Conditions: Neoplasms
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
The primary objective of the present study is to investigate the influence of co-administration of itraconazole and volasertib on the pharmacokinetic profile of volasertib without co-administration of itraconazole. Secondary objectives are to investigate safety, tolerability and preliminary therapeutic effects following intravenous administration of volasertib.

Detailed description:

Arms:
arm 1: Administration of volasertib in combination with itraconazole (Cycle 1) and afterwards alone (Cycle 2 and beyond).

Interventions: intervention 1: volasertib intervention 2: itraconazole
Intervention descriptions: intervention 1: Solution for infusion intervention 2: capsules

Protocol document:
Prot_000.pdf: 
  
Clinical Trial Protocol
Doc. No.: c01677062-09
EudraCT No.:
BI Trial No.:
2011-002367-23
1230.24
BI Investigational
Product:
Volasertib (lab code: BI 6727)
Title:
An open-label fixed sequence trial to investigate the potential drug-drug 
interaction of intravenous volasertib co-administered with a P-gp and 
CYP3A4 inhibitor (itraconazole p.o.) in patients with various solid 
tumours
Clinical Phase:
I
Trial Clinical 
Monitor:
Tel:  
 
Fax: 
Co-ordinating 
Investigator:
Tel.:
Fax:
Status:
Final Protocol (Revised Protocol (based on global amendment 3)
Version and Date:
4.0
           
30 Jan 2017
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
n.a.
Name of active ingredient:
volasertib 
Protocol date:
Trial number:
Revision date:
30 Jan 2017
18 Oct 2012
1230.24
Title of trial:
An open-label fixed sequence trial to investigate the potential drug-drug interaction of 
intrveneous volasertib co-administered with a P-gp and CYP3A4 inhibitor 
(itraconazole p.o.) in patients with various solid tumours
Co-ordinating         
Investigator:
Trial sites:
2 study centres   
Clinical phase:
I
Objectives:
Primary objective:
To investigate the influence of co-administration of itraconazole (a potent dual 
inhibitor of cytochrome P450 3A4 and P-gp) and volasertib on the pharmacokinetic 
profile of volasertib without co-administration of itraconazole
Secondary objectives:
To determine safety, tolerability and preliminary therapeutic effects following 
intravenous administration of volasertib
Methodology:
Uncontrolled, open-label, phase I volasertib DDI (drug-drug interaction) study with a 
dual P-gp and CYP3A4 inhibitor (itraconazole)
No. of patients: 
total entered:
24
each treatment:
All 24 patients will receive volasertib in combination with itraconazole and volasertib 
alone in two consecutive treatment cycles
Diagnosis :
Histo- or cytologically confirmed diagnosis of advanced/metastatic solid tumour 
refractory or not amenable to standard therapy
Main criteria
for inclusion:
Adult males and females with histologically or cytologically confirmed diagnosis of 
advanced, non resectable and / or metastatic solid tumour, for whom conventional 
treatment has failed, or for whom no therapy of proven efficacy exists, or who are not 
amenable to established forms of treatment
Test product:
volasertib
dose:
300 mg 
mode of admin.:
Intravenous 2 hour infusion on day 1 of each 21 day treatment cycle


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
n.a.
Name of active ingredient:
volasertib 
Protocol date:
Trial number:
Revision date:
30 Jan 2017
18 Oct 2012
1230.24
Perpetrator products:
itraconazole
dose:
200 mg qd for 18 days (total: 3600 mg)
mode of admin.:
oral 
Duration of treatment: Two cycles of treatment (with and without co-administration of itraconazole); 
repeated treatment cycles (volasertib monotherapy) in patients for whom clinical 
benefit is obtained
Pharmacokinetics
endpoints:
Primary endpoints: AUC0-tz and Cmax of volasertib and its metabolite CD 10899
Secondary endpoints: AUC0-oo of volasertib and its metabolite CD 10899
 
Plasma concentrations of itraconazole at selected time points
All PK measurements will be performed only in first two treatment cycles.
Efficacy assessment: 
Preliminary therapeutic effects will be evaluated by investigator assessment of 
response and clinical benefit
Safety assessment:
Adverse events according to Common Terminology Criteria for Adverse Events v3.0 
(CTCAE v3.0)
changes in safety lab, and in ECG
Statistical methods:
AUC0-tz and Cmax will be log-transformed prior to fitting an ANOVA model. This 
model will include effects for “treatment” and “subjects“. 90% confidence intervals 
will be computed for the primary endpoints, then back-transformed to the original 
scale to give the point estimator and interval estimates for the geometric mean ratio 
(Test / Reference).
Descriptive statistics for all other parameters and endpoints will be calculated.


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FLOW CHART
OVERALL DESIGN
Cycle 1
Cycle 2
Cycles ≥3
(optional -
for pts with 
clinical 
benefit)
Scree-
ning
volasertib & 
itraconazole
volasertib
volasertib 
EOT
FU


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TREATMENT CYCLE 1 (volasertib with itraconazole)
Visit
Day #
Planned Time
[h:min]
Approximate clock time 
of actual day [h.min]
Event and comment
Safety Laboratory2 (S), 
Coagulation (C)
PKplasmavolasertib + 
CD 10899, itraconazole
Vital signs (BP and PR), 
ECG (digital, triplicate)
Adverse events/
Con. med
SCREEN
-14 
to 
-4
screening1, ECOG
blood samples for additional 
screening lab parameters 
S2, C
X
1 
-4
-88:00
16:00
admission to trial site3 review 
of in-and exclusion criteria
▲
-3 
-72:00
8:00
itraconazole 200 mg
-2 
-48:00
8:00
itraconazole 200 mg
-1 
-24:00
8:00
itraconazole 200 mg
X10, 12
1
-0:30
7:30
blood samples for 
pharmacogenomics9
S
X
X
1
-0:05
7:55
itraconazole 200 mg
0:00
8:00
start of iv volasertib infusion, 
ECOG
▲
0:30
8:30
│
X4
1:00
9:00
│
X
X4
1:457
9:45
│
physical examination 
│
X
X
2:00
10:00
▼ 
end of iv volasertib infusion, 
ECOG
3:00
11:00
X
4:00
12:00
X
6:00
14:00
X11
X6
8:00
16:00
X11
12:00
20:00
X
2
24:00
8:00
itraconazole 200 mg
C
X12
X6
36:00
20:00
X11
3
48:00
8:00
itraconazole 200 mg
X12
4
72:00
8:00
itraconazole 200 mg
discharge from trial centre
subjects will continue to take 
itraconazole 200 mg once daily 
until Day 15 and would receive 
a diary card to note down the 
date and time of itraconazole 
intake at home
X11, 12
2
8
168:00
8:00
itraconazole 200 mg
S
X11, 12
X4


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Visit 
Day #
Planned Time
[h:min]
Approximate clock time 
of actual day [h.min]
Event and comment
Safety Laboratory2 (S), 
Coagulation (C)
PKplasmavolasertib + 
CD 10899, itraconazole
Vital signs (BP and PR), 
ECG (digital, triplicate)
Adverse events/
Con. med
3
15
336:00
8:00
itraconazole 200 mg last dose
physical examination, body 
weight, ECOG, tumour 
assessment, eligibility for 
further treatment cycle5
S, C
X11, 12
X4
│
│
│
│
48
22
504:00
8:00
X11
# Days are calculated as calendar days (example: in case a patient is starting (day 1) on 
Thursday, all visits (day 8, day 15, day 22,) should occur on a Thursday


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1.
Screening (to be performed between 14 and one day before drug administration) including patient information, 
informed consent, physical examination and review of vital signs/ECG/laboratory including drug, alcohol and 
virus screening; also to include demographics, determination of the body weight, smoking and alcohol history, 
relevant medical history, concomitant medication, review of inclusion/exclusion criteria at screening and 
pregnancy test in women of childbearing potential
2.
Safety lab includes haematology, and serum biochemistry. For detail see 5.2.3. Urinalysis (dipstick) is only 
performed at screening and EOT.
3.
Patients should be admitted to hospital at day -4 and stay until 72h after start of infusion
4.
Vital signs only
5.
Only patients with clinical benefit after volasertib treatment based on investigator´s assessment (clinical response, 
or absence of progression, or symptom improvement) will qualify for further participation in the trial. In case of 
symptom improvement despite disease progression a repeated cycle may be allowed upon the agreement of the 
clinical monitor and the investigator.
6.
ECG only
7.
Shortly before end of infusion.
8.
This visit may co-incide with visit 1 of treatment cycle 2
9.
Can be taken also at any later time point from those patients who received at least first cycle of volasertib.
10. Analysed for itraconazole only
11. Analysed for volasertib and CD 10899 metabolite only
12. PK sampling should be taken just before itraconazole intake


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TREATMENT CYCLE 2 (volasertib without itraconazole)
Visit
Day
Planned Time
[h:min]
Approximate clock time 
of actual day [h.min]
Event and comment
Safety Laboratory5 (S), 
Coagulation (C)
PKplasma volasertib and 
CD 10899
Vital signs (BP and PR), 
ECG (digital, triplicate)
Adverse events/
Con. med
1 
-1 
-17:00
15:00
admission to trial site1,2
▲
1
-0:306
7:30
review of in-and exclusion criteria
S
X
X
0:00
8:00
start of iv volasertib infusion, 
ECOG
▲   
0:30
8:30
│
X3
1:00
9:00
│
X
X3
1:458
9:45
│
physical examination 
X
X
2:00
10:00
▼ 
end of iv volasertib infusion, 
ECOG
3:00
11:00
X
4:00
12:00
X
6:00
14:00
X
X7
8:00
16:00
X
12:00
20:00
X
2
24:00
8:00
C
X
X7
36:00
20:00
X
3
48:00
8:00
X
4
72:00
8:00
discharge from trial centre
X
2
8
168:00
8:00
S
X
X3
3
15
336:00
8:00
X
49
22
504:00
8:00
physical examination, body 
weight, ECOG, tumour 
assessment, eligibility for further 
treatment cycle4
S, C
X
X3
1.
Patients should be admitted to hospital and stay until day 4 (72h after start of infusion)
2.
Pregnancy test in women of childbearing potential
3.
Vital signs only
4.
Only patients with clinical benefit after volasertib treatment based on investigator´s assessment (clinical response, 
or absence of progression, or symptom improvement) will qualify for further participation in the trial. In case of 
symptom improvement despite disease progression a repeated cycle may be allowed upon the agreement of the 
clinical monitor and the investigator.
5.
Safety lab includes haematology, and serum biochemistry. For detail see 5.2.3. Urinalysis (dipstick) is only 
performed at screening and EOT.
6.
For predose sampling of volasertib and CD 10899 in plasma, metabolic profiling, the time window is 2 hours 
before start of infusion.
7.
ECG only
8.
Shortly before end of infusion
9.
This visit may co-incide with visit 1 of treatment cycle 3


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SUBSEQUENT TREATMENT CYCLES (for patients with clinical benefit)
Study period
Treatment
EOT1
FU2
Visit
V1
V26
V36
V47
Day
1
8
15
22
(day range)
(±1)
(±1)
(±2)
Physical examination10
X
X
X
ECOG performance score10
X
X
X
X
Body weight10
X
X
X
Vital signs10
X
X
X
X
X
X
ECG 
X3
X
Tumour assessment8
X
X
X
Infusion of volasertib
X
Safety lab parameters4
X
X
X
X
X
Coagulation parameters4
X
X
X
Pregnancy test9
X
Adverse events
X
X
X
X
X
X5
Concomitant therapy
X
X
X
X
X
Termination of trial medication
X
Treatment with any other anti-
tumour drug
X
Patient status
X
X
Eligibility for further treatment 
cycle
X
X
1.
EOT, end of treatment. Assessments which are to be performed at the last visit (when a patient discontinues the 
study treatment)
2.
FU, follow-up. Follow-up visit should be performed 21 days after discontinuation of study drug
3.
ECG on visit V1 should be performed according to 5.2.4. After approval of the Protocol revision 3, ECG should 
be performed prior to and at the end of volasertib infusions as single reads using a local ECG machine. No central 
analysis of ECGs will be performed.
4.
Safety lab includes haematology and serum biochemistry. For detail see 5.2.3. Urinalysis (dipstick) is only 
performed at EOT. After approval of the Protocol revision 3, safety laboratory including coagulation parameters 
should be done only as medically indicated at discretion of the investigator. The results should be recorded in the 
source data only; documentation in the eCRF is not required. 
5.
In case adverse events were not yet recovered at the EOT visit or if new AEs occur that are considered drug related
6.
Optional visits at the investigators discretion, can be performed by phone as well
7.
Visit V4 may coincide with V1 of the following cycle in case the patient continues the study treatment
8.
Clinical response assessment after every cycle, radiological assessment at the investigator’s discretion. After 
implementation of the Protocol revision 3, this efficacy data will be recorded in the source data only; 
documentation in the eCRF is not required.
9.
Pregnancy test in women of childbearing potential after every other cycle, i,e. C4, C6, C8 etc.
10. After approval of the Protocol revision 3, physical examination, ECOG performance score, body weight, vital 
signs will be performed assessed/checked only as medically indicated at discretion of the investigator. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1. INTRODUCTION........................................................................................ 16
1.1 MEDICAL BACKGROUND .....................................................................................16
1.2 DRUG PROFILE ........................................................................................................16
2. RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ............................................................................................. 19
2.1 RATIONALE FOR PERFORMING THE TRIAL .................................................19
2.2 TRIAL OBJECTIVES................................................................................................20
2.3 BENEFIT - RISK ASSESSMENT.............................................................................20
3. DESCRIPTION OF DESIGN AND TRIAL POPULATION.................. 22
3.1 OVERALL TRIAL DESIGN AND PLAN................................................................22
3.1.1 Administrative structure of the trial ................................................................23
3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) ..............................................................................................23
3.3 SELECTION OF TRIAL POPULATION................................................................23
3.3.1 Main diagnosis for study entry..........................................................................24
3.3.2 Inclusion criteria.................................................................................................24
3.3.3 Exclusion criteria................................................................................................24
3.3.4 Removal of patients from therapy or assessments ..........................................26
3.3.4.1 Removal of individual patients.................................................................26
3.3.4.2 Discontinuation of the trial by the sponsor ..............................................26
3.3.5 Re-treatment criteria for repeated cycles ........................................................27
3.3.6 Handling of patients removed from active treatment/trial ............................27
4. TREATMENTS............................................................................................ 28
4.1 TREATMENTS TO BE ADMINISTERED .............................................................28
4.1.1 Identity of BI investigational product and comparator product(s)...............28
4.1.2 Method of assigning patients to treatment groups..........................................29
4.1.3 Selection of doses in the trial .............................................................................29
4.1.3.1 Potential dose reduction ...........................................................................29
4.1.3.2 Dose escalation scheme............................................................................30
4.1.4 Drug assignment and administration of doses for each patient.....................30
4.1.4.1 First cycle (combined volasertib and itraconazole administration)..........30
4.1.4.2 Second cycle (volasertib without itraconazole administration) ...............31


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4.1.4.3 Subsequent treatment cycles ....................................................................32
4.1.5 Blinding and procedures for unblinding..........................................................33
4.1.6 Packaging, labelling, and re-supply..................................................................33
4.1.7 Storage conditions ..............................................................................................33
4.1.8 Drug accountability............................................................................................34
4.2 CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT .............................................................................................................34
4.2.1 Rescue medication, emergency procedures, and additional treatment(s).....34
4.2.2 Restrictions..........................................................................................................35
4.2.2.1 Restrictions regarding concomitant treatment..........................................35
4.3 TREATMENT COMPLIANCE ................................................................................35
5. VARIABLES AND THEIR ASSESSMENT ............................................. 36
5.1 EFFICACY - CLINICAL PHARMACOLOGY ......................................................36
5.1.1 Endpoint of efficacy............................................................................................36
5.2 SAFETY .......................................................................................................................37
5.2.1 Endpoint(s) of safety ..........................................................................................37
5.2.2 Assessment of adverse events ............................................................................37
5.2.2.1 Definitions of adverse events ...................................................................37
5.2.2.2 Adverse event and serious adverse event reporting .................................38
5.2.3 Assessment of safety laboratory parameters ...................................................40
5.2.4 Electrocardiogram..............................................................................................41
5.2.5 Assessment of other safety parameters ............................................................44
5.2.5.1 Vital signs.................................................................................................44
5.2.6 Dose reducing volasertib toxicity ......................................................................44
5.3 OTHER.........................................................................................................................44
5.3.1 Other endpoint(s) ...............................................................................................44
5.3.2 Other assessment(s)............................................................................................45
5.3.2.1 Physical examination, height, body weight, and performance status.......45
5.3.2.2 Demographics and history........................................................................45
5.3.2.3 Concomitant diagnoses and/or therapy ....................................................45
5.4 APPROPRIATENESS OF MEASUREMENTS ......................................................47
5.4.1 Timing of assessments........................................................................................47
5.5 DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS ...........................................................................................48
5.5.1 Pharmacokinetic endpoint(s).............................................................................48
5.5.2 Methods of sample collection.............................................................................49
5.5.2.1 Blood sampling........................................................................................49


