Phase I, Non-randomized, Open-label, Multi-center Dose Escalation Trial of BI 836880 Administered by Weekly Repeated Intravenous Infusions in Patients With Advanced Solid Tumors.
Phase: PHASE1
Conditions: Neoplasms
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
TITLE PAGE
Document Number:
c03124055-06
EudraCT No.:
2015-001132-38
BI Trial No.:
1336.6
BI Investigational 
Product(s):
BI 836880
Title:
Phase I, non-randomized, open-label, multi-center dose escalation 
trial of BI 836880 administered by weekly repeated intravenous 
infusions in patients with advanced solid tumors.
Brief Title:
Weekly BI 836880 in patients with advanced solid tumors
Clinical Phase:
I
Clinical Trial Leader:
Phone: 
Fax: 
Coordinating 
Investigator:
Principal 
Investigator:
Phone: 
Fax: 
Tel 
Fax 
Status:
Final Protocol (Revised Protocol based on global amendment 3)
Version and Date:
Version:
Date:
Revised Protocol
4.0
13 Mar 2019
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2019 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.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 836880
Protocol date:
10 Dec 2015
Trial number:
1336.6
Revision date:
13 Mar 2019
Title of trial:
Phase I, non-randomized, open-label, multi-center dose escalation trial of BI 
836880 administered by weekly repeated intravenous infusions in patients with 
advanced solid tumors
Coordinating
Investigator:
Principal Investigator
Phone: 
Fax:
Tel 
Fax 
Trial site(s):
Multicentre-trial conducted in 2 countries
Clinical phase:
I
Objective(s):
To determine the maximum tolerated dose (MTD) and provide preliminary safety 
data of BI 836880 given as intravenous infusion and to determine recommended 
phase II dose. 
 
Methodology:
Non randomized, uncontrolled, open-label, dose escalation
No. of patients:
Approximately 40 patients to be enrolled
total entered:
Approximately 25 patients
each treatment:
Approximately 25 patients will receive study treatment
Diagnosis :
Advanced or metastatic/ refractory solid tumors

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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 836880
Protocol date:
10 Dec 2015
Trial number:
1336.6
Revision date:
13 Mar 2019
Main criteria
for inclusion:

Age > 18 years

Histologically or cytologically confirmed malignancy which is locally 
advanced or metastatic solid tumor, and either refractory after standard 
therapy for the disease or for which standard therapy is not reliably 
effective, e.g. patients do not tolerate or have contraindications to 
otherwise available standard therapy and tumour lesions evaluable for 
Dynamic contrast-enhanced (DCE) MRI at MTD

ECOG performance status < 2

Adequate hepatic, renal and bone marrow functions

Life expectancy > 3 months in the opinion of the investigator

Recovery from all reversible adverse events of previous anti-cancer 
therapies to baseline or CTCAE grade 1, except for alopecia (any grade) 
and sensory peripheral neuropathy CTCAE grade < 2
Test product(s):
BI 836880 and Diluent for BI 836880
dose:
Starting dose of 40 mg weekly infusion
mode of 
administration:
Intravenous weekly in a 21-day treatment course
Comparator products:
Not applicable
dose:
Not applicable
mode of 
administration:
Not applicable 
Duration of treatment:
Continuous treatment in the absence of disease progression or unacceptable
toxicity
Endpoints
Primary endpoint

Maximum Tolerated Dose (MTD)
Secondary endpoint

Drug related AEs leading to dose reduction or discontinuation during 
treatment period
Safety criteria:
Adverse events according to Common Terminology Criteria (CTCAE version  
4.03), incidence of dose limiting toxicities, physical examination, vital signs, safety 
laboratory parameters, ECOG
Statistical methods:
Descriptive and exploratory statistics analyses. Dose escalation guided by a 
Bayesian logistic regression model with over dose control

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FLOW CHART COURSE 1
Trial periods
Screening
Treatment course***
EOT*
EoR*
FU**
Course
1
Visit
Screen
V1
V2
V3
Day
-21 to -1
1
2
3
8 +2
15+2
EoT+42 d
Informed consent 1
x
Demographics
x
Medical  history
x
Inclusion/exclusion criteria
x
x
Physical examination2
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
Body temperature3
x
x
x
x
x
x
Blood pressure4,  heart rate
x
x
x
x
x
x
x
x
ECOG performance status
x
x
x
Administration of BI 836880 infusion
x
x
x
Safety Lab parameters5
x
x
x
x
x
Pregnancy test
x
x
x
Tumor assessment6
x
x
x
12-lead ECG7
x
x
x
x
x
x
Echocardiography8
x
x
Pharmacokinetics9
x
x
x
x
x
x
x
x (FU1)
Anti-drug antibodies10
x
x
x
x (FU1)

