.1.3
Biomarkers
Biomarker endpoints are outlined in Section 2.2.2.2. Only 
will be reported 
as listing in the CTR.
Biomarker data and parameters of a subject will be included in the biomarker listing if they are 
not flagged for exclusion due to a protocol deviation relevant to the evaluation of the biomarker 
(to be decided no later than in the Report Planning Meeting) or due to non-evaluability (as 
revealed during data analysis). Protocol deviations maybe similar to those listed for 
pharmacokinetics in Section 7.2.1.2.
Exclusion of a subject’s data will be documented in the CTR. Biomarker data and parameters 
of a subject which is flagged for exclusion will be reported with its individual values but will 
not be included in the listing.

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7.2.2
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. This model will include 
effects accounting for the following sources of variation: subjects and treatment. The effect 
'subjects' will be considered as random, whereas 'treatment' will be considered as fixed. The 
model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment  k,
= the overall mean,
sm = the effect associated with the mth subject,
m = 1, 2, ..., n
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject who received treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary endpoints 
(see Section 2.1) and their two-sided 90% confidence intervals (CIs) will be provided.
For each endpoint, the difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding adjusted means (Least Squares Means). 
Additionally their two-sided 90% confidence intervals will be calculated based on the residual 
error from the ANOVA and quantiles from the t-distribution. These quantities will then be 
back-transformed to the original scale to provide the point estimate and 90% CIs for each 
endpoint.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘subjects’ and ‘treatment’) considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.2.3
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be calculated according to the relevant BI 
internal procedures and will be assessed statistically using the same methods as described for 
the primary endpoints.

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7.2.5
Safety analyses 
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No hypothesis testing is planned.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the assigned treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/proportions will 
be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics will 
be used to analyse continuous (quantitative) data.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the time of the measurement or on 
the recorded time of AE onset (concept of treatment emergent AEs). Therefore, measurements 
performed or AEs recorded prior to first intake of trial medication will be assigned to the 

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screening period, those between first trial medication intake and end of REP (see Section 1.2.4) 
will be assigned to the treatment period. Events occurring after the REP but prior to next intake 
or end of trial termination date will be assigned to ’follow-up’. In case of two or more 
treatments, the follow-up will be summarized according to the previous treatment. These 
assignments including the corresponding time intervals will be defined in detail in the TSAP. 
Note that AEs occurring after the last per protocol contact but entered before database lock will 
be reported to Pharmacovigilance only and will not be captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP in 
order to provide summary statistics for time intervals, such as combined treatments, on-
treatment totals, or periods without treatment effects (such as screening and follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by treatment, 
system organ class, and preferred term. SAEs, AESIs (see Section 5.2.6.1), and other 
significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment sequence without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference range 
will be highlighted in the listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.2.6
Interim analyses
No interim analysis is planned.
7.3
HANDLING OF MISSING DATA
7.3.1
Safety
It is not planned to impute missing values for safety parameters.
7.3.2
Pharmacokinetics
Handling of missing PK data will be performed according to the relevant BI internal 
procedures. 
PK parameters that cannot be reasonably calculated based on the available drug concentration-
time data will not be imputed.
7.4
RANDOMISATION
The trial will not be randomised, thus this section is not applicable.

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7.5
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 16 subjects in the trial with the aim of ≥ 12 evaluable subjects, 
because this sample size is considered sufficient to achieve the aims of this exploratory trial. 
With this sample size, the following precision in estimating the ratio of geometric means 
(test/reference) can be expected with 95% probability. Precision is defined as the ratio of upper 
CI limit to the relative BA estimate. Note that the precision is independent of the actual ratio 
of geometric means.
The observed intra-individual coefficient of variation (gCV) for midazolam in previous trials
The observed intra-individual coefficient of variation for repaglinide in the previous trial
The observed intra-individual coefficient of variation for omeprazole in previous trials
 
With these results two scenarios are considered in this trial: a scenario with the gCV around 
25% and a scenario with the gCV roughly close to the highest observed value, 85%. Table 7.5: 
1 provides an overview of the achievable precision for estimating the ratio of geometric means 
(test/reference). For illustrative purposes, the expected 90% confidence intervals are displayed 
for different values of the ratios T/R of geometric means.