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5.6 BIOMARKER(S).........................................................................................................51
5.6.1 Endpoints based on biomarker(s).....................................................................51
5.6.2 Methods of sample collection.............................................................................51
5.6.3 Analytical determinations..................................................................................51
5.7 PHARMACODYNAMICS.........................................................................................51
5.7.1 Pharmacodynamic endpoints ............................................................................51
5.7.2 
Methods of sample collection.................................................................51
5.8 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP...............51
6. INVESTIGATIONAL PLAN...................................................................... 52
6.1 VISIT SCHEDULE.....................................................................................................52
6.2 DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS..........................52
6.2.1 Screening and run-in period..............................................................................52
6.2.2 Treatment period................................................................................................53
6.2.2.1 First Treatment Cycle...............................................................................53
6.2.2.2 Second Treatment Cycle ..........................................................................53
6.2.2.3 Subsequent treatment cycles (non-DDI) ..................................................54
6.2.2.3.1
Visit 1 (Day 1 of volasertib administration).......................................54
6.2.2.3.2
Visits 2 and 3 (day 8 and 15)..............................................................55
6.2.2.3.3
Visit 4 (day 22) ...................................................................................55
6.2.3 End of trial and follow-up period .....................................................................55
6.2.3.1 Visit at the end of treatment .....................................................................55
6.2.3.2 Follow-up visit .........................................................................................56
6.2.3.3 End of trial................................................................................................56
7. STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE............................................................................................. 57
7.1 STATISTICAL DESIGN - MODEL .........................................................................57
7.2 NULL AND ALTERNATIVE HYPOTHESES........................................................58
7.3 PLANNED ANALYSES .............................................................................................59
7.3.1 Primary analyses ................................................................................................59
7.3.2 Secondary analyses.............................................................................................60
7.3.2.1 Secondary pharmacokinetic parameters...................................................60
7.3.2.2 Safety and tolerability analyses................................................................60
7.3.3 Safety analyses....................................................................................................60
7.3.4 Interim analyses..................................................................................................61
7.3.5 Pharmacokinetic analyses..................................................................................61
7.3.6 Biomarkers, pharmacodynamic analyses and pharmacokinetic –
pharmacodynamic relationship.........................................................................61
7.3.8 Other analyses.....................................................................................................61
7.4 HANDLING OF MISSING DATA............................................................................62
7.4.1 Safety ...................................................................................................................62


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7.4.2 Plasma concentration - time profiles ................................................................62
7.4.3 Pharmacokinetic parameters ............................................................................62
7.4.4 Efficacy................................................................................................................63
7.5 RANDOMISATION....................................................................................................63
7.6 DETERMINATION OF SAMPLE SIZE..................................................................63
8. INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS .................................................................................................... 64
8.1 STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT....................................................................................................................64
8.2 DATA QUALITY ASSURANCE...............................................................................65
8.3 RECORDS ...................................................................................................................65
8.3.1 Source documents...............................................................................................65
8.3.2 Direct access to source data and documents....................................................65
8.4 LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS .......65
8.4.1 Listedness ............................................................................................................65
8.4.2 Expedited reporting to health authorities and IECs/IRBs .............................66
8.5 STATEMENT OF CONFIDENTIALITY ................................................................66
8.6 COMPLETION OF TRIAL.......................................................................................66
9. REFERENCES............................................................................................. 67
9.1 PUBLISHED REFERENCES....................................................................................67
9.2 UNPUBLISHED REFERENCES ..............................................................................68
10.
APPENDICES......................................................................................... 69
10.1
CLINICAL EVALUATION OF LIVER INJURY..........................................69
10.1.1
Introduction ............................................................................................69
10.1.2
Procedures...............................................................................................69
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)............................. 71


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ABBREVIATIONS
AE
Adverse Event
AUC
Area under the plasma concentration-time curve
AUC0-∞
Area under the plasma concnentration-time curve over the time interval 
from 0 to infinity
AUC0-tz
Area under the plasma concnentration-time curve over the time interval 
from 0 to the time of the last quantifiable data point
BLQ
CI
below the limit of quantification
Confidence Interval
CL
Total clearance of the analyte in plasma following intravenous infusion
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
Cpre,ss,N
Predose steady state plasma concentration of the analyte in plasma 
immediately before administration of the Nth dose
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
CYP3A4
DDI
DILI
Clinical Trial Report
Cytochrome P450 3A4
Drug-drug interaction
Drug-induced Liver Injury
DMC
Data Monitoring Committee
DRT
Dose Reducing Toxicity
ECG
ECOG
Electrocardiogram
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EDTA
Ethylendiaminetetraacetic acid
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
HPC
Human Pharmacology Centre
IB
Investigator’s Brochure
IEC
IMP
Independent Ethics Committee
Investigational Medicinal Product
IRB
Institutional Review Board
ISF
Investigator Site File
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
MDR1
Interactive Web-based Response System
Multidrug resistance protein 1
MedDRA
Medical Dictionary for Drug Regulatory Activities


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MRT
Mean residence time after intravenous infusion
MST
Medical Subteam
MTD
NOA
NOP
NOR
NOS
Maximum Tolerated Dose
not analyzed
no peak detectable
no valid result
no sample
OPU
PD
PG
PLK
Operative Unit
Progression of Disease
Pharmacogenomics
Polo-like kinase
p.o.
per os (oral)
PCC
P-gp
Protocol Challenge Committee
P-glycoprotein
q.d.
quaque die (once a day)
SAE
Serious Adverse Event
s.c.
subcutaneous
SPC
Summary of Product Characteristics
t1/2
Terminal half-life of the analyte in plasma
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
tmax
Time to maximum analyte plasma concentration 
tmax.ss
Time to maximum analyte plasma concentration at steady state
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
Vss
Apparent volume of distribution at steady state after intravenous infusion
Vz
Apparent volume of distribution during the terminal phase following an 
intravenous infusion


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Most advanced or metastatic human tumours are incurable despite the availability of a variety 
of conventional treatment modalities like surgery, cytotoxic drugs, radiation therapy, and 
combinations of these. Objective responses in patients with advanced disease, though 
frequently seen using conventional treatments, are often followed by tumour progression and 
death. Therefore the search for new therapeutic strategies has become an urgent priority.
Our understanding of tumour biology and cell cycle regulation in particular has increased 
considerably in recent years, preparing ground for novel targeted treatment principles. 
Mitotic kinases of the Polo family which are highly conserved in all eukaryotes have been 
identified as important regulators of cell division and its checkpoints (R04-0421). Polo-like 
kinase 1 (PLK-1) controls several key steps in the passage of cells through M phase: 1) 
initiation of entry into mitosis, 2) centrosome separation and maturation necessary for the 
formation of a bipolar mitotic spindle, 3) metaphase to anaphase transition and mitotic exit 
and 4) onset of cytokinesis (R04-0028). PLK-1 is a target of the DNA damage checkpoint 
(R04-0422). Failure of cell cycle checkpoints to arrest the cell after appropriate stimuli such 
as DNA damaging agents or radiation is a hallmark of tumour. These findings provide a 
rationale for pursuing PLK-1 inhibition as a therapeutic principle in oncology.
Recently mammalian PLK-1 was shown to be over-expressed in various human malignancies 
such as non-small cell lung cancer (R04-0031), colorectal cancer (R04-0034) and AML (P09-
09644). The functional relevance of PLK-1 was demonstrated in in vitro “knock down” 
experiments where PLK-1 inhibition induced cell cycle arrest and apoptosis in tumour cell 
lines (R04-0030, R04-0423). A potential role for PLK-1 over-expression in carcinogenesis 
was shown both in vitro and in vivo (R04-0321). Therefore PLK-1 inhibition represents a 
promising new therapeutic approach with a novel mode of action in oncology.
The 1230.24 trial will investigate the potential influence of co-administration of volasertib, a 
highly selective and potent PLK-1 inhibitor, with itraconazole, a potent P-gp inhibitor and 
cytochrome P450 3A4 inhibitor.
1.2
DRUG PROFILE
Volasertib is a highly selective and potent small molecule PLK inhibitor (P09-06192). The 
pharmacological profile of volasertib was evaluated in vitro in enzymatic assays, cellular 
cytotoxicity assays and assays examining cell cycle progression. In vivo efficacy of volasertib 
was determined in human tumour xenografts in nude mice.
In an enzymatic assay using human recombinant kinases volasertib potently inhibited Plk1 as 
well as the two closely related kinases Plk2 and Plk3 (IC50 values 0.87, 5, and 56 nmol/L, 
respectively). In contrast, assays using a panel of >50 other kinases failed to identify any 
inhibitory activity at concentrations up to 10 µmol/L demonstrating the high molecular 


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specificity of the compound. The compound was also tested for its cellular activity on a panel 
of tumour cell lines. Cytotoxicity in vitro and inhibition of PLK-1 in enzymatic assays was 
achieved at comparable concentrations. Activity was not dependent on cellular origin or 
molecular phenotype. Cell biological profiling revealed that volasertib induces a typical PLK-
1 mitotic arrest phenotype (G2/M arrest, abnormal mitotic figures) at similar concentrations. 
When comparing the activity in parental cell lines to the activity in the respective chemo-
resistant counterparts activity of volasertib was much better conserved than the activity of 
conventional chemotherapeutics such as taxanes or vincristine.
Efficacy of volasertib was shown in various xenograft models. Tumour regression up to 
complete cures of animals was demonstrated. Tumour regression was also shown in models 
of larger tumours. Doses shown to be effective were well tolerated and were administered to 
nude mice 1-2 times per week intravenously (P09-06192). 
The non-clinical safety profile of volasertib is considered favourable regarding the 
oncological indication and the anti-proliferative principle. In 3-cycle toxicity studies in dogs 
and rats mechanism -related side effects were observed in organs with high turnover as 
expected. Main target organs were the gastrointestinal tract (mucosal lesions), bone marrow 
and lymphoid. Complete reversibility even of severe lesions at higher doses was observed. 
Moreover no evidence for unspecific toxicity affecting other organs such as kidney or liver 
was found. However, an exploratory investigation on the cardiovascular system in pigs, given 
at very high doses of up to 30 mg/kg volasertib, showed that volasertib induced QT 
prolongation starting at a plasma level of 3700 nmol/L and slight QTcSE prolongation in 
chronically treated dogs starting at 36 mg/m2 at plasma levels of about 880 – 1090 nmol/L. 
The hERG channel was inhibited with an IC50 value of 2.4 µmol/L while the action potential 
in guinea pig papillary muscle was not affected up to 10 µmol/L. Based on these results, QT-
monitoring is continued in the clinical phase I and II trials with volasertib. More detailed 
information is provided in the Investigator’s Brochure (IB) (U05-2201).
Until October 2011 (time of data cut off for IB version 7), a total of 553 patients have been 
treated in clinical phase I and phase II trials with volasertib. Clinical Phase I safety data and 
preliminary Phase I and II data from ongoing trials show the compound to be safe with 
reversible suppression of haematopoiesis constituting the main side effect. The MTD for the 
d1q3w schedule was defined at 400 mg. 300 mg is used as the initial Phase II dose in the 
ongoing Phase II program in solid tumours (P10-07075). 
Besides suppression of haematopoiesis (resulting in anaemia, leuko-/neutropenia, 
thrombocytopenia), complications associated with cytopenias (e.g. neutropenic fever / 
infection, bleeding) and QT prolongation no other relevant non-specific effects of volasertib 
have been identified so far at the dose used in solid tumor trials (300 mg d1q21d). In the 
AML trial volasertib is administered more frequently (d1+15q28d) and the dose per 
administration was further escalated. At the higher doses investigated in AML mucositis was 
reported, an AE that is expected from the mode of action. 
1230.P1/P3/P4 7 106In the electrocardiogram (ECG) monitoring available data indicate the 
potential for dose dependant prolongations of QT using Fridericia’s correction algorithm 
(QTcF) at the time of Cmax, but no associated clinical events were reported. No other relevant 
unspecific toxicity has been observed as yet.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Although considerable progress has been made in understanding tumour biology as well as in 
developing more effective treatment regimens, most patients with locally advanced or
metastatic tumours will succumb to their disease. Thus, there is a substantial need for novel 
therapeutic strategies to improve the outcome for patients with advanced or metastatic 
malignancies for whom conventional treatment has failed, or for whom no therapy of proven 
efficacy exists.
Cell-cycle targeted therapies represent a novel and promising approach in these patients 
(R04-0415). Mitotic kinases regulating cell division and its checkpoints are considered 
particularly attractive targets for new therapies (R04-0421). Volasertib represents a new class 
of small molecules targeting and blocking activation of PLK with high selectivity and 
specificity. This compound induces cell cycle arrest, apoptosis and tumour shrinkage at 
tolerable doses in preclinical tumour models. In the clinical setting antitumour activity was 
reported in phase I and phase II trials (see IB).
This open label phase I trial 1230.24 will investigate the influence of co-administration of 
volasertib and itraconazole, a potent inhibitor of P-gp and cytochrome P450 3A4 in 
comparison to administration of volasertib without influencing itraconazole.
In vitro tests have shown that volasertib is a substrate of cytochrome P450 3A4 as well as a 
highly potent inhibitor of P-gp (U08-2116, U08-3450).
Volasertib distributes rapidly into a large volume (>4000 liters). The current PK data suggest 
that the terminal elimination half-life represents rather the slow re-distribution of Volasertib 
from deeper compartments into the blood stream than the elimination from the systemic 
circulation. Since that Volasertib is a P-gp substrate the distribution might be influenced by 
P-gp inhibitors.
Male and female patients with various solid tumours for whom conventional treatment has 
failed, or for whom no therapy of proven efficacy exists, or who are not amenable to 
established forms of treatment will be treated with volasertib in this study. Volasertib will be 
given as a single infusion over 120 minutes on day one of the study. Based on the safety 
profile from study 1230.1, the first in man trial of volasertib, the recommended phase II dose 
of 300 mg will be given.
Determination and quantification of the influence of co-administration of itraconazole and 
volasertib compared to volasertib without influencing factors is the primary endpoint of this 
trial. This effect will be evaluated in the first two treatment cycles. 
If clinical benefit from volasertib treatment is indicated, patients may receive additional 
cycles of volasertib. In these additional cycles no drug-drug interaction will be evaluated.
Patients who experience a clinical benefit, i.e. an objective tumour response or symptom 


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improvement or the absence of tumour progression and who have recovered from drug-
related adverse events from previous cycles are eligible for additional cycles of volasertib 
according to protocol.
Secondary endpoints of this trial are safety, tolerability and the assessment of preliminary 
therapeutic effects of volasertib.
2.2
TRIAL OBJECTIVES
The primary objective of the present study is to investigate the influence of co-administration 
of itraconazole (a potent dual inhibitor of cytochrome P450 3A4 and P-gp) and volasertib on 
the pharmacokinetic profile of volasertib without co-administration of itraconazole.
Secondary objectives are to investigate safety, tolerability and preliminary therapeutic effects
following intravenous administration of volasertib.
2.3
BENEFIT - RISK ASSESSMENT
The most relevant side effect of volasertib administration is expected to be a transient 
inhibition of proliferation of normal dividing cells in bone marrow and mucosal tissue. The 
side effects on bone marrow stem cells lead to a temporary decrease in the number of blood 
cells and platelets(reversible events of neutropenia, febrile neutropenia, thrombocytopenia 
and anaemia), as reported by the DLTs and adverse events in clinical trials. . Transient 
inhibition of haematopoiesis may be followed by clinical symptoms and complications as e.g. 
infections in neutropenic patients, bleedings in thrombocytopenic patients and fatigue in 
anaemic patients; respective drug related adverse event were reported in the clinical trials 
with volasertib. The majority of adverse events of CTCAE grade 3 or higher reported in 
clinical trials and considered related to volasertib are decrease of blood cells (anaemia, 
neutropenia and thrombocytopenia) and associated complications. Inhibition of mucosal 
proliferation may lead to gastrointestinal symptoms such as nausea or diarrhoea, although this 
finding was reported only in a limited number of patients so far. Other frequently reported 
adverse events were reported mostly with mild to moderate severity (nausea, decreased 
appetite, vomiting, constipation, alopecia).. These side effects are frequently seen in tumour 
patients treated with conventional cytotoxics or kinase inhibitors and can easily be monitored. 
Supportive treatment for these effects is available. 
QT prolongation was seen in preclinical models. QTcF prolongations in the 20-30ms range at 
Cmax were observed in the first phase I trial without occurrence of relevant clinical events. 
This observation will be further characterized by ECG monitoring in the phase I and II 
program. Mild to moderate cardiac lesions were seen in chronically treated dogs. Given that 
no cardiac events were reported in patients but clinical benefit was already observed in a 
heavily pre-treated Phase I patient population a positive risk-benefit ratio was concluded. 
Nevertheless, biomarkers for cardiotoxicity (Troponin, CK) and ECGs including QTc 
assessment will remain a part of the clinical safety monitoring in any phase I/II study.


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Cancer patients with advanced tumours and no further treatment options may benefit from 
tumour shrinkage, tumour stabilization or improvement of tumour-related symptoms as a 
result of treatment with volasertib. The potential benefit of therapy with volasertib is 
expected to outweigh the treatment related risks.
Restrictions for CYP3A4/Pgp inhibitors/inductors are only relevant for the drug-drug 
interaction part of the study, as these drugs may potentially interfere with the metabolism and 
distribution of volasertib. For the non-drug-drug interaction part other cytotoxic and 
anticancer immunotherapies are not allowed while CYP3A4/Pgp inhibitors/inductors are 
allowed.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´ 
safety.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This trial is an uncontrolled, open-label, sequential drug-drug interaction study of volasertib 
and itraconazole in tumour patients. Patients with advanced, non-resectable and/or metastatic 
solid tumours will be eligible for the study if conventional treatment has failed or if they are 
not amenable to established treatment options. Patients will be assessed for eligibility at a 
screening visit within 14 days prior to first drug administration. For the first treatment cycle 
patients will receive 200 mg of itraconazole starting 3 days before the first intravenous 
infusion of volasertib. On day 1 patients will receive an intravenous infusion with volasertib, 
whilst itraconazole dosing continues for 14 days/until 336 hours after volasertib infusion. PK 
samples will be taken until 504 hours after start of infusion.
After this 504 hours blood sample has been withdrawn and if none of the criteria for removal 
of patients from therapy or assessments is met (see section 3.3.4), patients will receive a 
second infusion of volasertib with clinical activities as outlined in the flow chart for treatment 
cycle 2. This cycle will be identical to the first cycle with the exception that no administration 
of itraconazole occurs in cycle 2.
The patients will be admitted to hospital for the time period of itraconazole administration 
from 88 hours before until 72 hours after start of infusion of volasertib in cycle 1 and the 
night before until 72 hours after start of infusion in treatment cycle 2, subsequent treatment 
cycles can be administered on an outpatient basis at the discretion of the investigator. The 
patients will visit the investigator at regular intervals as specified in the flow chart for 
determination of safety laboratory parameters, recording of adverse events and additional 
investigations as outlined in the flow chart. A radiological assessment of tumour response 
will be performed at discretion of the investigator.
Initially, patients will be treated sequentially. Single patient cohorts will be treated for the 
first cycle until three patients have completed the first cycle.
Thereafter, cohorts of 3 patients will be treated until the preliminary safety of volasertib in 
combination with itraconazole is confirmed (for details see section 4.1.3.1). 
After implementation of Protocol revision 3, safety laboratory parameters and additional 
investigations (weight, ECOG, vital signs, physical examination etc) as outlined in the Flow 
chart will be done as medically indicated at discretion of the investigator. Investigator will 
continue recording ECG prior and at the end of volasertib infusion to ensure patient safety. 
For this purpose investigator will use local ECG machine, centralized ECG analysis will be 
discontinued. 
Clinical response assessment after every cycle and radiological assessment at the 
investigator’s discretion will be continued to support the investigator´s decision on treatment 
continuation/discontinuation.