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Trial periods
Screening
Treatment course***
EOT*
EoR*
FU**
Course
1
Visit
Screen
V1
V2
V3
Day
-21 to -1
1
2
3
8+2
15+2
EoT+42 d
Biomarker : Myriad  Ang MAP panel11
x
x
x
Biomarker: free/total VEGF-A, Ang212
x
x
x
x
x
x
x
x (FU1)
Concomitant therapy
x
x
x
x
x
x
x
x
x
Adverse events13
x
x
x
x
x
x
x
x
x
DCE-MRI14
x
x
x
Completion of  trial medication
x
Completion of patient participation
x

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FLOW CHART COURSES 2 ONWARDS
Trial periods
Repeated treatment courses***
EOT*
EoR*
FU**
Course
2,3,4,5 onwards
Visit
V1
V2
V3
Day
1
2
3
8 +2
15+2
EoT+42 d
Physical examination2
x
x
x
x
x
Weight
x
x
Body temperature3
x
x
x
x
Blood pressure4,  heart rate
x
x(C2,C4)
x
x
x
x
ECOG performance status
x
x
Administration of  
BI 836880 infusion
x
x
x
Safety Lab parameters5
x
x
x
x
Pregnancy test
x
x
Tumor assessment6
x
x
x
12-lead ECG7
x
x (C2,C4)
x (C2,C4)
x (C2,C4)
x
Echocardiography8
x
x
Concomitant therapy
x
x
x
x
x
x
x
Adverse events13
x
x
x
x
x
x
x
DCE-MRI14
x ( C3, C5)
x
Completion of  trial medication
x
Completion of patient participation
x

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(C2, C3, C4, C5) = (courses 2, 3, 4 and 5)
FU1= first follow up visit
*End Of Treatment (EOT) must be performed within 21 days of the last administration of study drug. If last administration of the study drug occurs during a scheduled visit, 
examinations as defined for EOT should be performed instead of examinations for the scheduled visit.
EoR*= End of Residual Effect Period
**One Follow-up visit (FU1) should be performed 42 calendar days after the discontinuation of study drug for all patients. For patients who discontinue not due to progressive 
disease, additional FU visits will be performed at 6-week intervals plus /minus 3 days, until progression, lost to follow-up, start of another anti-cancer treatment, death.
After the interim data base lock additional FU visits are no longer required
***Treatment courses are 3 weeks in duration (21 days). All subsequent visit dates should be calculated based on Course 1 Visit 1 date. If one visit is skipped in case of treatment 
interruption patients may continue on treatment until the criteria for stopping medication are met (see Section 3.3.4)
1Written informed consent must be obtained before any trial specific screening assessments are performed.
2A complete physical examination (including cardiac, neurological, dermatological pulmological etc..) at screening and before the start of the treatment, EoT and End of Residual 
Effect Period (EoR). At further time points specified in the Flow Chart, physical examination should be limited to the assessment of the actual health status (including, evaluation 
of blood pressure, ECG, lab safety parameters, AEs, concomitant therapies, ECOG, as applicable). After the interim data base lock, physical examination, ECOG performance 
status are no longer mandatory at the specific visits but will be performed at the investigator’s discretion. Findings will be documented in the eCRF only if qualifying as (S)AE 
3Body Temperature: whenever possible the same method should be used for body temperature measurement in one patient. Body temperature > 38°C  must be re assessed 1 hour 
after. After the interim data base lock body temperature is no longer mandatory at specific visits but will be performed at the investigator’s discretion. Findings will be documented 
in the eCRF only if qualifying as (S)AE
4Blood Pressure : Systolic and diastolic blood pressure as well as pulse rate (electronic or by palpation, count for 1 minute) will be measured after 5 minutes of rest in seated 
position. The blood pressure measurement should be performed three times at each time point (refer to Appendix 10.2 and Appendix 10.4 for detailed time points). After the 
interim data base lock blood pressure is no longer mandatory at specific visits but will be performed at the investigator’s discretion. Findings will be documented in the eCRF only 
if qualifying as (S)AE
5Haematology, biochemistry and coagulation parameters will be performed locally. Previous safety lab: investigations are acceptable if performed within 72 hours prior to the first 
treatment administration. For details see Section 5.3.3 After the interim data base lock safety laboratory tests will be performed at investigator’s discretion based on the standard 
medical care. Findings will be documented in the eCRF only if qualifying as (S)AE
6Tumor assessment will be performed every 6 weeks after start of treatment with BI 836880 (in the week preceding the start of treatment course 3, 5, 7, 9, 11...) and should include 
CT scans or MRI. Imaging not older than 28 days at start of treatment will suffice as screening images and don’t have to be repeated. The EOT tumor assessment is optional if 
performed in the previous 4 weeks. In the event of any treatment interruption or treatment delay, the tumor assessment should follow the original schedule
After the interim data base lock, frequency of tumor assessment may be adapted according to local standard of care and in agreement with the sponsor if the patient is deriving 
clinical benefit (e.g. CR, PR or SD > 6 months).   

