Conditions: Neoplasms
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 65
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to identify the maximum tolerated dose (MTD) of BI 6727 therapy in terms of drug-related adverse events. Secondary objectives are the collection of overall safety and antitumour efficacy data and the determination of the pharmacokinetic profile of BI 6727.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None arm 6: None arm 7: None arm 8: Infusion over 1 hour (1h) in course 1 and over 2 hours (2h) in course 2. arm 9: Infusion over 2 hours (2h) in course 1 and over 1 hours (1h) in course 2. arm 10: None arm 11: None arm 12: None

Interventions: intervention 1: BI 6727
Intervention descriptions: intervention 1: BI 6727

Protocol document:
Prot_000.pdf: 
Boehringer Ingelheim  
Belgium 
 
ABCD 
Clinical Trial Protocol 
 
EudraCT No.: 
 
BI Trial No.: 
2005-002500-42 
 
Investigational 
Product(s): 
BI 6727  
Title: 
An open phase I single dose escalation study of BI 6727 administered 
intravenously in patients with advanced solid tumours with repeated 
administration in patients with clinical benefit 
Clinical Phase: 
I 
Trial Clinical 
Monitor: 
Phone:
       Fax:    
E-mail : 
Principal 
Investigator: 
Phone:
         Fax: 
 
E-mail:
Status, Version, and 
Date of Protocol: 
Final, 3 October 2005 
 
Planned Dates of 
Trial: 
October 2005 – February 2007 
 
Page 1 of 69 
Proprietary confidential information 
© 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 2 of 69 
SIGNATURE PAGE(S)  
Trial Clinical Monitor 
  
  
 
 Date 
 
 
  
 
 
 
 
 
 
Trial Statistician 
  
  
 
 Date 
 
  
 
 
 
 
 
Team Member Medicine 
  
  
 
 Date 
 
  
 
 
 
 
 
 
Therapeutic Area 
  
  
 
 Date 
 
 
  
 
 
 
 
 
Trial Clinical 
Pharmacokineticist 
  
  
 
 Date 
 
  


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 3 of 69 
 
 
 
 
PRINCIPAL 
INVESTIGATOR SIGNATURE 
 
________________ 
 
 
 
 
STUDY TITLE: An open phase I single dose escalation study of BI 6727 
            administered intravenously in patients with advanced solid tumours with repeated 
            administration in patients with clinical benefit 
 
 
 
 
STUDY NUMBER: 1230.1.............................................................................. 
 
 
 
 
I herewith certify that I agree to adhere to the trial protocol 
and to all documents referenced in the trial protocol. 
 
 
 
INVESTIGATOR:
 SIGNATURE:___________________ 
 
 
AFFILIATION: 
 
 
 
 
 
 
 
 
 
 
 
 
DATE: 
 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 4 of 69 
LOCAL SIGNATURES 
(PRINCIPAL INVESTIGATOR OF SITE AND CLINICAL MONITOR LOCAL) 
 
CLINICAL MONITOR 
LOCAL: 
 
 
Name 
 
Date 
 
Organisation/Department 
 
 
 
 
 
 
 
 
 
 
 
I herewith certify that I agree to adhere to the trial protocol and to all documents 
referenced in the trial protocol. 
 
PRINCIPAL 
INVESTIGATOR (site): 
 
 
 
 
 
 
Name 
 
Date 
 
Organisation/Department  
 
 
 
 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 5 of 69 
CLINICAL TRIAL PROTOCOL SYNOPSIS 
Name of company: 
Tabulated 
Trial Protocol 
 
 
 
Name of finished product:  
NA 
Name of active ingredient: 
 
BI 6727  
 
Protocol date 
Trial number 
Planned study period 
03 October 2005 
1230.1 
10/2005 – 02/2007 
Title of study: 
An open phase I single dose escalation study of BI 6727 administered 
intravenously in patients with advanced solid tumours with repeated administration 
in patients with clinical benefit 
Investigator : 
Study centre : 
Clinical phase: 
I 
Objectives: 
Safety, maximum tolerated dose (MTD), pharmacokinetics, efficacy  
Methodology: 
Uncontrolled, open label, dose escalation 
No. of subjects entered:  
 
total: 
Up to 80 
 
each treatment: 
3 to 6 per level, 24 at MTD 
Diagnosis and main 
criteria for inclusion 
Patients with a confirmed diagnosis of an advanced and/or metastatic solid tumour 
refractory to standard therapy or not amenable to standard therapies 
Test product(s) : 
BI 6727  
 
dose: 
Start dose of 12 mg 
 
mode of admin. : 
Intravenous, once every 21 days 
Reference therapy: 
     n.a. 
 
dose: 
 
 
mode of admin. :  
Duration of treatment:     Single dose, repeated treatment courses in patients with clinical benefit 
Criteria for efficacy: 
Tumour response, time to progression, pharmacokinetic profile of BI 6727 
Criteria for safety: 
Adverse events according to common terminology criteria for adverse events 
(CTCAE) v.3.0, laboratory evaluations, patient performance, vital signs 
Statistical methods: 
  descriptive statistics 
Kaplan Meier method for time to progression analysis 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 6 of 69 
FLOW CHART: INITIAL TREATMENT COURSE 
Study Periods 
 
Screening 
Treat-
ment 
Observation after Treatment 
EOTf 
FU 
 
 
course 1 
 
 
 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
Day 
(day range) 
-14 - 0 
1 
2 
3 
5 
(±1) 
8 
(±1) 
15 
(±1) 
22 
(±2) 
 
 
Informed Consent and 
Subject Information 
x 
 
 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
 
Genotyping 
 
xj 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
In- /Exclusion Criteria 
x 
x 
 
 
 
 
 
 
 
 
Physical Examination  
x 
 
 
 
 
 
 
 
x 
xb 
ECOG performance 
score 
x 
x 
 
 
 
 
 
x 
x 
x 
Pregnancy test 
x 
 
 
 
 
 
 
 
 
 
MRI, CTa 
x 
 
 
 
 
 
 
xa 
 
x 
EUS, US (optional) 
x 
 
 
 
 
 
 
x 
 
x 
Body weight 
x 
x 
 
 
 
 
 
 
x 
 
ECG 
x 
xk 
 
 
 
 
 
x 
 
xb 
Infusion BI 6727 
 
x 
 
 
 
 
 
 
 
 
Vital Signs 
x 
x  
x 
x 
x 
x 
x 
x 
x 
 
Safety lab parameters 
x 
x 
x 
x 
x 
x 
x 
x 
 
xb 
Tumour markersi 
x 
 
 
 
 
 
 
x 
 
 
Urine examination 
x 
 
x 
 
 
 
 
 
x 
 
Pharmacokinetics 
(plasma) 
 
xc 
xc 
xc 
xc 
xc 
xc 
 
 
 
Pharmacokinetics 
(urine) 
 
xh 
xh 
xh 
 
 
 
 
 
 
Adverse Events 
 
x 
x 
x 
x 
x 
x 
x 
x 
xe 
Concomitant Therapy 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Tumour assessmenta 
x 
 
 
 
 
 
 
xa 
 
x 
Conclusion of Subject 
Participation 
 
 
 
 
 
 
 
 
x 
 
a according to RECIST guidelines. Imaging and assessment are required at the end of every other treatment course. 
b optional 
c for time schedule of pharmacokinetic sampling refer to table (Appendix 10.2), plasma samples have to be drawn 
from the opposite arm of the infusion. For patients having central venous access, BI 6727 may be administered 
using this device and PK samples obtained from either forearm. Intensive PK blood sampling performed in 
Course 1 only; for repeated courses PK blood sampling performed at the end of infusion (1:00h) after 24:00h, 
168:00 h and after 336:00h (Appendix 101.2). 
e if not yet recovered at the end of the previous course and in case of new adverse events if drug related 
f end of treatment; investigations which have to be performed at the last visit (when a patient discontinues the 
study) 
g data from visit 8 may be used in case EOT examinations were done within the past four weeks 
FU= follow up visits until progression, lost to follow up or treatment with another anti-cancer drug 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 7 of 69 
h one blank urine will be sampled prior to the infusion on visit 2 (at least two 2 mL aliquots), additionally urine 
will be collected for 24 h intervals (0-24 and 24-48 h) 
i in applicable tumour types of the underlying disease (c.f. 5.2.5) 
j Six (6) mL blood collected into an EDTA tube and processed as outlined in Appendix  10.3.3 for Cytochrome 
P450 (CYP2D6, CYP2C19, CYP2C9) and N-acetyltransferase (NAT2) genotyping  
k before administration and directly after completion of infusion 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 8 of 69 
FLOW CHART: REPEATED TREATMENT COURSES 
 
Study Periods 
 
Repeated treatment courses 
EOTf 
FU 
Visit 
1 
2 
3 
4 
5 
 
 
Day 
(day range) 
1 
2 
8 
(±1) 
15 
(±1) 
22 
(±2) 
 
 
Physical Examination  
xg 
 
 
 
 
x 
xb 
ECOG performance 
score 
x 
 
 
 
x 
x 
x 
Pregnancy test 
x 
 
 
 
 
 
 
MRI, CTa 
 
 
 
 
xa 
 
x 
EUS, US (optional) 
 
 
 
 
x 
 
x 
Body weight 
x 
 
 
 
 
x 
 
ECG 
xk 
 
 
 
x 
 
xb 
Infusion BI 6727 
x 
 
 
 
 
 
 
Vital Signs 
x  
x 
x 
x 
x 
x 
 
Safety lab parameters 
xg 
x 
x 
x 
x 
 
xb 
Urine examination 
xg 
x 
 
 
 
x 
 
Pharmacokinetics 
(plasma) 
xc 
xc 
xc 
xc 
 
 
 
Adverse Events 
xd 
x 
x 
x 
x 
x 
xe 
Concomitant Therapy 
xd 
x 
x 
x 
x 
 
 
Tumour assessmenta 
 
 
 
 
xa 
 
x 
Conclusion of Subject 
Participation 
 
 
 
 
 
x 
 
a according to RECIST guidelines. Imaging and assessment are required at the end of every other treatment course. 
b optional 
c for time schedule of pharmacokinetic sampling refer to table (Appendix 10.2), plasma samples have to be drawn 
from the opposite arm of the infusion. Intensive PK blood sampling performed in Course 1 only; for repeated 
courses PK blood sampling performed at the end of infusion (1:00h) after 24:00h, 168:00h and after 336:00h 
(Appendix 10.2). 
d update only 
e if not yet recovered at the end of the previous course and in case of new adverse events if drug related 
f end of treatment; investigations which have to be performed at the last visit (when a patient discontinues the 
study) 
g data from last visit of previous course (day 22 ± 2 ) may be used in case examinations were done within the past 
four weeks 
FU= follow up visit until progression, lost to follow up or treatment with another anti-cancer drug 
k  before administration and directly after completion of infusion of course 3 in eligible patients, further analyses 
in case of changes during prior courses  
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 9 of 69 
TABLE OF CONTENTS 
SIGNATURE PAGE(S) ...................................................................................... 2 
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................ 5 
FLOW CHART: INITIAL TREATMENT COURSE .................................... 6 
FLOW CHART: REPEATED TREATMENT COURSES ............................ 8 
TABLE OF CONTENTS ................................................................................... 9 
ABBREVIATIONS ........................................................................................... 13 
1. 
INTRODUCTION ................................................................................ 16 
1.1 
MEDICAL BACKGROUND ............................................................................ 16 
1.2 
DRUG PROFILE ............................................................................................... 16 
1.3 
RATIONALE FOR PERFORMING THE TRIAL ........................................ 17 
1.4 
BENEFIT / RISK ASSESSMENT .................................................................... 18 
2. 
TRIAL OBJECTIVES ......................................................................... 19 
2.1 
GENERAL AIM / PRIMARY OBJECTIVE .................................................. 19 
2.2 
PRIMARY ENDPOINT .................................................................................... 19 
2.3 
SECONDARY ENDPOINT(S) ......................................................................... 19 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION.......... 20 
3.1 
OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION ....................... 20 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) ..................................................................................... 20 
3.3 
SELECTION OF TRIAL POPULATION ...................................................... 20 
3.3.1 
Inclusion criteria............................................................................................ 20 
3.3.2 
Exclusion criteria ........................................................................................... 20 
3.3.3 
Retreatment criteria ...................................................................................... 21 
4. 
TREATMENTS .................................................................................... 22 
4.1 
TREATMENTS TO BE ADMINISTERED .................................................... 22 
4.1.1 
Identity of investigational product(s) .......................................................... 22 
4.1.2 
Methods of assigning patients to treatment groups ................................... 22 
4.1.3 
Selection of doses in trial............................................................................... 22 
4.1.4 
Selection and timing of doses for each patient ............................................ 22 
4.1.5 
Preparation of the infusion solution and of the sample for analysis. ....... 23 
4.1.6 
Selection and timing of doses for each subject ............................................ 23 
4.1.7 
Blinding .......................................................................................................... 24 
4.1.8 
Packaging, labelling and re-supply .............................................................. 24 
4.1.9 
Storage conditions ......................................................................................... 24 
4.2 
CONCOMITANT THERAPY .......................................................................... 24 
4.2.1 
Rescue medication and additional treatment(s) ......................................... 25 
4.2.2 
Restrictions..................................................................................................... 25 
4.3 
TREATMENT COMPLIANCE ....................................................................... 25 
5. 
OBSERVATIONS ................................................................................ 26 
5.1 
EFFICACY / CLINICAL PHARMACOLOGY ............................................. 26 
5.1.1 
PRIMARY ENDPOINT .................................................................................... 26 
5.1.2 
SECONDARY ENDPOINTS ............................................................................ 26 
5.2 
SAFETY .............................................................................................................. 26 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 10 of 69 
5.2.1. 
Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) ......... 26 
5.2.2. 
Adverse Events .............................................................................................. 27 
5.2.3. 
Physical examination, height, body weight, performance status  and 
electrocardiogram ......................................................................................... 28 
5.2.4. 
Vital signs ....................................................................................................... 29 
5.2.5. 
Laboratory examinations.............................................................................. 29 
5.2.6. 
Significant adverse events ............................................................................. 30 
5.3 
OTHER ............................................................................................................... 30 
5.3.1. 
Demographics and history ............................................................................ 30 
5.3.2. 
Concomitant diagnoses and/or therapies .................................................... 30 
5.4 
APPROPRIATENESS OF MEASUREMENTS ............................................. 31 
5.5 
DRUG CONCENTRATION MEASUREMENTS / PHARMACOKINETICS
 .............................................................................................................................. 31 
5.5.1 
Methods and timing of sample collection .................................................... 31 
5.5.1.1 Plasma sampling for pharmacokinetics ...................................................... 31 
5.5.1.2 Urine sampling for pharmacokinetics (in course 1 only) ........................... 32 
5.6 
BIOMARKER / PHARMACODYNAMIC SAMPLING ............................... 33 
5.6.1 
Methods and timing of sample collection .................................................... 33 
5.7 
PHARMACOKINETIC / PHARMACODYNAMIC RELATIONSHIP ...... 33 
5.8 
DATA QUALITY ASSURANCE ..................................................................... 33 
6. 
INVESTIGATIONAL PLAN ............................................................. 34 
6.1 
VISIT SCHEDULE ............................................................................................ 34 
6.1.1. 
Visit schedule in initial treatment course .................................................... 34 
6.1.1.1. Visit 1 – screening visit .............................................................................. 34 
6.1.1.2. Visit 2 – day 1 ............................................................................................. 34 
6.1.1.3. Visit 3 – day 2 ............................................................................................. 34 
6.1.1.4. Visit 4 – day 3, visit 5 – day 5 (±1), visit 6 – day 8 (±1) and visit 7 – day 
15(±1) ......................................................................................................... 34 
6.1.1.5. Visit 8 – day 22 (± 2) .................................................................................. 34 
6.1.2. 
Visit schedule in repeated treatment courses.............................................. 34 
6.1.2.1. Visit 1 – day 1 ............................................................................................. 34 
6.1.2.2. Visit 2 – day 2 ............................................................................................. 34 
6.1.2.3. Visit 3 – day 8 (±1), visit 4 – day 15 (±1)  and visit 5 – day 22 (±2) ......... 35 
6.2 
TRIAL PROCEDURES AT EACH VISIT ..................................................... 35 
6.2.1 
Screening phase ............................................................................................. 35 
Visit 1 – Screening visit (day -14 to day 0) ............................................................... 35 
6.2.2 
Treatment phase(s) ........................................................................................ 35 
6.2.2.1. Treatment phase in course 1 ....................................................................... 35 
Visit 2 – day 1 ............................................................................................................ 35 
Visit 2 – day 1, day of BI 6727 administration .......................................................... 35 
Visit 3 - day 2 ............................................................................................................ 37 
Visit 4 - day 3 ............................................................................................................ 37 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 11 of 69 
Visit 5 - day 5 (± 1) .................................................................................................... 37 
Visit 6 - day 8 (± 1) and Visit 7 - day 15 (± 1) .......................................................... 38 
Visit 8 - day 22 (±2) ................................................................................................... 38 
6.2.2.2. Treatment Phase in repeated treatment courses .......................................... 38 
Visit 1 – day 1 ............................................................................................................ 38 
Visit 1 – day 1, day of BI 6727 administration .......................................................... 38 
Visit 2 – day 2 ............................................................................................................ 40 
Visit 3 - day 8 (± 1) and Visit 4 - day 15 (± 1) .......................................................... 40 
Visit 5 – day 22 (± 2) ................................................................................................. 40 
6.2.3 
End of trial and follow-up............................................................................. 41 
Termination of trial medication – End of trial .......................................................... 41 
Follow up visit ............................................................................................................... 41 
6.2.4. 
Missed visits ................................................................................................... 41 
6.3 
REMOVAL OF PATIENTS FROM THERAPY ASSESSMENT ................ 41 
6.3.1 
Replacement of patients ................................................................................ 42 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ..................................................................................... 43 
7.1 
STATISTICAL DESIGN / MODEL ................................................................ 43 
7.1.1. 
Safety and tolerability evaluation ................................................................ 43 
7.1.2. 
Pharmacokinetic evaluation ......................................................................... 43 
7.1.3. 
Therapeutic efficacy evaluation ................................................................... 44 
7.2 
NULL AND ALTERNATIVE HYPOTHESES .............................................. 44 
7.3 
PLANNED ANALYSES .................................................................................... 44 
7.3.1 
Primary analyses ........................................................................................... 44 
7.3.2 
Secondary analyses ........................................................................................ 45 
7.3.3 
Safety analyses ............................................................................................... 46 
7.3.4 
Interim analyses ............................................................................................. 46 
7.4 
HANDLING OF MISSING DATA .................................................................. 47 
7.5 
RANDOMISATION .......................................................................................... 47 
7.6 
DETERMINATION OF SAMPLE SIZE ........................................................ 47 
8. 
ADMINISTRATIVE MATTERS ....................................................... 49 
8.1 
ETHICS ............................................................................................................... 49 
8.1.1 
Institutional Review Board or Independent Ethics Committee ................ 49 
8.1.2 
Informed Consent and Patient Information ............................................... 49 
8.2 
RECORDS .......................................................................................................... 50 
8.2.1 
Drug accountability ....................................................................................... 50 
8.2.2 
Emergency code break .................................................................................. 50 
8.2.3 
Case Report Forms (CRFs) .......................................................................... 50 
8.2.4 
Source documents .......................................................................................... 51 
8.2.5 
Direct access to source data / documents .................................................... 52 
8.3 
QUALITY ASSURANCE AUDIT .................................................................... 52 
8.4 
PROCEDURES .................................................................................................. 52 
8.4.1 
Adverse events ............................................................................................... 52 
8.4.2 
Emergency procedures .................................................................................. 54 
8.5 
RULES FOR AMENDING PROTOCOL ....................................................... 54 
8.6 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR ..................... 54 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 12 of 69 
8.7 
STATEMENT OF CONFIDENTIALITY ....................................................... 54 
8.8 
PUBLICATION POLICY ................................................................................. 54 
8.9 
COMPLETION OF TRIAL .............................................................................. 55 
9. 
REFERENCES ..................................................................................... 56 
9.1 
PUBLISHED REFERENCES ........................................................................... 56 
9.2 
UNPUBLISHED REFERENCES ..................................................................... 56 
10. 
APPENDICES ...................................................................................... 57 
10.1 
HANDLING OF PLASMA AND URINE DATA AND DERIVATION OF 
PHARMACOKINETICS PARAMETERS ..................................................... 57 
10.2 
BLOOD SAMPLING TIME SCHEDULE ...................................................... 62 
 