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3.1.1
Administrative structure of the trial
The trial will be performed by investigators and study nurses experienced in phase I trials and 
in conducting drug-drug interaction trials. Safety laboratory tests will be performed at the 
investigator site. Pharmacokinetic evaluations will be performed by Boehringer Ingelheim.
On-site monitoring will be performed by a CRO appointed by Boehringer Ingelheim.
All trial relevant documentation will be stored at a CRO and will be harmonised with 
Boehringer Ingelheim’s CTMF at the end of the trial. Trial relevant documentation which 
must remain at the trial site will be filed in the investigator site file (ISF) at the investigator 
site.
The principal investigator who will sign the clinical trial report of this trial has been 
appointed by Boehringer Ingelheim. The principal investigator has experience in these types 
of trials and investigations.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
The primary objective of this study is to determine the influence of co-administration of 
volasertib with itraconazole on the pharmacokinetics of volasertib in comparison to volasertib 
alone in cancer patients. No control group will be recruited.
The intra-individual comparison is preferred as each of the subjects will serve as his own 
control and the precision is therefore expected to be higher than with a group comparison. 
The fixed sequence is considered appropriate for an unbiased investigation of the volasertib 
PK due to the neglible carry-over effect from the first treatment cycle and because unspecific 
time effects on the volasertib PK are not to be expected.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 24 patients, at least 8 male and 8 female, will be recruited for this study (see 
Section 7.6). Patients not completing treatment cycle 2 will be replaced (see Section 3.3.4.1).
24 patients will be recruited for this study in order to have at least data for 24 patients 
completing the first treatment cycle with co-administration of itraconazole and volasertib and 
the second cycle with volasertib. The recruitment period is expected to last approximately 12 
months.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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3.3.1
Main diagnosis for study entry 
Adult male and female patients with histo- or cytologically confirmed diagnosis of advanced 
/ metastatic solid tumour.
3.3.2
Inclusion criteria
Patients must meet all of the following inclusion criteria to be eligible for entry into the 
trial:
1. Patients with histologically or cytologically confirmed diagnosis of advanced, non 
resectable and / or metastatic solid tumour, for whom conventional treatment has 
failed, or for whom no therapy of proven efficacy exists, or who are not amenable to 
established forms of treatment based on the investigator’s assessment
2. Male or female
3. Age ≥18 and ≤70 years 
4. Written informed consent consistent with ICH-GCP and local legislation
5. Eastern Cooperative Oncology Group (ECOG) performance score ≤ 2
6. Recovery from CTCAE Grade ≥ 2 therapy-related toxicities from previous chemo-, 
hormone-, immuno-, or radiotherapy (except alopecia)
3.3.3
Exclusion criteria
Patients presenting with any of the following will not be included in the trial:
1. Serious concomitant non-oncological disease considered by the investigator to be 
incompatible with the protocol
2. Active infectious disease
3. Viral hepatitis, HIV infection
4. Clinical evidence of active brain metastasis or leptomeningeal disease during the past 
6 months 
5. Second malignancy currently requiring active therapy (except for hormonal / 
antihormonal treatment e.g. in prostate or breast cancer)
6. Absolute neutrophil count less than 1,500/mm3
7. Platelet count less than 100,000/mm3
8. Total bilirubin greater than 1.5 mg/dL (> 26 µmol/L, SI unit equivalent)
9. Aspartate amino transferase (AST) and / or alanine amino transferase (ALT) greater 
than 2.5 times the upper limit of normal (if related to liver metastases greater than five 
times the upper limit of normal)
!"# Serum creatinine greater than 2x ULN.
11. QTcF prolongation > 470 ms or QT prolongation deemed clinically relevant by the 
investigator (e.g., congenital long QT syndrome).The QTcF will be calculated as the 
mean of the 3 ECGs taken at screening 


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12. Male patients who are sexually active and having a partner with childbearing potential 
and unwilling to use a medically acceptable method of contraception during the trial 
and for at least six months after end of active therapy
13. Female patients with childbearing potential and unwilling to use a medically 
acceptable method of contraception during the trial and for at least six months after 
end of active therapy. Woman of childbearing potential (premenopausal female) is 
defined as the female who is not surgically sterilised by hysterectomy or bilateral 
tubal ligation or post-menopausal for at least 12 months.
14. Treatment with other investigational drugs or participation in another clinical trial 
within the past four weeks prior to start of therapy or concomitantly with this trial
15. Chemo-, radio- immuno-, or molecular-targeted cancer-therapy within the past four 
weeks prior to start of therapy or concomitantly with this trial. This restriction does 
not apply to steroids, bisphosphonates hormonal / antihormonal treatment (e.g. in 
prostate or breast cancer).
16. Patients unable to comply with the protocol
17. Alcohol abuse more than an average 3 units of alcoholic beverages per day or more 
than 21 units per week (1 unit equals 0.5 pint [285 mL] of beer or lager, 1 glass [125 
mL] of wine, 25 mL shot of 40% spirit)) or drug abuse
18. Life expectancy less than 12 weeks
19. Potent CYP 3A4 and P-glycoprotein inhibitors other than the study drug or inducers 
between one week prior to first drug administration or expected treatment with a 
respective drug until the last PK sample is collected
a) Strong CYP 3A4 inhibitors: atazanavir, clarithromycin, indinavir, 
itraconazole (other then study drug), ketoconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin
b) CYP 3A4 inducers: carbamazepine, rifampicin
c) P-gp inhibitors: cyclosporine, erythromycin, itraconazole (other then study 
drug), ketoconazole, quinidine, phenobarbital salt with quinidine, ritonavir, 
valspodar, verapamil
d) P-gp inducers: hypericum perforatum, rifampicin
20. History of allergy/hypersensitivity (including allergy to study drug or its excipients) 
based on the investigator’s assessment
21. Excessive physical activities (within one week prior to administration and until the 
last PK sample is taken)
Exclusion criteria specific for this study:
22. Veins unsuitable for blood sampling and infusion
For study restrictions refer section 4.2.2.


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
A patient must be withdrawn from the trial if any of the following criteria apply:

The patient withdraws consent (patients are free to discontinue their participation in this 
study at any time without the need to justify the decision).
In this event, the patient will be asked to have an end of treatment investigation and the data 
collected until the point in time when withdrawal occurred will be included in the final 
analysis of the trial data. No further follow-up will be performed if the patient does not agree 
to further visits however patients might be contacted to obtain information on patient’s status.
A patient must be withdrawn from active treatment if any of the following apply:

The patient requests discontinuation of active treatment but agrees to be followed-up

The patient is no longer able to receive active treatment (e.g. due to adverse events, 
surgery, concomitant diagnoses, concomitant therapies or administrative reasons). The 
investigator may also stop a patient’s treatment if the patient is no longer able to attend 
study visits e.g. due to worsening of disease

Unacceptable toxicity occurs which does not recover to a degree that allows treatment 
continuation 

Further dose reductions are considered necessary but would not be permitted according to 
the protocol
Treatment may be stopped in an individual patient after discussion between the sponsor and 
the investigator if eligibility criteria are violated and/or the patient fails to comply with the 
protocol, e.g. no adherence to restrictions, non-attendance at study assessments.
The EOT information should be obtained. All patients who end active treatment (but not the 
trial) will be followed up as described in section 6.2.3.
Patients who were withdrawn during the first treatment cycle with co-administration of 
itraconazole and volasertib or during second treatment cycle with volasertib will be replaced, 
whereas patients withdrawn at a later stage will not be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site,
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial  
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial.


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4. Any other administrative reasons, including discontinuation of the clinical development 
program with volasertib
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Re-treatment criteria for repeated cycles
To continue treatment with further cycles, the following criteria must be met:
1. Clinical benefit after volasertib treatment based on investigator´s assessment (clinical 
response, or absence of progression, or symptom improvement). In case of symptom 
improvement despite disease progression a repeated cycle may be allowed upon the 
agreement of the clinical monitor and the investigator
2. a) Neutrophils ≥ 1 500/mm3 and platelets ≥ 100 000/mm3  
b) In case criterion 2a) is not fulfilled, the peripheral blood should be re-evaluated at 
weekly intervals. As soon as criterion 2a) is met, the treatment should be continued 
unless other criteria for discontinuation or withdrawal apply (see section 3.3.4.1).
3. Acceptable tolerability (according to the investigator judgment) and recovery from 
drug related AEs to CTCAE levels that allow further treatment 
4. Unacceptable toxicities (according to 5.2.6) are recovered to pre-treatment values or 
CTCAE Grade 1, whichever is higher 
3.3.6
Handling of patients removed from active treatment/trial
All withdrawals will be documented and the reason for end of treatment recorded and 
discussed, as necessary, in the final report of the trial.
As soon as a patient is withdrawn from the trial, the next scheduled visit and the EOT should 
be performed if feasible. Every effort should be made to follow-up patients in case an AE is 
still ongoing at the time of withdrawal / at the EOT visit.
Patients who withdraw prior to first treatment will not be included in the analysis. They will 
be entered into the trial data base, the reason for withdrawal documented and reported 
descriptively and by patient listing in the final report of this trial.
Patients who do not complete the first two cycles will be replaced.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Volasertib will be administered to the patients in two consecutive treatment cycles on day 1 
of a 21 day treatment cycle. The first volasertib infusion will occur after pretreatment with 
itraconazole from Day-3 to Day 1. Itraconazole will be continued for another 14 days after 
volasertib administration. In the second cycle, volasertib will be administered without 
itraconazole.
Repeated treatment cycles (≥3) of volasertib monotherapy can be administered in patients for 
whom clinical benefit is obtained.
Volasertib doses will be calculated as free base of the chloride salt. 1.00 mg volasertib (free 
base) equals 1.18 mg volasertib chloride salt.
In case of unexpected toxicity due to concomitant medication of volasertib and itraconazole, 
a reduced dose of 250 mg or 200 mg may be administered to the patients.
4.1.1
Identity of BI investigational product and comparator product(s)
Substance:
volasertib
Pharmaceutical form:
Solution for infusion (to be diluted with saline 0.9% before 
administration)
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
2 mg/mL (200 mg/ 100 mL vial or 350 mg / 175 mL vial)
Posology:
Infusion over 120 minutes
Route of administration:
intravenous
Daily dose:
300 mg 
Duration of use:
Single dose on day 1 of a 3 week cycle
Perpetrator Drug:
Substance:
itraconazole (Orungal®)
Pharmaceutical form:
capsules
Source:
Unit strength:
100 mg / capsule
Posology:
daily 200 mg
Route of administration:
oral
Daily dose:
200 mg
Duration of use:
18 days (three days before administration of volasertib, 
continuing from Day 1 till Day 15)


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4.1.2
Method of assigning patients to treatment groups
This section is not applicable in this study.
4.1.3
Selection of doses in the trial
The data obtained from clinical studies performed to date does not indicate a deviation from 
dose-proportionality for volasertib within the dose ranges 12-125 mg and 200-450 mg when 
volasertib is administered as a constant intravenous infusion.
To meet the objectives of the study, the dose investigated was designed to cover the dose 
where clinical efficacy is anticipated. The selected dose for iv administration in the present 
study is the recommended phase II dose for solid tumour trials (P11-14366).
4.1.3.1
Potential dose reduction
Reduction of starting dose
Initially, patients will be treated sequentially. Single patients will be treated for the first cycle 
until three patients have completed the first cycle. 
Thereafter, cohorts of 3 patients will be treated until the preliminary safety of volasertib in 
combination with itraconazole is confirmed. 
If more than 1 out of 6 patients experiences unacceptable toxicity (DRT, Section 5.2.6) 
during the first treatment cycle, the dose of volasertib for subsequent patients will be 
deescalated to 250 mg in the first and second treatment period. 
If more than 1 out of 6 patients treated at a volasertib dose of 250 mg experiences 
unacceptable toxicity during the first treatment cycle, the dose of volasertib for subsequent 
patients will be further deescalated to 200 mg in the first and second treatment period. 
The highest dose for which the incidence of unacceptable toxicity is no more than 1 out of 6 
will be used as the dose of volasertib for the first and second treatment cycle of all further 
patients included in the trial (MTD, cf. Section 5.2.6).
Dose reduction in individual patients
If a patient experiences unacceptable toxicity (DRT, Section 5.2.6) the patient can continue 
volasertib treatment at a lower dose if criteria for retreatment are met (see Section 3.3.5). 
Each occurrence of DRT will lead to a dose reduction by 50 mg of any subsequent volasertib 
infusion(s). No dose reduction of volasertib below 200 mg is allowed. 
If a patient experiences a DRT at the 200 mg dose, i.e. a dose reduction to <200 mg would be 
required, the volasertib treatment will be permanently discontinued and the patient will move 
to the EoT visit.


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When a dose reduction of volasertib occurs, this applies to all subsequent cycles with no 
possibility to dose escalation back to the previous dose.
4.1.3.2
Dose escalation scheme
A patient who is eligible to continue therapy with volasertib beyond the 2nd cycle (see Section 
3.3.5) may either be treated with the original dose or may receive a higher dose in the third 
and subsequent cycles. The dose can be increased by 50 mg after each cycle ≥2 up to a 
maximum dose of 350 mg in case of clinical benefit and good tolerability in the completed 
cycle (i.e., non-hematological drug related adverse events of less than CTCAE Grade 2 and / 
or hematological drug related adverse events of less than CTCAE Grade 3). Dose escalation 
will occur only upon agreement between investigator and sponsor. Patients should continue 
on the higher dose in all subsequent treatment cycles if well tolerated. The decision to 
escalate the dose can be made at the end of cycles ≥2. No dose increases above 350 mg are 
allowed. After dose escalation to the 350 mg subsequent dose reductions are allowed as per 
Section 4.1.3.1.
4.1.4
Drug assignment and administration of doses for each patient
4.1.4.1
First cycle (combined volasertib and itraconazole administration)
The treatment to be evaluated is as outlined in Table 4.1.4.1: 1 below: 


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Table 4.1.4.1: 1
Treatments to be administered in the first treatment cycle
Treat-
ment
Substance
Formulation
Unit strength 
To be 
reconstituted with
Total dose [mg]
oral
itraconazole
capsules
100 mg per capsule
N/A
3600 mg (18 times 200 
mg)
iv
volasertib
solution for 
infusion
vial of 200 mg 
(calculated as free 
base) /100 ml, 2 
vials to be used or
vial of 350 mg 
(calculated as free 
base) / 175 ml, 1
vial to be used
isotonic saline
300, potential dose 
reductions according to 
section 4.1.3.1
Itraconazole will be administered to the patients in 24 hour intervals, after meal, starting 72 
hours before administration of the first intravenous infusion of volasertib and will continue to 
be given in 24 hour intervals up to Day 15 / 336 hours thereafter.
On day 1, volasertib will be administered to the patients as a two hour infusion between 8:00 
and 10:00 h in the morning. The administration of the formulation will be performed under 
the supervision of the investigating physician or a designee. Cancer patients will receive an iv 
volasertib (dose according to section 4.1.3.1).
For preparation of the volasertib infusion solution, the preconcentrate of volasertib will be 
diluted in 0.9% physiological NaCl. For further details on the preparation of the infusion 
solution, please refer to the “Dilution and Handling of Clinical Trial Drug” document filed in 
the ISF.
4.1.4.2 Second cycle (volasertib without itraconazole administration)
The treatment to be evaluated is as outlined in Table 4.1.4.2: 1 below: 


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Table 4.1.4.2: 1
Treatments to be administered in the second treatment cycle
Treat-
ment
Substance
Formulation
Unit strength 
To be reconstituted 
with
Total dose [mg]
iv
volasertib
solution for 
infusion
vial of 200 mg 
(calculated as 
free base) /100 
ml, 2 vials to 
be used or
vial of 350 mg 
(calculated as 
free base) / 
175 ml, 1 vial 
to be used
isotonic saline
300
potential dose 
reductions according 
to section 4.1.3.1
On day 1 of treatment cycle 2, volasertib will be administered to the patients as a two hour 
infusion between 8:00 and 10:00 h in the morning. The administration of the formulation will 
be performed under the supervision of the investigating physician or a designee. Cancer 
patients will receive an iv dose of 300 mg volasertib (calculated as free base) whereas dose 
reduction is possible.
The procedure for preparing the infusion solution is as described for treatment cycle 1. 
4.1.4.3
Subsequent treatment cycles
Patients who are eligible for subsequent cycles (>2) of treatment with volasertib (for criteria 
to continue treatment see section 3.3.5) will receive volasertib as long as neither patient nor 
investigator requests treatment discontinuation. Volasertib will be administered as described 
for treatment cycle 1.
For possible dose reduction and dose escalation see sections 4.1.3.1 and 4.1.3.2.