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7Triplicate 12-Lead resting digital electrocardiogram (3xECG taken approximately 2-3 minutes apart) will be performed at screening and will be repeated at visits (refer to 
Section 5.3.4 and Appendix 10.4 for detailed time point).
After the interim data base lock, ECG will be performed as clinically indicated on local machine and the assessment will be done by the investigator. Shipment of ECGs to central 
vendor is no longer required
8Echocardiography will be performed locally at screening (not older than 7 days before start of treatment) and at EoT. During treatment period, echocardiography will be 
conducted only if clinically indicated. After the interim data base lock findings related to echocardiography will be reported in the eCRF only if qualifying as (S)AE
13AEs must be collected and reported from signing the informed consent onwards through the end of treatment (including Residual Effect Period, REP): all AEs (serious and non-
serious) and all AESIs must be collected and reported from signing the informed consent onwards through the end of treatment (including Residual Effect Period, REP). After the 
end of treatment (including the REP) during the extended follow-up period until the individual patient’s end of trial: all related SAEs and all related AESIs must be collected and 
reported.  After the individual patient’s end of trial: the investigator does not need to actively monitor the patient for AEs but should only report relevant SAEs and relevant AESIs 
of which the Investigator may become aware of (Please refer to Section 5.3.6 and Section 6.2.3.3)
14DCE-MRI measurements will be done only for suitable patients with preferably liver metastases > 2cm. DCE-MRI measurement will be done during the screening period, 1 
week after first administration of BI 836880 (C1V2), after the 2nd treatment course (C3V1) and after the 4th treatment course (C5 V1) in absence of progressive disease. In case 
patient stopped treatment for other reasons than progressive disease, DCE-MRI should still be conducted as long as patient is in Follow up for progression. Time points for 3rd and 
4th imaging, depending on when patient stopped treatment, have to be adapted as 6 weeks and 12 weeks after 1st infusion
(refer to Section 5.5.1)
After the interim data base lock, DCE-MRI measurement is no longer mandatory

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART COURSE 1 ...................................................................................................4
FLOW CHART COURSES 2 ONWARDS...........................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................15
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....18
RATIONALE FOR PERFORMING THE TRIAL.........................................18
2.1
TRIAL OBJECTIVES........................................................................................18
2.2
BENEFIT-RISK ASSESSMENT.......................................................................19
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................21
OVERALL TRIAL DESIGN AND PLAN .......................................................21
3.1
3.1.1
Administrative structure of the trial .................................................................23
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................24
SELECTION OF TRIAL POPULATION .......................................................24
3.3
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................26
3.3.4
Removal of patients from therapy or assessments...........................................27
Removal of individual patients .............................................................................27
3.3.4.1
3.3.5
Discontinuation of the trial by the sponsor.......................................................28
4.
TREATMENTS...................................................................................................29
TREATMENTS TO BE ADMINISTERED.....................................................29
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........29
4.1.2
Method of assigning patients to treatment groups...........................................30
4.1.3
Selection of doses in the trial..............................................................................30
4.1.4
Drug assignment and administration of doses for each patient......................32
Re-treatment criteria .............................................................................................33
4.1.4.1
Dose reduction scheme .........................................................................................33
4.1.4.2
4.1.5
Blinding and procedures for unblinding...........................................................33
Blinding.................................................................................................................33
4.1.5.1
Unblinding and breaking the code ........................................................................34
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................34
4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34