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Table 7.5: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a 2-period fixed sequence trial 
(N=12)
gCV [%]
Precision upper 
CL / relative BA 
estimate
Ratio [%]*
Lower CL [%]
Upper CL [%]
20
1.214
80
65.88
97.15
20
1.214
100
82.35
121.43
20
1.214
125
102.94
151.79
25
1.273
80
62.84
101.85
25
1.273
100
78.55
127.31
25
1.273
125
98.19
159.13
30
1.334
80
59.99
106.68
30
1.334
100
74.99
133.36
30
1.334
125
93.73
166.69
80
1.993
80
40.14
159.44
80
1.993
100
50.17
199.30
80
1.993
125
62.72
249.13
85
2.061
80
38.82
164.86
85
2.061
100
48.53
206.07
85
2.061
125
60.66
257.59
90
2.128
80
37.59
170.26
90
2.128
100
46.99
212.82
90
2.128
125
58.73
266.03
*Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 4.2.1.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU regulation 
536/2014, and other relevant regulations. Investigators and site staff must adhere to these 
principles. Deviation from the protocol, the principles of ICH GCP or applicable regulations 
will be treated as ‘protocol deviation’.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. As a general rule, no trial results should be 
published prior to finalisation of the CTR.
The terms and conditions of the insurance coverage are made available to the investigator and 
the subjects and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB / Independent Ethics Committee 
(IEC and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH-GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The investigator 
or delegate obtains written consent of the subject’s own free will with the informed consent 
form after confirming that the subject understands the contents. The investigator or 
 delegate 
must sign (or place a seal on) and date the informed consent form. If a trial collaborator has 
given a supplementary explanation, the trial collaborator also signs (or places a seal on) and 
dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.

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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment of 
critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk Management 
Plan or alternative plan, in line with the guidance provided by ICH Q9 and ICH-GCP E6, for 
fully outsourced trials, documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.8.
Electronic Study Documentation System:
In 
 a validated 
electronic study documentation system (ClinBaseTM or successor Trial Complete Early Phase 
(TCEP)) is used for processing information and controlling data collected in clinical trials. In 
addition to its function as a procedure control system, the study documentation system serves 
as databases. Instead of being entered into CRFs, selected data are directly entered into the 
system.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include all 
observations and other data pertinent to the investigation. Source data as well as reported data 
should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, original, 
and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must be 
explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the subject, documented 
in their medical records, would be acceptable.

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Before providing any copy of subjects’ source documents to the sponsor, the investigator must 
ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, and 
social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the subject eligible for the clinical trial.
Data directly entered into ClinBaseTM or TCEP (that is, without prior written or electronic 
record) are considered to be source data. The place where data are entered first will be defined 
in a trial specific Source Data Agreement. The data in ClinBaseTM or TCEP are available for 
inspection at any time.
8.3.2
Direct access to source data and documents
The investigator/institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents described 
in Section 8.3.1. The sponsor will also monitor compliance with the protocol and GCP.

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8.3.3
Storage period of records
Trial site:
The trial site(s) must retain the source and essential documents (including ISF) according to 
the local requirements valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
To ensure confidentiality of records and personal data, only pseudonymised data will be
transferred to the sponsor by using a participant identification number instead of the trial
participant’s name. The code is only available at the site and must not be forwarded to the 
sponsor. In case participant’s records will be forwarded e.g. for SAE processing or adjudication 
committees, personal data that can identify the trial participant will be redacted by the site prior 
to forwarding. Access to the participant files and clinical data is strictly limited: personalised 
treatment data may be given to the trial participant’s personal physician or to other appropriate 
medical personnel responsible for the trial participant’s welfare. Data generated at the site as a 
result of the trial need to be available for inspection on request by the participating physicians, 
the sponsor’s representatives, by the IRB/IEC and the regulatory authorities.
A potential data security breach will be assessed regarding the implications for rights and
privacy of the affected person(s). Immediate actions as well as corrective and preventive 
actions will be implemented. Respective regulatory authorities, IRBs/IECs and trial 
participants will be informed as appropriate.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and future 
use of biological samples and clinical data, in particular