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4.1.5
Blinding and procedures for unblinding
Not applicable. This trial will be performed according to an open-label design.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
Investigational product
Volasertib will be supplied in 100 and 175 mL vials containing 200 / 350 mg volasertib, 
respectively. Examples of the labelling of the medication will be found in the investigator site 
file (ISF). Volasertib will be labelled according to Annex 13 with trial number, medication 
number, name of product and strengths or identification code, pharmaceutical dosage form, 
quantity of dosage units, route and mode of administration, term ‘clinical trial use‘ (domestic 
language), sponsor name and address, storage conditions, use-by date, investigator name.
Medication will be delivered to the investigators pharmacy where the total dose per patient 
will be prepared upon request from the investigator. For preparation of the volasertib infusion 
solution, the preconcentrate will be diluted in 0.9% sodium chloride. The content of more 
than one vial may be needed for the administration of the requested dose. For further details, 
please refer to the ISF.
Perpetrator
Itraconazole will be acquired as commercial product from the European market. According to 
Hungarian regulations, itraconazole will be regarded as IMP. Itraconazole primary packaging 
will be unchanged and will be re-labelled by Boehringer Ingelheim Pharma GmbH & Co. KG 
according to Annex 13 with trial number, medication number, name of product and strengths 
or identification code, pharmaceutical dosage form, quantity of dosage units, route and mode 
of administration, term ‘clinical trial use‘ (domestic language), sponsor name and address, 
storage conditions, use-by date, investigator name and the term "Keep out of reach of 
children" (domestic language).
Please refer to section 4.1.8 for drug accountability. All used, partially used and unused IMP 
will be destroyed at the site and will not be returned to the sponsor. Double signatures of 
study staff will be required for this on-site destruction.
4.1.7
Storage conditions
Volasertib solution for infusion as well as itraconazole will be stored in the hospital 
pharmacy in a limited access area at the temperature indicated on the trial drug label.


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4.1.8
Drug accountability
The investigator will receive the investigational drugs (volasertib and itraconazole) delivered 
by the sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee, 

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

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 or immediately imminent 
signing of the clinical trial protocol, 
The investigator must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each patient, and the return to the sponsor or alternative disposition 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 product(s) and trial patients. The 
investigator will maintain records that document adequately that the patients were provided 
the doses specified by the CTP and reconcile all investigational product(s) received from the 
sponsor. At the time of return to the appointed CRO, the investigator / pharmacist / 
investigational drug storage manager must verify that no remaining supplies are in the 
investigator’s possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
All concomitant therapies to provide adequate care may be given as clinically necessary (for 
restrictions see 4.2.2). All concomitant therapies administered during the course of the study 
must be recorded in the eCRF. Trade name, indication, and dates of administration will be 
documented.
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication to reverse the action of volasertib is not available. Potential side effects of 
volasertib should be treated symptomatically. Symptomatic treatment of side effects or 
tumour-associated symptoms is allowed. During the first cycle, the use of growth factors such 
as granulocyte colony stimulating factor (G-CSF) for treatment of haematotoxicity is not 
encouraged except for life-threatening circumstances. After the first cycle, G-CSF is allowed 
at the discretion of the investigator and must be recorded in the eCRF.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Additional chemo-, immuno-, hormone, radio-, or molecular-targeted cancer-therapy is not 
permitted during the study. These restrictions do not apply to steroids and bisphosphonates as 
well as to hormonal / antihormonal treatment e.g. in prostate or breast cancer. For symptom 
control, palliative radiotherapy may be permitted after discussion with the BI Clinical 
Monitor.
The following potent CYP 3A4 and P-glycoprotein inhibitors or inducers are not permitted 
from one week prior to first drug administration until the last PK sample is collected:
Strong CYP 3A4 inhibitors: atazanavir, clarithromycin, indinavir, ketoconazole, itraconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin
CYP 3A4 inducers: carbamazepine, rifampicin
P-gp inhibitors: cyclosporine, erythromycin, ketoconazole, itraconazole, quinidine, 
phenobarbital salt with quinidine, ritonavir, valspodar, verapamil
P-gp inducers: hypericum perforatum (St. John´s wort), rifampicin
4.3
TREATMENT COMPLIANCE
The study medication will be administered orally every 24 hours (itraconazole) or as an 
intravenous 120 minute infusion (volasertib) under supervision of the investigator or 
designee.


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5.
VARIABLES AND THEIR ASSESSMENT
A total amount of 238.5 mL blood will be taken per patient during the first two treatment 
cycles of the study. This amount includes blood samples for laboratory parameters and 
pharmacokinetic purposes. This volume of blood is considered to be acceptable from medical 
point of view.
Blood samples for PK should be processed as soon as possible and within 30 minutes of 
collection while stored on ice.
Table 5:1
Number of blood samples and total blood volume collected for the 
DDI part of the trial (cycles 1 and 2)
Assessment
total # samples
mL of blood
per sample
Total volume
of blood (mL)
Clinical Laboratory 
(Screening and Follow-up visits)
Haematology (2)
Biochemistry (2)
Coagulation (2)
Serology (1)*
3.0
8.5
4.5
8.5
40.5
Coagulation
3
4.5
13.5
Haematology 
5
3.0
15.0
Biochemistry
5
8.5
42.5
Pharmacokinetic samples
- volasertib and CD 10899 in 
plasma, itraconazole**
29
4.0
116.0
Pharmacogenomic sample
2
2.0+9.0
11.0
Total volume of blood to be drawn
238.5
* Only at screening
** For itraconazole aliquot only in cycle 1
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoint of efficacy
Preliminary therapeutic effects (clinical benefit as e.g. tumour response, stable disease or 
symptom improvement) will be assessed by investigator response assessment (clinical 
assessment after every cycle, radiological and other assessments at investigator’s discretion).
The investigator will perform a clinical assessment at the time points specified in the Flow 
Chart (i.e. at time points for physical examination). An evaluation will be performed to 
determine whether the patient appears to be clinically benefitting from trial drugs. The 
clinical assessment together with other assessments (e.g. radiology) if applicable will be the 
basis for the investigator´s decision on continuation or discontinuation of an individual 
patient in the trial.
After implementation of the Protocol revision 3, the efficacy data (clinical response 
assessment performed after every cycle, radiological assessment at the investigator’s 


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discretion) will not be recorded in the eCRF, investigator should capture this information 
only in the source data. 
5.2
SAFETY
5.2.1
Endpoint(s) of safety
ECG and clinical lab tests. Furthermore, adverse events will be assessed.
After implementation of the Protocol revision 3, safety laboratory tests should be done as 
medically indicated at discretion of the investigator. The results are not required to be entered 
in the eCRF, only to be captured in the source data (see section 5.2.3). 
ECG  should be performed prior to and at the end of volasertib infusions as single reads using 
a local ECG machine without performing central ECG review (see section 5.2.4). 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Intensity of adverse event
During the study, all AEs will be recorded in the eCRF. The events will be graded according 
to the NCI-CTCAE Version 3 (R04-0474).


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Causal relationship of adverse event
Medical judgment should be used to determine the relationship, 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. Assessment of causal relationship should be recorded in the case report forms. 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
If a SAE is reported, the causal relationship must be provided by the investigator for all trial 
drugs, i.e. the BI trial drug and for all other trial drugs (i.e. perpetrator).
Worsening of underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF.
Changes in vital signs, ECG, physical examination and laboratory test results 
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator.
Protocol-Specified Significant Events
The following is considered as Protocol-Specified Significant Event:
Hepatic injury defined by the following alterations of liver parameters:  
an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood draw sample or
an isolated elevation of AST and / or ALT ≥5 fold ULN (without an elevation of 
bilirubin)
Patients showing these lab abnormalities need to be followed up according to             
Appendix 10.1.2 of this clinical trial protocol and the “DILI checklist” provided in             
the ISF.
Protocol-specified significant events are to be reported in an expedited manner similar to 
SAEs, even if they do not meet any of the seriousness criteria – for details please see Section 
5.2.2.2.
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the observational phase (=21 days 
after last drug administration)) will be collected, documented and reported to the sponsor by 


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the investigator on the appropriate eCRFs / SAE reporting forms. After this defined 
observational period only AEs and SAEs related to the study drug and/or study design have 
to be reported by the investigator. Reporting will be done according to the specific definitions 
and instructions detailed in the ‘Adverse Event Reporting’ section of the Investigator Site 
File. 
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
section 5.2.2.1. 
The investigator also has the responsibility to report any AEs occurring once informed 
consent has been signed and through 21 days after last dose of study administration. Any AEs 
reported to the sponsor during this phase must be documented in the safety database.AEs that 
are not yet recovered at the End of Treatment (EOT) visit will be followed until recovery or, 
in case of persistence, sufficient characterization of the toxic effects has been achieved and 
the investigator and the BI Clinical Monitor agree not to pursue them further.
Table 5.2.2.2:1
AE/SAE reporting requirements
Time period
Reporting requirements
Screening until 21 days after 
last drug intake
Report all AEs, SAEs regardless of relatedness. This includes all deaths.
Post-treatment 
(>21 days after last drug 
intake)
Report AEs and SAEs which are considered related to study drug or study 
design/ procedures. 
Please note: Acc. to this rule also Death will only be reported as SAE if 
considered study drug or study design/procedure related.
Patients may be admitted to hospital during selected phases of the study for administrative 
reasons, e.g., collection of blood for pharmacokinetic purposes. Hospitalizations for 
administrative reasons and other hospitalizations already planned at the screening visit need 
not be reported as a SAE when they are performed “as planned”.
The investigator must report the following events via fax using the SAE form immediately 
(within 24 hours) to the sponsor: SAEs and non-serious AEs occurring at the same time as an 
SAE and/or which are medically related to the SAE(s), and protocol-specified significant 
events. With receipt of any further information to these events, a follow-up SAE report has to 
be provided. SAEs and non-serious AEs must include a causal relationship assessment made 
by the investigator.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event. If the event description is correct, the item 


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“serious” needs to be ticked and an SAE has to be reported in expedited fashion following the 
same procedure as above. The list of these adverse events can be found via the RDC-system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs becomes available. 
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the Investigator Site File). The 
outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
Blood samples will be collected from venous blood at the time points indicated in the flow 
chart. Laboratory tests listed will be performed at the study sites and may be performed 
within 2 days prior to the visit day to allow a rapid decision whether the patient may be 
eligible for further therapy or not. All reference values of laboratory tests performed at study 
site should be provided to Boehringer Ingelheim.
Laboratory tests will include the parameters listed in Table 5.2.3:1.


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Table 5.2.3:1
Laboratory tests
Hematology
red blood cell count (RBC), haemoglobin, hematocrit, medium corpuscular volume 
(MCV), white blood cell count (WBC) with differential count, and platelets
Biochemistry
glucose, sodium, potassium, calcium, creatinine, aspartate amino transferase 
(AST), alanine amino transferase (ALT), alkaline phosphatase, gamma-glutamyl 
transferase (GGT) lactate dehydrogenase (LDH), total bilirubin, urea, total protein, 
albumin, uric acid, creatine phosphokinase (CPK) and troponin T
Coagulation 
parameters
prothrombin time (PT), international normalized ratio (INR) where therapeutically 
indicated and partial thromboplastin time (PTT)
Urinalysis (only at 
screening and EOT)
nitrite, protein, glucose, ketone bodies, urobilinogen, urine bilirubin,  erythrocytes, 
leucocytes, pH (all by urine dipstick)
Additional lab 
parameters for 
screening
hepatitis B surface antigen, hepatitis C antibody, HIV-1 and HIV-2 antibody (all 
qualitative)
urine drug screening, alcohol breath test
These parameters will be assessed at time points specified in the flow chart. In case of 
toxicity, adequate and more frequent blood sampling may be performed at the discretion of 
the investigator. In case of grade 4 neutropenia, blood must be collected seven days after the 
first occurrence of grade 4 neutropenia at the latest.
In case of pathological findings, further evaluation should be performed and the findings 
documented.
After approval of Protocol revision 3, safety laboratory examinations should be done as
medically indicated at discretion of the investigator. The results are not required to be entered
in the eCRF; documentation in the source data is sufficient. Only in case of findings that are 
qualifying as an (S)AE the respective (S)AE will be reported (eCRF and SAE form if 
applicable). 
5.2.4
Electrocardiogram
12-lead ECGs of 10 sec duration will be recorded after 5 minutes rest in supine position with 
every infusion of volasertib (prior to the start of infusion and immediately prior to the end of 
the volasertib infusion), additional ECGs will be recorded at all time points outlined in the 
flow chart. If ECG is in the same time point as safety lab, PK or PG sampling ECG should be 
recoded always before blood sampling. All ECGs must be digitally recorded in triplicate 
using dedicated equipment provided by a CRO. Study activities will be performed using radio 
controlled clocks. All other equipment using non-radio controlled clocks will be 
synchronized to the radio controlled watches before drug administration.


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Twelve-lead resting digital triplicate ECGs will be performed at the following visits:

Screening

Cycle 1 Visit 1:
o
Day 1, within 30 min prior to start of infusion of volasertib
o
Day 1, immediately prior to the end of infusion of volasertib (1:45 after start 
of infusion). The infusion should not be finished yet at that sampling time 
point.
o
Day 1, 3 hours after the start of infusion;
o
Day 1, 6 hours after the start of infusion
o
Day 2, 24 hours after the start of the infusion

Cycle 2 Visit 1:
o
Day 1, within 30 min prior to start of infusion of volasertib
o
Day 1, immediately prior to the end of infusion of volasertib (1:45 after start 
of infusion). The infusion should not be finished yet at that sampling time 
point.
o
Day 1, 3 hours after the start of infusion;
o
Day 1, 6 hours after the start of infusion
o
Day 2, 24 hours after the start of the infusion

Cycle 3 Visit 1
o
Prior to the start of volasertib infusion
o
Immediately prior to the end of infusion of volasertib (1:45 after start of 
infusion). The infusion should not be finished yet at that sampling time point.

End of treatment (EoT)
The recording will be checked for pathological results (to be recorded as baseline conditions 
or AEs according to 5.2.2.1) and signed by the investigator. In addition, a centralized 
evaluation of all 12-lead ECGs recorded will be performed by a CRO. 
The QTcF for each time point will be calculated as the mean of the 3 ECGs taken at that time 
point. The machine will calculate the QTcF each time but the investigator will calculate the 
mean of the 3 QTcF values obtained from the machine.
Additional ECGs should be performed whenever the investigator deems necessary.
In case of QTcF > 470 ms PRIOR to the planned start of infusion of volasertib, the trial drug 
should not be administered. Any other obvious potential reason for the QTcF prolongation 
(e.g. concomitant medication) should be investigated and eliminated if possible. The patient 
will be asked to lie down and relax for some time (at least 30 minutes). Then the QTcF will 


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be re-checked in triplicate. It is acceptable to give the volasertib infusion if the QTcF 
recovers to ≤470 ms on the repeat triplicate ECG just prior to the infusion. If the patient’s 
ECG does not improve (i.e, QTcF does not become ≤470 ms) upon resting, new ECGs should 
be performed at later time points;, volasertib should be administered as soon as QTcF is <470 
ms. 
In case of QTcF change from baseline (meaning prior to start of current infusion) > 60 ms 
with absolute QTcF ≤500 ms (Grade 2 CTCAE version 3.0) AFTER receiving volasertib, it is 
mandatory that patient remain at the investigative site after administration of volasertib for 
further ECG monitoring. The investigator will initiate further diagnostics (e.g. check 
electrolytes and check concomitant therapy that may be contributing to QTcF prolongation) 
and if required provide adequate treatment according to medical standards. The patient will 
be discharged from the investigative site after resolution of ECG findings (e.g. when the 
QTcF value is ≤470 ms on a single observation). If the patient qualifies for a subsequent 
volasertib administration (see Section 3.3.5), the dose of volasertib may be reduced by 50 mg 
(see Section 4.1.3.1) at the investigator’s discretion depending on the benefit/risk ratio 
assessed by the investigator. 
In case of QTcF prolongation to > 500 ms absolute (Grade 3 CTCAE version 3.0) AFTER 
receiving volasertib, it is mandatory that patient remain at the investigative site after 
administration of volasertib for further ECG monitoring. The investigator will initiate further 
diagnostics (e.g. check electrolytes and check concomitant therapy that may be contributing 
to QTcF prolongation) and if required provide adequate treatment according to medical 
standards. The patient will be discharged from the investigative site after resolution of ECG 
findings (e.g. when the QTcF value is ≤470 ms on a single observation). If the patient 
qualifies for a subsequent volasertib administration (see Section 3.3.5), the dose will be 
reduced (see Section 4.1.3.1). The volasertib infusion subsequent to the occurrence of QTcF 
>500 ms must be performed under a continuous ECG monitoring, with the possibility to 
transfer the patient to an intensive care unit in case of any issue.
In case of occurrence of symptoms suggestive of arrhythmia related to QTcF prolongation, 
patient will be hospitalized, a cardiologic evaluation will be performed and treatment 
provided according to medical standards. In case of occurrence of symptoms of left 
ventricular insufficiency, a cardiologic evaluation by a cardiologist and an echocardiogram 
must be performed.
In case of drug related ECG changes and whenever the investigator deems necessary, 
additional ECG monitoring will be performed in the respective and later cycles of treatment. 
After implementation of the Protocol revision 3, ECG  should be performed prior to and at 
the end of volasertib infusions as single reads using a local ECG machine without performing 
central ECG review. Only in case of findings that are qualifying as an (S)AE the respective 
(S)AE will be reported (eCRF and SAE form if applicable).