 
 
 
 
 
 
 
 
 
10.4. TUMOUR ASSESSMENT ACCORDING TO RECIST ..................................... 65 
10.4.1 
Tumour assessment ....................................................................................... 65 
10.4.2 
Evaluation of target lesions .......................................................................... 66 
10.4.3 
Evaluation of non-target lesions ................................................................... 66 
10.4.4 
Evaluation of best overall response ............................................................. 66 
10.4.5 
Handling of missing tumour lesion measurements .................................... 68 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 13 of 69 
ABBREVIATIONS 
AE 
Adverse Event 
BI 
Boehringer Ingelheim 
CA 
Competent Authority 
CML 
Clinical Monitor Local 
CRA 
Clinical Research Assistant/Associate 
CRF/eCRF 
Case Report Form / electronic Case Report Form 
CTMF 
Clinical Trial Master File 
CRO 
Clinical Research Organisation 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
DLT  
Dose limiting toxicity 
DNA  
Desoxyribonucleic acid 
ECC  
Endogenous creatinine clearance 
ECG 
Electrocardiogram 
ECOG  
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EDTA  
Ethylendiaminetetraacetic acid 
EOT  
End of treatment 
EUS 
 
endoultrasonography 
FDA 
Food and Drug Administration 
fe0-24/48  
 
Fraction of analyte eliminated in urine from time point 0 to 
time point 24/48 
fet1-t2 
 
 
Fraction of analyte eliminated in urine from time point t1 to 
time point t2 
FU 
 
 
Follow up 
GCP 
Good Clinical Practice 
gCV 
 
geometric coefficient of variation 
 
 
gMean  
 
geometric mean 
HR 
heart rate 
HPLC-MS/MS 
High performance liquid chromatography, tandem mass 
spectrometry 
ICH 
International Conference on Harmonisation 
IEC /EC 
(Independent) Ethics Committee 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 14 of 69 
IND 
Investigational New Drug 
INR 
 
International normalised ratio 
IRB 
Institutional review board 
ISF  
Investigator Site File 
LDH  
Lactate dehydrogenase 
MCV  
Medium corpuscular volume 
MRI 
 
Magnetic resonance imaging 
MRT  
Mean residence time of the analyte in the body after 
intravenous administration 
MTD  
Maximum tolerated dose 
NC 
 
Next course 
NOA  
 
Not analyzed 
NOP 
No peak detectable 
NOR  
No valid result 
NOS  
No sample 
No. 
Number 
OPU 
Operative Unit (of BI) 
PD 
 
Progressive disease 
PK 
 
 
Pharmacokinetics 
PLK-1  
 
Polo-like kinase 1 
PR 
Partial response 
PR-interval 
interval between the beginning of the P wave and beginning 
of the Q wave (seconds).  Also called the PQ interval 
PT 
 
Prothrombin time 
PTT 
 
Partial thromboplastin time 
QRS 
duration of the QRS wave form (seconds) 
QT-interval 
interval from the beginning of the Q wave to the end of the T 
wave on an ECG (seconds) 
QTc 
QT interval, corrected for heart rate (seconds) 
QTcB 
QT interval, corrected for heart rate according to Bazett's 
formula (seconds) = measured QT / (square root of preceding 
RR interval) 
QTcF 
QT interval, corrected for heart rate according to Fridericia's 
formula (seconds) = measured QT / (cube root of preceding 
RR interval) 
RBC  
Red blood cell count 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 15 of 69 
RECIST 
 
Response evaluation criteria in solid tumours 
RR-interval 
interval between R waves (seconds) 
SAE 
Serious Adverse Event 
SD 
 
Stable disease 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
 
 
terminal half-life of the analyte in plasma 
tmax 
 
 
time from dosing to maximum concentration 
US 
Utrasonography 
Vss 
 
 
Apparent volume of distribution at steady state following 
intravascular administration 
Vz 
 
Apparent volume of distribution during the terminal phase λz 
following an intravascular dose 
WBC  
White blood cell count 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 16 of 69 
1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Many advanced or metastatic human cancers 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 cancer 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 cancer. These findings provide a rationale 
for pursuing PLK-1 inhibition as a therapeutic principle in oncology. 
Recently mammalian PLK-1 was shown to be overexpressed in various human cancers such as 
non-small cell lung cancer (R04-0031) and colorectal cancer (R04-0034). 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 cancer cell lines (R04-0030, R04-0423). A 
potential role for PLK-1 overexpression 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 1230.1 trial will investigate safety and preliminary efficacy of BI 6727, a highly selective 
and specific PLK-1 inhibitor to be administered intravenously to patients with advanced or 
metastatic cancers. 
1.2 
DRUG PROFILE 
BI 6727 is a highly selective and potent small molecule Polo-like kinase 1 inhibitor. The 
pharmacological profile of BI 6727 was evaluated in vitro in enzymatic assays, cellular 
cytotoxicity assays and assays examining cell cycle progression. In vivo efficacy of BI 6727 
was determined in human tumour xenografts in nude mice.  
In an enzymatic assay using human recombinant PLK-1 the molecular potency of BI 6727 was 
in the low nanomolar range. More than 45 kinases tested in parallel with PLK-1 were not 
inhibited demonstrating the high molecular 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 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 17 of 69 
that BI 6727 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 BI 6727 was much better 
conserved than the activity of conventional chemotherapeutics such as taxanes or vincristine. 
Efficacy of BI 6727 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.  
The non-clinical safety profile of BI 6727 is considered favorable regarding the oncological 
indication and the antiproliferative 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. More 
detailed information is provided in the Investigator’s Brochure. 
No clinical data exist for BI 6727 administered to patients. Clinical data from the Polo-like 
kinase 1 inhibitor BI 2536 currently under investigation in clinical trials show good tolerability 
with haematotoxicity (neutropenia) constituting the dose limiting toxicity. No relevant 
unspecific toxicity has been observed as yet. Evidence for clinical antitumour activity has been 
observed. 
1.3 
RATIONALE FOR PERFORMING THE TRIAL 
This open label Phase I dose escalation trial 1230.1 is the first in man trial with BI 6727 in 
cancer patients. The trial will investigate safety and efficacy of this specific Polo-like kinase 1 
inhibitor in cancer patients.  
Patients with various solid tumours who have either failed conventional treatment, or for whom 
no therapy of proven efficacy exists, or who are not amenable to established forms of treatment 
will be treated with BI 6727 in this study. BI 6727 will be given as a single infusion over 60 
minutes on day one of the study. Based on the 3-cycle non-clinical safety studies a 
recommended starting dose of 12 mg will be given.  
Determination of the maximum tolerated dose (MTD) is the primary endpoint of this trial. 
MTD will be evaluated in patients receiving the first course of BI 6727. Depending on the drug 
related toxicity observed in this study three to six patients will be treated per dose tier. To 
increase the safety database at the MTD a total of 24 patients will be enrolled at MTD.  
Secondary endpoints of this trial are safety, pharmacokinetic profile of BI 6727 and the 
assessment of antitumour efficacy.  
Patients who experience a clinical benefit, i.e. an objective tumour response or symptom 
improvement or the absence of tumour progression and who have recovered from drug-related 
adverse events from previous courses are eligible for an additional course of BI 6727 according 
to protocol. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 18 of 69 
1.4 
BENEFIT / RISK ASSESSMENT 
Although considerable progress has been made in understanding cancer 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 who have failed conventional treatment, 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). BI 6727 represents a new class of small 
molecules targeting and blocking activation of PLK-1 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 these effects may hopefully translate into 
tumour remissions in patients without further treatment options.  
The most relevant side effect of BI 6727 administration is expected to be a transient inhibition 
of proliferation of normal dividing cells in mucosal tissue and bone marrow. Thymic atrophy 
seen in toxicological studies is not deemed relevant in the target population of adult cancer 
patients. Inhibition of mucosal proliferation may lead to gastrointestinal symptoms such as 
nausea or diarrhoea. The side effects on bone marrow stem cells may lead to a temporary 
decrease of blood cells and platelets. These side effects are frequently seen in cancer patients 
treated with conventional cytotoxics or targeted therapies and can easily be monitored. 
Supportive treatment for these effects is available. In contrast to many established 
antiproliferative agents no unspecific toxic effects have been identified for BI 6727 in 
preclinical studies. The QT-prolongation observed at high doses in an animal model are not 
expected to impair clinical development of the compound. Nevertheless ECG monitoring will 
be performed and analysed centrally by a core lab. 
In ongoing clinical trials with the Polo-like kinase 1 inhibitor BI 2536 good tolerability has 
been demonstrated. Haematotoxicity with predominant neutropenia constituted dose limiting 
toxicity. The neutropenia was quickly reversible and did not accumulate after repeated courses 
in the patients treated so far. No unspecific toxicity, no toxicity relating to kidneys or liver and 
no cardio-or neurotoxicity have been documented so far. Evidence for antitumour efficacy has 
been observed.   
Cancer patients with advanced tumours and no further treatment options may benefit from 
tumour shrinkage, tumour stabilisation or improvement of tumour-related symptoms induced 
by BI 6727. The potential benefit of therapy with BI 6727 is expected to outweigh the 
treatment related risks.  
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 19 of 69 
2. 
TRIAL OBJECTIVES 
2.1 
GENERAL AIM / PRIMARY OBJECTIVE 
The primary objective of this trial is to identify the maximum tolerated dose (MTD) of  
BI 6727 therapy in terms of drug-related adverse events. 
Secondary objectives are the collection of overall safety and antitumour efficacy data and the 
determination of the pharmacokinetic profile of BI 6727. 
2.2 
PRIMARY ENDPOINT 
The primary endpoint of this trial is the determination of the Maximum Tolerated Dose (MTD) 
of BI 6727. 
2.3 
SECONDARY ENDPOINT(S) 
1) 
Incidence and intensity of drug-related adverse events according to common 
terminology criteria for adverse events (CTCAE) v.3.0, laboratory evaluations, patient 
performance and vital signs 
2) 
Tumour responses and time to progression after BI 6727 treatment  
3) 
Pharmacokinetic parameters of BI 6727 (for parameters cf. section 7.1.2.). 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 20 of 69 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION 
Due to the methodology of this trial (dose escalation), it is not possible to predict the number 
of patients necessary to reach the objectives. An estimated total of up to 80 patients might be 
necessary to establish MTD. A total of 24 patients will be treated at MTD. Actual accrual will 
depend on the number of dose levels tested and the adverse events observed. Patients non 
evaluable with respect to MTD will be replaced. Patients with a histologically or cytologically 
confirmed diagnosis of a malignant solid tumour refractory or not amenable to standard 
therapies are eligible for this trial. It is planned to have the trial performed at one centre, 
depending on enrolment more centres may be initiated. 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) 
This is an open label, uncontrolled trial in patients with advanced solid tumours following a 
fixed dose escalation design. The aim of this trial is to assess the MTD of BI 6727 
administered at escalating doses using a toxicity-guided approach. 
3.3 
SELECTION OF TRIAL POPULATION 
Patients with advanced solid tumours will be eligible for this trial. 
A log of all patients screened will be maintained in the ISF at the investigational site. 
3.3.1 
Inclusion criteria 
1) 
Patients with confirmed diagnosis of advanced, non resectable and / or metastatic 
solid tumours, who have failed conventional treatment, or for whom no therapy of 
proven efficacy exists, or who are not amenable to established forms of treatment  
2) 
Age 18 years or older 
3) 
Written informed consent consistent with ICH-GCP and local legislation 
4) 
Eastern Cooperative Oncology Group (ECOG, R01-0787) performance score ≤ 2 
5) 
Recovery from CTCAE Grade 2 - 4 therapy-related toxicities from previous chemo-, 
hormone-, immuno-, or radiotherapies (except alopecia) 
The 18 additional patients recruited at the MTD must also meet the following criterion: 
6) 
Measurable tumour deposits (RECIST) by one or more techniques (CT, MRI)  
3.3.2 
Exclusion criteria 
1) 
Serious illness or concomitant non-oncological disease considered by the investigator 
to be incompatible with the protocol 
2) 
Pregnancy or breastfeeding 
3) 
Active infectious disease or known chronic Hepatitis B/Hepatitis C infection 
4) 
Clinical evidence of active brain or leptomeningeal disease during the past 12 months  


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 21 of 69 
5) 
Second malignancy currently requiring active therapy 
6) 
Absolute neutrophil count less than 1500 / mm3 
7) 
Platelet count less than 100 000 / mm3 
8) 
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) 
10) 
Serum creatinine greater than 1.5 mg / dl (> 132 µmol / L, SI unit equivalent) 
11) 
Known history of relevant QT-prolongation, e.g. long QT-syndrome 
12) 
Women and men who are sexually active and unwilling to use a medically acceptable 
method of contraception 
13) 
Treatment with other investigational drugs or participation in another clinical trial 
within the past four weeks before start of therapy or concomitantly with this trial 
(except for present trial drug) 
14) 
Chemo-, radio or immunotherapy within the past four weeks before start of therapy or 
concomitantly with this trial. This restriction does not apply to steroids and 
bisphosphonates. 
15) 
Patients unable to comply with the protocol 
16) 
Active alcohol or drug abuse 
 
3.3.3 
Retreatment criteria 
Patients with a clinical benefit after a course of BI 6727 (clinical response, absence of 
progression or symptom improvement) and who have recovered from any clinically relevant 
drug-related AE are eligible for a further treatment course. In case of symptom improvement 
despite disease progression a repeated course may be allowed in agreement between the 
clinical monitor and the investigator.  
Patients experiencing DLT are eligible for further treatment courses with BI 6727 at one dose 
tier below as soon as recovery from drug related toxicities allows further treatment. Patients 
eligible for a further (repeat) treatment course will not start treatment before 22 (± 2) days 
after start of the previous course. If an interruption of more than 6 weeks as counted from the 
start of the previous treatment course is necessary, the patient must be removed from this trial. 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 22 of 69 
4. 
TREATMENTS 
4.1 
TREATMENTS TO BE ADMINISTERED 
4.1.1 
Identity of investigational product(s) 
Substance (INN): 
BI 6727 
Pharmaceutical form: 
Solution for infusion 
Source: 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength: 
0,5 mg /mL (vials with 100 mL). 
Daily dose: 
See section 4.1.3 
Duration of use: 
Single dose 
Route of administration: intravenous 
Posology: 
Infusion over 60 min 
 