Sample and data usage have to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external storage facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

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
A fit for the purpose documentation (e.g. biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified 
in the ICF
8.6
TRIAL MILESTONES
The first act of recruitment represents the start of the trial is defined as the date when the first 
subject in the whole trial signs informed consent.
The end of the trial is defined as the date of the last visit of the last subject in the whole trial 
(‘Last Subject Completed’).
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the laws of each member state. 
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last subject
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim International GmbH, 
 
.
The trial will be conducted at the 
 
 under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF. The investigators will have access to the BI web portal Clinergize to access 
documents provided by the sponsor.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all required 
trial activities, in order to 

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

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
Ensure appropriate training and information of local Clinical Trial Mangers
(CT Managers), Clinical Research Associates
(CRAs), and investigators of 
participating trial sites
Zongertinib will be provided by the 
 
. Repaglinide, midazolam and omeprazole will be obtained by the trial site 
from a public pharmacy.
Safety laboratory tests will be performed by the local laboratory of the trial site (
 
).
Analyses of zongertinib concentrations in plasma will be performed at 
 
Analyses of repaglinide concentrations in plasma will be performed at 
 
.
Analyses of midazolam concentrations in plasma will be performed at 
 
.
Analyses of omeprazole concentrations in plasma will be performed at 
 
.
Analyses of 
concentrations in plasma will be performed at 
 
Analyses of the Liquid Biopsy will be performed under the responsibility Boehringer 
Ingelheim Pharma GmbH & Co. KG, 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI according to BI SOPs or a 
contract research organisation appointed by BI.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be found 
in the ISF.

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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
P04-02212
Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, 
Desai M, Miller M, Hall SD. The effect of echinacea (Echinacea purpurea 
root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther; 2004; 
75(1); 89-100. 2004-02-28
P10-00100
Turpault S, Brian W, Horn R van, Santoni A, Poitiers F, Donazzolo Y, 
Boulenc X. Pharmacokinetic assessment of a five-probe cocktail for CYPs 
1A2, 2C9, 2C19, 2D6 and 3A. Br J Clin Pharmacol; 2009; 68(6); 928-935. 
2010-01-14
P12-10638
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions: final 
(21 June 2012, CPMP/EWP/560/95/Rev. 1). 
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9.2
UNPUBLISHED REFERENCES
c32836122
 
 Investigator's
Brochure BI 1810631 1479-P01. Current version.
c42938800
, BEAMION-Lung 1: 
An open label, Phase I dose escalation trial, with dose confirmation and 
expansion, of BI 1810631 as monotherapy in patients with advanced or 
metastatic solid tumors with HER2 aberrations, 1479-0001, 08 Dec 2023
n00278549
 Evaluation of Induction Potential of Cytochrome P450 Isoforms 
by BI 1810631 in Cultured Human Hepatocytes, 2004201. 27 Aug 2020
c40238724
 15. TABLES, FIGURES AND 
LISTINGS REFERRED TO IN THE TEXT VD, 1479-0003
n00279936
BI 1810631: Assessment of CYP induction potential in primary 
human hepatocytes using the basic models R3 and F2 according to FDA 
and EMA guidance, A012/20STC, B7042, 23 Sep 2020

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10.
APPENDICES
Not applicable.

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11.
DESCRIPTION OF GLOBAL AMENDMENT
11.1
GLOBAL AMENDMENT 1
Date of amendment
18 Mar 2024
EudraCT number
EU number
2023-510263-35-00
BI Trial number
1479-0014
BI Investigational Medicinal 
Product(s)
Zongertinib (BI 1810631)
Title of protocol
The effect of multiple doses of zongertinib on the 
single-dose pharmacokinetics of midazolam, 
omeprazole and repaglinide in healthy male 
subjects (an open-label, 2-period, fixed-sequence 
trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1)   4.1.1
2)   4.1.6
Description of change
1) Substitution of commercially available drug 
products (i.e. trial products 2,3, and 4) by approved 
alternatives containing the same active 
pharmaceutical ingredient via non-substantial 
amendment.
2) Permission for trial site to obtain commercially 
available drug products from public pharmacies or 
wholesale.
 