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5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Vital signs (blood pressure (BP) and pulse rate after 5 minutes supine rest) will be recorded at 
the screening visit and with every volasertib infusion at the following time points: pre-
infusion (after ECG) and 30 (+ 10), 60 (±10), 105 (-10) and 180 (±10) minutes after start of 
infusion of volasertib, on days 8 (168h) and 15 (336h) in the first two treatment cycle, at 
every visit during subsequent cycles, EOT and at FU.
After implementation of the Protocol revision 3, Vital signs should be collected as medically 
indicated at discretion of the investigator. The results are not required to be entered in the 
eCRF; documentation in the source data is sufficient. Only in case of findings that are 
qualifying as an (S)AE the respective (S)AE will be reported (eCRF and SAE form if 
applicable).
5.2.6
Dose reducing volasertib toxicity
Dose reducing volasertib toxicity (DRT) (i.e. unacceptable volasertib toxicity) is defined as:

Drug related CTCAE Grade 3 or greater non-haematological toxicity (except emesis 
or diarrhoea responding to supportive treatment; if drug related nausea, vomiting or 
diarrhea is sufficiently treated but nevertheless of grade ≥3 severity, this is 
considered), 
or

Drug related CTCAE Grade 4 neutropenia for more than 7 days
or 

Drug related CTCAE Grade 4 thrombocytopenia.
Patients who have experienced an unacceptable toxicity are eligible for re-treatment with 
volasertib at a reduced dose of volasertib as per section 4.1.3.1.
The maximum tolerated dose of co-administration of itraconazole and volasertib (MTD) is 
defined as the highest dose for which the incidence of DRT is no more than 1 out of 6 
patients.
5.3
OTHER
5.3.1
Other endpoint(s)
This section is not applicable in this study.


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5.3.2
Other assessment(s)
5.3.2.1
Physical examination, height, body weight, and performance status
A general physical examination will be performed at screening, at the end of each infusion in 
cycles 1 and 2, 15 days after start of infusion in cycle 1 and 21 days after start of infusion in 
cycle 2 as well as at the end of the treatment. The same investigator should perform this 
examination. Physical examination will include measurement of height and body weight and 
the evaluation of the ECOG performance score. Height will be documented only once at 
screening. Weight and ECOG score will also be assessed when volasertib treatment is started 
and at the end of the treatment. ECOG will also be assessed at the last visit of each cycle.
After approval of Protocol Revision 3, physical examinations, weight, and ECOG 
performance score should be done as medically indicated at discretion of the investigator. 
The results are not required to be entered in the eCRF; documentation in the source data is 
sufficient. In case of findings that are qualifying as an (S)AE the respective (S)AE will be 
reported (eCRF and SAE form if applicable).
5.3.2.2
Demographics and history
Demographics (sex, birth date, race), information on smoking and alcohol status, and baseline 
conditions will be collected during the screening.
History of tumour will also be obtained. The type of tumour, the date of first histological 
diagnosis (month and year may be sufficient), and the primary tumour site will be reported 
into the eCRF. The differentiation grade (not specified, poorly differentiated, moderately 
differentiated, well differentiated), the number and location of metastatic sites as well as the 
stage according to the tumour, (lymph) node, metastasis (TNM) classification and the
 / American Joint Committee on Cancers (AJCC) 
classification will be provided as obtained at diagnosis. It will also be recorded whether 
visceral involvement, bone involvement or soft tissue involvement is present (yes, no, 
unknown). Previous surgery will be reported. Previously administered radio-, chemo-, 
immuno-, molecular-targeted, and hormone therapy will be reported including start and end 
dates (month and year may be sufficient), the therapy protocol with the number of cycles 
(chemo-, immunotherapy), the best response obtained (complete response, partial response, 
stable disease, progressive disease, unknown) as well as whether the therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. Concerning previous radiotherapy the total 
radiation dose and radiation field will be recorded.
5.3.2.3
Concomitant diagnoses and/or therapy
Concomitant diagnoses and/or therapies present at study entry and/or during screening will be 
recorded in the eCRF.


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5.4
APPROPRIATENESS OF MEASUREMENTS
The assessments which will be performed in this study are standard, and generally recognised 
as being reliable, accurate and relevant.
5.4.1
Timing of assessments
Date and exact clock time of drug administration as well as of PK sampling must be 
recorded. The designation “before” on study Day 1 refers to the time period of 2 hours prior 
to drug administration, i.e. study measurements and assessments scheduled to occur “before” 
must be performed and completed within 2 hours prior to drug administration. For data 
management purposes, this pre-dose period is referred to in the flow chart and section 5.2 as 
-0:30 h.
A time window of +/- 5 % of the time from dosing to scheduled sample timepoint will be 
allowed for PK blood sampling. Nominal times should be adhered to as closely as possible. 
PK sampling time deviations of more than 5% will be identified and their handling discussed 
no later than at the last RPM before preliminary snapshot generation.
The duration of the volasertib infusion (planned 120 min) as well as interruptions if 
applicable will be documented (start and end time of the infusion) in the eCRF. Every attempt 
will be made to adhere to an infusion time of 120 min for volasertib with a constant infusion 
rate.
In the event assessments are planned for the same scheme time, the order of the assessments 
should be arranged in such a way that ECG will be performed before vital signs, followed by 
blood sampling. Blood sampling times should be adhered to as closely as possible.


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Blood for pharmacokinetic analysis will be collected at specified time points during the first 
and the second treatment cycle (see FlowChart) to determine the plasma concentration of 
volasertib, its clinical relevant metabolite CD 10899 (if feasible) and itraconazole. Further 
exploratory analysis for identification of drug metabolites could be done if applicable. If 
these additional analyses are performed, the results will be reported separately. The actual 
sampling date and time for blood samples will be documented in the eCRF. These actual 
sampling times will be used for determination of pharmacokinetic parameters. 
Please note that for a valid PK analysis, it is of utmost importance to document the exact 
clock time of trial medication administration. The duration of the volasertib infusion (planned 
2 hours) will be documented (start and end time of the infusion as well as interruptions) in the 
eCRF. Every attempt will be made to adhere to an infusion time of 2 hours for volasertib with 
a constant infusion rate.
5.5.1
Pharmacokinetic endpoint(s)
Pharmacokinetic parameters will be evaluated by means of noncompartmental analysis. The 
derivation of pharmacokinetic parameters is described in detail in the internal SOP 001-
MCS-36-472_RD-01.
Primary endpoints (volasertib and CD 10899):

maximum measured plasma concentration (Cmax)

area under the plasma concentration-time curve over the time interval from zero 
to the last quantifiable drug plasma concentration after dose administration (AUC0-tz)
Secondary endpoint (volasertib and CD 10899):

area under the plasma concentration-time curve over the time interval from zero 
extrapolated to infinity (AUC0-∞)


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All pharmacokinetic measurements will be performed only in first two treatment cycles.
5.5.2
Methods of sample collection
Actual date and time of blood collection together with the patient number should be recorded 
in the eCRF. 
5.5.2.1
Blood sampling
During the trial PK blood samples will be collected to determine the concentration of 
volasertib, its metabolite CD 10899 (if feasible) and itraconazole in plasma.
PK blood samples before start of infusion and shortly before end of infusion will be taken 
from a forearm vein contralateral to the infusion site. For patients having a central venous 
catheter, volasertib may be administered using this device and PK blood samples should be 
obtained from either forearm. For planned times please refer to the Flow Chart.
Cycle 1:
For quantification of plasma concentrations of volasertib, the metabolite CD 10899, and 
itraconazole, around 4 mL of venous blood will be taken in a potassium EDTA 
(ethylendiaminetetraacetic acid)-anticoagulant blood drawing tube (e.g. Vacutainer® or 
Monovette) at the time points specified in the FlowChart. 
The sampling tubes have to be mixed immediately with the anticoagulant by gently inverting 
about 10 times. Vigorous shaking should be avoided to prevent haemolysis. The whole blood 
is to be centrifuged at 4-25°C at approximately 3000 rpm (~2100 g) for at least 15 minutes. 
Centrifugation should be done within 60 min after sampling. The blood samples should be 
stored at room temperature or below until centrifugation.
From each blood sample, transfer immediately three aliquots of EDTA plasma (at least 
500 µL each, aliquot 1 for volasertib/CD 10899, aliquot 2 for itraconazole, and aliquot 3 as 


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back-up) into carefully and unique labelled cryovials. Blood sample should be transferred 
always into three aliquots independent of analysis that will be performed for this time point.
Please check the patient number and planned sampling time. The visit, the exact time 
(hh:mm, 24 h-clock time) and date (month in letter) of sampling are to be recorded in the 
eCRF. 
Cycle 2:
For quantification of plasma concentrations of volasertib and its metabolite CD 10899 around 
4 mL of venous blood will be taken in a potassium EDTA (ethylendiaminetetraacetic acid)-
anticoagulant blood drawing tube (e.g. Vacutainer® or Monovette) at the time points 
specified in the FlowChart. 
The sampling tubes have to be mixed immediately with the anticoagulant by gently inverting 
about 10 times. Vigorous shaking should be avoided to prevent haemolysis. The whole blood 
is to be centrifuged at 4-25°C at approximately 3000 rpm (~2100 g) for at least 15 minutes. 
Centrifugation should be done within 60 min after sampling. The blood samples should be 
stored at room temperature or below until centrifugation.
From each blood sample, transfer immediately two aliquots of EDTA plasma (at least 600 µL 
each, aliquot 1 for volasertib/CD 10899 and aliquot 2 as back-up) into carefully and unique 
labelled cryovials. Please check the patient number and planned sampling time. The visit, the 
exact time (hh:mm, 24 h-clock time) and date (month in letter) of sampling are to be recorded 
in the eCRF.
The plasma samples have to be stored at -20°C or below at the clinical site until shipment on 
dry ice to the analytical laboratory. They also will be stored at the analytical laboratory at 
-20°C or below until analysis.


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5.6
BIOMARKER(S) 
During the course of the study no biomarker will be determined. 
5.6.1
Endpoints based on biomarker(s) 
This section is not applicable in this study.
5.6.2
Methods of sample collection
This section is not applicable in this study.
5.6.3
Analytical determinations
This section is not applicable in this study.
5.7
PHARMACODYNAMICS
This section is not applicable in this study.
5.7.1
Pharmacodynamic endpoints
This section is not applicable in this study.
5.7.2 
Methods of sample collection
This section is not applicable in this study.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
In this study, no pharmacokinetic-pharmacodynamic relationship will be studied.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
The patients will stay at the investigator site from the evening before first itraconazole 
administration (day -4) until day 4 of the first cycle as well as from the day before 
intravenous infusion of volasertib until 72 hours after start of infusion of the second cycle 
(day -1 until day 4). Ambulatory visits will happen 168 hours (day 8), 336 hours (day 15) and 
504 hours (day 22) after start of infusion, where the last visit may coincide with day 1 of 
consecutive treatment cycles. In this case the blood sample for PK has to be taken before 
administration of the study drug. 
Procedures will be performed as outlined in the flow chart. In third and subsequent treatment 
cycles the patient will visit the investigator at regular intervals as specified in the flow chart 
(visit 2 and 3 are optional visits at the investigator’s discretion) for determination of safety 
laboratory parameters, recording of adverse events and additional procedures as outlined in 
the flow chart. If a patient misses a visit and the patient reports to the investigator between 
this and the next scheduled visit, the missed visit should be performed with the actual date 
and the reason should be given for the delayed visit. The next visit, however, should take 
place as scheduled relative to the first administration of the trial drug in the treatment cycle.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period
The screening phase (screen visit) i.e. after informed consent and prior to the first 
administration of the trial drug may be up to 14 days in duration. After written informed 
consent has been obtained, the investigator should perform the procedures required for 
screening within 14 days and prior to the first treatment within the trial.
The following will be obtained and / or performed:

Informed consent and patient information

Demographics (sex, birth date, race)

Medical history (oncological, relevant non-oncological, smoking status, alcohol 
consumption)

Physical examination including body height, weight, vital signs and ECOG performance 
score

Patient eligibility (inclusion and exclusion criteria)

Concomitant therapy

Drugs of abuse in urine and alcohol breath test

Resting 12-lead ECG

Safety laboratory (no repeat examination in case a safety laboratory investigation has 
been performed within 14 days before the screening visit), including urine dipstick


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
Coagulation parameters
pregnancy test for women of childbearing potential - women of childbearing potential 
(premenopausal female patient) is defined as the female patient who is not surgically 
sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least 12 
months. 
6.2.2
Treatment period
6.2.2.1
First Treatment Cycle
The first treatment cycle will be performed under partially hospitalised conditions: For 
detailed timing of the assessments please refer to the flow chart.

Physical examination

Review of in- and exclusion criteria

ECOG performance score

Body weight

ECG

Vital signs 

Oral administration of itraconazole in 24 hour intervals

Intravenous administration of volasertib

Blood sampling for determination of volasertib, CD 10899 
concentrations in plasma

Blood sampling for pharmacogenetics

Safety lab parameters (without urinalysis)

Coagulation parameters

Occurrence of AEs since enrolment

Changes in concomitant therapy

Clinical tumour assessment

Review of patient eligibility for repeated treatment cycles
6.2.2.2
Second Treatment Cycle
The second treatment cycle will be performed under partially hospitalised conditions: For 
detailed timing of the assessments please refer to the flow chart.

Physical examination

Review of in- and exclusion criteria

ECOG performance score

Body weight

ECG

Vital signs 

Intravenous administration of volasertib

Blood sampling for determination of volasertib and CD 10899 concentrations in plasma


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
Safety lab parameters (without urinalysis)

Coagulation parameters

Occurrence of AEs since enrolment

Changes in concomitant therapy

Clinical tumour assessment

Review of patient eligibility for repeated treatment cycles

pregnancy test for women of childbearing potential - women of childbearing potential 
(premenopausal female patient) is defined as the female patient who is not surgically 
sterilised by hysterectomy or bilateral tubal ligation, or post-menopausal for at least 12 
months.
6.2.2.3
Subsequent treatment cycles (non-DDI)
After implementation of Protocol revision 3, safety laboratory parameters and additional 
investigations (body weight, ECOG, vital signs, physical examination etc) at subsequent 
treatment cycles will be done as medically indicated at discretion of the investigator. 
Investigator will continue recording ECG prior and at the end of volasertib infusion to ensure 
patient safety. For this purpose investigator will use local ECG machine, centralized ECG 
analysis will be discontinued. Findings that are qualifying as an (S)AE the respective (S)AE 
will be reported (eCRF and SAE form if applicable).
Clinical response assessment will be done after every cycle, radiological assessment at the 
investigator’s discretion. After implementation of the Protocol revision 3, this efficacy data 
will be recorded in the source data only; documentation in the eCRF is not required.
6.2.2.3.1 Visit 1 (Day 1 of volasertib administration)
On the treatment day, the following will be obtained and / or performed:

Physical examination

ECOG performance score

Body weight

ECG

Vital signs

Clinical tumour assessment

Safety lab parameters (without urinalysis)

Coagulation parameters

Administration of volasertib

Occurrence of AEs since enrolment

Changes in concomitant therapy


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6.2.2.3.2 Visits 2 and 3 (day 8 and 15)
Visits 2 and 3 are optional from the second cycle onwards; the visits may be omitted at the 
discretion of the investigator. At these visits, the following will be obtained and / or 
performed:

Vital signs

Occurrence of AEs since last visit

Changes in concomitant therapy

Safety lab parameters (without urinalysis)
6.2.2.3.3 Visit 4 (day 22)
Visit 4 (day 22) is the last visit in the repeated treatment cycle. This visit may coincide with 
day 1 of the following treatment cycle. Examinations which are due at both the present visit 
and the day of volasertib administration need only to be documented once:

Physical examination

ECOG performance score

Body weight

Vital signs

Occurrence of AEs since last visit

Changes in concomitant therapy

Safety lab parameters (without urinalysis)

Coagulation parameters

Tumour assessment at the end of each cycle

Review of patient eligibility for repeated treatment cycles

pregnancy test after every other cycle for women of childbearing potential - women of 
childbearing potential (premenopausal female patient) is defined as the female patient 
who is not surgically sterilised by hysterectomy or bilateral tubal ligation, or post-
menopausal for at least 12 months.
6.2.3
End of trial and follow-up period
6.2.3.1
Visit at the end of treatment
The end of treatment (EOT) information should be obtained when the patient concludes 
active treatment in the trial, along with the information obtained at the visit scheduled for that 
time point. If the patient concludes the trial mid-way through a treatment cycle and not at the 
end of a treatment cycle, the required end of cycle information should also be collected at this 
time.
The following will be obtained and / or performed:


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
Termination of patient's active treatment (including reason for termination or if applicable 
premature discontinuation of trial, date of last administration of the trial drug)

Patient status: in case the patient had PD the date of first diagnosis of PD has to be 
recorded

Physical examination, ECOG score, body weight, and vital signs

ECG

Safety laboratory, including coagulation parameters and urinalysis 

Occurrence of AEs since last visit

Changes in concomitant therapy

Clinical tumour assessment
6.2.3.2
Follow-up visit
Follow-up visits will be performed after the EOT visit for patients who are not eligible for 
further treatment cycles until progression of disease, death, treatment with any other anti-
tumour therapy, patient is lost to follow-up, or agreement between sponsor and principal 
investigator not to pursue further follow up visits.
Follow-up visits should be performed at 3 months intervals or earlier if appropriate. Follow-
up visits may also be performed by telephone interview in case the patient is unable to visit 
the investigator. 
The following will be obtained and / or performed.