4.1.2 
Methods of assigning patients to treatment groups 
Not applicable. This is a dose escalation trial. 
4.1.3 
Selection of doses in trial 
4.1.3.1. First course of administration of BI 6727 
The starting dose will be 12 mg. As long as no patient of an ongoing dose tier develops drug-
related toxicity beyond Grade 1 according Common Terminology Criteria for adverse events 
(CTCAE) during the initial treatment course the dose will be escalated by up to 100% in new 
patients. As soon as any patient of an ongoing dose tier experienced drug-related toxicity 
Grade 2 or higher escalation steps of not more than 50% will be allowed thereafter. Should 
dose limiting toxicity (DLT) be observed in 1/6 patients treated in a cohort and escalation 
continues this will be in steps of not more than 35%. Before entering patients at a higher dose 
level it will be ensured that all patients at an ongoing dose level have completed the initial 
course of BI 6727 dosing. The decision regarding the incremental size of the dose escalation 
steps will only be taken after discussion between the sponsor and the clinical investigator 
considering toxicity data from each patient cohort. Prior to inclusion of a new patient the 
investigator has to confirm the respective dose with the clinical monitor of the sponsor. 
4.1.3.2. Additional courses of BI 6727 
The dose of BI 6727 will be the dose administered in the previous course, unless the patient 
experienced dose limiting toxicity. Patients experiencing DLT are eligible for further treatment 
courses at one dose tier below. 
4.1.4 
Selection and timing of doses for each patient 
Each vial of BI 6727 contains 100 mL of a 0.5 mg/mL solution. 
The procedure to prepare the infusion solution is the following: 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 23 of 69 
Determine the amount of solution which needs to be added to the 500 mL infusion bags 
according to the dose level (e.g. dose of 12 mg = 24 mL Volume). 
Withdraw the respective amount of NaCl 0.9% from the infusion bag.  
Add the respective amount of BI 6727 solution to the infusion bag and mix 
Take a 5 mL sample (corresponding to 1% total volume) out of the mixed prepared ready to 
use solution and store (the sample should not be cooled or frozen). The sample needs to be 
labelled with the right pre-printed, adhesive label. 
Solution is ready to be infused to the patient by using an infusion pump (infusion duration 60 
minutes). 
4.1.5 
Preparation of the infusion solution and of the sample for analysis. 
Each vial of BI 6727 contains 100 mL of a 0.5 mg/mL solution. 
The procedure to prepare the infusion solution is the following: 
Determine the amount of solution which needs to be added to the 500 mL infusion bags 
according to the dose level (e.g. dose of 12 mg = 24 mL Volume). 
Withdraw the respective amount of NaCl 0.9% from the infusion bag.  
Add the respective amount of BI 6727 solution to the infusion bag and mix 
Take a 5 mL sample (corresponding to 1% total volume) out of the mixed prepared ready to 
use solution and store (the sample should not be cooled or frozen). The sample needs to be 
labelled with the right pre-printed, adhesive label. 
Solution is ready to be infused to the patient by using an infusion pump (infusion duration 60 
minutes). 
4.1.6 
Selection and timing of doses for each subject 
BI 6727 will be administered as a short infusion over 60 minutes using an infusion pump, on  
day 1 of each course (the start and end time of the infusion needs to be documented in the e-
CRF). Immediately following the infusion of BI 6727 the infusion tubing will be washed with 
100 mL physiological sodium chloride (0.9% NaCl) solution for a maximum duration of 10 
minutes (The end time of the washing step needs to be documented in the e-CRF). BI 6727 
should be administered strictly intravenously. 
Initially, three patients will be treated per dose level. When at the ongoing dose level one 
patient experiences drug-related dose limiting toxicity (DLT; for definition, please refer to 
section 5.2.1) the number of patients treated at that dose level will be increased to a maximum 
of six evaluable patients. When no further patient experiences DLT the dose will be escalated 
to the next level. When two or more patients experience DLT in any dose cohort, other than the 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 24 of 69 
expansion cohort at MTD level, enrolment into this dose cohort will be stopped. In order to 
define the maximum tolerated dose (MTD) three additional patients will be treated at one dose 
tier below unless six have already been treated at that dose tier. The MTD (see also section 
5.2.1) is the highest dose at which not more than one patient out of six experiences DLT (R01-
0028). Should safety data of patients treated at the next lower dose indicate a sufficient safety 
margin another escalation to an intermediate dose can be chosen after discussion between the 
investigator and the clinical monitor. 
Once the MTD is determined patient enrolment at higher dose tiers will be suspended. Further 
patients will be included at the MTD level until a total of 24 patients will have been treated at 
the MTD.  
4.1.7 
Blinding 
Not applicable, this is an open label trial. 
4.1.8 
Packaging, labelling and re-supply 
BI 6727 will be supplied in 100 mL vials containing 50 mg BI 6727, respectively. Medication 
will be labelled with: trial number, medication number, contents, name and strength of product, 
pharmaceutical dosage form, route of administration, directions for use, storage conditions, 
term “for clinical trial use only”, use-by date, batch number and sponsor. 
Examples of the labelling of the medication will be found in the investigator site file (ISF). 
Medication will be delivered to the hospital's pharmacy where the total dose per patients will 
be prepared upon request from the investigator. The content of several vials may be needed for 
administration of the requested dose. For this purpose the medication will be filled in plastic 
bags prefilled with sodium chloride so that the trial drug can be administered as one single 
infusion to the patient. For details concerning the preparation of the infusion solution, please 
refer to section 4.1.4. 
4.1.9 
Storage conditions 
BI 6727 will be stored in the hospital pharmacy in a limited access area at room temperature. 
4.2 
CONCOMITANT THERAPY 
Concomitant medications, or therapy to provide adequate care, may be given as clinically 
necessary.  
All concomitant (non-oncological) therapies starting or changing during the course of the study 
are allowed but should be recorded in the e-Case Report Form (eCRF) except for vitamins, 
appetisers or nutrient supplements. Trade name, indication, and dates of administration will be 
documented. If patients receive parenteral nutrition during the study, the components need not 
be specified in detail. It should just be indicated as 'parenteral nutrition' and the form be 
completed. If a patient needs anaesthesia, it will be sufficient to indicate 'anaesthesia' without 
specifying the details. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 25 of 69 
4.2.1 
Rescue medication and additional treatment(s) 
Rescue medication to reverse the action of BI 6727 is not available. Potential side effects of BI 
6727 have to be treated symptomatically (see also section 5.2). Symptomatic treatments of side 
effects or tumour-associated symptoms are allowed. 
4.2.2 
Restrictions 
Additional chemo-, immuno-, hormone - or radiotherapy is not allowed during the study. These 
restrictions do not apply for steroids and bisphosphonates. For symptom control palliative 
radiotherapy may be permitted after discussion with the BI Clinical Monitor. 
For patients of the expansion cohort at MTD, the impact of any palliative radiotherapy 
administered on evaluable lesions has to be documented. 
4.3 
TREATMENT COMPLIANCE 
The study medication will be administered as a single intravenous 60 minute infusion under 
supervision of the investigator or dedicated personnel. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 26 of 69 
5. 
OBSERVATIONS 
Safety, pharmacokinetic and efficacy data will be collected and evaluated. 
5.1 
EFFICACY / CLINICAL PHARMACOLOGY 
Efficacy as secondary endpoint will be assessed by analysing the tumour response to therapy 
and time to progression in all patients with measurable disease. 
5.1.1 
PRIMARY ENDPOINT 
Not applicable since this study focuses on safety endpoints. The primary endpoint for safety is 
described in section 5.2.1. 
5.1.2 
SECONDARY ENDPOINTS 
Response will be assessed by tumour measurements and will be evaluated according to the 
response evaluation criteria in solid tumours (RECIST, see ISF, R01-0754). 
The investigator along with his / her radiologist will record the target and non-target lesions at 
baseline. One to ten target lesions should be identified at baseline and recorded in the eCRF. 
The same method of assessment and the same technique should be used to characterise each 
reported lesion at baseline and during follow-up. Lesions in previously irradiated areas may not 
be considered measurable at baseline. However, new lesions occurring in previously irradiated 
areas have to be considered for assessment of tumour response. 
Response (complete response CR, partial response PR), stable disease (SD) and progression 
(progressive disease, PD) will be evaluated in this study using the international criteria 
proposed by the RECIST Committee. Changes in only the largest diameter (unidimensional 
measurement) of the tumour lesions are used in the RECIST criteria. For more details see also 
Appendix 10.4 "Tumour assessment according to RECIST". 
5.2 
SAFETY 
5.2.1. 
Maximum tolerated dose (MTD) and dose limiting toxicity (DLT) 
The maximum tolerated dose is defined as: 
The dose of BI 6727 which is one dose tier below that dose at which two or more out of a 
maximum of six patients experienced DLT. At the maximum tolerated dose, no more than one 
patient out of six patients may experience DLT, i.e. MTD is defined as the highest dose studied 
for which the incidence of dose-limiting toxicity is no more than 17% (i.e. 1/6 patients) during 
the first course. 
For definition of DLT, it is essential that patients are treated sufficiently according to 
supportive care standards. Patients with treatable adverse events that are not sufficiently treated 
need to be replaced. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 27 of 69 
Dose limiting toxicity is defined as: 
drug related CTCAE grade 3 or 4 non haematological toxicity (except emesis or 
diarrhoea responding to supportive treatment), or 
drug related CTCAE grade 4 neutropenia for seven or more days and / or complicated 
by infection, or 
CTCAE Grade 4 thrombocytopenia . 
The MTD will be defined on the basis of DLT observed during the first course of dose 
escalation cohorts. However, for those patients who receive a further infusion, unusual or 
unexpected toxicities will be considered for the purposes of confirming the MTD.  
Patients with a clinical benefit after a course of BI 6727 (symptom improvement, clinical 
response or absence of progression) and who recovered from drug related adverse events are 
eligible for a further treatment course. In case of symptom improvement despite disease 
progression a repeated course may be allowed in agreement between the clinical monitor and 
the investigator. All DLT’s occurring during the first or repeated treatment courses will be 
reported as significant adverse events. 
5.2.2. 
Adverse Events 
All patients will be monitored carefully during and after the treatment courses of BI 6727. 
During the trial, all adverse events (AE) will be recorded in the eCRF as described in section 
8.4 of this protocol. The events will be graded according to the CTCAE v3.0 (attached to the 
ISF). 
Adverse events with onset within 21 days after the previous administration of therapy with  
BI 6727 are considered as on treatment. Adverse events which are not yet recovered at the end 
of treatment (EOT) visit will be followed up until recovery or in case of persistence sufficient 
characterisation of the toxic effects has been achieved and the investigator and the clinical 
monitor agree to not further pursue them. Adverse events occurring during the follow-up 
period after the EOT visit will be reported in case they are serious or considered drug-related 
by the investigator. 
Hospitalisations for administrative reasons or hospitalisations already planned prior to 
informed consent need not be reported as an SAE. Progressive disease (PD) will not be 
reported as an SAE if it is considered the natural course of the disease but will be recorded in 
the eCRF. Disease progression will be analyzed as part of the efficacy evaluation. Pre-existing 
conditions at baseline other than the disease will be not recorded as Adverse Events if they 
remain unchanged during the trial. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 28 of 69 
5.2.3. 
Physical examination, height, body weight, performance status  
and electrocardiogram 
A general physical examination will be performed at screening and at the end of the treatment. 
The same investigator should perform this examination. Physical examination will include 
measurement of height and of body weight and the evaluation of the ECOG performance score. 
Height will be documented only once at screening of course 1. Weight and ECOG score will 
also be assessed when BI 6727 treatment is started and at the end of the treatment. ECOG will 
also be assessed at the last visit of each course. 
12-lead resting electrocardiograms (ECG) will be performed at baseline, at visit 2 before and at 
the end of BI 6727 infusion and at the last visit of each course. In patients eligible for repeated 
courses of treatment ECGs should be done at visit 2 of the third course (second repeated 
course) before and at the end of infusion of BI 6727, at the last visit of that course and 
whenever the investigator deems necessary. In case of drug related ECG changes additional 
ECG monitoring will be performed in the respective and later courses of treatment. Except for 
the screening ECG all ECGs have to be digitally recorded using dedicated equipment provided 
by a CRO
. ECG recordings will be done at the following time 
points: 
• 
One ECG during the screening examination (no digital monitoring needed) 
• 
On day 1 a series of three consecutive ECGs prior to start of infusion of BI 6727 
(approx. experimental time -0:15 min) 
• 
On day 1 a series of three consecutive ECGs after end of infusion of BI 6727 (approx. 
experimental time 1h 15 min) 
• 
On day 1 of course 3 a series of three consecutive ECGs prior to start of infusion of BI 
6727 (approx. experimental time -0:15 min) 
• 
On day 1 of course 3 a series of three consecutive ECGs after end of infusion of BI 
6727 (approx. experimental time 1h 15 min)   
• 
At the visit 8 of the first course and visit 5 of the third course a series of three 
consecutive ECGs 
The recordings will be checked for pathological results (to be recorded as AEs) by the 
investigator. In addition a centralised evaluation of all 12-lead ECGs recorded during day 1 of 
courses 1 and 3, visit 8 of course 1 and visit 5 of course 3 will be performed by a CRO 
. This analysis will include the determination RR-intervals, PR-intervals, QRS-
intervals, QT-intervals. The CRO is also in charge of a safety overread of ECGs (one ECG out 
of every series of three) which will be done by a board-certified cardiologist.  To allow for a 
heart rate correction of QT intervals according to Fridericia’s formula (QTcF = QT/RR-1/3) or 
other methods the QT intervals will be matched to the preceding RR intervals. 
Physical examination will be performed prior to each course. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 29 of 69 
5.2.4. 
Vital signs 
Vital signs (blood pressure (BP) and pulse rate after 2 minutes supine rest) will be recorded at 
the screening visit and at the following time points: pre-infusion and 20 (± 5), 65 (± 10), 120 
(± 30) and 240 (± 30) minutes after start of infusion of BI 6727, at every visit of the 
observation phase and at EOT. 
5.2.5. Laboratory examinations 
Blood samples will be collected from venous blood at the times indicated in the flow chart. 
Laboratory tests will include the following safety lab parameters: 
• haematology 
red blood cell count (RBC), haemoglobin, haematocrit, medium 
corpuscular volume (MCV), white blood cell count (WBC) and differential, platelets 
• biochemistry 
glucose, sodium, potassium, calcium, creatinine, aspartate amino transferase (AST), alanine 
amino transferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, urea, 
serum protein electrophoresis (total protein, albumine, α1-globulines, α2-globulines, β-
globulines, γ-globulines), uric acid, creatine phosphokinase (CPK). In case of pathological 
CPK further evaluation (e.g. by Troponin assays) should be performed and the findings 
documented. 
• coagulation parameters 
prothrombin time (PT), international normalised ratio (INR) where therapeutically indicated 
and partial thromboplastin time (PTT) (at day 1 before start of infusion and at day 2) 
• tumour markers 
in applicable tumour types markers will be taken at screening and at visit 8 (visit 5 of repeated 
courses) e.g.: PSA, AFP, β-HGG, CA 125, CEA, CA 19-9, NSE, TPA, CA 15.3,  
CYFRA 21-1, chromogranine, thyreoglobuline.   
These parameters will be assessed as specified in the flow chart. In case of toxicity adequate 
and more frequent blood sampling is at the discretion of the investigator. In case of grade 4 
neutropenia, blood has to be collected seven days after first occurrence of grade 4 neutropenia. 
In case laboratory investigations have been performed within two weeks prior to screening, 
these values may be used for screening and no repeat laboratory examination is requested for 
the purpose of the trial. 
• Urine (pH, glucose, erythrocytes, leukocytes, protein, nitrite) will be analysed by dipstick 
(semiquanitative measurements; -, +, ++, +++) during the screening visit, at visit 3 of initial 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 30 of 69 
treatment course, at visit 1 and 2 of repeated treatment courses and at the end of treatment 
visit. In case of pathological findings, further evaluation should be performed and the 
findings documented. A pregnancy test will be performed at screening and immediately 
before any further administration of BI 6727 in women of childbearing potential. 
5.2.6. Significant adverse events 
Reaching DLT has to be recorded as a significant adverse event. 
5.3 
OTHER 
5.3.1. 
Demographics and history 
 
Demographics (sex, birth date, race), information on smoking and alcohol status, and baseline 
conditions will be collected during the screening visit and updated information will be 
collected at the first visit of additional courses. 
History of cancer will also be obtained. The type of cancer, 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 Union 
Internationale Contre le Cancer (UICC) / 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 surgeries will be reported. Previously administered chemo-, immuno-, and 
hormone therapy will be reported including start and end dates (month and year may be 
sufficient), the therapy protocol with the number of courses (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. Concomitant diagnoses and/or therapies 
 