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CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....35
4.2.2
Restrictions ..........................................................................................................35
Restrictions regarding concomitant treatment ......................................................35
4.2.2.1
Restrictions on diet and life style..........................................................................36
4.2.2.2
4.3
TREATMENT COMPLIANCE........................................................................36
5.
VARIABLES AND THEIR ASSESSMENT ....................................................37
TRIAL ENDPOINTS..........................................................................................37
5.1
5.1.1
Primary Endpoint(s)...........................................................................................37
5.1.2
Secondary Endpoint(s) .......................................................................................37
ASSESSMENT OF EFFICACY........................................................................37
5.2
ASSESSMENT OF SAFETY.............................................................................38
5.3
5.3.1
Physical examination ..........................................................................................39
5.3.2
Vital Signs............................................................................................................39
5.3.3
Safety laboratory parameters ............................................................................40
5.3.4
Electrocardiogram (ECG)..................................................................................41
5.3.5
Other safety parameters.....................................................................................41
5.3.6
Assessment of adverse events.............................................................................41
Definitions of AEs ................................................................................................41
5.3.6.1
Adverse event collection and reporting ................................................................44
5.3.6.2
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................46
5.4.1
Assessment of Pharmacokinetics.......................................................................46
5.4.2
Methods of sample collection .............................................................................47
5.4.3
Analytical determinations ..................................................................................47
5.4.4
Pharmacokinetic - Pharmacodynamic Relationship .......................................48
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................48
5.5
5.5.1
Imaging Pharmacodynamic endpoints..............................................................49
OTHER ASSESSMENTS...................................................................................50
5.6
5.6.1
Demographic and medical history.....................................................................50
5.6.2
Immunogenicity assessment...............................................................................51
APPROPRIATENESS OF MEASUREMENTS..............................................51
5.7
6.
INVESTIGATIONAL PLAN.............................................................................52
VISIT SCHEDULE.............................................................................................52
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................52
6.2
6.2.1
Screening period..................................................................................................53
6.2.2
Treatment period(s)............................................................................................53
6.2.3
Follow Up Period and Trial Completion...........................................................53
End of treatment visit............................................................................................53
6.2.3.1
Residual effect period (REP) ................................................................................54
6.2.3.2
Follow-up period for progression .........................................................................54
6.2.3.3
Trial completion for an individual patient ............................................................54
6.2.3.4
54
6.2.3.5
Trial completion....................................................................................................

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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56
STATISTICAL DESIGN – MODEL ................................................................56
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................59
7.2
PLANNED ANALYSES.....................................................................................59
7.3
7.3.1
Primary endpoint analyses.................................................................................59
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................59
INTERIM ANALYSES ......................................................................................63
7.4
HANDLING OF MISSING DATA ...................................................................63
7.5
RANDOMISATION ...........................................................................................64
7.6
DETERMINATION OF SAMPLE SIZE .........................................................64
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........65
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................65
DATA QUALITY ASSURANCE ......................................................................65
8.2
RECORDS...........................................................................................................66
8.3
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................66
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................66
8.4
STATEMENT OF CONFIDENTIALITY........................................................66
8.5
END OF TRIAL..................................................................................................66
8.6
PROTOCOL VIOLATIONS .............................................................................67
8.7
9.
REFERENCES....................................................................................................68
PUBLISHED REFERENCES............................................................................68
9.1
UNPUBLISHED REFERENCES......................................................................72
9.2
10.
APPENDICES.....................................................................................................73
INSTRUCTIONS FOR USE..............................................................................73
10.1
10.1.1
Instruction for Pharmacists ...............................................................................73
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................73
10.2
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.6
AND DATA SCENARIOS .................................................................................80
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................85

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ABBREVIATIONS
ABPM
Ambulatory Blood Pressure Measurement 
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine amino transferase
ANC
Absolute neutrophil count
Ang2
Angiopoeitin2
AST
Aspartate amino transferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BLQ
Below the limit of quantification
BP
Blood Pressure
CA
Competent Authority
CBPM
Conventional Blood Pressure Measurement
CI
Confidence Interval
CPL
Clinical Program Leader
CPPL
Clinical Pharmacology Program Leader
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
CTMF 
Clinical Trial Master File 
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DCE-MRI
Dynamic Contrast-Enhanced Magnetic Resonance Imaging
DEDP
Drug Exposure During Pregnancy
DBP
Diastolic Blood Pressure
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DSB
Data Safety Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic Acid
EoR
End of Residual effect period
EOT
End of Treatment
EudraCT
European Clinical Trials Database
EWOC
Escalation with overdose control
FC
Flow Chart
FU
Follow up
FDA
Food and Drug Administration

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GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HNSTD
Highest No-Severely Toxic Dose
IB
Investigator’s Brochure
IC
Informed Consent
ICH 
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
Ktrans
Volume transfer constant obtained from DCE-MRI data
LMWH
Low Molecular Weight Heparin
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTD
Maximum Tolerated Dose
NCA
Non Compartmental Analysis
NCI
National Cancer Institute
NOA
Not Analysed
NOAEL
No Observed Adverse Effect Level
NOP
No Peak detectable
NOR
No valid Result
NOS
No Sample
NSAID
Nonsteroidal Anti-Inflammatory Drug
NYHA
New York Heart Association
OPU
Operative Unit
p.o
Per os (oral)
PD
Progressive Disease
PLGF
Placenta Growth Factor
PK/PD
Pharmacokinetics/Pharmacodynamics
PR
Partial Response
QT 
QT interval corrected for heart rate
QTcf
QT interval corrected for heart rate according to Fridericia’s formula
eDC
Electronic Data Capture
RECIST
Response Evaluation Criteria In Solid Tumors
REP
Residual Effect Period
RP2D
Recommended Phase II Dose 
SAE
Serious Adverse Event
SD
Stable Disease
SBPM
Self-Blood Pressure Measurement
SOP
Standard Operation Procedure
SUSAR
Suspect Unexpected Serious Adverse Event
TDMAP
Trial Data Management and Analysis Plan
Tie2
Receptor of the TIE Family