Occurrence of AEs since last visit in case they are considered drug-related

Follow-up of AEs in case they were not yet recovered at EOT

ECOG performance score

Treatment with any other anti-tumour drug

Patient status: date of and reason for death (if applicable), date of progression (in case, the 
patient experienced PD)
If visit is performed by telephone interview at least information on progression, date of 
progression and date of death should be obtained.
After approval of Protocol Revision 3, Follow-up is completed 21 days after discontinuation 
of study drug.
6.2.3.3 End of trial
The clinical trial will be considered completed as soon as the last patient has died or was lost 
to follow-up. If patients are still on treatment at the time the trial report is written, these 
patients will either be included in a follow-up trial or alternatively kept on treatment in this 
trial. If patients are kept on treatment in this trial then additional data will be reported in an 
adequate format in appropriate reporting timelines after all of these patients will have 
completed follow-up.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
Objectives
The primary objective of the present study is to investigate the influence of co-administration 
of itraconazole, a potent dual inhibitor of cytochrome P450 3A4 and P-gp, and volasertib 
(Test, T) on the pharmacokinetic profile of volasertib without co-administration of 
itraconazole (Reference, R). Therefore the relative bioavailability of volasertib will be 
assessed. 
Design
The study will be conducted according to an open-label, randomised, fixed sequence design. 
The comparisons will be intra-individual (each subject serves as his own control) and the 
precision is therefore expected to be higher than with a between-subject comparison [R94-
1529]. The uncontrolled design with respect to potential time effects is unavoidable but still 
expected to deliver valid results on the volasertib PK.
Primary endpoints
Relative bioavailability of volasertib and its main metabolite CD 10899 is primarily to be 
determined on the basis of the parameters AUC0-tz, and Cmax (see Section 5.5.1). The 
derivation of these primary parameters is given in the internal SOP 029-DCP-102.
Secondary endpoints
The AUC0-∞of volasertib and its main metabolite CD 10899 will be statistically assessed 
using the same methods as described for the primary endpoints.
The derivation of these PK parameters is presented in the internal SOP 029-DCP-102.
Safety and tolerability will be determined on the basis of the following parameters: adverse 
events, ECG, and clinical lab tests. 


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The derivation of these PK parameters is presented in the internal SOP 001-MCS-36-
472_RD-01.
If deemed necessary, statistical assessments will be conducted.
Model
The statistical model used for the analysis of the primary and secondary PK endpoints will be 
an ANOVA (analysis of variance) model on the logarithmic scale. This model will include 
effects accounting for the following sources of variation: ‘subject’ and ‘treatment’. The effect 
‘subject’ will be considered as random, whereas the ‘treatment’ effect will be considered as 
fixed. For tests on treatment effects, the denominator sum of squares will be the sum of 
squares for error in the comparison R – T. The model is described by the following equation
ykm = µ + sm + k + ekm , where
ykm = logarithm of response measured on subject m receiving treatment k,
µ = 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.
The subdivision into male / female subjects is not expected to have influence on the intra-
individual treatment comparisons and therefore 'sex' is not a model term.
In case the MTD of co-administration of itraconazole and volasertib is less than 300mg, dose 
will be considered in the ANOVA model to correct for the different starting doses of the 
patients. The model will take into account the dose proportionality established for volasertib. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of volasertib in combination with itraconazole compared 
volasertib alone will be investigated descriptively by applying the average bioequivalence 
method to the ratio between PK parameters (AUC0-tz and Cmax ). No confirmatory hypothesis 
will be tested.


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7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The pharmacokinetic parameters AUC0-tz and Cmax will be log-transformed (natural 
logarithm) prior to fitting the ANOVA model. The difference between the expected means 
for log(T)-log(R) will be estimated by the difference in the corresponding Least Square 
Means (point estimate) and 2-sided 90% confidence intervals based on the t-distribution will 
be computed. These quantities will then be back-transformed to the original scale to give the 
point estimator and interval estimates for the geometric mean intra-subject ratio between 
response under test and response under reference.
All evaluable subjects who received at least one dose of volasertib will be included in the 
pharmacokinetic analysis. Subjects who are considered as not evaluable will be listed with 
their individual plasma concentrations and individual pharmacokinetic parameters, however, 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters or other statistical assessment.
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Noncompartmental pharmacokinetic analyses of the plasma 
concentration-time data will be performed using a validated software program, e.g. 
Winnonlin Version 5.2. Only concentrations within the validated concentration range will be 
used for the calculation of pharmacokinetic parameters. For pre-dose samples, the actual 
sampling time will be set to zero.
Plasma concentrations will be plotted graphically versus time for all evaluable subjects as 
listed in the drug plasma concentration-time tables. For the presentation of the mean profiles, 
the geometric and arithmetic mean and the planned blood sampling times will be used. If the 
actual sampling time deviates significantly from the planned time, the corresponding plasma 
concentration will be excluded from the calculation of descriptive statistics.
The following descriptive statistics will be calculated for analyte concentrations as well as for 
all pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, 
maximum, arithmetic coefficient of variation, geometric mean, and geometric coefficient of 
variation. The data format for descriptive statistics of concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of pharmacokinetic 
parameters will be calculated using the individual values with the number of decimal places 
as provided by the evaluation program. Then the individual values as well as the descriptive 
statistics will be reported with three significant digits in the clinical trial report. 


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7.3.2
Secondary analyses
7.3.2.1
Secondary pharmacokinetic parameters
Relative bioavailability will not be assessed for secondary pharmacokinetic parameters. Apart 
from this, the same methods as described for primary pharmacokinetic endpoints will be used 
to analyse the secondary endpoints.
7.3.2.2
Safety and tolerability analyses 
Refer to section 7.3.3 for a description of the analysis of safety and tolerability.
7.3.3
Safety analyses
All patients who receive at least one dose of study drug will be included in the safety 
evaluation. Safety analyses will be performed in accordance with BI standards.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Adverse events occurring prior to drug administration will be assigned to the 
screening period. Adverse events occurring within 21 days of most recent volasertib infusion 
will be considered to be on treatment.
Independent of this rule, the relationship of an adverse event to the study drug treatments will 
be assessed by the investigator. Adverse event information as reported in the eCRFs will be 
aggregated in a two step process. First, multiple recordings (AE occurrences) of the same 
adverse event will be combined into one AE episode (collapsing). The second step will 
combine all of the AE episodes of an adverse event into one AE record as needed for by-
patient summaries (condensing). 
Reporting of adverse events and laboratory data will follow the standard BI procedures. The 
analysis of adverse events will comprise various frequency tabulations. Tables will be 
produced for treatment cycle 1 (co-administration of volasertib and itraconazole), treatment 
cycle 2 (volasertib alone) and for all treatment cycles combined. DRTs and the MTD (see 
Section 5.2.6) will be reported.
Laboratory values will be listed, tabulated and compared with their reference ranges. They 
will also be assessed with regard to possible changes compared to baseline values and with 
regard to the comparison of the first and second treatment cycle. The frequency of possible 
clinically significant abnormalities will be tabulated.
Safety will also be assessed by evaluation of physical examination (see Section 7.3.8), vital 
signs (blood pressure, pulse rate) and 12-lead ECG. Change from screening and/or baseline 
as well as change between treatment cycle 1 and 2 will be compared descriptively.


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7.3.4
Interim analyses
No formal interim analysis is planned. However a review of all data relevant for safety will 
be performed after the first three patients were included. In case of unacceptable toxicity, the 
dose of drug might be reduced to 250 mg or 200 mg according to the dose deescalation 
scheme in Section 3.1. Therefore, reviews of safety will be performed after cohorts of three 
patients have been dosed.
7.3.5
Pharmacokinetic analyses
Refer to Section 7.3.1, 7.3.2.1 and 7.3.8 for primary, secondary 
 
analyses.
7.3.6
Biomarkers, pharmacodynamic analyses and pharmacokinetic –
pharmacodynamic relationship
This section is not applicable in this study.
7.3.8
Other analyses
Preliminary therapeutic effects of volasertib based on the investigator response assessment 
will be summarised descriptively.
Physical examination data will be summarised descriptively.
Demographics, tumour history as well as concomitant diagnoses and/or therapy will be 
summarised descriptively.


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7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma concentration - time profiles
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not 
analyzed), BLQ (below the limit of quantification), and NOP (no peak detectable) will be 
ignored and not replaced by zero at any time point (applies also to the lag phase). Descriptive 
statistics of concentrations at specific time points will be calculated only when at least 2/3 of 
the individuals have concentrations within the validated concentration range. The overall 
sample size to decide whether the “2/3 rule” is fulfilled will be based on the total number of 
samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA, NOP are 
included).
7.4.3
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. All other BLQ/NOP values of the profile will be ignored.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis. 

If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the tables in 
section 15 of the clinical trial report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. PK parameters which cannot be determined will be identified 
by "not calculated" (NC).


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7.4.4
Efficacy
With respect to efficacy evaluations, it is not planned to impute missing values.
7.5
RANDOMISATION
This is a fixed sequence design; no randomization to a treatment or sequence is necessary.
7.6
DETERMINATION OF SAMPLE SIZE
The planned sample size of 24 evaluable patients is not based on a power calculation, but is 
conventional, and is judged as being adequate for the objectives of this study. This sample 
size considers that patients who were withdrawn during the first treatment cycle will be 
replaced. Ideally, the patients should be subdivided 12+12 into male and female subjects but 
for practical reasons a minimum of 8 subjects of each sex is acceptable.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study patients against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
Hungarian data protection regulations will apply to the personal data generated throughout 
this trial.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND 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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’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 patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs 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
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB  review and 
regulatory inspection, providing direct access to all related source data / documents. eCRFs 
and all source documents, including progress notes and copies of laboratory and medical test 
results must be available at all times for review by the sponsor’s clinical trial monitor, auditor 
and inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA) / on 
site monitor and auditor may review all eCRFs, and written informed consents. The accuracy 
of the data will be verified by reviewing the documents described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For the BI 6727 this is the current version of the Investigator’s Brochure (U05-2201) or the 


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Company Core Data Sheet (CCDS). The current versions of these reference documents are to 
be provided in the ISF. No AEs are classified as listed for matching placebo, study design, or 
invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated 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 and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient out, unless specified differently in section 6.2.3 of the CTP) or 
early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P09-06192
Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, 
Haslinger C, Garin-Chesa P, Adolf GR. BI 6727, a Polo-like kinase inhibitor 
with improved pharmacokinetic profile and broad antitumor activity. Clin 
Cancer Res 2009;15(9):3094-3102.
P09-09644
Renner AG, Santos C dos, Recher C, Bailly C, Creancier L, Kruczynski A, 
Payrastre B, Manenti S. Polo-like kinase 1 is overexpressed in acute myeloid 
leukemia and its inhibition preferentially targets the proliferation of leukemic 
cells. Blood 2009;114(3):659-662
P10-07075
Gil T, Schoffsky P, Awada A, Dumez H, Bartholomeus S, Selleslach J, Taton 
M, Fritsch H, Glomb P, Munzert GM. Final analysis of a phase I single dose-
escalation study of the novel polo-like kinase 1 inhibitor BI 6727 in patients 
with advanced solid tumors. 46th Ann Mtg of the American Society of 
Clinical Oncology (ASCO), Chicago, 4 - 8 Jun 2010 J Clin Oncol
2010;28(15S)(Suppl):248S Abstr 3061
P11-14366
Schoffski P, Awada A, Dumez H, Gil T, Bartholomeus S, Wolter P, Taton M, 
Fritsch H, Glomb P, Munzert G. A phase I, dose-escalation study of the novel 
Polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid 
tumours. 20th EORTC-NCI-AACR Symp on Molecular Targets and Cancer 
Therapeutics, Geneva, 21 - 24 Oct 2008; 46th Ann Mtg of the American 
Society of Clinical Oncology (ASCO), Chicago, 4 - 8 Jun 2010 European 
Journal of Cancer, Article in Press, Available online 24 November 2011, doi: 
10.1016/j.ejca.2011.11.001 Eur J Cancer 2012;48(2):179-186.
R04-0028 
Donaldson MM, Tavares AAM, Hagan IM, Nigg EA, Glover DM. The mitotic 
roles of polo-like kinase. J Cell Sci 2001;114(13):2357-2358.
R04-0030
Liu X, Erikson RL. Polo-like kinase (Plk)1 depletion induces apoptosis in 
cancer cells. Proc Natl Acad Sci USA 2003;100(10):5789-5794.
R04-0031 
Wolf G, Elez R, Doermer A, Holtrich U, Ackermann H, Stutte HJ, et al. 
Prognostic significance of polo-like kinase (PLK) expression in nonsmall cell 
lung cancer. Oncogene 1997;14:543-549.
R04-0034 
Takahashi T, Sano B, Nagata T, Kato H, Sugiyama Y, Kunieda K, et al. 
(2003) Polo-like kinase 1 (PLK1) is overexpressed in primary colorectal 
cancers.Cancer Sci 2003;94(2):148-52.


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R04-0321 
Smith MR, Wilson ML, Hamanaka R, Chase D, Kung H, Longo DL, et al. 
Malignant transformation of mammalian cells initiated by constitutive 
expression of the polo-like kinase. Biochem Biophys res Commun 
1997;234(2):397-405
R04-0415
Swanton C. Cell-cycle targeted therapies. Lancet Oncol 2004;5:27-36
R04-0421 
Nigg EA. Mitotic kinases as regulators of cell division and its checkpoints. 
Nat Rev Mol Cell Biol 2001;2:21-32.
R04-0422 
Smits VAJ, Klompmaker R, Arnaud L, Rijksen G, Nigg EA, Medema RH. 
Polo-like kinase-1 is a target of the DNA damage checkpoint. Nature Cell Biol 
2000;2:672-676.
R04-0423 
Spaenkuch-Schmitt B, Bereiter-Hahn J, Kaufmann M, Strebhardt K. Effect of 
RNA silencing of polo-like kinase-1 (PLK1) on apoptosis and spindle 
formation in human cancer cells. J Natl Cancer Inst 2002;94(24):1863-1877.
R04-0474
Cancer therapy evaluation program, common terminology criteria for adverse 
events, Version 3.0, DCTD, NCI, NIH, DHHS, 31 March 2003, Publish Date: 
12 December 2003.
R94-1529 
Chow SC, Liu JP, editors. Design and Analysis of Bioavailability and 
Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
9.2
UNPUBLISHED REFERENCES
U05-1984
 Synthesis of [benzamide-carbonyl-14C]BI 6727 CL3,
15 August 2005.
U05-2201
Investigator’s Brochure: BI 6727, Version 7, 24 May 2012.
U08-2116
Volasertib Solution for Infusion 100 mL (2 mg/mL).7 July 2011
U08-3450
Investigation in the permeability 
and interaction with P-glycoprotein of BI 6727 CL3 using the Caco-2 cell in 
vitro absorption model.25 June 2008


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in section 5.2.2.1 (Protocol-Specified
Significant Events), are to be further evaluated using the following procedures:
10.1.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48
to 72 hours and provide additional blood sample to the central laboratory for automatic reflex
testing of the below listed laboratory parameters. Only in case whereby the central laboratory
is not immediately available (e.g. if the logistics are such that the patient´s repeat specimen
would not reach the central laboratory in a reasonable timeframe), ALT, AST, and bilirubin
(total and direct) will be evaluated by local laboratory and results are made available to the
investigator and to BI as soon as possible. If in such a case ALT and/or AST ≥3 fold ULN
combined with an elevation of total bilirubin ≥2 fold ULN or an isolated elevation of AST 
and / or ALT (without an elevation of bilirubin) are confirmed, results of the
laboratory parameters described below must be made available to the investigator and to BI
as soon as possible.
In addition,

obtain detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF

obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the “DILI checklist” provided in the ISF

obtain history of exposure to environmental chemical agents (consider home and work
place exposure) according to the “DILI checklist” provided in the ISF
and report these via the CRF.
Biochemistry:
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, ceruloplasmin, α-1 antitrypsin,
transferrin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology:
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HBsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-
HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, 
Antimitochondrial antibody, Epstein Barr virus (VCA IgG, VCA IgM), cytomegalovirus 


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(IgG, IgM), herpes simplex virus (IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), 
toxoplasmosis (IgG, IgM)


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11.DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
10 Dec 2012
EudraCT number
2011-002367-23
BI Trial number
1230.24
BI Investigational Product(s)
Volasertib
Title of protocol
An open-label fixed sequence trial to 
investigate the potential drug-drug interaction 
of intravenous volasertib co-administered with 
a P gp and CYP3A4 inhibitor (itraconazole 
p.o.) in patients with various solid tumours
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
TREATMENT CYCLE 1 (volasertib with 
itraconazole) flow chart
Description of change
Change 1:
Footnote 10. was added
Change 2:
Footnote 11. was added
Change 3:
Footnote 12. was added
Rationale for change
Changes 1 and 2:
To specify volasertib and CD 10899 metabolite
and/or itraconazole to be analysed at certain 
timepoints.
Change 3:
To clarify PK sampling in relation to itraconazole 
intake.
Section to be changed
5.2.4 Electrocardiogram


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Description of change
Change 1:
PGx changed to PG
Change 2 and 3:
nabios was deleted
Rationale for change
Change 1:
Typo correction.
Changes 2 and 3:
Another vendor will provide central ECG.
Section to be changed
5.3.3 Pharmacogenomic evaluation
Description of change
To specify PG sampling time and correct tubes to 
be used
Rationale for change
Minor clarifications to PG sampling.
Section to be changed
5.5.2.1 Methods of sample collection, Blood 
sampling
Description of change
Change 1:
A sentence was added for central venous catheter.
Change 2:
Following sentence was added: “Blood sample 
should be transferred always into three aliquots 
independent of analysis that will be performed for 
this time point.”
Rationale for change
Change 1:
To clarify taking PK blood sample at patients 
with central venous catheter.
Change 2:
To clarify PK sample handling.
Number of global amendment
2
Date of CTP revision
12 June 2014
EudraCT number
2011-002367-23
BI Trial number
1230.24
BI Investigational Product(s)
Volasertib
Title of protocol
An open-label fixed sequence trial to 
investigate the potential drug-drug interaction 
of intravenous volasertib co-administered with 
a Pgp and CYP3A4 inhibitor (itraconazole 
p.o.) in patients with various solid tumours
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 


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Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
CLINICAL TRIAL PROTOCOL SYNOPSIS
Description of change
Change 1:
‘Objective’ was changed to ‘endpoint’.
Change 2:
A sentence was added for PK measurements.
Change 3:
‘Assessment’ was added for efficacy and safety.
Rationale for change
Change 1:
The mentioned parameters are endpoints no 
objectives.
Change 2:
PK samples are taken only in the first two 
treatment cycles.
Change 3:
To clarify these parameters.
Section to be changed
ABBREVIATIONS
Description of change
Aet1-t2, CLR,t1-t2 and fe t1-t2 parameters were 
deleted.
Rationale for change
Typo; urine sample is not collected thus these 
parameters are not calculated.
Section to be changed
4.1.1. Identity of BI investigational product and 
comparator product(s)
Description of change
Change 1:
175 mL vial was added with content.
Change 2:
Content for 100 mL vial was deleted for daily 
dose.
Rationale for change
Changes 1:
In next IMP re-supply 175 mL vials will be 
provided instead of 100 mL; both vial sizes will 
be permitted to usage.
Change 2:
Content was applicable only for 100 mL vial.
Section to be changed
Table 4.1.4.1: 1 Treatments to be administered in 
the first treatment cycle
Description of change
175 mL vial was added with content as well as 
no. of vial to be used.