Concomitant diagnoses and/or therapies present at study entry and/or during screening and 
relevant to the patient’s safety during the trial as judged by the Investigator, will be recorded in 
the eCRF. 
5.3.3. 
Genotyping for Pharmacokinetics 
One blood sample will be collected for cytochrome P 450 (CYP2D6, CYP2C19, CYP2C9) and 
N-acetyltransferase (NAT2) genotyping to evaluate the possible influence of their 
polymorphism on the pharmacokinetic profile of BI 6727. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 31 of 69 
In order to analyse the pharmacokinetic data in more detail, an investigation should help to 
clarify if different interindividual areas under the concentration time curves at same dosages 
might be explained by the respective genotypes. These results could help to elucidate the 
maximal tolerable dose. 
To perform such analysis, EDTA-anticoagulated blood samples for DNA isolation will be 
collected once at visit 2 after separate informed consent.  
Only testing for genes involved in drug metabolism will take place and that no polymorphisms 
of genes which might predispose for different diseases will be analysed. Only frequent 
functional polymorphisms will be analyzed. 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
Not applicable.  
5.5 
DRUG CONCENTRATION MEASUREMENTS / PHARMACOKINETICS 
Date and exact clock time of administration (start and end time of infusion) as well as of 
pharmacokinetic sampling times must be recorded. These actual sampling times will be used 
for determination of pharmacokinetic parameters.  
The designation “before”/”predose” on study day 1 refers to the time period of 0:05 before 
drug administration (see Appendix 10.2), i.e. study measurements and assessments scheduled 
to occur “before”/”predose” have to be performed and completed 0:05 prior to drug 
administration/start of infusion. 
5.5.1 
Methods and timing of sample collection 
5.5.1.1 Plasma sampling for pharmacokinetics 
A total amount of 42 mL blood will be taken per subject during the initial treatment course of 
the study for pharmacokinetic purposes. Subsequent courses will require 12 mL of blood for 
pharmacokinetic sampling. The samples need to be taken in the opposite arm, not in the 
infusion arm. For patients having central venous access, BI 6727 may be administered using 
this device and PK samples obtained from either forearm. 
For quantification of analyte plasma concentrations, 3 mL of blood will be taken in an EDTA 
(ethylendiaminetetraacetic acid)-anticoagulant blood drawing tube at the following time points: 
During the initial treatment course: 
At visit 2 – day 1: before drug administration and at 0:15, 0:30, 0:45, 1:00*, 1:30, 2:00, 4:00, 
8:00 hours after start of infusion (*immediately prior to end of infusion of BI 6727). 
At visit 3 – day 2: 24:00 hours after start of infusion 
At visit 4 – day 3: 48:00 hours after start of infusion 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 32 of 69 
At visit 5 – day 5 (±1 day): planned time 96:00 hours after start of infusion  
At visit 6 – day 8 (±1 day): planned time 168:00 hours after start of infusion  
At visit 7 – day 15 (±1 day): planned time 336:00 hours after start of infusion 
During additional courses plasma samples will be taken at the following time points: 
At visit R1 – day 1: prior to the end of infusion (1:00)  
At visit R2 – day 2: 24:00 after start of infusion 
At visit R3 – day 8 (±1 day): planned time 168:00 hours after start of infusion  
At visit R4 – day 15 (±1 day): planned time 336:00 hours after start of infusion  
Until shipment on dry ice to the analytical laboratory, the plasma samples will be stored at 
 –20°C or below at the clinical site and stored at the analytical laboratory at –20°C or below 
until analysis.  
Detailed handling instructions for plasma samples are provided in Appendix 10.3.  
5.5.1.2 Urine sampling for pharmacokinetics (in course 1 only)  
A blank urine sample will be collected prior to drug administration and two 2 mL aliquots 
retained to check for analytical interference. A protocol start time of -2:00 and a stop time of 
-2:00 will be used for database setup. All urine voided during the sampling intervals 0-24 and 
24-48 hours after administration will be collected in containers. Patients have to empty their 
bladder at the end of each sampling interval. The urine weight/volume (weight will be set equal 
to volume, i.e. 1 kg = 1 L, without correction for specific gravity of urine) for each collection 
interval will be documented (the weight of the empty and the filled container needs to be 
documented) and two 2 mL aliquots will be stored for bioanalytical measurement. 
Until shipment on dry ice to the analytical laboratory, the urine samples will be stored at  
–20°C or below at the clinical site and stored at the analytical laboratory at –20°C or below 
until analysis.  
Detailed handling instructions for urine samples are provided in Appendix 10.3. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 33 of 69 
5.6 
BIOMARKER / PHARMACODYNAMIC SAMPLING 
5.6.1 
Methods and timing of sample collection 
In applicable tumour types markers will be taken at screening and at visit 8 (visit 5 of repeated 
courses) e.g.: PSA, AFP, β-HGG, CA 125, CEA, CA 19-9, NSE, TPA, CA 15.3,  
CYFRA 21-1, chromogranine, thyreoglobuline.  (c.f. 5.2.6). 
5.7 
PHARMACOKINETIC / PHARMACODYNAMIC RELATIONSHIP 
No analysis of pharmacokinetic/pharmacodynamic relationship is planned. 
5.8 
DATA QUALITY ASSURANCE 
A quality assurance audit of this trial may be conducted by the sponsor or sponsor’s designees. 
The quality assurance auditor will have access to all medical records, the investigator’s trial 
related files and correspondence, and the informant consent documentation that is relevant to 
this clinical trial. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 34 of 69 
6. 
INVESTIGATIONAL PLAN 
This is an open label, uncontrolled trial in patients with various solid tumours following the 
3+3 design with dose escalation (R04-0569). The aim is to assess the MTD of BI 6727 
administered at escalating doses. 
Patients meeting the inclusion and exclusion criteria and who have given their written informed 
consent are eligible for participation in the trial. 
Three to six patients each will be administered BI 6727 at a certain dose level. For exact dosing 
details refer to section 4.1.3.1. A total of 24 patients will be treated at the MTD. 
6.1 
VISIT SCHEDULE 
6.1.1. 
Visit schedule in initial treatment course 
6.1.1.1. Visit 1 – screening visit 
The screening visit has to be performed within day -14 and the day before first administration 
of BI 6727. 
6.1.1.2. Visit 2 – day 1 
Visit 2 is the day of administration of BI 6727. 
6.1.1.3. Visit 3 – day 2 
Visit 3 is the day after the first administration of BI 6727. 
6.1.1.4. Visit 4 – day 3, visit 5 – day 5 (±1), visit 6 – day 8 (±1) and visit 7 – day 15(±1) 
Visits 4 through 7 should be performed on days 3, 5 (±1), 8 (± 1) and 15 (±1). 
6.1.1.5. Visit 8 – day 22 (± 2) 
Visit 8 should be performed on day 22 (±2).  
6.1.2. 
Visit schedule in repeated treatment courses 
6.1.2.1. Visit 1 – day 1 
Visit 1 is the day of administration of BI 6727. 
6.1.2.2. Visit 2 – day 2 
Visit 2 is the day after the first administration of BI 6727. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 35 of 69 
6.1.2.3. Visit 3 – day 8 (±1), visit 4 – day 15 (±1)  
and visit 5 – day 22 (±2) 
Visits 4 through 5 should be performed on days 8 (± 1); 15 (± 1) and 22 (± 2) 
6.2 
TRIAL PROCEDURES AT EACH VISIT 
6.2.1 
Screening phase 
Visit 1 – Screening visit (day -14 to day 0) 
• 
informed consent 
• 
demographics (sex, birth date, race) 
• 
history (oncological and relevant non oncological) 
• 
patient eligibility (in- and exclusion criteria) 
• 
physical examination including resting ECG, body weight, height, vital signs (blood 
pressure, pulse rate) and ECOG performance score 
• 
pregnancy test in women of childbearing potential 
• 
concomitant therapy 
• 
Endosonography or ultrasound of primary or metastatic marker lesions (optional) 
• 
tumour assessment. MRI and CT scans should not be older than 4 weeks 
• 
tumour markers (in applicable tumour types of the underlying disease) 
• 
laboratory examination including safety lab parameters (haematology including 
differential, biochemistry, coagulation parameters), urine dipstick  
6.2.2 
Treatment phase(s) 
6.2.2.1. Treatment phase in course 1 
Visit 2 – day 1 
Visit 2 – day 1, day of BI 6727 administration 
• 
patient eligibility (in- and exclusion criteria) 
• 
final confirmation of dose tier 
• 
changes in concomitant therapies 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 36 of 69 
• 
occurrence of adverse events (AEs) since enrolment 
• 
body weight 
• 
ECOG performance score 
• 
blood sampling for cytochrome P450 (CYP2D6, CYP2C19, CYP2C9) and NAT2 
genotyping  
immediately before administration of BI 6727: 
• 
resting ECG (series of three consecutive ECGs using dedicated equipment)  
• 
vital signs (blood pressure, pulse rate) 
• 
safety lab parameters (haematology including differential, biochemistry) 
• 
Pharmacokinetic blood sampling: obtain predose blood sample (-0:05) (refer section 
10.3 for sample handling). The date and time of sampling must be recorded in the 
eCRF.  
• 
Pharmacokinetic urine sampling: obtain predose urine sample (at least two 4 mL 
aliquots) 
following administration of BI 6727 (start of infusion: 0:00) (the infusion rate needs to be 
constant during the whole infusion, deviations need to be documented in the eCRF. Duration 
(start and stop time of infusion) and actual dose administered need to be documented): 
• 
vital signs (blood pressure, pulse rate) at 20 (± 5 minutes), 65 (± 10 minutes), 120 (2 
hours; ± 30 minutes) and 240 minutes (4 hours; ± 30 minutes) after start of infusion 
• 
Pharmacokinetic blood sampling: obtain blood samples at the following time points: 
0:15, 0:30, 0:45, 1:00 (immediately prior to end of infusion of BI 6727), 1:30, 2:00, 
4:00, 
8:00 h after start of infusion of BI 6727 (refer section 10.3 for sample handling). Blood 
samples have to be taken in the opposite arm of the infusion arm. For patients having 
central venous access, BI 6727 may be administered using this device and PK samples 
obtained from either forearm. The date and time of blood sampling must be recorded in 
the eCRF. 
• 
Pharmacokinetic urine sampling: start urine sampling (0-24 h, only in first course) 
• 
adverse events occurring during and after infusion 
• 
changes in concomitant therapy 
• 
resting ECG (series of three consecutive ECGs using dedicated equipment) 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 37 of 69 
Visit 3 - day 2 
• 
vital signs (blood pressure, pulse rate)  
• 
Pharmacokinetic blood sampling: obtain blood sample 24:00 h after start of infusion of  
BI 6727 (refer section 10.3 for sample handling). The date and time of blood sampling 
must be recorded in the eCRF. 
• 
Pharmacokinetic urine sampling: collect urine container from first interval and place 
new container for second interval to patients disposal (24-48 h, only in first course) 
(refer to section 10.3 for sample handling). 
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry, coagulation parameters 
• 
urine dipstick 
Visit 4 - day 3  
• 
vital signs (blood pressure, pulse rate)  
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry  
• 
Pharmacokinetic blood sampling: obtain blood sample 48:00 h after start of infusion of  
BI 6727 (refer to section 10.3 for sample handling). The date and time of blood 
sampling must be recorded in the eCRF. 
• 
Pharmacokinetic urine sampling: collect urine container from second interval  
(24-48 h, only in first course) (refer section 10.3 for sample handling). 
Visit 5 - day 5 (± 1) 
• 
vital signs (blood pressure, pulse rate)  
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry  