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TME
Translational Medicine Expert 
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSE
Turbo Spin Echo
TSTAT
Trial Statistician
ULN
Upper Limit of Normal
UPCR
Urine Protein to Creatinine Ratio
VEGF
Vascular Endothelial Growth Factor

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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Cancer remains an important health problem with 14.1 million new cancer cases, 8.2 million
cancer deaths and 32.6 million people living with cancer (within 5 years of diagnosis) in 2012
worldwide (R14-2220). Most patients with locally advanced and/or metastatic tumors are not
curable and died due to their disease. There is therefore a substantial need for novel
therapeutic strategies to improve the outcome of patients with advanced or metastatic
malignancies who have failed conventional therapies, or for whom no therapy of proven
efficacy exists. In the last decade, several novel compounds targeting specific cellular
components or tumor environment, including tumor vasculature and angiogenesis have been
developed based on increasing understanding of cancer biology and cell regulation.
Angiogenesis is considered as a key process in tumor growth (R12-2552). Once a certain
tumor size is reached, existing blood vessels are no longer sufficient and new blood vessels 
are required to continue growth. Acquisition of the angiogenic phenotype can result from 
genetic changes or local environmental changes that lead to the activation of endothelial cells. 
One way for a tumor to activate endothelial cells is through the secretion of pro-angiogenic
growth factors (e.g. vascular endothelial growth factor, angiopoietin2, etc.) which then bind
to receptors on nearby dormant endothelial cells that line the interior of vessels.
Vascular endothelial growth factor plays a major role in angiogenesis. Blockade of VEGF
axis has proven to represent an efficacious treatment for patients with advanced malignancies
when given in combination with cytotoxic “backbone” therapy.
Angiopoietin2 (Ang2), a ligand of the Tie2 receptor, play an important role in angiogenesis
and it’s in vivo inhibition results in tumor growth inhibition and vasculature changes (R12-
3593).
Both pro-angiogenic pathways (VEGF/VEGF-R and Ang-2/Tie2) have been reported to
synergize and to crosstalk (R14-5320, R14-5323). The anticipated clinical benefit of
VEGFxAng2 dual inhibition would be the modulation of tumor angiogenesis and reduced
tumor growth rate.
Developement of anti-angiogenic agents targeting pro-angiogenic factors is a valid concept
which showed clinical efficacy in monotherapy (mainly with tyrosine kinase inhibitors: TKI)
and/or in combination with standard treatment (chemotherapies) (R05-2504, R09-5764,
R12-5190, R14-5143, R14-5142, R14-3261, R13-5295, R14-5374, R12-0021, R14-5318).
DRUG PROFILE
1.2
The Nanobody® technology was originally developed following the discovery that camelidae
(camels and llamas) possess fully functional antibodies that lack light chains. These heavy
chain antibodies contain a single variable domain (VHH) and two constant domains (CH2 
and CH3). The cloned and isolated VHH domain is a stable polypeptide harbouring the full

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antigen-binding capacity of the original heavy-chain antibody. These newly discovered VHH
domains form the basis of a new generation of therapeutic antibodies named Nanobodies
(R15-1719).
BI 836880 is a genetic fusion protein of one VEGF-A-binding and one Ang2-binding
single domain antibodies (VHH, Nanobody®). The two single domain antibody moieties are
linked via a human serum albumin-binding Alb11 domain, serving as half-life extension, and
glycine-serine linkers between the domains. The protein has a molecular mass of 40.7 kDa
(c02353882).
BI 836880 potently binds to both hVEGF165 and hVEGF121 with similar affinity in the low
nanomolar to sub-nanomolar range and completely inhibits binding of hVEGF165 to
VEGFR. BI 836880 potently binds to human Ang2 with an affinity constant estimated to be
KD=16pM and potently inhibited and fully blocked human Ang2 binding to Tie2 with an
IC50 of 50pM in the presence of human serum albumin (c02353882).
BI 836880 is highly potent and showed in vivo monotherapy efficacy (tumor growth
inhibition) in several tumor xenograft representing colon cancer (CXF 243), non-small cell
lung cancer (LXFE 211, LXFE 1422), mammary cancer (MAXF 401), ovarian cancer
(OVXF 1353), pancreatic cancer (PAXF 546) and renal cell cancer (RXF 1220)
(c02353882).
BI 836880 cross-reacts to cynomolgus VEGF, as well as mouse, rat and cynomolgus Ang2
which points to cynomolgus monkey as the most suitable species for toxicology assessment.
Based on this, a 13-week repeat dose administration of BI 836880 was performed in
cynomolgus monkeys. Animals received weekly BI 836880 intravenous doses by a 5-minute
infusion at doses of 0 (vehicle only), 1, 10 and 60 mg/kg for a total of 14 doses followed by a
13-week recovery period. BI 836880 was well tolerated up to the highest dose of 60 mg/kg.
No mortality was attributed directly to BI 836880 administration. But one monkey in the
10 mg /kg dose tier had to be euthanized due to an important immunogenic reaction.
BI 836880 did not demonstrate any effects on neurological, renal, or cardiovascular functions
including electrocardiograms (ECGs). In the monkey presenting the immunogenic reaction,
membranoproliferative glomerulopathy in the kidney was observed. This finding was 
considered as a secondary response to immune complex deposition in the glomeruli and not 
directly related to BI 836880 administration.
No BI 836880 related adverse changes in body weight, food consumption or clinical
observations were noted. BI 836880 did not result in ocular changes, changes in physical
examination parameters.
No adverse or BI 836880-related changes in hematology, chemistry, coagulation or urinalysis
were observed (c02353882).
BI 836880 administration resulted in a microscopic growth plate cartilage change (increased
zone of hypertrophy) in the sternum of the males in the ≥10 mg/kg dose groups. This change
was of minimal in severity and was considered not adverse since it was not expected to