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Rationale for change
As of next IMP re-supply both vial sizes will be 
permitted to usage.
Section to be changed
Table 4.1.4.2: 1 Treatments to be administered in 
the second treatment cycle
Description of change
175 mL vial was added with content as well as 
no. of vial to be used.
Rationale for change
As of next IMP re-supply both vial sizes will be 
permitted to usage.
Section to be changed
4.1.6 Packaging, labelling, and re-supply
Description of change
Change 1:
175 mL was also added as well as 350 mg 
respectively.
Rationale for change
In next IMP re-supply 175 mL vials will be 
provided instead of 100 mL.
Section to be changed
5.2.1
Endpoint(s) of safety
Description of change
Adverse event was deleted as endpoint, however 
added that it will be also assessed.
Rationale for change
Adverse event is not an endpoint.
Section to be changed
5.2.2.1 Definitions of adverse events
Description of change
Isolated elevation of AST and / or ALT clarified.
Rationale for change
Typo correction.
Section to be changed
5.5.1 Pharmacokinetic endpoint(s)
Description of change
Change 1:
SOP number corrected.
Change 2:
‘Objective’ was changed to ‘endpoint’.
Change 3:
AUC0-tz336 hours changed to the last 
quantifiable drug plasma concentration after dose 
administration.
Change 4:
Under Other objectives the last three parameters 
were deleted.
Change 5:
A sentence was added for PK measurements.
Rationale for change
Change 1:
To reflect current applicable SOP.
Change 2:
The mentioned parameters are endpoints no 
objectives.
Change 3:
To clarify AUC0-tz  
Change 4:
Typo; urine sample is not collected thus these 
parameters cannot be calculated.


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Change 5:
PK samples are taken only in the first two 
treatment cycles.
Section to be changed
7.1 STATISTICAL DESIGN - MODEL
Description of change
Change 1:
Ae0-tz, fe0-tz, CLR,t1-t2 parameters were deleted.
Change 2:
SOP number corrected.
Change 3:
A sentence was added for statistical assessments.
Rationale for change
Change 1:
Typo; urine sample is not collected thus these 
parameters are not calculated.
Change 2:
To reflect current applicable SOP.
Change 3:
Statistical assessments are not described clearly.
Number of global amendment
3
Date of CTP revision
30 Jan 2017
EudraCT number
2011-002367-23
BI Trial number
1230.24
BI Investigational Product(s)
Volasertib
Title of protocol
An open-label fixed sequence trial to 
investigate the potential drug-drug interaction 
of intravenous volasertib co-administered with 
a Pgp and CYP3A4 inhibitor (itraconazole 
p.o.) in patients with various solid tumours
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only


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Section to be changed
Title Page
Description of change
Trial clinical monitor name and telephone number 
were changed. 
Rationale for change
Trial clinical monitor has been changed in the 
trial. 
Section to be changed
Flowchart (subsequent treatment cycles)
Description of change
Change 1: Physical examination, ECOG 
performance score, body weight, vital signs, ECG 
Safety lab parameters, coagulation parameters 
were updated.
Change 2: Follow up visit should  be performed 
21 days after discontinuation of study drug. 
Rationale for change
Due to discontinuation of the Volasertib program 
the procedures of the study have been simplified 
and to be done in accordance with local standard 
of care. ECG will not be centrally evaluated and 
to be performed by using local ECG device. 
Section to be changed
3.1 Overall trial design and plan
5.1.1 Endpoints of efficacy
5.1.2 Endpoints of safety 
5.2.3 Assessment of safety laboratory parameters
5.2.4 Electrocardiogram 
5.2.5.1 Vital signs
5.3.2.1 Physical examination, height, body weight 
and performance status
6.2.2.3 Subsequent treatment cycles (non-DDI) 
Description of change
Text stating that physical examination, ECOG 
performance score, body weight, vital signs, ECG 
Safety lab parameters, coagulation parameters 
will be done in accordance with local standard of 
care. ECG will not be centrally evaluated and to 
be performed by using local ECG device.
Efficacy data will be recorded in the source data 
only; documentation in the eCRF is not required.
Rationale for change
Due to discontinuation of the Volasertib program 
the procedures of the study have been simplified 
and to be done in accordance with local standard 
of care. 
Section to be changed
6.2.3.2 Follow up visit
Description of change
Follow up visit should be performed 21 days after 
discontinuation of study drug. 
Rationale for change
Due to discontinuation of Volasertib program the 
procedures of the study have been simplified and 
to be done in accordance with local standard of 
care.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01677062
9.0
clinical-trial-protocol-revision-3
An open-label fixed sequence trial to investigate the potential drug-drug interaction
of intravenous volasertib co-administered with a P-gp and CYP3A4 inhibitor
(itraconazole p.o.) in patients with various solid tumours
Approval–Clinical Monitor
30 Jan 2017 13:56 CET
Approval-Team Member Medicine
30 Jan 2017 15:37 CET
Approval-Therapeutic Area
31 Jan 2017 08:54 CET
Author-Trial Clinical
Pharmacokineticist
31 Jan 2017 16:40 CET
Author-Trial Programmer
03 Feb 2017 15:41 CET
Verification-Paper Signature
Completion
06 Feb 2017 15:33 CET


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01677062
9.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c02097092-03
BI Trial No.:
1230.24
Title:
An open-label fixed sequence trial to investigate the potential 
drug-drug interaction of intravenous volasertib co-administered 
with a P-gp and CYP3A4 inhibitor (itraconazole p.o.) in patients 
with various solid tumors.  
Investigational
Product(s):
Volasertib, BI 6727
Responsible trial 
statistician:
Phone:
Fax:
Date of statistical 
analysis plan:
24 July 2014 REVISED
Version:
Revised
Page 1 of 31
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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......9
5.
ENDPOINTS ........................................................................................10
5.1
PRIMARY ENDPOINTS..................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................10
5.2.1
Key secondary endpoint................................................................................10
5.2.2
Other Secondary endpoints..........................................................................10
5.4.1 
Safety and tolerability endpoints ................................................................11
5.4.4 
Electrocardiogram........................................................................................12
6.
GENERAL ANALYSIS DEFINITIONS...........................................15
6.1
TREATMENTS..................................................................................................15
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................15
6.3
PATIENT SETS ANALYSED..........................................................................17
6.5
POOLING OF CENTRES ................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................19
6.6.1
AE dates and times........................................................................................19
6.6.2
Missing plasma concentrations and pharmacokinetic parameters ..........19
6.6.3
ECG ................................................................................................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................20
7.
PLANNED ANALYSIS.......................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........21
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................22
7.3
TREATMENT COMPLIANCE .......................................................................22
7.4
PRIMARY ENDPOINTS..................................................................................22
7.5
SECONDARY AND FURTHER ENDPOINTS..............................................23
7.5.1
Key secondary endpoint................................................................................23
7.5.2
Other Secondary endpoints..........................................................................23
7.7
EXTENT OF EXPOSURE................................................................................24
7.8
SAFETY ANALYSIS.........................................................................................24
7.8.1 
Adverse Events ..............................................................................................24
7.8.2
Laboratory tests............................................................................................25
7.8.3 
ECG ................................................................................................................26


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7.8.4 
Vital signs.......................................................................................................28
7.8.5 
Physical examination.....................................................................................28
8.
REFERENCES.....................................................................................29
10.
HISTORY TABLE...............................................................................31


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LIST OF TABLES
Table 6.2: 1
Important protocol violations..........................................................................16
Table 6.3: 1
Patient sets analyzed........................................................................................18
Table 10: 1
History table ....................................................................................................31


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP 
Term
Definition / description
AE
Adverse Event
AUC
Area under the plasma concentration-time curve
AUC0-∞
Area under the plasma concentration-time curve over the time interval 
from 0 to infinity
AUC0-tz
Area under the plasma concentration-time curve over the time interval 
from 0 to the time of the last quantifiable data point
BLQ
below the limit of quantification
bpm 
Beats per minute
CI
Confidence Interval
CL
Total clearance of the analyte in plasma following intravenous infusion
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady state
Cpre,ss,N
Predose steady state plasma concentration of the analyte in plasma 
immediately before administration of the Nth dose
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
CYP3A4
DDI
DILI
Clinical Trial Report
Cytochrome P450 3A4
Drug-drug interaction
Drug-induced Liver Injury
DMC
Data Monitoring Committee
DRT
Dose Reducing Toxicity
ECG
ECOG
Electrocardiogram
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form


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Term
Definition / description
EDC
Electronic Data Capture
EDTA
Ethylendiaminetetraacetic acid
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
HR
Heart rate
IB
Investigator’s Brochure
IEC
IMP
Independent Ethics Committee
Investigational Medicinal Product
IRB
Institutional Review Board
ISF
Investigator Site File
i.v.
Intravenous
IVRS
Interactive Voice Response System
IWRS
MDR1
Interactive Web-based Response System
Multidrug resistance protein 1
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRT
Mean residence time after intravenous infusion
ms
Milliseconds
MST
Medical Subteam
MTD
NOA
NOP
NOR
NOS
Maximum Tolerated Dose
not analyzed
no peak detectable
no valid result
no sample
OPU
PD
PG
PLK
Operative Unit
Progression of Disease
Pharmacogenomics
Polo-like kinase
p.o.
per os (oral)
PCC
Protocol Challenge Committee


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Term
Definition / description
P-gp
P-glycoprotein
PR interval
ECG interval from the start of P wave to the start of the QRS complex
q.d.
quaque die (once a day)
QRS complex
Combination of a Q wave, an R wave, and an S wave
QT interval
ECG interval from the start of the QRS complex to the end of the T wave
QTc interval
General term for QTcF and QTcB intervals
QTcB interval
QT interval, heart rate corrected using Bazett's formula
QTcF interval
QT interval, heart rate corrected using Fridericia's formula
RR interval
ECG interval from the peak of the R wave to the peak of the subsequent R 
wave
SAE
Serious Adverse Event
s.c.
Subcutaneous
SPC
Summary of Product Characteristics
t1/2
Terminal half-life of the analyte in plasma
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
ter in die (3 times a day)
tmax
Time to maximum analyte plasma concentration 
tmax.ss
Time to maximum analyte plasma concentration at steady state
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
Vss
Apparent volume of distribution at steady state after intravenous infusion
Vz
Apparent volume of distribution during the terminal phase following an 
intravenous infusion


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization.
SAS® Version 9.2 (or later version) will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The changes to the planned analysis are as follows:
The CTP lists primary endpoint AUC0-tz as AUC0-336, which is a typographical error and 
has been corrected as AUC0-504 in its second revision.
The CTP specifies that “in case that MTD of co-administration of itraconazole and volasertib 
is less than 300mg, dose will be considered in the ANOVA model to correct for the different 
starting doses of the patients.” However, after first three patients treated on the initial dose 
level 300mg for the combination therapy, MTD de-escalated immediately to 250mg and all 
subsequently enrolled patients were treated on 250mg in cycle 1. Very few patients had 
further intra-individual dose reduction to 200mg during cycle 2 mono-therapy. Due to the 
sparse data available on the dose levels other than the MTD 250mg, the primary analysis set 
for pharmacokinetic endpoints will be restricted among the patients who were treated on 
250mg in both cycle 1 and cycle 2. The single patient who was treated on 300mg in both 
cycle 1 and cycle 2 will also be included in the primary analysis. In addition, a sensitivity 
analysis will be conducted by including patients with intra-dose reduction during cycle 2 after 
dose normalization.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Relative bioavailability of volasertib and its main metabolite CD10899 will be investigated 
primarily on the basis of the following pharmacokinetic parameters: 
CTP: The following primary endpoints will be determined for volasertib and its main 
metabolite CD 10899:

AUC0-tz
(area under the plasma concentration-time curve of the analyte in plasma 
over the time interval from zero to 504 hours or last actual measure time)

Cmax
(maximum measured plasma concentration of the analyte in plasma)
The primary objective is to estimate the relative bioavailability of a single dose of volasertib 
and its main metabolite CD10899 when administered alone (volasertib monotherapy) 
compared with co-administered with itraconazole (200mg once daily) in cancer patients with 
various solid tumors.  The relative bioavailability is primarily to be determined on the basis 
of geometric mean ratios of the primary pharmacokinetic endpoints AUC0-tz, and Cmax
measured under the combination therapy period relative to mono therapy period. The 
derivation of these primary pharmacokinetic endpoints is given in the internal SOP 001-
MCS-36-472_RD-01(6).
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint 
As no key secondary endpoints have been specified in the protocol, this section is not
applicable.
5.2.2
Other Secondary endpoints
PK endpoints
The AUC0-∞of volasertib and its main metabolite CD 10899 will be statistically assessed 
using the same methods as described for the primary endpoint.


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5.4.1 
Safety and tolerability endpoints
The assessment of safety and tolerability will be based on

Adverse events
o
Drug related AE
o
AE leading to dosage reduction
o
AE leading to permanent treatment discontinuation
o
Serious AE


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
Safety laboratory tests

Physical examination (height, weight, ECOG)

Vital signs (blood pressure and pulse rate)
For details please refer to the CTP Section 5.2 and 5.3.
5.4.4
Electrocardiogram


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The following endpoints will be regarded for the electrocardiogram (ECG) analysis:

Absolute QTcF intervals at each time point

QTcF changes from individual baseline at each point in time: (QTcF post-baseline 
measurement obtained at each time point) – (individual baseline QTcF measurement)
The above endpoints will also be computed for the uncorrected QT interval, for heart rate
(HR), PR interval and QRS complex. HR will be derived from RR intervals as described in
section 7.8.3.
. The classifications will be performed separately for cycle 1 and cycle 2 as well as using the 
maximum on-treatment value over the entire mono-therapy period (≥ 2 cycles) per patient.

QTcF values at individual baseline and maximum post-baseline:

≤450 ms

>450 ms to ≤470 ms

>470 ms to ≤500 ms

>500 ms 

QT values at individual baseline and maximum post-baseline:

≤500 ms

>500 ms 

QTcF increase from individual baseline to the maximum post-baseline value:
Intervals for a given patient as

≤30 ms

>30 ms to ≤60 ms

>60 ms

QT increase from individual baseline to the maximum post baseline value:
Intervals for a given patient as

≤60 ms

>60 ms 

Increase from individual baseline ≥ 25% and absolute value >200 ms of all on-treatment 
values in PR interval for a given patient

Increase from individual baseline ≥ 25% and absolute value >110 ms of all on-treatment 
values in QRS interval for a given patient
All endpoints derived for the QTcF interval will also be derived for the QTcB interval. The 
derivation of each QTc interval from the RR and QT intervals is described in section 7.8.3.


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The QTc threshold of 470 ms is used to be consistent with the Common Terminology Criteria 
for Adverse Events (CTCAE), version 3.0, which is widely accepted as a standard for 
describing and managing safety findings in clinical studies of anticancer therapy. The other 
QT/QTc thresholds are in accordance with the ICH E14 Guideline.
Notable findings (defining outliers for the QT/QTc interval) at any on-treatment time point 
for a given patient are defined as

Maximum increase from individual baseline to on-treatment value in QTc interval > 60 
ms

QT/QTc > 500 ms in any on-treatment value which is not present at individual 
baseline
All endpoints involving the ‘individual baseline’ will also be derived for the ‘combined 
baseline’ (refer to Section 6.7).
ECG endpoints will also include cardiologist’s assessments. In particular, findings of 
abnormal rhythm, conduction, morphology, ST segment changes, T wave abnormalities and 
myocardial infarction will be explored.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In total, it was planned to include 24 patients in this two period trial with a fixed treatment 
sequence:
Treatment A: Day -3 to Day 15 of cycle 1: daily 200mg itraconazole
Day 1 of cycle 1: Single dose volasertib infusion 300mg
Treatment B: Day 1 of cycle 2 (Day 23 starting from Day 1 of cycle 1): Single dose 
volasertib infusion 300mg
For detail of dosage and formulation see section 4.1 in CTP. For detailed information on the 
handling of the treatment in the O*C views refer to Technical TSAP ADS plan
Time intervals for safety analysis are defined below. The analyses for safety endpoints will 
focus the on-treatment period of volasertib and contrast the safety profile within first cycle 
and second cycle during the study period. In addition, the safety endpoints will be 
summarized for the entire volasertib mono-therapy period.
Screening period: Screening to first dose of Itraconazole.
Itraconozole induction period: Start of first dose of Itraconazole to start of first dose of 
volasertib.
First cycle combo-therapy period: Start of first dose of volasertib to the start of the second 
cycle if patients received the second cycle mono-therapy, or to the 21 days after the first 
volasertib administration date if patients discontinued after the first cycle.
Second cycle mono-therapy period: Start of second dose of volasertib to the start of the cycle 
3 if patients received cycle 3 mono therapy, or to the 21 days after second volasertib 
administration date if patients discontinued after the second cycle.
Mono-therapy period: Start of the second dose of volasertib to the last dose of volasertib plus 
21 days.
Post-treatment period: After 21 days after last dose of volasertib.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Table 6.2: 1 contains the categories in which important PVs are classified. Categories for 
manually assessed important PVs, i.e. important PVs that are detected manually at the sites 
and cannot be detected through the database, are not shown in this table but will be finalised 
before DBL and documented in the final BRPM minutes.
Consistency checks will be prepared for identifying violations of time windows.