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 38 of 69 
• 
Pharmacokinetic blood sampling: obtain blood sample 72:00, or 96:00, or 120:00 h after 
start of infusion of BI 6727 (respectively at day 4, or day 5, or day 6) (refer to section 
10.3 for sample handling). The date and time of blood sampling must be recorded in the 
eCRF. 
Visit 6 - day 8 (± 1) and Visit 7 - day 15 (± 1)  
• 
vital signs (blood pressure, pulse rate)  
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry  
• 
Pharmacokinetic blood sampling: obtain blood sample at visit 6 (planned time: 168:00 
hours after start of infusion of BI 6727) and at visit 7 (planned time: 336:00 hours after 
start of infusion), respectively (refer to section 10.3 for sample handling). The date and 
time of blood sampling must be recorded in the eCRF. 
Visit 8 - day 22 (±2) 
Visit 8 is the last visit of the initial treatment course. This visit may coincide with day 1 of the following treatment 
course. Examinations which are due on both present visit and the day of  
BI 6727 administration need to be documented only once (in the day 22 visit). 
• 
vital signs (blood pressure, pulse rate)  
• 
ECOG performance score 
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry, coagulation parameters 
• 
Endosonography or sonography (optional)  
• 
resting ECG (series of three consecutive ECGs using dedicated equipment) 
6.2.2.2. Treatment Phase in repeated treatment courses 
Visit 1 – day 1 
Visit 1 – day 1, day of BI 6727 administration 
• 
patient eligibility (in- and exclusion criteria) 
• 
update of medical history 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 39 of 69 
• 
physical examination including body weight, height, vital signs (blood pressure, pulse 
rate). Data from last visit of preceding course may be used in case examinations were 
done within the past 4 weeks. 
• 
ECOG performance score 
• 
laboratory examination including safety lab parameters (haematology including 
differential, biochemistry, coagulation parameters). Data from last visit of preceding 
course may be used in case examinations were done within the past 4 weeks. 
• 
urine dipstick. Data from last visit of preceding course may be used in case 
examinations were done within the past 4 weeks. 
• 
pregnancy test in women of childbearing potential 
• 
changes in concomitant therapies 
• 
occurrence of adverse events (AEs) since last visit 
immediately before administration of BI 6727: 
• 
resting ECG (series of three consecutive ECGs in third treatment course using dedicated 
equipment) at -0:15 min  
• 
vital signs (blood pressure, pulse rate) 
following administration of BI 6727 (start of infusion: 0:00) (the infusion rate needs to be 
constant during the whole infusion, deviations need to be documented in the eCRF. Duration 
(start and stop time of infusion) and actual dose administered need to be documented): 
• 
resting ECG (series of three consecutive ECGs using dedicated equipment directly after 
completion of BI 6727 infusion (1h 15 min)  
• 
vital signs (blood pressure, pulse rate) at 20 (± 5 minutes), 65 (± 10 minutes), 120 (2 
hours; ± 30 minutes) and 240 minutes (4 hours; ± 30 minutes) after start of infusion 
• 
Pharmacokinetic blood sampling: obtain blood samples 1:00 h (immediately prior to 
end of infusion of BI 6727) after start of infusion of BI 6727 (refer section 10.3 for 
sample handling). Blood samples have to be taken in the opposite arm of the infusion 
arm. For patients having central venous access, BI 6727 may be administered using this 
device and PK samples obtained from either forearm. The date and time of blood 
sampling must be recorded in the eCRF. 
• 
adverse events occurring during and after infusion 
• 
changes in concomitant therapy 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 40 of 69 
Visit 2 – day 2 
• 
vital signs (blood pressure, pulse rate)  
• 
Pharmacokinetic blood sampling: obtain blood sample 24:00 h after start of infusion of 
BI 6727 (refer section 10.3 for sample handling). The date and time of blood sampling 
must be recorded in the eCRF. 
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry, coagulation parameters 
• 
urine dipstick 
Visit 3 - day 8 (± 1) and Visit 4 - day 15 (± 1)  
• 
vital signs (blood pressure, pulse rate)  
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry  
• 
Pharmacokinetic blood sampling: obtain blood sample at visit 3 (planned time: 168:00 
hours after start of infusion of BI 6727) and at visit 4 (planned time: 336:00 hours after 
start of infusion of BI 6727), respectively (refer section 10.3 for sample handling). The 
date and time of blood sampling must be recorded in the eCRF. 
Visit 5 – day 22 (± 2) 
• 
vital signs (blood pressure, pulse rate)  
• 
ECOG performance score 
• 
adverse events  
• 
changes in concomitant therapy 
• 
safety lab including haematology, biochemistry, coagulation parameters 
• 
tumour assessment at the end of every other course: 
MRI or CT if in accordance with RECIST or otherwise clinically indicated 
• 
Endosonography or sonography optional 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 41 of 69 
• 
resting ECG (series of three consecutive ECGs using dedicated equipment) in third 
course of treatment 
6.2.3 
End of trial and follow-up 
Termination of trial medication – End of trial 
The following will be obtained and / or performed: 
• 
physical examination including vital signs, body weight and ECOG performance score 
• 
adverse events 
• 
laboratory examinations: urine dipstick 
The conclusion of patient participation should be completed for all patients together with their 
last visit. The conclusion of patient participation will be completed during the final visit (day 
22) for patients treated per protocol. For patients, who were withdrawn or dropped out of the 
trial, the end of trial investigations should be completed at the last visit. 
Imaging and tumour assessment need to be done only if not yet performed within the past three 
weeks. 
Follow up visit 
All patients who completed a treatment course (all visits performed including visit at day 22) 
and are not eligible for a further course will be followed up until progression, lost to follow up 
or treatment with another anti-cancer drug. The intervals for follow up are every six weeks for 
the first 3 months and then every three months, respectively. At each follow up visit adverse 
events will be reported in case they were not recovered at the end of treatment of the last 
course. Performance of physical examination and ECG as well as determination of safety lab 
parameters is optional. The ECOG performance score will be reported. No tumour assessment 
is requested if the patient has progressive disease and/or received another anti-cancer therapy. 
CT or MRI examinations will be handled according to the RECIST guideline. 
6.2.4. 
Missed visits 
If a visit is missed and the patient reports to the investigator between this visit and the next one, 
the missed visit should be done with the actual date and the reason should be given for the 
delayed visit. The next visit, however, should take place at the scheduled time after 
administration of the trial drug. 
6.3 
REMOVAL OF PATIENTS FROM THERAPY ASSESSMENT 
A patient has to be withdrawn from the trial if:  
• 
the patient withdraws consent 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 42 of 69 
• 
the patient is no longer able to participate in the trial (e.g. adverse events, surgery, 
concomitant diagnoses, concomitant therapies or administrative reasons); in such case 
the Investigator’s reason for a patient removal must be recorded in the appropriate page 
of the eCRF. 
• 
eligibility criteria are violated 
All withdrawals will be documented and the reason for withdrawal recorded and discussed, as 
necessary, in the final report of the trial. 
The patients are free to discontinue their participation in this study at any time. The 
investigator may also stop patient’s participation, if the patient is no longer able to attend study 
visits e.g. due to worsening of disease. A patient can be withdrawn after discussion between 
the sponsor and the investigator if eligibility criteria are violated or the patient fails to comply 
with the protocol (e.g. non-compliance to study visits, see 6.3.1). 
6.3.1 
Replacement of patients 
Patients withdrawn or patients who miss more than one visit during their first treatment course 
will be replaced. Patients who miss one visit may be replaced after discussion between the 
sponsor and the investigator. 
Patients who withdraw due to DLT will not be replaced. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 43 of 69 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
7.1 
STATISTICAL DESIGN / MODEL 
This phase I trial will be performed to determine the safety, tolerability, MTD, 
pharmacokinetics and preliminary therapeutic effects of BI 6727 (cf. 2.2. and 2.3. for definition 
of endpoints) in patients with various advanced and/or metastatic solid tumours for whom no 
established antitumour treatment options are available. 
The dose escalation procedure is described in 4.1.3. Cohorts of patients will be entered 
sequentially into escalating dosage tiers with the aim to identify the maximum tolerated dose of 
BI 6727. 
This study is open-label, which allows the safety of each dosage of BI 6727 to be assessed 
before treating additional patients with higher doses. Patients will not be randomized; they will 
be assigned to the cohort that is being filled at the time the patient is ready to enter the trial. 
7.1.1. 
Safety and tolerability evaluation 
Safety and tolerability of BI 6727 will be assessed in terms of changes in laboratory 
parameters, vital signs, the incidence and severity and causality of adverse events and of 
toxicities according to CTCAE criteria version 3.0. The results will be reported for each dose 
level separately as well as in terms of overall means, if appropriate. 
The results will be displayed for the first course and overall courses separately. 
7.1.2. 
Pharmacokinetic evaluation 
If feasible, the following PK parameters will be calculated: 
Cmax (maximum concentration of the analyte in plasma) 
tmax (time from dosing to maximum concentration) 
AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity)  
AUC0-tz (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to the last quantifiable time point tz) 
%AUC0-tz (the percentage of the AUC0-∞ that is obtained by extrapolation) 
λz (terminal rate constant in plasma), t1/2 (terminal half-life of the analyte in plasma) 
MRT (mean residence time of the analyte in the body after intravenous administration) 
CL (total clearance of the analyte in the plasma after intravascular administration) 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 44 of 69 
Vz (apparent volume of distribution during the terminal phase λz following an intravascular 
dose) 
Vss (apparent volume of distribution at steady state following intravascular administration) 
Ae0-24/48 (amount of analyte that is eliminated in urine from the time point 0 to time point 24 
and 48 h respectively)  
fe0-24/48 (fraction of analyte eliminated in urine from time point 0 to time point 24 and 48 h 
respectively) 
CLR,0-24/48 (renal clearance of the analyte from the time point 0 to time point 24 and 48 h 
respectively)  
The pharmacokinetic parameters Cmax, AUC0-∞ and AUC0-tz will be descriptively explored 
concerning dose proportionality. 
7.1.3. 
Therapeutic efficacy evaluation 
Tumour response will be the parameter for therapeutic efficacy. Tumour response will be 
evaluated according to the RECIST guidelines (see ISF). Tumour response will be assessed by 
the amount of patients with complete response (CR), partial response (PR), stable disease (SD) 
or progressive disease (PD), respectively. The number of patients with objective response (i.e. 
CR or PR) will be provided per dose level. 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
All analyses in this trial are descriptive and exploratory by nature. Any statistical tests are 
performed only to provide a statistical framework from which to view the results and providing 
aid for planning further studies. No formal statistical inferences are foreseen. 
7.3 
PLANNED ANALYSES 
Only one analysis population (the treated set) will be considered for efficacy and safety 
analyses. No Per protocol population will be used for analyses, however protocol violations 
will be described. 
Treated Set consists of all patients who received at least one application of BI 6727 
7.3.1 
Primary analyses 
Non evaluable patients will be replaced. The total number of study patients depends on the 
toxicity encountered. Patients who are evaluable for toxicity but not for efficacy need not be 
replaced. 
The primary endpoint for this study is the tolerability and safety of BI 6727 as reflected by the 
Maximum Tolerated Dose (MTD) of BI 6727 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 45 of 69 
Determination of MTD will be done using data from patients receiving the first course of  
BI 6727.  Depending on the drug related toxicity observed in this study, up to six patients will 
be treated in each dose cohort.  To increase the safety database at the presumed Phase II dose, a 
total of 24 patients will be enrolled at MTD.  
MTD will be defined as the dose of BI 6727 that is one dose cohort below that dose at which 
two or more out of a maximum of six patients experienced DLT. At the maximum tolerated 
dose, no more than one patient out of six patients may experience Dose Limiting Toxicity 
(DLT, for definition, see section 5.2.1). 
MTD will be defined on the basis of DLT observed during the first course. However, for those 
patients who receive a further infusion, unusual or unexpected toxicities will be considered for 
the purposes of confirming the MTD 
To assess safety of BI 6727, all DLT’s occurring during the first or repeated treatment courses 
will be reported as significant adverse events. 
7.3.2 
Secondary analyses 
The secondary analysis will evaluate safety, pharmacokinetics and tumour response. 
• 
Pharmacokinetic analyses 
All evaluable subjects 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. 
A subject is considered to be not evaluable if the subject has an important protocol violation 
relevant to the evaluation of pharmacokinetics or has insufficient data.  
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, geometric coefficient of 
variation (refer also to 10.1). 
Refer to Appendix 10.1 for details concerning handling and derivation of pharmacokinetic 
parameters. 
If sufficient patients are entered into the study, covariates such as gender, age, and weight may 
be exploratively investigated for their potential influence on pharmacokinetic parameters. 
Exploratory analyses will compare the area under the plasma concentration-time profile and 
the maximum plasma concentration with considered relevant safety, efficacy, and 
pharmacodynamic endpoints. 
• 
Efficacy analyses 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 46 of 69 
Tumour response, objective response (CR, PR), and best overall response will be analysed 
descriptively according to the RECIST criteria (see section 5.1.2 and Appendix 10.4) at the end 
of every other treatment course.  
For patients with no measurable lesion the overall response will be assessed as NEV (compare 
Table 10.4.4: 2). If data allow the assessment of the non-target lesion will be described in a 
explorative subgroup analysis. 
The time to tumour progression will be defined as the time from first treatment administration 
to cancer progression or death due to the cancer under study. 
7.3.3 
Safety analyses 
Key measures of safety will include: 
• 
the incidence and intensity (according to CTCAE criteria version 3.0) of adverse events 
• 
time course and distribution of patients by maximum CTCAE grade; and  
• 
time course of laboratory changes 
The type, number and intensity of adverse events will indicate how well BI 6727 is tolerated. 
Haematological toxicity such as thrombocytopenia, neutropenia and leukopenia as well as non-
haematological toxicity will be evaluated continuously by using the CTCAE scheme. 
Specific AE expected to be associated with BI 6727 may be described more accurately.   
Frequency distributions and other descriptive statistical measures will be used to examine these 
variables. The time course of the changes and the reversibility will be displayed. 
Descriptive statistics for ECG, in addition to abnormalities and other notable findings will also 
be analysed. 
All data will be presented in the following segments: 
• 1. First course of BI 6727 
• 2. Data collected overall courses of BI 6727 
7.3.4 
Interim analyses 
A pharmacokinetic interim analysis will be performed as soon as pharmacokinetic data of a 
sufficient number of patients are available and clean. A repeat pharmacokinetic interim 
analysis will be performed if requested. In contrast to the final pharmacokinetic calculations, 
the interim analysis will be based on planned sampling times rather than on actual times. 
Therefore, minor deviations of interim and final results may occur. The interim analysis will 
provide mean concentration-time profiles and summary statistics of pharmacokinetic 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 47 of 69 
parameters/individual values without trial subject identification. The interim results will be 
distributed to the Investigator/trial team 
7.4 
HANDLING OF MISSING DATA 
Every effort will be made to obtain complete information on all adverse events, with particular 
emphasis on potential dose limiting toxicities.   
If not stated otherwise, missing data will not be imputed and remain missing. Potential outliers 
will be reported and analysed as observed. 
Tumour evaluation : see RECIST criteria (see ISF, R01-0754) and Appendix 10.4.5 "Handling 
of missing tumour lesion measurement".  
Time to progression:  
Patients for whom no tumour assessments are available within the six weeks prior to 
discontinuation from treatment will be examined on a case by case basis. In case of early stop 
not related to the disease, patients will be censored at time of EOT. 
Pharmacokinetic evaluation: For details refer to Appendix 10.1. 
7.5 
RANDOMISATION 
In this open label, phase I, dose-escalating study, randomisation is not applicable. 
Patients will be assigned, not randomized, into escalating dosage groups by order of admission 
into the trial.  Differences in patient characteristics among dosage tiers will be examined 
carefully for any possible effects on the assessment of the maximum tolerated dose or tumour 
response. 
7.6 
DETERMINATION OF SAMPLE SIZE 
In oncology trials six patients at the MTD are regarded sufficient to determine DLT. 
TABLE 7.6: 1 exhibits the probabilities of two or more out of six patients to be observed with 
DLT for some assumed underlying rates of DLT in the population of all patients. With the 
escalation scheme in this trial, there will be a probability of at least 80 % for two or more 
patients to exhibit DLT, if the underlying individual probability for a patient to reach DLT is 
42 % or larger. 
TABLE 7.6: 1 
Assumed population rates of dose limiting toxicity 
Individual probability of 
observing DLT 
0.40 
0.42 
0.45 
Probability of observing DLT in 
two or more out of six patients 
0.77 
0.80 
0.84 
Source: Probabilities calculated from the cumulative distribution function of the binomial  
distribution with n=6 and varying p's 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 48 of 69 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 49 of 69 
8. 
ADMINISTRATIVE MATTERS 
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, version as of October 1996, in accordance with the ICH Harmonised 
Tripartite Guideline for Good Clinical Practice (GCP)  
Insurance Cover:  
The Sponsor (Boehringer Ingelheim) will take out no-fault insurance cover for all subjects 
included in the study. The conditions of this insurance cover are available to the Investigator 
and the subjects in the ISF (Investigator Site File) 
8.1 
ETHICS 
8.1.1 
Institutional Review Board or Independent Ethics Committee 
The trial will not be initiated before the protocol and informed consent and subject information 
form have been reviewed and received approval / favourable opinion from the Independent 
Ethics Committee (IEC) and implicit approval by the Competent Authority. Should a CTP 
Amendment be made that needs IEC approval and authority notification, the changes in the 
CTP will not be instituted until the Amendment and revised informed consent (if appropriate) 
have been reviewed and received approval / favourable opinion from the local IEC. A CTP 
Amendment intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately providing that the appropriate regulatory authorities and IEC are 
notified as soon as possible and an approval is requested. CTP Amendments only for logistical 
or administrative changes may be implemented with notification to the IEC only. 
The constitution of the IEC must meet the requirements of the participating country / countries. 
A list of the IEC members, with names and qualifications, needs to be provided. The Sponsor 
must provide the name and address of the IEC along with a statement from the IEC that it is 
organised according to GCP and the applicable laws and regulations. The IEC must also 
perform all duties outlined by the requirements of the participating country / countries. For 
trials performed under an US IND:  The US IND requirements outlined in the US Code of 
Federal Regulations must also be met. 
8.1.2 
Informed Consent and Patient Information 
Prior to subject participation in the trial, written informed consent must be obtained from each 
subject (or the subject’s legally accepted representative) according to the regulatory and legal 
requirements of the participating country / countries. Each signature must be dated by each 
signatory and the informed consent and any additional subject information form retained by the 
Investigator as part of the study records. A signed copy of the informed consent and any 
additional subject information must be given to each subject or the subject’s legally accepted 
representative.  
The subject must be 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 subject. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 50 of 69 
The subject 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 IEC members, and by inspectors from regulatory authorities.   
Should a CTP Amendment become necessary, the subject consent form and subject 
information form may need to be revised to reflect the changes to the CTP. It is the 
responsibility of the Sponsor to ensure that an amended consent form is reviewed and received 
approval / favourable opinion from the IEC, and that it is signed by all subjects subsequently 
entered in the trial and those currently in the trial, if affected by the Amendment. 
8.2 
RECORDS 
8.2.1 
Drug accountability 
Drug supplies, which will be provided by the Sponsor (or a CRO appointed by the Sponsor), 
must be kept in a secure, limited access storage area under the storage conditions defined by 
the Sponsor. Where necessary, a temperature log must be maintained to make certain that the 
drug supplies are stored at the correct temperature. 
The Investigator / Pharmacist / Investigational Drug Storage Manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each subject, and the 
return to the Sponsor or alternative disposition of unused product(s). These records will include 
dates, quantities, batch/serial numbers, expiry dates, and the unique code numbers assigned to 
the investigational product(s) and trial subjects. The Investigator / Pharmacist / Investigational 
Drug Storage Manager will maintain records that document adequately that the subjects 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 Sponsor (or appointed CRO), the Investigator / 
Pharmacist / Investigational Drug Storage Manager must verify that all unused or partially used 
drug supplies have been returned by the clinical trial subject and that no remaining supplies are 
in the Investigator’s possession. 
8.2.2 
Emergency code break 
Not applicable in this open label trial. 
8.2.3 
Case Report Forms (CRFs) 
All of the clinical data will be captured via electronic data capture (EDC) using the Oracle 
Clinical Remote Data Capture system, a web-based tool. The investigator site staff will enter 
and edit the data via a secure network, with secure access features (username, password and 
secure identification – an electronic password system).  A complete electronic audit trail will 
be maintained.  The investigator will approve the data using an electronic signature (Ref: 21 
CFR Part 11), and this approval is used to confirm the accuracy of the data recorded. 
Electronic CRFs (eCRFs) will be used for all patients. The investigator’s data will be 
accessible from the investigator’s site throughout the trial. Relevant medical history prior to 
enrolment will be documented at the baseline visit. Thereafter during the trial, narrative 
statements relative to the patient’s progress during the trial will be maintained. The electronic 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 51 of 69 
CRFs must be kept current to reflect patient status at each phase during the course of the trial. 
The patients must not be identified on the electronic CRF by name. Appropriate coded 
identification (i.e. Patient Number) must be used. The investigator must make a separate 
confidential record of these details (patient identification code list) to permit identification of 
all patients enrolled in a clinical trial in case follow-up is required. While a trial is ongoing and 
until the access to the database has been terminated, there will be no Documentation of 
Changes (DOCs). All changes will be requested from the investigator through the EDC system. 
If a change is necessary once the investigator has no further access to the database, a DOC will 
be sent to the investigator for confirmation of the change. The investigator’s signature <for 
Japan> or seal is requested to show he/she agrees with the change that was made. The original 
DOC is kept by the investigator. 
Copies of the electronic CRF together with all data changes made will be supplied to the 
investigator at the end of the trial. The investigator will be responsible for retaining all records 
pertaining to the trial as specified in the appropriate contract. 
8.2.4 
Source documents 
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the eCRFs (electronic CRFs) 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 study; also current medical records must be available. 
The following data to be reported on the eCRF need to be included and derived from the source 
documents: 
Subject identification (gender, date of birth) 
Subject participation in the study (substance, study number, subject number) 
Dates of Subject’s visits 
Medical history (including trial indication and concomitant diseases, if applicable) 
Medication history 
Adverse Events (onset date) 
Serious Adverse Events (onset date) 
Concomitant therapy (onset date, changes) 
Originals or copies of laboratory results (in validated electronic format if available) 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 52 of 69 
Originals or copies of X-rays and Ultrasound findings, ECG results, EEG results, 
pneumological findings, endoscopic findings and other results based on hard copies of medical 
equipment 
Conclusion of Subject’s Participation in the study 
All data that has been documented in the eCRF must be documented in the source data 
8.2.5 
Direct access to source data / documents 
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC 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 and 
inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA) / on site 
monitor may review all eCRFs, and written informed consents. The accuracy of the data will 
be verified by reviewing the documents described in Section 8.2.4. 
8.3 
QUALITY ASSURANCE AUDIT 
A quality assurance audit of this trial may be conducted by the sponsor or sponsor’s designees.  
The quality assurance auditor will have access to all medical records, the investigator’s trial-
related files and correspondence, and the informed consent documentation that is relevant to 
this clinical trial. 
8.4 
PROCEDURES 
8.4.1 
Adverse events 
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. 
All adverse events occurring during the course of the clinical trial (i.e., from signing the 
informed consent onwards through the observational phase) will be collected, documented and 
reported to the sponsor by the investigator according to the specific definitions and instructions 
detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File. 
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 representing a significant hazard, which is comparable to the aforementioned 
criteria. 
All adverse events, serious and non-serious, will be fully documented on the appropriate 
CRF(s) / eCRFs. For each adverse event, the investigator will provide the onset, end, intensity, 
treatment required, outcome, seriousness and action taken with the investigational drug. The 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 53 of 69 
investigator will determine the relationship of the investigational drug to all AE as defined in 
the 'Adverse Event Reporting' Section of the Investigator Site File.  
The basis for judging the intensity of the AE as well as the causal relationship between the 
investigational product and the AE is described below. 
Intensity of event 
According to CTCAE criteria version 3.0 (see ISF) 
Causal relationship 
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. <For 
Japan> The reason for the decision on causal relationship needs to be provided in the CRF. 
• 
Yes: 
There is a reasonable causal relationship between the investigational drug 
administered and the AE.  
• 
No: 
There is no reasonable causal relationship between the investigational drug 
administered and the AE.  
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. 
any active comparator or placebo according to the trial design). 
The investigator has the obligation to report AEs during the specified observational phase. If 
defined in the CTP, the investigator also has the responsibility to report AEs occurring in a 
certain period after a patient completes the trial. Any AEs reported to the sponsor during this 
phase must be documented in the safety database. 
If not stipulated differently in the ISF, SAEs are to be reported to the sponsor using the BI 
Serious Adverse Event Report Form including a documented causal relationship assessment 
and providing as much detail regarding the SAE as possible. With receipt of follow-up 
information, all remaining fields on the SAE form are to be completed or updated. 
Any serious or significant AE, whether or not considered related to the investigational product, 
and whether or not the investigational product has been administered, must be reported 
immediately by telephone / fax to the sponsor. Expedited reporting of serious adverse events, 
e.g. suspected unexpected serious adverse reactions (SUSARs), will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
ISF. 
Following every such telephone / fax reports, the Clinical Monitor must provide a written 
report of the serious or significant AE and any sequelae to Corporate Drug Safety according to 
the appropriate Corporate SOP(s). These narratives, which confirm the information collected 
by telephone, may give additional information not available at the time of the initial report. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 54 of 69 
8.4.2 
Emergency procedures 
Not applicable.  
8.5 
RULES FOR AMENDING PROTOCOL 
All CTP amendments must be documented, dated and signed by all signatories (or their 
successors) of the original protocol. This also applies to any local amendment that may become 
necessary. Amendments need to be submitted to the IEC for review/approval and to the 
competent authority (CA) for approval. 
8.6 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR 
Boehringer Ingelheim reserves the right to discontinue the trial at any time for the following 
reasons: 
1.) Failure to meet expected enrolment goals, 
2.) emergence of any efficacy/safety information that could significantly affect continuation of 
the trial <if applicable>, or any other administrative reasons, i.e. <add pre-specified 
reasons>, 
3.) violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial. 
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason). 
8.7 
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 IEC and the regulatory authorities, i.e. the CA. 
8.8 
PUBLICATION POLICY 
Boehringer Ingelheim is as much as possible dedicated to support process of free exchange of 
relevant scientific information.  Any publication of the result of this trial must be consistent 
with the Boehringer Ingelheim publication policy.  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 finalization of the 
Clinical Trial Report (CTR). 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 55 of 69 
8.9 
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/patient out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.  


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 56 of 69 
9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES 
R04-0028 
Donaldson MM, Tavares AA, Hagan IM, Nigg EA, Glover AM. The mitotic 
roles of Polo-like kinase. J Cell Sci. 2001;114:2357-2358. 
 
R04-0030 
Liu X, Erikson RE. 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, 
Altmannsberger HM, Rübsamen-Weigmann H, Strebhardt K. Prognostic 
significance of polo-like kinase (PLK) expression in non-small cell lung cancer. 
Oncogene 1997;14:543-549. 
 
R04-0034 
Takahashi T, Sano B, Hagata T, Kato H, Sugiyama Y, Kunieda K, Kimura M, 
Okano Y, Saji S. Polo-like kinase (PLK)1 is overexpressed in primary 
colorectal cancers. Cancer Sci 2003;94(2):148-152. 
 
R04-0321  
Smith MR, Wilson ML, Hamanaka R, Chase D, Kung H, Longo DL, Ferris DK. 
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. 
Nature Rev 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. 
 
R04-0569 
Kang SH, Ahn CW. An investigation of the traditional algorithm-based designs 
for Phase 1 cancer trials. Drug Information Journal 2002; 36:865-873. 
 
9.2 
UNPUBLISHED REFERENCES 
U05-2201 
 Investigator’s Brochure: BI 6727 CL3 Cancer. 23 September 2005 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 57 of 69 
10. 
APPENDICES 
10.1 
HANDLING OF PLASMA AND URINE DATA AND DERIVATION OF 
PHARMACOKINETICS PARAMETERS 
Analyte plasma concentrations will be plotted graphically versus time for all subjects as listed 
in the analyte plasma concentration-time tables.  For the presentation of the mean profiles, the 
arithmetic/geometric mean and the planned blood sampling times will be used. 
Concentrations will be used for calculations in the format that is reported in the bioanalytical 
report.  The data format for descriptive statistics of concentrations will be identical with the 
data format of the respective concentrations.  For the calculation of pharmacokinetic 
parameters, only concentrations within the validated concentration range will be used.  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.  The actual sampling times will be used.  For predose samples, 
the actual sampling time will be set to zero.   
Concentration data identified with NOS (no sample available), 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 including the 
pre-dose value).  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). 
Non-compartmental pharmacokinetic parameters will be determined using WinNonlin or 
another validated program. 
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 and/or NOP values of the profile will be ignored. 
If the predose concentration before the first dose is less than or equal to 5% of Cmax value in 
that subject, the subject’s data without any adjustments can be included in all pharmacokinetic 
measurements and calculations (i.e., the predose value will not be changed to zero).  If the 
predose value is greater than 5% of Cmax, the subject should be dropped from all statistical 
evaluations. The individual pharmacokinetic parameters can be calculated and listed 
separately. 
Every effort will be made to include all concentration data in an analysis. If not possible, a case 
to case-to-case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis.  