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negatively affect bone growth. Increased thickness of the growth plate zone of hypertrophy is
a known effect of angiogenesis inhibitors such as Bevacizumab.
The pharmacokinetics (PK) and immunogenicity of BI 836880 were investigated in
cynomolgus monkeys following a single intravenous (i.v.) at 3 dose levels. BI 836880
demonstrated an unexpected dose-dependent clearance and a supra-proportionally AUC0-∞
increase with the increase of dose. Among the nine monkeys in this study, six monkeys were
ADA positive post-dose at one or more of the sampling time points. In the 13-week toxicity
and toxicokinetics, BI 836880 exposure (Cmax and AUC0-168) increased approximately dose-
proportionally from 1 to 60 mg/kg in weeks 1, 4 and 13. There was a moderate (~ 2-fold)
accumulation of BI 836880 after repeated dosing. The Cmax and AUC0-168 values were similar
between the male and female monkeys at the same dose level in each sampling week. The
discrepancy in dose proportionality between these two studies is likely due to the difference
in sampling. More sampling time points (up to 42 days post dosing) in the single dose PK
study allowed better characterization of the later portion of the concentration-time profiles
(after ~ 240 h), where dose-dependent clearance was more pronounced.
No clinical experience has been gained in humans so far.
For a more detailed description of the drug profile refer to the current Investigator’s Brochure
(IB) which is included in the Investigator Site File (ISF)

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Angiogenesis is the formation of new blood vessels from pre-existing vasculature and is a
key process in tumor growth. The Ang2/Tie2 and the VEGF/VEGFR2 pathways have been
identified as key pathways mediating tumor angiogenesis (R13-0448). Multiple studies have 
described increased VEGF levels in a variety of human cancers and the VEGF expression 
levels have been correlated with poor survival (R15-1720). The VEGF neutralizing 
monoclonal antibody bevacizumab has demonstrated anti-tumor activity in clinical trials and 
is currently approved for several indications and settings, mainly in combination with 
standard chemotherapy regimens (R15-1222).
Studies in mice have shown that Ang2, a ligand of the Tie2 receptor, controls vascular
remodeling by enabling the functions of other angiogenic factors, such as VEGF (R12-3593).
Ang2 is primarily expressed by endothelial cells, strongly induced by hypoxia and other
angiogenic factors and has been demonstrated to regulate tumor vessel plasticity, allowing
vessels to respond to VEGF and FGF2 (R12-3834).
The inhibition of Ang2 is currently being tested in Phase II/III trials of the peptibody
Trebananib in ovarian cancer. In a randomized Phase III trial in patient with recurrent ovarian
cancer Trebananib was tested in combination with paclitaxel compared to chemotherapy
alone and demonstrated improvement in PFS (7.2 month vs 5.4 months, HR 0.66 95% CI
0.57-0.77, p< 0.0001) (R14-5440).
Unfortunately, the anti-tumor activity of VEGF blockers and Ang2 blockers is not durable 
and only a limited number of patients benefit from such therapies. New therapeutic strategies 
are needed to improve outcome of metastatic/advanced cancer patients.
Pre-clinical data demonstrate that improved efficacy can be achieved by combined inhibition
of VEGF and Ang2 (R14-5320, R14-5323). This observation was confirmed by internal data
(c02353882).
This supports testing BI 836880 in human with the objective to improve patients’ outcome.
First step for this clinical development is to define the safety profile of BI 836880 and the
recommended dose for further development.
TRIAL OBJECTIVES
2.2
Primary objective:

To determine the maximum tolerated dose (MTD) of BI 836880 given as weekly 
intravenous infusion and to determine recommended phase II dose.
Secondary objective:

To provide preliminary safety data 

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BENEFIT-RISK ASSESSMENT
2.3
BI 836880 has not been tested in human so far. In the 13-week toxicology study in
cynomolgus monkeys, BI 836880 was well tolerated up to the highest tested dose of
60 mg/kg.
Anti-VEGF or anti-VEGF-R antibodies have been largely tested in clinic with a well-defined
safety profile. Most commonly reported adverse events with such compounds are fatigue,
hypertension, proteinuria, diarrhea and bleeding (epistaxis). Severe adverse events include
gastrointestinal perforations, tumor haemorrhage and arterial thromboembolism (R14-3588,
R14-3261).
There is less clinical experience with anti-Ang2 compared to VEGF pathway blockade
clinical experience. The most advanced anti-angiopoietin compound (Trebananib) in
development is in Phase III in combination with chemotherapy (R14-5440). Other anti-Ang2
compounds are currently in early stage of clinical development (R15-1645, R15-1646, R15-
1648). From this clinical experience the most commonly reported side effects are fatigue and 
gastro-intestinal symptoms (diarrhea, nausea and vomiting). No bleeding or thromboembolic 
events were reported with this class of compound. Of note, almost all tested anti-Ang2 
molecules failed to define a MTD (R15-1646, R15-1648).
Limited clinical experience of dual blockade is available. Recently, Phase I data of the
bispecific human anti-Ang2/anti VEGF-A antibody (RG7221) were reported. MTD was not
reached with only one dose limiting toxicity (DLT) reported (fatal pulmonary hemorrhage).
Hypertension was the most common observed adverse event (R15-1644).
Based on this clinical available data it is expected that blockade of both targets will result in
similar side effects as anti-VEGF and anti-Ang2 blockade. Based on the phase I trial results
of RG7221 no increase in side effect severity is anticipated with BI 836880. It is anticipated
that the safety profile of BI 836880 will most likely include fatigue, hypertension,
proteinuria, gastro-intestinal side effects and bleeding.
Previous clinical experience with nanobodies in different disease showed acceptable safety
profile with no specific side effect related to this technology (R13-2303).
Because additional adverse event not previously observed with anti-VEGF and anti-Ang2
may also occur in humans, and taking in consideration BI 836880 toxicology study results,
patients will be closely monitored for the development of adverse events that may results
from BI 836880 administration, with a special attention to renal function and immunogenic
side effect.

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Although rare, a potential for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´
safety (see also Section 5.3.6.1)
Because of the early stage of development of BI 836880 no reproduction toxicity or 
genotoxicity studies were performed. Because of advanced stage of the disease of phase I 
studies populations, women of childbearing potential can be included in this study. To 
minimize the risk of unintentional exposure of an embryo or foetus to the investigational 
drug, women of childbearing potential must agree to the requirements for pregnancy testing 
and contraceptive methods described in this protocol.
A Data Safety Board (DSB) will be appointed to periodically review and monitor data from 
the trial (refer to Section 3.1.1).
Overall, BI 836880 is expected to have an acceptable safety profile and an adequate
risk/benefit in patients with locally advanced or metastatic solid tumor who are either
refractory after standard therapy for the disease or for which standard therapy is not reliably
effective.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a Phase I, multi-centre, non-randomized, uncontrolled, open-label, dose escalating 
study of BI 836880 administered intravenously. The eligible patient population will be 
patients with advanced solid tumors. Dose escalation will be guided by a Bayesian logistic 
regression model with over dose control (details refer to Section 7), restricted to a maximum 
200% dose increment for the first dose escalation and maximum of 100% dose increment for 
dose >120 mg. At any time during the trial, it will not be permitted to escalate to a dose 
which does not fulfil the escalation with overdose control (EWOC) criterion (refer to Section 
7). 
For any dose-escalation cohort, at least 2 patients will be required. At first dose level, first 
patient will be treated and observed for at least 2 weeks before allowing the second patient to 
receive BI 836880 infusion. For subsequent dose levels within dose escalation, each patient 
in a given cohort (dose level) will be observed for a minimum of 48 hours after first BI 
836880 application before allowing treatment for subsequent patient in the same cohort .
In case only 2 patients are evaluable and neither has experienced a DLT within the first 
course, then dose-escalation can occur based on these 2 patients. However, should one of 
these 2 patients experience a DLT in the first course, a third patient will be enrolled at the 
same dose level. After all patients in a cohort have either experienced a DLT or have been 
observed for at least one course (3 weeks) without a DLT, the Bayesian model will be 
updated with the newly accumulated data. The overdose risk will then be calculated for each 
dose, and escalation will be permitted to all doses which fulfil the EWOC criterion and the 
dose escalation scheme according to Section 4.1.3. Decision on further recruitment (dose
escalation, de-escalation or cohort expansion) will be made by a Data Safety Board (DSB)
based on the collected safety data as well as other data (e.g. PK/PD data) when available. 
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The Bayesian logistic regression model 
will be re-run to confirm that the dose-level still fulfils the EWOC criterion. Decision will be 
made whether the next patients will be enrolled on the same dose level, or if they will be 
enrolled to a lower dose level.