Rationale for change
1) Potential drug supply shortages for commercially 
available drug products.
2) Potential drug supply shortages for commercially 
available drug products.

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11.2
GLOBAL AMENDMENT 2
Date of amendment
17 May 2024
EudraCT number
EU number
2023-510263-35-00
BI Trial number
1479-0014
BI Investigational Medicinal 
Product(s)
Zongertinib (BI 1810631)
Title of protocol
The effect of multiple doses of zongertinib on the 
single-dose pharmacokinetics of midazolam, 
omeprazole and repaglinide in healthy male 
subjects (an open-label, 2-period, fixed-sequence 
trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1) Title page, Lay title
2) Flowchart Period 1, Visit 2, Day 3
3) Flowchart Period 2, Visit 4, Day 3 and Day 16
4) 1.2.3.
5) 1.4.2, Table 1.4.2: 1
6) 3.3.3
7) 3.3.4.1
8) 4.1.4
9) 4.2.2.2
10) 6.1
11) 6.2.2
Description of change
1) Lay title was changed to:
A study in healthy men to test whether zongertinib 
affects how 3 other medicines (midazolam, 
omeprazole, and repaglinide) are taken up and 
processed in the body

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2 - 5) Extension of in-house confinement following 
administration of midazolam from 12 to 24 hours
6) Addition of exclusion criterion 26:
ALT (alanine transaminase), AST (aspartate 
transaminase), or serum creatinine above upper 
limit of normal range at screening examination, 
confirmed by a repeat test; 
 
 
confirmed 
by a repeat test
7) Addition of withdrawal criterion for individual 
subjects from treatment:
The subject exhibits an AE of CTCAE grade 3 or a 
serious AE (SAE)
8 - 9) Change in ambulatory dosing days following 
extension of in-house confinement following 
administration of midazolam from 12 to 24 hours; 
adjustment of wording regarding fasting in Section 
4.2.2.2 to the change of ambulatory/in-house time 
intervals; actual fasting intervals remain unchanged
10) Change in in-house dosing days following 
extension of in-house confinement following 
administration of midazolam from 12 to 24 hours
11) Extension of treatment periods 1 & 2 by one 
day following extension of in-house confinement 
following administration of midazolam from 12 to 
24 hours
Rationale for change
1 - 5) Upon request by ethics committee (RFI part 
II)
6 - 7) Upon health authority / ethics committee
request (RFI part I)
8 - 11) Upon request by ethics committee (RFI part 
II)

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11.3
GLOBAL AMENDMENT 3
Date of amendment
12 Jul 2024
EudraCT number
EU number
2023-510263-35-00
BI Trial number
1479-0014
BI Investigational Medicinal 
Product(s)
Zongertinib (BI 1810631)
Title of protocol
The effect of multiple doses of zongertinib on the 
single-dose pharmacokinetics of midazolam, 
omeprazole and repaglinide in healthy male 
subjects (an open-label, 2-period, fixed-sequence 
trial)
Substantial Global Amendment due to urgent safety reasons 
Substantial Global Amendment 
Non-substantial Global Amendment 
Section to be changed
1. Synopsis (Trial product 3)
2. 4.1.1 (Trial product 3)
3. 5.4.1.1
Description of change
1-2. Change of Antra MUPS® 20 mg 
magensaftresistente Tabletten to Omeprazol 
STADA® protect 20 mg magensaftresistente 
Tabletten
3.
Deletion of the reference to the shipment of 
the third aliquot for 
.
Rationale for change
1-2. Drug supply shortage of Antra MUPS® 20 mg 
magensaftresistente Tabletten on the German 
market
3.
Clarification regarding the sample collection 
for 
: there is no third :
aliquot, thus the deleted sentence should be 
omitted.

 
 
 
 
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The effect of multiple doses of zongertinib on the single-dose pharmacokinetics of
midazolam, omeprazole and repaglinide in healthy male subjects (an open-label,
2-period, fixed-sequence trial)
Author-Trial Statistician
12 Jul 2024 16:17 CEST
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Completion
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