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 58 of 69 
• 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 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.  Pharmacokinetic parameters which cannot be determined will be 
identified by "not calculated" (NC). 
Cmax and tmax: Individual Cmax and tmax values will be directly determined from the plasma 
concentration time profiles of each subject. If the same Cmax concentration occurs at different 
time points, tmax is assigned to the first occurrence of Cmax. 
Estimation of λz: Τhe apparent terminal rate constant λz will be estimated from a regression of 
ln(C) versus time over the terminal log-linear disposition portion of the concentration-time 
profiles. The log-linear profiles, which include the regression line through the terminal points, 
will be checked via visual inspection, and it will be determined whether the regression 
appropriately represents the terminal slope. A minimum of three points will be used in the 
determination of λz. If the last concentration-time point increases, this time point may be 
included if the t1/2 estimate is reasonable. If λz is not determinable then consequently only 
parameters not requiring λz will be reported. In addition, the lower (tλz,start) and upper (tλz,end) 
limit on time for values to be included in the calculation of λz will be listed. 
t1/2: The terminal half-life will be calculated from the terminal rate constant using the equation 
z
2
/
1
2
ln
t
λ
=
 
AUC: The area under the curve will be calculated using the linear up/log down algorithm. If an 
analyte concentration is equal to or higher than the preceding concentration, the linear 
trapezoidal method will be used. If the analyte concentration is smaller than the preceding 
concentration, the logarithmic method will be used. 
Linear trapezoidal rule (t2 > t1 and Ct2 ≥ Ct1): 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 59 of 69 
The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: 
(
) (
)
t2
t1
1
2
t2
-
t1
C
C
t
t
0.5
AUC
+
×
−
×
=
 
Logarithmic trapezoid rule (t2 > t1 and Ct2 < Ct1): 
The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed by: 
(
) (
)
(
)
t1
t2
t1
t2
1
2
t2
t1
/C
C
ln
C
C
t
t
AUC
−
×
−
=
−
 
AUC0-∞: The area under the plasma concentration-time curve over the time interval from 0 
extrapolated to infinity will be calculated according to the following equation 
z
tz
tz
-
0
-
0
 
C'
AUC
AUC
λ
+
=
∞
 
where C'tz is the concentration predicted by the regression line for the time tz (time of last 
measurable concentration of the analyte in plasma). The area under the concentration-time 
curve over the time interval from 0 to the last quantifiable plasma concentration (AUC0-tz) will 
be calculated by the linear up/log down method as described above. 
%AUCtz-∞: The percentage of the AUC0-∞ will be obtained by extrapolation according to the 
following equation: 
100
 
AUC
AUC
 
AUC
 
  
AUC
 
%
-
0
tz
-
0
-
0
tz
×
−
=
∞
∞
∞
−
 
MRT: The mean residence time after intravenous bolus injection will be calculated as follows: 
∞
−
∞
−
=
0
0
AUC
AUMC
 
MRT
 
 In order to compare the mean residence time after intravenous bolus administration (MRT) 
and intravenous infusion (MRTinf), the following equation will be used in addition, where T 
represents the infusion time. 
)
0.5
(T
MRT
MRT
inf
×
−
=
 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 60 of 69 
The area under the first moment curve from time 0 to infinity (AUMC0-∞) is calculated 
according to: 
2
∞
λ
+
λ
×
+
=
z
tz
z
tz
tz
-
0
-
0
C'
tz
 
C'
 
AUMC
AUMC
 
CL: The total clearance after intravenous administration will be determined according to the 
following equation: 
∞
−
=
0
AUC
Dose
 
CL
 
(F = absolute bioavailability factor) 
Vz: The apparent volume of distribution during the terminal phase after intravascular 
administration will be determined according to the following equation: 
 
λ
CL
V
z
z =
 
Vss: After single intravenous bolus administration or intravenous infusion when the mean 
residence time has been adapted as described above, the distribution volume in the steady state 
will be calculated according: 
ss
ss
ss
MRT
CL
V
×
=
 
fet1-t2: The fraction excreted is calculated according to 
100
Dose
Ae
fe
t2
-
t1
t2
-
t1
×
=
 
where Aet1-t2 is the total quantity of the analyte that is excreted in urine over the time interval t1 
to t2. This may represent the product of urine volume and urine analyte concentration for one 
time interval, as well as the cumulative amounts excreted calculated as the sum of the excreted 
amounts of subsequent time intervals. 
 
 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 61 of 69 
CLR,t1-t2: The renal clearance (CLR) will be calculated as the quotient of the quantity of the 
analyte that is excreted in urine from the time point t1 until the time point t2 (Aet1-t2) and the 
area under the concentration-time curve within the same time interval (AUCt1-t2). 
t2
t1
t2
t1
t2
t1
R,
AUC
Ae
CL
−
−
−
=
 
gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), 
will be calculated by the formulae: 
[
])
ln(x
exp
)
ln(x
 
exp
gMean
i
n
1
i
i
n
1
=
⎥⎦
⎤
⎢⎣
⎡
=
∑
=
 
[
] 1
))
Var(ln(x
 
exp
  
100
gCV(%)
i
−
⋅
=
 
where 
[
]
2
n
1
i
i
i
i
)
ln(x
)
ln(x
1
n
1
))
Var(ln(x
∑
=
−
−
=
. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 62 of 69 
10.2 
BLOOD SAMPLING TIME SCHEDULE 
Visit 
Day 
Course 
Time Point [hh:min] 
CRF Time/
planned 
time 
Sample 
No 
Repeated 
course 
2 
1 
1 
-0:05 
-0:05 
1 
 
 
 
 
0:00 
Start of infusion 
0:00 
 
 
 
 
 
0:15 
0:15 
2 
 
 
 
 
0:30 
0:30 
3 
 
 
 
 
0:45 
0:45 
4 
 
 
 
 
1:00 
Immediately prior to 
end of infusion of 
BI 6727 
1:00 
5 
CnR1 
 
 
 
1:30 
1:30 
6 
 
 
 
 
2:00 
2:00 
7 
 
 
 
 
4:00 
4:00 
8 
 
 
 
 
8:00  
8:00  
9 
 
3 
2 
1 
24:00  
24:00  
10 
CnR2 
4 
3 
1 
48:00 
48:00 
11 
 
5 
5 
1 
96:00 
96:00 
12 
 
6 
8 
1 
168:00 
168:00 
13 
CnR3 
7 
15 
1 
336:00 
336:00 
14 
CnR4 
 
       Cn = number of course (n ≥ 2) 
For repeated courses blood sampling will be performed 1:00 h after start of infusion 
(immediately prior to end of infusion) and 24:00, 168:00 and 336:00 h after drug 
administration. 
Please note: Blood samples during infusion have to be taken in the opposite arm of the infusion 
arm.  


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 63 of 69 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 64 of 69 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 65 of 69 
 
 
 
 
10.4. TUMOUR ASSESSMENT ACCORDING TO RECIST 
10.4.1 
Tumour assessment 
Measurable disease 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques (CT, 
MRI) or as ≥10 mm with spiral CT scan. All tumour measurements must be recorded in 
millimetres (or decimal fractions of centimetres). 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes). In the case of skin lesions, documentation by 
colour photography, including a ruler to estimate the size of the lesion, is recommended. 
Conventional CT and MRI. These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm. 
Ultrasound. Ultrasound should not be used to measure tumour lesions. The same holds true for 
endoscopy or laparoscopy. 
Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 20 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable 
disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not confirmed or 
followed by CT or MRI), and cystic lesions are all non-measurable. 
Target lesions 
All measurable lesions up to a maximum of five lesions per organ and ten lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). A sum of the longest diameter for all target lesions will be 
calculated and reported as the baseline sum longest diameter. The baseline sum longest 
diameter will be used as reference by which to characterize the objective tumour response. 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 66 of 69 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Non-target lesions include measurable lesions that exceed the 
maximum numbers per organ or total of all involved organs as well as non-measurable lesions. 
Measurements of these lesions are not required, but the presence or absence of each should be 
noted throughout follow-up. 
10.4.2 
Evaluation of target lesions 
Complete Response (CR): 
disappearance of all target lesions 
Partial Response (PR): 
at least a 30 % decrease in the sum of the longest diameter of 
target lesions, taking as reference the baseline sum longest diameter 
Progressive Disease (PD): 
at least a 20 % increase in the sum of the longest diameter of 
target lesions, taking as reference the smallest sum longest diameter recorded since the 
treatment started or the appearance of one or more new lesions 
Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum longest diameter since the treatment 
started 
10.4.3 
Evaluation of non-target lesions 
Complete Response (CR): 
disappearance of all non-target lesions 
Incomplete Response/ Stable  
Disease (SD): 
persistence of one or more non-target lesion(s) 
Progressive Disease (PD): 
appearance of one or more new lesions and / or unequivocal 
progression of existing non-target lesions 
10.4.4 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression / recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement (overall response, Table 10.4.4: 1). 
The overall responses for all combination of tumour response (target and non-target lesions) 
with and without appearance of new lesion is given in Table 10.4.4: 1 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 67 of 69 
Table 10.4.4: 1 
Overall responses for target and non-target lesions with and without 
appearance of new lesion 
Target lesions 
non-target lesions 
new lesions 
overall response 
CR 
CR 
no 
CR 
CR 
incomplete response / SD 
no 
PR 
PR 
non-PD 
no 
PR 
SD 
non-PD 
no 
SD 
PD 
any 
yes or no 
PD 
any 
PD 
yes or no 
PD 
any 
any 
yes 
PD 
 
The examinations should be performed at screening and in line with RECIST after every 
second course of treatment if the patient qualifies for further courses. Tumour measurements at 
earlier time points after start of study treatment may be performed if clinically indicated as 
assessed by the investigator. Tumour measurements during the follow-up period after 
discontinuation of the study treatment are optional. Imaging results can be used at screening if 
they were done within the previous four weeks, i.e. no repeat investigation is requested for the 
purpose of the study. 
To be assigned a status of CR, PR, or SD, changes in tumour measurements should be 
confirmed by repeat assessments that should be performed according to RECIST. 
In the case that an assessment of the target and non-target lesion of a patient could not be made 
by the investigator the category "non-evaluable" (NEV) should be used. In case of absence of 
non-target lesion at baseline the category of NEV has to be used. The overall responses for all 
combination of tumour response (target and non-target lesions) with and without appearance of 
new lesion and non-evaluable lesion measurements is given in Table 10.4.4: 2 


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 68 of 69 
Table 10.4.4: 2 
Overall responses for target and non-target lesions with and without 
appearance of new lesion and non-evaluable lesion measurements 
Target lesions 
non-target lesions 
new lesions 
overall response 
NEV 
Any, except of PD 
no 
NEV 
NEV 
PD 
yes or no 
PD 
Any, except of PD 
NEV 
no 
response criteria of 
target lesion 
PD 
NEV 
yes or no 
PD 
any 
any 
yes 
PD 
 
If the overall response is NEV the additional categories (NEVCP and NEVCNP) will be used. 
Description see Table 10.4.4: 3. In the case that a tumour measurement was not performed 
please see handling of missing value (section 10.4.5). 
Table 10.4.4: 3 
Tumour response criteria in the case of no assessment of the tumour by 
the investigator 
Label of tumour response 
Shortcut 
Tumour Response 
Non-evaluable, clinically not 
progressive 
NEVCNP 
No assessment of the tumour is possible, but 
the investigator rated the patient’s disease 
status as clinically not progressive 
Non-evaluable, clinically 
progressive 
NEVCP 
No assessment of the tumour is possible, but 
the investigator rated the patient’s disease 
status as clinically progressive 
 
10.4.5 
Handling of missing tumour lesion measurements 
One to ten target lesions (not exceeding 5 lesions per organ) should be identified at screening. 
These lesions should be followed up with the same method(s) used at screening and their size 
will be recorded in millimetres.  
If target lesions selected at baseline become non-evaluable (i.e. different technique used or 
missing of tumour lesion measurement, etc), the following rules will be applied 
• 
Analysing strategies:  


 
 Final 03 October 2005 
BI Trial No.: 1230.1 
Page 69 of 69 
missing imaging at one time point: if there are lesion measurements during the next 
course then the non-evaluable tumour evaluation will be reassessed as follows - in case 
of objective response and stable disease the previous tumour evaluation will be assessed 
as non-evaluable but no progressive disease (NEVNPD censored with reassessment 
REASS), the time point of the following non-evaluable measurement will be used for 
tumour response duration. In the case of progressive disease the previously non-
evaluable measurement will be reassigned with non-evaluable but progressive disease 
(NEVPD censored with reassessment REASS). 
• 
one of the tumour lesions was missed but tumour imaging will be performed within one 
week of the scheduled time point - this new imaging will be used 
• 
for determination of time of tumour response - the latest time point will be used except 
in the case of progressive disease when the earliest time point will be used. 
 

SAP_001.pdf: 
Trial Statistical Analysis Plan
T-09-1043-02
BI Trial No.:
1230.1
Title:
An open phase I single dose escalation study of BI 6727 
administered intravenously in patients with advanced solid 
tumours with repeated administration in patients with clinical
benefit
Responsible trial 
statistician:
Phone:
Fax:    
Phone:
Fax:    
Date of statistical 
analysis plan:
07 AUG 2009 SIGNED
Version:
SECOND
Page 1 of 42
Proprietary confidential information
2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 2
1.
TABLE OF CONTENTS
Page
1.
TABLE OF CONTENTS............................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS.....................................................................5
3.
INTRODUCTION.......................................................................................8
3.1
CLINICAL OBJECTIVES .................................................................................8
3.2
STATISTICAL DESIGN / MODEL ..................................................................8
3.3
NULL AND ALTERNATIVE HYPOTHESES ................................................8
3.4
STATISTICAL SOFTWARE.............................................................................9
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY..........10
5.
ENDPOINTS..............................................................................................11
5.1
PRIMARY ENDPOINTS..................................................................................11
5.2
SECONDARY ENDPOINTS............................................................................11
5.2.1 Tumour response....................................................................................11
5.2.2 Time-to-Event .........................................................................................12
5.2.3 Eastern Cooperative Oncology Group (ECOG) Performance Score 13
5.2.4 Adverse events ........................................................................................13
5.2.5 Laboratory parameters..........................................................................14
5.2.6 Tumour markers ....................................................................................15
5.3
OTHER ENDPOINTS.......................................................................................16
5.3.1 Demographics .........................................................................................16
5.3.3 Extent of exposure..................................................................................16
5.3.5 ECG .........................................................................................................17
5.3.5.1
ECG - Assessment for patients of the extension cohort for additional 
QT/QTc analysis.........................................................................................18
5.3.5.2
ECG - All other patients .............................................................................18
6.
GENERAL ANALYSIS DEFINITIONS ................................................19
6.1
TREATMENTS..................................................................................................19
6.1.1 Treatment regimens / study intervals...................................................19
6.1.2 Randomised treatment...........................................................................19
6.1.3 Specification of treatments for analyses...............................................19
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................21
6.3
PATIENT SETS ANALYSED..........................................................................23
6.5
POOLING OF CENTRES ................................................................................24
6.6
HANDLING OF MISSING DATA AND OUTLIERS...................................24
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................26
6.8
GENERAL CALCULATION RULES ............................................................26
7.
PLANNED ANALYSIS ............................................................................27
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........28


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 3
7.1.1 Disposition of patients............................................................................28
7.1.2 Important protocol violations................................................................28
7.1.3 Demographic and other baseline...........................................................28
7.4
PRIMARY ENDPOINTS..................................................................................28
7.5
SECONDARY ENDPOINTS............................................................................28
7.6
EXTENT OF EXPOSURE................................................................................29
7.7
SAFETY ANALYSIS.........................................................................................29
7.7.1 Adverse events ..........................................................................................29
7.7.1.1
Maximum tolerated dose and dose limiting toxicity ..................................29
7.7.1.2
Adverse events............................................................................................30
7.7.2 Laboratory data......................................................................................31
7.7.3 Vital signs................................................................................................32
7.7.4 ECG .........................................................................................................32
7.7.4.1
ECG - Assessment for patients of the extension cohort for additional 
QT/QTc analysis.........................................................................................32
7.7.4.1.1 Central tendency analysis ...........................................................................33
7.7.4.1.2 Categorical endpoints / outlier analyses .....................................................33
 
4
7.7.4.2
ECG - Assessment for all other patients.....................................................35
8.
REFERENCES..........................................................................................36


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 4
LIST OF TABLES
Table 6.1.3: 1 Definition of the label of the analysing treatment, analysis numbers, the labels 
using for displaying in the tables, start date and end date ...............................19
Table 6.2: 1     Listing of protocol violations...........................................................................21


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 5
2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis Data Set
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ALKP
Alkaline phosphatase
BI
Boehringer Ingelheim
BMI
Body mass index
bpm
Beats per minute
°C
Degree centigrade
CPK
Creatinine phosphokinase
CR
Complete response
CT
Concomitant therapies
CTR
Clinical trial report
CTCAE
Common terminology criteria for adverse events Version 3.0
CTP
Clinical trial protocol
DLT
Dose limiting toxicity
DQRM
Data quality review meeting
eCRF
Electronic case report form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
GGT
γ-Glutamyl transpeptidase


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 6
Term
Definition / description
HR
Heart rate [bpm]
ICH
International Conference on Harmonization
INR
International normalized ratio of prothrombin time
max
Maximum
MedDRA
Medical dictionary for drug regulatory activities
min
Minimum
MTD
Maximum tolerated dose
N
Number of non missing observations
n. a.
Not applicable
NEV
Non-evaluable
NEVCNPD
Non-evaluable but clinically not progressive disease
NEVCPD
Non-evaluable but clinically progressive disease
O*C
Oracle clinical database 
PD
Progressive disease
PFS
Progression free survival
PK
Pharmacokinetic
PR
Partial response
PT
Preferred term
PTT
Partial thromboplastin time
PV
Protocol violation
QTcF
QT interval, corrected according to Fridericias formula [ms]
RECIST
Response evaluation criteria in solid tumours
REML
Restricted maximum likelihood


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 7
Term
Definition / description
SAE
Serious adverse event
SD
Stable disease
SD
Standard deviation
SOC
System organ class
SOP
Standard operating procedure
WBC
White blood cell count


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 8
3.
INTRODUCTION
This Trial Statistical Analysis Plan (TSAP) provides further details on the statistical analyses 
described in the Clinical Trial Protocol (CTP) dated 3rd October 2005, and subsequent 
amendments (3) up to 26th June 2008.
 