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Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
A
Entrance criteria not met
A1
Inclusion criteria not met
Inclusion criteria 6 not met as specified in the 
protocol as this is safety related; see SOP)
Other inclusion criteria violation will be 
manually reviewed.
A2
Exclusion criteria not met
Laboratory criteria 6-11, 19.
Violations on other exclusion criteria will be 
manually reviewed.
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing
B2
Informed consent too late
Informed consent date <actual consent date> 
was after Visit 1 date <Visit 2 date>
C
Trial medication and 
randomization


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Table 6.2: 1 (continued)
Important protocol violations
Category/
Code
Description
Example/Comment
C1.1
Non-compliance
Missing itraconazole doses during either pre-
volasertib administration period or on the day 
of volasertib administration is considered 
IPV..
C1.2
Non-compliance
Missing itraconazole doses in the post-
volasertib administration period will be 
documented and reviewed case by case
C2.1
Volasertib infusion late
Volasertib infusion not immediately after 
medicine preparation will be documented and 
reviewed case by case
D
Concomitant medication
D2
Prohibited medication use
•
Strong inhibitors of CYP3A4
•
Inducers of CYP3A4
•
Inhibitors of P-gp
•
Inducers of P-gp (CTP 4.2.2.1)
E
Missing data (for primary 
endpoints)1
E4
Certain violations of 
procedures used to measure 
primary and secondary data
Un-evaluable PK results for reasons other than 
study discontinuation.
F
Incorrect timing (for 
primary and secondary 
endpoints)2
F5
Certain violations of the time 
schedule used to measure 
primary and secondary data
KEY:
Hb = haemoglobin, Hct = Haematocrit, Tx = transfusion, PPS – Per Protocol Set
6.3
PATIENT SETS ANALYSED

Treated set (TS):
This patient set includes all patients who were  documented to have taken at least one 
dose of volasertib. This is the full analysis set population in the sense of ICH-E9. It is 
used for safety analysis.

Primary pharmacokinetic set (pPKS):                                                                         
This subject set includes all patients in the TS who were treated on the same dosage


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(250mg and 300mg) in the first two cycles and provided complete PK measures
without important protocol violations.

Sensitivity pharmacokinetics set (sPKS)
This subject set includes all patients in the TS who provided complete PK measures in the 
first two cycles without important protocol violations.

ECG analysis set (ECGS): This patient set includes all patients in the treated set who
provide at least one matching pair of QT measurements available pre-dose and after 
drug administration. Patients with an artificial pacemaker will be excluded.
Table 6.3: 1
Patient sets analyzed
Patient set
Class of endpoint
TS
pPKS
sPKS
ECGS
Primary (PK) endpoints 
X
X
Safety endpoints
X
ECG endpoints
X
Demographic data/Medical 
history and Concomitant 
diagnosis, Concomitant 
therapy
X
Important PVs
X
Disposition
X
6.5
POOLING OF CENTRES
This section is not applicable because the study was performed in only two centres.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
6.6.1
AE dates and times
It is not planned to impute missing values, with exception of missing AE start dates and 
times. These are imputed according to BI standards (see DM&SM “Handling of missing and 
incomplete AE dates”)(3)
6.6.2
Missing plasma concentrations and pharmacokinetic parameters
Handling of missing PK data will be performed according to the BI standard procedure 
“Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies” 
[001-MCS-36-472_RD-01] (4) and [001-MCS-36-472] (6).
Plasma concentration-time profiles and descriptive statistics of concentration data
CTP: Drug concentration data identified with NOS (no sample available), NOR (no valid 
result), NOA (not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule 
also applies also to the lag phase, including the predose values).
Pharmacokinetic parameters and their descriptive statistics
CTP: In the non-compartmental analysis, concentration data identified with NOS, NOR, and 
NOA will not be considered. BLQ and NOP values in the lag phase will be set to zero. The 
lag phase is defined as the period between time zero and the first time point with a 
concentration above the quantification limit. All other BLQ/NOP values of the profile will be 
ignored.
6.6.3
ECG
If replicate ECG recordings are missing, the arithmetic means per time point will be
computed with the reduced (1 or 2) number of recordings. If single cardiac cycles (also 
denoted as beats or waveforms) are missing, the arithmetic means per single ECG will be 
computed with the reduced (1, 2 or 3) number of cardiac cycles. If individual baseline values 
(i.e. pre-infusion ECGs) of all treatment cycles are missing, the combined baseline will be 
imputed by the screening value, while the individual baseline will be considered missing. If 
the screening value is missing, both baselines will be considered missing. The combined 
baseline will be computed as the mean of all available individual baselines over all treatment 
cycles. In all cases where the recording time of the planned pre-infusion ECG is after the start 
of infusion, change from individual baseline will be set to missing and the mistimed pre-
infusion ECG will be flagged in the listing displaying the individual baseline values. The 
combined baseline will be computed without mistimed individual baselines. If individual 
baselines of all infusions/courses are mistimed, the combined baseline will be imputed by the 
screening value (in accordance with the rules above).


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline for cycle 1 analyses is the last measurement before the first drug intake in first
period; The baseline for cycle 2 analyses is the last measurement before the first drug intake 
in the second period. The baseline for the mono-therapy is the last measurement before the 
first drug intake in the second peirod.
ECG
1. Individual baseline of ECG is defined as the mean of the triplicate at the time point 
closest to but prior to the start of infusion for each administration of volasertib.
2.  Combined baseline of ECG is defined as the mean of all individual baselines of ECG 
across the volasertib administrations.
CTP: For planned individual plasma concentration sampling times refer to the CTP Flow 
Chart. While these nominal times should be adhered to as closely as possible, the actual 
sampling times will be recorded and used for determination of pharmacokinetic parameter.
Adherence to time windows will be checked via consistency check listings at the 
RPM/DBLM. The PK measure at 1 hour 45 mins after Volasertib infusion starts will be 
checked to make sure if it is measured before stop of the infusion. 


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the standards defined in the BI corporate 
guideline “Reporting of clinical trials and project summaries” (5).
The individual values of all subjects will be listed, sorted by treatment sequence, subject 
number and visit. The listings will be included in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables for non-PK parameters. 
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment. Percentages will be rounded to one decimal place. The category ‘missing’ will be 
displayed only if there are actual missing values. Percentages will be based on all subjects in 
each subject set.
Units of variables should be given in the titles or column/row descriptors in square brackets 
(e.g. [mg]).
CTP: The following descriptive statistics will be calculated for plasma concentrations as 
well as for all primary and secondary PK parameters: N, arithmetic mean, standard 
deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean, 
and geometric coefficient of variation. The data format for descriptive statistics of 
concentrations will be identical with the data format of the respective concentrations. The 
descriptive statistics of PK parameters will be calculated using the individual values with the 
number of decimal places as provided by the evaluation program. Then the individual values 
as well as the descriptive statistics will be reported with 3 significant digits in the clinical 
trial report.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on TS. The 
following variables will be displayed: Gender, Race, Age, Baseline height, weight, body 
surface area, and body mass index. smoking and alcohol status, baseline ECOG


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7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant disease will be coded using the coding system of the Medical Dictionary for 
Drug Regulatory Activities (MedDRA). Concomitant medications will be coded using the 
World Health Organization Drug Dictionary (WHO-DD). The coding version number will be 
displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be noted by a "No" in the respective column.
7.3
TREATMENT COMPLIANCE
It is not intended to list compliance separately. Any deviations from complete intake will be 
addressed in the RPM/DBLM (see Section 6.2).
7.4
PRIMARY ENDPOINTS
The relative bioavailability will be investigated based on the PK parameters AUC0-tz and Cmax
for volasertib and its main metabolite CD10899, respectively.
The statistical model used for the analyses will be a repeated measure ANOVA (analysis of 
variance) model on the logarithmic scale and will be based on both the primary and 
sensitivity PKS.
CTP: The statistical model used for the analysis of AUC0-tz, Cmax of volasertib and CD10899
will be an analysis of variance (ANOVA) model with repeated measure on the logarithmic 
scale. The effect ‘subject’ will be considered as random, whereas the effect ‘treatment’ will 
be considered as fixed. The model is described by the following equation:
ykm
= µ + τk + sm + εkm, where
ykm
= logarithm of response (AUC0-tz or Cmax) in subject m receiving treatment k,
µ
= the overall mean, 
τk
= the k-th treatment effect, k = 1, 2,
sm
= the effect associated with the m-th subject, m=1,…n,
εkm
= the random error associated with the m-th subject receiving treatment k.
CTP: The PK parameters AUC0-tz and Cmax will be log-transformed (natural logarithm) prior 
to fitting the ANOVA model. The difference between the expected means for log(T)-log(R) 
will be estimated by the difference in the corresponding least square means (point estimate) 
and 2 sided 90% confidence intervals based on the t-distribution will be computed. These 
quantities will then be back-transformed to the original scale to give the point estimator 


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(geometric mean) and interval estimates for the intra-subject ratio of the geometric means for 
treatments test and reference.
As stated in the CTP, in case the tolerable dose of volasertib is less than the initial dose level 
300mg, dose would be included as a covariate in the ANOVA model. However, as a 
consequence of immediate dose de-escalation after first three patients treated on 300mg and 
two of them discontinued after cycle 1, tolerable dose was de-escalated to 250mg and all 
subsequently enrolled patients were treated on 250mg. Due to the limited dose levels and
sparse data available on 300mg, instead of including dose as an additional covariate in the 
ANOVA model according to the CTP, primary analysis using ANOVA model on log 
transformed PK endpoints will be performed based on the clean cohort of patients who were 
treated on equal dose levels (either 250mg or 300mg) throughout both cycles 1 and 2. In 
addition, a sensitivity analysis will be performed by including the patients with further intra-
individual dose reduction from 250mg to 200mg in cycle 2. In the sensitivity analysis, dose
proportionality (BI 1230.5, BI 1230.23) will be applied on individuals with dose reduced to 
200mg during cycle 2 volasertib mono therapy to rescale the PK measures. However, since 
dose proportionality was not established for the combination therapy of volasertib + 
itraconazole, dose normalization will not be applied on the patient who was treated on 300mg 
in both cycle 1 and 2.
7.5
SECONDARY AND FURTHER ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Other Secondary endpoints
CTP: The AUC0-∞ of volasertib and its main metabolite CD 10899 will be statistically 
assessed using the same methods as described for the primary endpoint. Relative 
bioavailability will not be assessed for secondary pharmacokinetic parameters. 
Relative bioavailability will be assessed for secondary pharmacokinetic parameters for 
volasertib and CD10899.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS.
7.8
SAFETY ANALYSIS
All patients who receive at least one dose of volasertib will be included in the safety analyses.
This is the treated set defined in Section 6.3.
7.8.1 
Adverse Events
The analysis of adverse events will focus on events that occurred during the on-treatment 
period, defined from the first treatment administration until 21 days after the last 
administration for all patients who receive at least one administration of the study treatment 
regimen. Tables will display the results within each cohort defined by the starting dosage of 
volasertib.
The analysis of adverse events will be performed within each of the following three time 
periods separately (Section 6.1): 

First cycle volasertib+ itraconazole combo-therapy period 

Second cycle volasertib mono-therapy period

Continued volasertib mono-therapy period. 
The AEs occurred during screening period, itraconazole induction period, and post-study 
period (Section 6.1) will be listed. 
Standard tabulations arranged by MedDRA SOC and preferred term (PT) will include: 

the overall incidence of adverse events (AE)

AE intensity graded according to the common terminology criteria for adverse events 
(CTCAE) version 3


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
AE judged to have been related to trial medication

AE leading to dosage reduction 

AE leading to permanent treatment discontinuation

AE identified associated with the protocol-specified significant event

Serious AE
Listings will be produced for the following AEs

Infections
Listings will be prepared of patients who are identified as having experienced any of the 
following AEs. Identification will be based upon modified MedDRA SMQ and HLT
groupings.

Mucositis

QT prolongation

Cardiac, combining the following SMQ 
-
Cardiac failure
-
Ischaemic heart disease
-
Cardiac arrhythmia terms

Hemorrhages SMQ

Hepatic
-
AE identified by the SMQ 
-
Listing of all ALT, AST, Tbili, and ALK over time, for patients with
-
1) any ALT or AST ≥3x ULN combined with elevation of total bilirubin ≥ 2x 
ULN at the same time or
-
2) an isolated elevation of AST and/or ALT≥5x ULN (without an elevation of 
bilirubin)
7.8.2
Laboratory tests
Special care must be taken to review the lab data because the data are entered manually at the 
sites.  Any corrections will be documented.


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Primary laboratory tests are defined as:

Low values (-):calcium, creatinine clearance, haemoglobin, neutrophils,  platelets, 
potassium,  sodium, and total WBC

High values (+): Alkaline Phosphatase, ALT, AST, CK, Creatinine, LDH, Total 
Bilirubin,  troponin T, and  uric acid 
All other labs collected will be classified as secondary.  
The following analyses will be presented for the primary laboratory tests:
•
descriptive statistics for change from baseline (uses normalized values)
•
for the worst value during treatment, and  
•
the last value during treatment
•
frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment (excludes Troponin I, uses standardized values), and 
•
frequency of patients with possible clinically significant abnormalities (uses 
standardized values).
For secondary parameters, the analyses will be restricted to:

frequency of patients with possible clinically significant abnormalities.
GFR will be calculated from creatinine using the Cockcroft-Gault transformation.  GFR will 
be calculated from normalized creatinine using Cockcroft-Gault.   In this calculation, if 
normalized creatinine is less than the standard lower limit, then it was set equal to the limit. 
All lab tables should be footnoted to indicate that values were excluded if they were collected 
more than 21 days after the stop of treatment.
7.8.3 ECG
Derivation of ECG variables
Three replicate digital ECG recordings will be collected at each time point. Each of the 3 
recorded single ECGs will then be evaluated for cardiac intervals, which comprise the RR
interval, PR interval, QT interval, and QRS complex. Measurements of these intervals will be 
made on the 4 (possibly consecutive) cardiac cycles (also denoted as beats or waveforms)
from the lead chosen (usually lead II). The measurements of the cardiac cycles will be stored 
in the database, i.e. usually 12 values per time point. The 4 cardiac cycles will be averaged 
prior to the calculation of HR and HR-corrected QT intervals QTcF and QTcB. 
HR will be derived from the RR interval as:


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HR [bpm] = 60 000 / RR [ms]
QTc intervals will be calculated using Fridericia’s and Bazett’s formulae (QTcF and QTcB, 
respectively):
QTcF [ms] = (1000 / RR)1/3 × QT [ms]
QTcB [ms] = (1000 / RR)1/2 × QT [ms]
Further aggregation of the 3 replicate QT/QTc intervals and HRs at each scheduled time point 
will be performed using arithmetic means. These values will be used for the derivation of the 
ECG endpoints as they are specified in Section 5.4.4.
ECG analysis
The analyses of the ECG endpoints will be based on the FAS ECG, i.e., patients with 
artificial pacemakers will be excluded from the evaluation (descriptive statistics, frequency 
tables). Any notable finding (see Section 5.4.4) occurring in these patients will be flagged in 
the listings and has to be described separately in the clinical trial report.
All analyses described below will be applied to ‘change from individual baseline’ and 
‘change from combined baseline’ (see Section 6.7). The interpretation will focus on the 
results involving “change from individual baseline”. The analysis involving “change from 
combined baseline” will serve as sensitivity analysis.
Absolute values and change from baseline in QTcF interval, QTcB interval, QT interval, PR 
interval, HR, and QRS complex will be summarised descriptively by cycle and measurement 
timepoints.
Frequency tables will be provided for all categorical endpoints. Frequencies of the increases 
in QTcF, QTcB and QT intervals above thresholds such as 450 ms, 470 ms, and 500 ms 
between baseline and treatment period will be displayed in two-way shift tables.
Frequencies of patients with notable findings will be displayed as well.
Frequency tables by overall clinical interpretation and a new onset (not present at baseline) of 
an abnormal finding will be generated.
To evaluate the appropriateness of the QT correction methods, slopes of the relationship of 
QT/QTc interval versus RR interval will be estimated by applying a random coefficient 
model. The model will be applied to log-transformed single ECG data (i.e., to the mean of 
four cardiac cycles). The corresponding model includes the (natural) logarithm of RR as fixed 
continuous covariate and the (natural) logarithm of QT/QTc as the dependent variable and a 
random intercept and slope to account for inter-individual variability.


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7.8.4 
Vital signs
Blood pressure (BP) and pulse rate (PR) will be described with respect to changes compared 
to baseline values at each of the follow-up time points.
7.8.5 
Physical examination
Height, weight, ECOG will be summarized using mean, median and range at each assessment 
time point.


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8.
REFERENCES
1
001-MCG-160_RD-01: "TSAP annotations", current version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
4
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.
5
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.
6
001-MCS-36-472_RD-01: “Noncompartmental 
Pharmacokinetic/Pharmacodynamic Analyses of Clinical Studies”.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
5-May-14
None
This is the first version TSAP.
Revision 1
23-July-14
Section 
ECG analyses sections revised. Safety 
endpoints are moved out of secondary 
endpoints to align with the protocol..