3.1
CLINICAL OBJECTIVES
The primary objective of this trial is to determine the Maximum Tolerated Dose (MTD) of 
BI 6727 therapy in terms of drug-related adverse events.
Secondary objectives are the collection of overall safety and anti-tumour efficacy data and 
the determination of the pharmacokinetic profile of BI 6727. 
3.2
STATISTICAL DESIGN / MODEL
This phase I trial was performed according to an uncontrolled, open label, accelerated dose 
titration design to determine the MTD of BI 6727 in patients with advanced solid tumours.
The design is that of a 3+3 fixed dose escalation design (R01-0028) using a toxicity guided 
approach.
Patients with advanced solid tumours were eligible for this trial. BI 6727 was given as a short 
infusion over 60 minutes on day 1 of each three week treatment course during the escalation 
phase. The additional patients treated at the phase II recommended dose of 300 mg to 
investigate QTc changes, were assigned to one of two infusion time schedules: BI 6727-1h-
infusion in course 1 and BI 6727-2h-infusion in course 2 or BI 6727-2h-infusion in course 1 
and BI 6727-1h-infusion in course 2. The infusion schedule in courses 3 and higher was 
always the one hour infusion time.
Patients were not randomized, instead they were selected by the investigators and assigned to 
the cohort being filled at the time the patient was ready to enter the trial. Thus, the analyses 
will focus on the exploratory description of the results of each cohort, rather than comparing 
cohorts.
3.3
NULL AND ALTERNATIVE HYPOTHESES
All analyses in this trial are descriptive and exploratory by nature. Any statistical tests are 
performed only to provide a statistical framework from which to view the results and plan 
further studies. No formal statistical inferences are foreseen.


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 9
3.4
STATISTICAL SOFTWARE
A trial database within the Oracle ClinicalTM (O*C) database system was used to store the 
study data.
The evaluation of the clinical and the PK data and the statistical analyses will be performed 
within the validated working environment CARE (Clinical data Analysis and Reporting 
Environment), including SAS® (current version 8.2, by
 
 
The calculation of the pharmacokinetic parameters will be performed with WinNonlin®
(Professional Network version 5 .0.1,


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 10
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Some newly created endpoints regarding tumour response are created and explained within 
the TSAP.
 
Following Amendment 3, a more extensive analysis of electrocardiograms (ECG) is planned 
on the additional cohort of 14 patients. The main aim of this cohort was to investigate QTc 
changes in parallel with PK sampling during and after intravenous infusion of BI 6727 
300 mg dose over 1 hour and over 2 hours. For this set of 12 patients a different analysis of 
ECG data is planned (see Section 7.7.4.1).


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 11
5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary objective (to find the MTD) is determined from the primary endpoint, DLT.
Maximum tolerated dose (MTD):
MTD is defined as the highest dose studied for which the incidence of DLT in an individual 
dose cohort is at most 33% during the first course.
Additionally, all information, including DLT from later treatment courses, will be considered 
in the final determination of the dose recommended for Phase II.
5.2
SECONDARY ENDPOINTS
5.2.1
Tumour response 
For solid tumours, evaluation of tumour response will be assessed according to the Response 
Evaluation Criteria in Solid Tumours (RECIST) definition. The overall response of target and 
non-target lesions together with or without the appearance of new lesions as reported by the 
investigator is assessed on a four point categorical scale as complete response (CR), partial
response (PR), stable disease (SD), and progressive disease (PD) according to the RECIST 
criteria (R01-0754). However, for the analyses within this TSAP, a modified version of the 
RECIST criteria will be used, in order to best handle measurements that are non-evaluable 
(NEV). 
 Basically, an algorithm is used to 
determine the outcome, depending on whether the NEV measurement is for target / non-
target lesions. If it is still not possible to determine the outcome based upon the algorithm, 
then a clinical assessment will be used.
Tumour responses will be analysed based on the ‘Overall response’ question that is asked 
directly from the Electronic Case Report Form (eCRF). Additionally, clinical progression 
will be taken into account. It will not be checked whether the answer of the overall response 
assessment was based on RECIST only or already incorporates clinical progression, i.e. no 
differentiation will be made between NEVCPD or PD.
Using the RECIST criteria combined with the presence or absence of clinical progression, 
several endpoints will be analysed and created. Whilst some are at each tumour assessment 
(unconfirmed), others are summary measures over time (confirmed / best).
Note that for the case of non-target responses, level=2 refers to ‘Incomplete response / Stable 
disease / Partial response’.
The main endpoints with their corresponding definitions are as defined below:
Unconfirmed Overall Response: 
 
As noted above, for some patients the overall response 
as reported by the investigator also includes information about clinical progression and is 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 12
assigned to progressive disease as soon as a patient experiences clinical progression.  For that 
reason this endpoint is referred to Unconfirmed Overall Response and not to Unconfirmed 
RECIST Overall Response. Analogous to RECIST, the endpoint Unconfirmed Overall 
Response will be made up of 6 potential outcomes with 5 ordered levels:
Unconfirmed Overall Response
Abbreviation
Level
Complete response
CR
1
Partial response
PR
2
Stable disease
SD
3
Non-evaluable but clinically non progressive disease
NEVCNPD
4
Progressive disease or Non-evaluable but clinically progressive 
disease
PD or 
NEVCPD
5
Unconfirmed Best Overall Response: This is the best of the individual ‘Unconfirmed Overall 
Responses’, recorded from the start of the treatment until PD. 
Unconfirmed Best Objective Response: If the ‘Unconfirmed Best Overall Response’ is either 
CR or PR, then this Unconfirmed Best Objective Response is Yes. Otherwise it is No.
Additional supportive endpoints are:
Clinical Benefit: Clinical benefit is defined as the absence of disease progression (no PD or 
NEVCPD) during a course.
Confirmed objective response: To confirm an objective status here, changes in tumour 
measurements must be confirmed by at least one later assessment that must be performed ≥
28 days after the criteria for CR or PR are first met without having an assessment of PD or 
NEVCPD.
5.2.2
Time-to-Event
Both, formal and informal summary analyses on time-to-event endpoints will be performed. 
That is to say, Kaplan-Meier analyses will be performed, and summary statistics will be 
calculated.
 
Progressive disease: Progressive disease (PD or NEVCPD) is level=5 as outlined in the 
endpoint ‘Unconfirmed Overall Response’ in Section 5.2.1 above. 
Date of progressive disease is the earliest of:
1) date of progression (progdt) recorded on course in e-CRF corresponding to first 
recurrence of progressive disease 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 13
2) date of progression recorded (progdt) on end of trial in e-CRF if first recurrence of 
progressive disease was at end of trial
3) date of progressive disease recorded on post-study follow-up of eCRF 
4) death date (in the case of none of 1-3 being available)
Patients administered a new additional other anti-cancer therapy recorded in the e-CRF but 
not presenting with progressive disease before the start of this new anti-cancer therapy will be 
censored at the date of last radiological imaging before the new anti-cancer therapy has 
started.
Patients not administered another anti-cancer therapy and not presenting with progressive 
disease or death during the trial will be censored at the date of the last imaging during which 
the patient was evaluable and did not have the event. Alternatively, if there is an investigators 
assessment after this, then the date of the NEVCNPD will be used.
Progression-free survival (PFS) [in days] is therefore the time from first administration of 
trial medication to the earlier of progressive disease or death. (Date of PD as above – date of 
first administration of trial medication + 1).
Progression-free survival (PFS) censored [in days] is therefore the time from first 
administration of trial medication to the date of last imaging (or NEVCNPD as above). (Date 
of last imaging – date of first administration of trial medication + 1, or Date of NEVCNPD –
date of first administration of trial medication + 1).
5.2.3
Eastern Cooperative Oncology Group (ECOG) Performance Score 
ECOG score: The scale of ECOG score is defined as a six point categorical scale as described 
in (R01-0787) ranging from 0 (asymptomatic) to 5 (death). Calculation was to be carried out 
for each patient, for each first visit of each treatment course, each last visit of each treatment 
course, the end of treatment and the follow up visit. 
ECOG score change from baseline to end of treatment will be calculated, and defined as
= ECOG score at end of treatment – ECOG score at baseline.
Scale of ECOG score change: The ECOG score changes from baseline score will be 
categorized on a three point categorical scale: deteriorated, unchanged, and improved. 
Improvement or deterioration of performance status will require a decrease or an increase 
from baseline, respectively, of at least one point on the ECOG scale.
5.2.4
Adverse events
Adverse events (AEs) are defined as the same preferred term (PT) after collapsing of two 
events less than 24 hours apart.
Intensity of adverse events is scaled according to Common Terminology Criteria of Adverse 
Event (CTCAE version 3.0, R06-1666). 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 14
A separate listing for all patients who developed the following events will be generated. 

AEs with CTCAE grade ≥ 3,

DLT,

serious AEs, or,  

significant AEs as defined in Section 7.7.1.2
5.2.5
Laboratory parameters
In this trial the original laboratory values will be converted into standard units and CTCAE 
grades for parameters which have a CTCAE criteria (For definition of CTCAE grade for 
laboratory values, 
). For this study, the laboratory 
parameters and their functional groups 
 
together with the direction of concern, 
which were to be recorded and which have a CTCAE criteria are:-
Haematology: Haemoglobin (-), white blood cell (WBC) (-) and Platelets (-)
Differentials: Neutrophils (-) and Lymphocytes (-)
Coagulation: International normalized natio of prothrombin time (INR) (+) and Partial 
thromboplastin time (PTT) (+)
Electrolytes: Sodium (+ and -), Potassium (+ and -) and Calcium (+ and -)
Enzymes: Aspartate aminotransferase (AST) (+), Alanine aminotransferase (ALT) (+) and 
Alkaline phosphatase (ALKP) (+)
Substrates: Total bilirubin (+),Glucose (+ and -), Creatinine (+), Albumin (-) and Creatinine 
Phosphokinase (CPK) (+)
+  (-) means the higher (lower) the value the worse the toxicity. (+ and -) means the 
parameter can be considered as hyper or hypo.
It is important to note that these are only the parameters that have a CTCAE criteria, and that 
other parameters were recorded which have no CTCAE criteria.
Laboratory parameters were to be recorded for each patient on days 0-3, 5, 8, 15 and 22 of 
first treatment course, and all except days 3 and 5 at subsequent treatment courses. Recording 
of standard laboratory parameters was optional at follow-up. Changes from baseline will be 
calculated for each day of the first treatment course where measured, the last visit of each 
treatment course and the end of the trial. For the CTCAE grades, some changes from other 
time-points will also be calculated. 
The baseline, last value on treatment and corresponding change from baseline will be 
presented using N, median and interquartile range. This will be done for all continuous 
laboratory parameters using the Boehringer Ingellheim (BI) normalised values, except, 
however, in the case of WBC differentials (Neutrophils and Lymphocytes) which have been 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 15
recorded in percentage. These have been re-derived to normalised values in such a way that 
the accuracy of decimal places is maintained for longer. 
Patients with clinically relevant laboratory abnormalities, 
will be 
summarised.
Note: For calculating the change in CTCAE grade from baseline/ pre-dose level, patients with 
a CTCAE grade of -9 will be reviewed on a case-by-case basis. If there is no suggestion that 
the corresponding laboratory value is of clinical significance, these values will be changed to 
-7 and treated as a CTCAE grade of 0 for analyses. All other values with CTCAE grade -9 
will be regarded as CTCAE grade -8. Values with a CTCAE grade of -8 will either be 
removed from analyses concerning determination of baseline and worst CTCAE grade or if 
needed the category “not covered by CTC criteria” will be included. Values with CTCAE 
grades of -7 and -8 will be displayed in two separate listings.
In a similar manner, patients with a CTCAE grade of -1 will be reviewed on a case-by-case 
basis. For uric acid, values with CTCAE grade -1 will be regarded as either CTCAE grade 3
or CTCAE grade 1, depending on whether accompanied with physiological consequences or 
not.
The worst post baseline laboratory value and its CTCAE grade over all treatment courses will 
be calculated for each laboratory parameter specified above. 
The time to worst CTCAE value [in days] will be defined as the time from first 
administration of trial medication to the first occurrence of the worst CTCAE grade. (Date of 
first occurrence of worst CTCAE grade – date of first administration of trial medication + 1).
The last value on treatment will be determined using a similar algorithm to the adverse 
events, and presented descriptively. 
The change of the CTCAE grade of the lab value will be calculated

from baseline to the last laboratory value on treatment 

from baseline to the worst value on treatment 
5.2.6
Tumour markers
Selected tumour markers will be recorded at baseline and visit 8, and again at visit 5 of 
repeated courses. These parameters are outlined in Section 5.2.5 of the CTP. However, 
specific attention will be paid to the markers CA-125, CA 19-9 etc. These will be presented 
in listings.


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 16
5.3
OTHER ENDPOINTS
5.3.1
Demographics 
Only derived endpoints are defined here. Standard demographic and baseline characteristics
(sex, age, race, etc.) are used as recorded in the eCRF.
Body Mass Index (BMI)




2
2
]
[
]
[
/
m
height
kg
weight
m
kg
BMI

Time from first histological diagnosis [years] is the time between the date of first histological 
diagnosis and the date of informed consent: 
Time [years] = (informed consent - date of first histological diagnosis + 1)[days] / 365.25
Age at the first Histological diagnosis [years]:
Age [years] = INT(date of first histological diagnosis – birthday)[days] / 365.25,
where the INT function truncates the decimal portion of the value of the argument.
 
 
 
 
5.3.3
Extent of exposure
Number of days of administration [N]: Cumulative number of days with an administration of
treatment.
Number of courses initiated [N]: course initiated means that the patients received at least one 
administration of BI 6727 in the initiated course.
Number of courses completed [N]: A course is considered completed if one of the following 
is true:


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 17

Another course was initiated.

The patient was observed in the trial until at least 21 days after the last administration 
of trial medication of the respective course or stopped the trial due to DLT or PD.
Total observation time [in days] = (Date of last observation from the eCRF – first 
administration of trial medication date in course 1 + 1).
Cumulative total dose [mg] = Sum of doses (administered dose of BI 6727) calculated across 
all courses.
Total exposure time to the trial drug [days] = duration of “on treatment period” = MINIMUM 
(date of last trial drug administration of the last course + 21 days, death if occurring earlier 
than 21 days after the last administration) – date of first administration in the first course + 1 
day.
 
 
.
5.3.5
ECG

QTcF changes from baseline at each point in time: the QTcF post baseline measurement 
obtained at time t minus baseline QTcF measurement at time t.
The above endpoint will also be computed for the uncorrected QT interval and for the heart 
rate (HR). The heart rate (HR) will be derived from RR intervals.

New*) onset of QT/QTcF > 500 ms (notable prolongation)

New*) onset of QTcF > 470 ms

New*) onset of QTcF > 450 ms
*): “New” means not present at any time pre-dose


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 18

Categories of the QTcF increase from baseline to the maximum value:
intervals for a given patient as QTcF 30 ms, 30 ms < QTcF 60 ms, QTcF > 60 ms, 
(the latter increase reflects a notable change)

Categories of the QT increase from baseline to the maximum value:
intervals for a given patient as QT > 60 ms (the latter increase reflects a notable change)

PR and QRS changes from baseline at each point in time

PR, QRS and HR percentage changes from baseline at each point in time
 
 
5.3.5.1
ECG - Assessment for patients of the extension cohort for additional QT/QTc 
analysis
Three consecutive ECGs were recorded
at screening, and

prior to the start of the infusion (baseline)

5 minutes before the end of the infusion,
(i.e. around 1 hour, if infusion duration is 1 hour or around 2 hours, if infusion duration is 
2 hours, respectively)

1 hour after the end of the infusion,
(i.e. around 2 hour, if infusion duration is 1 hour or around 3 hours, if infusion duration is 
2 hours, respectively)

4 hours

24 hours
after the end of infusion of Courses 1 and 2
5.3.5.2
ECG - All other patients
Resting ECG was recorded prior to the start of the infusion (baseline) of treatment courses 1 
and 3, directly after the end of the infusion, and again at the end of the treatment course. A 
series of three consecutive ECGs using dedicated equipment were recorded.


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 19
6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
6.1.1
Treatment regimens / study intervals
The treatment regimens/study phases with short label, sort order and start date/time included 
in the treatment set-up in O*C (actual treatment set-up) 
 
6.1.2
Randomised treatment
Codes, decodes and sort order for initial treatment labels 
6.1.3
Specification of treatments for analyses
“Analysing treatment” will be used for reporting of treatment emergent AEs and to 
differentiate between screening, on-treatment and post-study safety data. The inequalities 
start date (in Table 6.1.3: 1 below) ≤ onset date of AE < end date will determine whether the 
AE will be assigned to the “analysing treatment” or not.
The labels of the analysing treatment, analysing numbers (analno), the labels used for 
displays in the tables as well as start date and end date to be used for reporting of AEs and 
laboratory values in the CTR, are seen in the table below.
Table 6.1.3: 1 Definition of the label of the analysing treatment, analysis numbers, the labels 
using for displaying in the tables, start date and end date
Label of the 
analysing 
treatment 
(ANALLBL)
Analysis 
number 
(ANALNO)
Label for the 
columns 
displayed in 
the tables
Start date 
End date
Screening
5
Date of informed 
consent
If date of 
informed consent  
= date of 
administration 
then the start date 
for "Screening"-
period will be 
derived as date of 
informed consent 
– 1 day
Start date of treatment 
course 1 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 20
Table 6.1.3: 1 Definition of the label of the analysing treatment, analysis numbers, the labels 
using for displaying in the tables, start date and end date - continued
Label of the 
analysing 
treatment 
(ANALLBL)
Analysis 
number 
(ANALNO)
Label for the 
columns 
displayed in 
the tables
Start date 
End date
Treatment 
course 1 
analysis
4
- use treatment 
specification 
of the initial 
treatment 
and column 
‘NAME in 
E_TPATT’
Date of first 
administration of  
BI 6727 within the 
treatment course 1
Date of first 
administration of BI 
6727 within the 
treatment course 2,
Or,
Start date of actual 
treatment post-study.
Treatment 
course 1  
analysis
4
Total
Date of first 
administration of  
BI 6727 within the 
treatment course 1
Date of first 
administration of BI 
6727 within the 
treatment course 2,
Or,
Start date of actual 
treatment post-study.
All course 
analysis 
3
- use the 
treatment 
specification 
of the initial 
treatment 
 
and column 
‘NAME in 
E_TPATT’
Date of first 
administration of  
BI 6727 within 
treatment course 1
Start date of post-
study interval 
 
All course 
analysis 
3
Total
Date of first 
administration of  
BI 6727 within the 
treatment course 1
Start date of post-
study interval 
 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 21
Table 6.1.3: 1 Definition of the label of the analysing treatment, analysis numbers, the labels 
using for displaying in the tables, start date and end date - continued
Label of the 
analysing 
treatment 
(ANALLBL)
Analysis 
number 
(ANALNO)
Label for the 
columns 
displayed in 
the tables
Start date 
End date
Post-study
6
- use the 
treatment 
specification 
of the initial 
treatment 
and column 
‘NAME in 
E_TPATT’
Start day of post-
study-interval
Date of Data Base 
lock+1day
6.2
IMPORTANT PROTOCOL VIOLATIONS
Due to the fact that this is a phase I study, no per protocol population is needed, however 
important protocol violations (PV) should be identified for patients in the treated set (see 
Section 6.3). Any PV which may affect safety, efficacy or the patient’s rights will be 
determined.
PVs are summarised into categories and are coded in O*C. 
 
 
 
 
 
Table 6.2: 1 Listing of protocol violations
Category/
Code
Description
Comment/Example
Efficacy 
(E), Safety 
(S) or 
Right (R)
A
Inclusion/Exclusion Criteria
A1
Criteria related to safety
A1.1
Patient has condition that may cause 
additional risk from study medication
IN 2, 5
EX 1, 3-5, 11, 13
S


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 22
Table 6.2: 1 Listing of protocol violations – continued
Category/
Code
Description
Comment/Example
Efficacy 
(E), Safety 
(S) or 
Right (R)
A1.2
Patient has laboratory assessments that 
may cause additional risk
EX 6-10
S
A1.3
Patient is unable to comply with the 
protocol
EX 15
S
A2
Criteria related to efficacy
A2.1
Patient does not have trial diagnosis
IN 1
E
A2.2
Patient does not have ECOG score ≤ 2 
IN 4
A2.3
Chemo-, radio-, or immunotherapy within 
the past four weeks before start of therapy 
or concomitant with this trial. This does 
not apply to steroids and biphosphonates.
EX 14
E
A2.4
Patient does not have any measurable 
tumour deposits (RECIST), only for 
additional patients recruited at the MTD.
IN 6
E
A3
Any other criteria not met that are 
considered relevant at DQRM/BPRM
n.a.
E/S
B
Legal criteria
B1
Informed consent not given
IN 3
R
B2
Informed consent after visit 1
R
B3
Patient < 18 years old
IN 2
R
B4
Men or women who are sexually active 
and unwilling to use a method of 
contraception, women who are pregnant or 
breastfeeding
EX 2, 12
R
C
Administration of trial medication not 
in accordance with the protocol
C1
BI 6727 taken before PK sampling at visit 
2 (treatment course1)
As entered in e-CRF.
Create listing, decision at 
DQRM/BPRM.
E
C2
Criteria for repeated treatment 
eligibility
C2.1
Patient continuing on study medication 
despite experiencing progressive disease 
and/or clinical progression.
Create listing, decision at 
DQRM/BPRM.
S


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 23
Table 6.2: 1 Listing of protocol violations – continued
Category/
Code
Description
Comment/Example
Efficacy 
(E), Safety 
(S) or 
Right (R)
C2.2
Patient continuing on study medication 
after experiencing drug-related clinically 
relevant AE and/or DLT without following 
recovery.
Create listing, decision at 
DQRM/BPRM.
S
C2.3
Patient continuing on study medication 
after delaying a treatment course for more 
than 6 weeks.
Create listing, decision at 
DQRM/BPRM.
S
D
Concomitant medication
D1
Any other chemotherapy, immunotherapy 
or radiotherapy during the trial
Create listing, decision at 
DQRM/BRPM.
S, E
E
Missing data
E1
Missing PK and administration data
E1.1
Missing PK sampling date and/or time
Create listing, decision at 
DQRM/BRPM.
E
E1.2
Missing BI 6727 administration date 
and/or time
Create listing, decision at 
DQRM/BRPM.
E
E2
Missing response data
E2.1
Baseline scan of tumour measurement not 
within four weeks prior to treatment.
Create listing, decision at 
DQRM/BRPM.
E
E2.2
Different imaging techniques were used 
for lesion measurement(s) during trial.
Create listing, decision at 
DQRM/BRPM.
E
E2.3
Missing image(s) at one or more time 
points.
Create listing, decision at 
DQRM/BRPM.
E
6.3
PATIENT SETS ANALYSED
Only one analysis population (Treated Set) will be considered for efficacy and safety (except 
ECG).
The Treated Set consists of all patients who received at least one application of the BI drug 
BI 6727.


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 24
Trial medication is defined as BI 6727.
First administration of trial medication is defined as date of first administration of BI 6727.
ECG
Per protocol set (PPS):
This is a subset of the Treated Set, restricted to patients, who have an ECG assessment in 
both courses (e.g. patients, who were replaced will be excluded).
6.5
POOLING OF CENTRES
There are only two centres in this trial. In general centres will be pooled. Due to the fact that 
a centre effect can not be excluded, specific analyses might be performed by centre 
additionally. Apart from that, centre effects will be described descriptively.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
If not stated otherwise, missing data will not be imputed and remain missing.
 
.
Adverse Event
Missing or incomplete AE dates are imputed according to BI standards (
 
PK data
Missing data and outliers of PK data is handled according to
 
 
ECOG Performance Score
In case of non-available values of ECOG score at the time point before first administration 
the score measured just before administration on day 1 of first course will be considered as 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 25
baseline. In case the ECOG score was not determined at the end of treatment visit, the last
ECOG score available will be used instead.
 
 
 
Date of progression (progdt)
If progression date (progdt) is missing for the evaluation of progression free survival, the 
corresponding visit date/examination date (visdt/examdt) is taken instead.
 
 
 
 
ECG
If one or two of the three consecutive ECG measurements is missing the available data will 
be used for that point in time.
Assessment of ECG for patients of the extension cohort for additional QT/QTc analysis:
If one baseline measurement is missing, this will be replaced by the other baseline 
measurement. If both baseline measurements are missing, this will be replaced by the 
measurement obtained at screening. Otherwise, baseline is missing and the patient is 
excluded for that endpoint.
Assessment of ECG for all other patients:


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 26
If one baseline measurement is missing, this will be replaced by the other baseline 
measurement. If both measurements are missing, the baseline is missing and the patient is 
excluded for that endpoint.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flow chart on page 6-8 of the CTP.
Unless otherwise specified, baseline is defined as the time-point closest to but prior to first 
administration of trial medication in the first treatment phase, where the first administration 
of trial medication is defined in Section 6.3 above. 
However, in the case of laboratory data, if the time is missing but the date of lab assessment 
is equal to the first medication date,
 
. This will then become the 
baseline value. 
ECG
Baseline ECG is available from two courses. To account for possible variations between the 
study days, two different baseline definitions will be used:
1. Individual baseline is defined as the mean of the triplicate at the time-point closest to but 
prior to the start of the infusion of each treatment course, i.e. each treatment course has its 
own baseline.
2. Combined baseline is defined as the mean of the (two) triplicates at the time-point closest 
to but prior to the start of the infusion of both treatment courses, i.e. a common baseline is 
used for both treatment courses.
6.8
GENERAL CALCULATION RULES
Months = days / 30,  Years = days / 365.25 = months / 12
 
 
 
 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 27
7.
PLANNED ANALYSIS
For the production of summary tables, standard programs 
 will be used if 
available.
The following standard descriptive statistical parameters will be the basis for displays in 
summary tables of continuous variables.
 
N
Number of non-missing values
Min
Minimum value
Q1
Lower quartile (25% percentile)
Median
Median value
Q3
Upper quartile (75% percentile)
Max
Maximum value
 
 
The following standard descriptive statistical parameters will be displayed in frequency tables 
of categorical or categorised variables:
N
number of non-missing observations
%
percentage
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 28
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
7.1.1
Disposition of patients
For patient disposition the standard descriptive table will be populated. Additionally, patients 
with discontinuations by initial treatment and the reasons will be listed.
7.1.2
Important protocol violations
A listing with the number of patients with protocol violations by initial treatment will be 
created in Section 15 of the CTR.
7.1.3
Demographic and other baseline
Standard descriptive analysis and summary tables for all patients treated by initial treatment 
will be created for demography, smoking/alcohol status, physical examination, ECOG, 
tumour information and oncology history.
 
 
 
 
 
 
7.4
PRIMARY ENDPOINTS
The primary objective is to find the MTD. Refer to Section 7.7.1 for a description of the 
analysis of safety and tolerability, the primary objectives of this trial.
7.5
SECONDARY ENDPOINTS
The following endpoints relating to tumour response will be summarised descriptively in 
tables, by initial treatment:

Unconfirmed Overall Response at all timepoints

Unconfirmed Best Overall Response


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 29

Unconfirmed Best Objective Response

Clinical Benefit

Confirmed Best Objective Response
Progression Free Survival: If applicable, for PFS a Kaplan-Meier analyses will be performed
on the MTD dose group and other cohorts of interest, depending on the final DLT results. 
Additionally, this information will be listed, including whether or not the endpoint has been 
censored.
For the ECOG score, the following endpoints will be summarised in tables:

ECOG score changes at the end of treatment

Scale of ECOG score changes at the end of treatment.
The analysis of PK parameters is performed 
and will be reported 
separately by the PK department within BI. 
The calculation of the pharmacokinetic parameters as well as the descriptive analysis of the 
concentration values and the descriptive and comparative analysis of the pharmacokinetic 
parameters is based on the 
 reference document.
Tables and figures for concentrations values and PK parameters will be created according to 
the reference document ‘Graphs and Tables for Clinical Pharmacokinetic Noncompartmental 
Analyses’.
7.6
EXTENT OF EXPOSURE
Standard descriptive analyses over all treatment courses will be performed. This will include 
a summary of the variables already described in Section 5. This descriptive analysis will 
comprise a mixture of frequency and percentages, as well as summary statistics.
 
.
7.7
SAFETY ANALYSIS
The primary analysis is for determination of MTD. No statistical model is foreseen allowing 
assessment of MTD, descriptive analysis is confined to a listing by dose group. The purpose 
of these tables is to summarize and document the data that led to the selection of MTD.
7.7.1 Adverse events
7.7.1.1
Maximum tolerated dose and dose limiting toxicity
A summary of the number of patients with DLT in treatment course 1 will be given by initial 
treatment.


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 30
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.7.1.2
Adverse events
AE analysis will be performed for all treatment periods and for the first treatment course.
The analyses of AEs will be descriptive in nature and will follow the standard procedure laid 
down in the DM & SM (including all required tables and listings) (current guideline 001-
MCG-156 'Handling and Summarization of AE Data for CTR and Integrated Summaries'). 
AEs will be coded with the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA version 10.0). The version number will be displayed as a footnote in the 
respective tables and listings. The system organ classes will be sorted according to the 
standard sort order specified by EMEA, preferred terms will be sorted alphabetically (within 
system organ class).
Each patient can be observed during the trial under several doses. Analysing the AE of all 
treatment courses will be carried out under the initial treatment. No formal statistical analysis 
is planned for the safety comparison. 
The analysis of AEs will be based on the concept of treatment emergent AEs. AEs will be 
distinguished for the treatment course in which the subjects are on-treatment as well as for 
screening, and post-study 
 The actual 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 31
dosage of BI 6727 administered on the day each AE starts will also be derived and will be 
included in the listing. Listings of screening events will not be sorted by initial treatment 
(Table 6.1.3: 1). But post-study listings will be sorted by initial treatment.
According to the BI standards, multiple recordings of AEs will be collapsed to episodes on 
the lowest level term and multiple episodes will be condensed to records on the PT and 
system organ class (SOC) level. CTCAE grade will be an additional criterion for collapsing 
and condensing AEs. The maximum CTCAE grade will be assigned to episodes and records. 
CTCAE grade and DLT information will be displayed in AE listings. MedDRA levels for 
condensing will be SOC and PT.
According to ICH E3 (International Conference on Harmonisation Efficacy 3), AEs classified 
as ‘other significant’ will include those non-serious and non-significant AEs with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) those identified by the Trial clinical monitor/Investigator at a BRPM. 
An overall summary of AEs with additional columns ‘CTCAE’,’DLT (yes/no)’ and 'total' 
will be presented.
AE flags and attributes
An AE flag will be defined for patients who developed an AE that was CTCAE grade ≥ 3, 
DLT, or serious AE (SAE).
An AE attribute "CTCAE grade 3/4 or 5 combined with drug relation" will be derived to 
avoid incorrect condensing.  Consider, for instance, a patient with coincident drug-related 
abdominal pain with CTCAE 1, and non-related vomiting with CTCAE 3.  Without the new 
attribute these AEs would be reported as drug-related Grade 3/4 under the SOC 
Gastrointestinal disorder. With the new AE attribute these AE would be excluded.
An additional AE attribute “Drug relationship combined with seriousness of the AE” is 
needed similarly to the AE attribute "CTCAE grade 3/4 or 5 combined with drug relation"
described above.
Frequency of patients with AEs will be summarised by treatment, primary SOC and PT. 
Separate tables will be provided for patients with other significant AEs, for patients with 
significant non-serious AEs and for patients with SAEs. Additionally, there will be a 
summary table presenting maximum CTCAE grade for each AE, as well as patients who 
developed AEs with CTCAE grade greater than 3, DLT, SAE, and significant AEs. 
AE of special interest (User-defined AE categories): these will be the same as for project 
1216.P1 (BI 2536). Frequency tables and listings for these AE categories will be provided.
7.7.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will follow the standard 
procedure laid down in the DM & SM (Guideline 'Display and Analysis of Laboratory Data').


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 32
Patients will be counted under the initial treatment. Separate listings for patients treated under 
different doses will be created. The analysis of laboratory data will use the same ‘analysing 
treatments’ as described for the AEs.
Single time courses by initial treatment will be used to display laboratory values over time. 
The graphs may be truncated if sufficient data is not available. These graphs will be displayed 
in Chapter 16.1.9.2 for the following parameters, using the BI normalised values for 
Haematology and Differentials, and the multiples of the ULN for Substrates and Enzymes:
Haematology: Haemoglobin, WBC count and Platelets
Differentials: Neutrophils (absolute count)
Substrate: Creatinine, Total Bilirubin and Creatinine Phosphokinase
Enzymes: AST, ALT and γ-Glutamyl transpeptidase (GGT)
In addition, laboratory tests will be analysed within the treatment courses as defined below. 
Maximum CTCAE grades will be tabulated by treatment course and over the entire trial.
Where applicable, standard CTCAE grading Shift tables from first visit to end of trial will be 
generated in Appendix 16.1.9.2.
Number of patients treated [N (%)]
Number of patients with maximum change of CTCAE grade [N (%)]
Number of patients with transition of CTCAE grade:

from baseline to the last value on treatment [N (%)]

from baseline to the worst grade on treatment [N (%)]

from worst to the last value on treatment [N (%)]
Clinically relevant abnormalities 
) will also be summarised.
7.7.3
Vital signs
Descriptive statistics of absolute values (and change from baseline) for vital signs (including 
body weight) will be provided by initial treatment and planned time or visit of the first 
treatment course and over all treatment courses.
7.7.4
ECG
7.7.4.1
ECG - Assessment for patients of the extension cohort for additional QT/QTc 
analysis
All analyses described in this section will be performed using the Treated Set.


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 33
7.7.4.1.1 Central tendency analysis
The endpoint, QTcF change from individual baseline at each point in time (cf. Section 5.3.1, 
endpoint 1, cf. section 6.7), will be analysed using a linear mixed-effects model for repeated 
measures data.
This model will include the following effects ‘sequence’, ‘course’, ‘treatment’ (both infusion 
types i.e. 1 hour duration and 2 hours duration) and ‘time’ as fixed, categorical effects, 
‘patient within sequences’ as a random, categorical effect, the interaction effect 
‘treatment*time’ as well as the continuous, fixed covariate of baseline value. The blocking 
effect specified by the SUBJECT variable within the repeated SAS statement (effect ‘time’) 
is patient*course implying that the values of ‘time’ are correlated within each subject’s 
course. This model will use all observed data available. The variance covariance structure for 
the main analysis will be '‘Compound symmetry’. Should the estimated G matrix be not 
positive definite, ‘patient within sequences’ will be included as fixed effect.
The endpoint, QTcF change from combined baseline at each point in time (cf. Section 5.3.1, 
endpoint 1, cf. section 6.7), will be analysed using the same model as described above, except 
that ‘patient within sequences’ will be removed from the model.
The SAS® procedure MIXED will be used involving the restricted maximum likelihood 
(REML)-estimation and the Kenward and Roger approximation of denominator degrees of 
freedom. Details of the programming code are described in the Analysis Data Set (ADS)
plan, section 3 (Program Modules).
For the pairwise comparisons of the different treatments at each time-point the differences 
between the expected means for the BI 6727 infusions at each sampling point will be 
estimated by the difference in the corresponding Least-Squares Means and two-sided 90 % 
confidence intervals based on the t-distribution will also be computed. The 1-hour infusion is 
considered as the reference while the 2-hour infusion is considered as the test treatment, i.e. 
the difference ‘2-hour infusion - 1-hour infusion’ will be computed.
The analysis described above will also be performed for the endpoints QTcF/HR change from 
baseline at each point in time.
 
 
7.7.4.1.2 Categorical endpoints / 
Frequency tables will be provided for categorical endpoints.
 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 34


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 35
 
 
 
 
 
 
 
 
 
 
 
.
7.7.4.2
ECG - Assessment for all other patients
All analyses described in this section will be performed using the Treated Set.
Patient 
, who received a dose of 127 mg/kg, will be included in the 125 mg/kg dose group 
for the analysis.
The quantitative QTcF, QT and HR endpoints will also be summarised descriptively for each 
treatment using statistical parameters such as N, mean, SD, min, median, max. These 
analyses will also be performed using PPS.
Endpoints for the PR and QRS intervals (
 will be 
summarised using standard descriptive statistics.
Frequency tables will be provided for categorical endpoints.
 
Frequencies of patients with threshold increases from baseline in the QT/QTcF intervals 
(cf. Section 5.3.1, endpoints 5 and 6) will be displayed.
 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 36
8.
REFERENCES
R01-0028
Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. 
‘Accelerated titration designs for phase I clinical trials in oncology.’ J Natl 
Cancer Inst 1997 ;89 (15) :1138 -1147.
R01-0754 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, 
Verweij J, Glabbeke M van, Oosterom AT, Christian MC, Gwyther SG. New 
guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer 
Inst 2000;92(3):205-216
R01-0787
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, 
Carbone PP. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655
R06-1666
’Common Terminology Criteria for Adverse Events v3.0 (CTCAE)’
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 37


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 38


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 39


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 40


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 41


Boehringer Ingelheim 
TSAP for BI Trial No: 1230.1
Page 42