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Figure 3.1: 1Study design
All patients eligible after the screening will be administrated with BI 836880 weekly 
infusion. In case the patient shows a stable disease or even a response, the study treatment 
will continue until one of the withdrawal criteria listed in Section 3.3.4 is met.
An estimated of about 25-30 patients will be necessary to establish MTD and confirm RP2D.
Confirmation of the RP2D will be made based on all available safety, PK and 
Pharmacodynamics (PD) data at all treatment courses and all dose levels.
All patients will have regular evaluations for assessment of safety parameters as detailed in 
the Flow Chart.
An End of trial (EOT) evaluation is to be completed when a patient permanently discontinues 
the study drug, for any reason listed in Section 3.3.4.
A Follow-up evaluation will be completed 42 days after permanent discontinuation of the 
study drug. Refer to the Flow Chart for details. This visit will be defined as the last visit in 
the on-study period for the trial.
For adverse event collection, please refer to Section 5.3.6.
Further PK/PD 
Further safety assessment
Anti-tumor activity
Dose escalation
Screening: Up to 21 
days before treatment 
start
(28 days for tumor 
imaging imaging)
Treatment starting dose BI 
836880 
at  40 mg
Qw dosing 
Bayesian model with EWOC: 
Dose recommendation after every 
dose cohort
At least 2 patients per cohort
Data Safety Board:
Determination of MTD and RP2D
EOT within 21
days of the last 
administration 
of study drug 
1 Follow 
up visit
Or
Additional 
Follow up 
visits every 
6 weeks for 
patients 
who 
discontinue 
not due to 
Progressive 
disease, 
until PD or 
lost to 
follow up 
or start of 
anti-cancer 
therapy, 
death
Residual period = EOT + 42 days

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After the interim data base lock, the study is considered completed when the last patient in 
the study has discontinued the study treatment and completed the EoR visit (see Section 
6.2.3.5).
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim and will be conducted in two (2) sites. 
Additional sites may be added to boost the recruitment and recruitment may vary between 
sites. 
The study will be performed by investigators specialized in the treatment of advanced cancers 
and experienced in phase I trials in oncology.
A DSB will be appointed to evaluate DLT, overall safety and other available data (e.g. PK 
data) and confirm dose escalation steps. DSB will also evaluate all available data to confirm 
the Recommended Phase II dose, as well as the decision for a tumor type expansion cohort.
Members of the DSB will be investigators of participating trial sites, Trial Statistician
(TSTAT), Clinical Program Leader (CPL), Clinical Trial Leader (CTL) and BI Lead Risk 
Management Physician. Clinical Pharmacology Program Leader (CPPL) and Translational 
Medicine Expert (TME) can be invited as needed, especially for discussion of PK/PD and 
biomarker.
Minimum data for dose escalation decision will be described in the DSB charter. 
On-site monitoring will be performed by BI or by CRO authorized by Boehringer Ingelheim. 
Pharmacokinetic analyses will be performed by Boehringer Ingelheim or a CRO authorized 
by Boehringer Ingelheim. 
Exploratory biomarker analyses will be performed by BI and/or a dedicated CRO/ laboratory 
authorized by Boehringer Ingelheim.
Routine safety laboratory exams will be performed by local laboratories.
All relevant trial documentation will be stored in Boehringer Ingelheim Trial Master File 
(TMF) at BI. In addition, each site will have an Investigator Site File (ISF) containing all trial 
documents relevant for the site.
Boehringer Ingelheim has appointed a Trial Clinical Leader (CTL), responsible for 
coordinating all required activities, in order to:
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local Clinical Trial Manager (CTM), 
Clinical Research Associates (CRAs), and Investigators of participating countries.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information
can be found in the ISF.

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A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
This open label, single arm, dose-escalation trial is designed to determine the MTD and 
Recommended Phase II dose of BI 836880 monotherapy. No control group is planned. Dose 
escalation and cohort size will be determined based on a Bayesian logistic regression model 
with overdose control. An escalation with overdose control design will increase the chance of 
treating patients at efficacious doses while reducing the risk of overdosing. This design is 
based on practical experience and is a preferable algorithmic method due to its superior 
ability to identify the dose with the desired toxicity rate and its allocation of a greater 
proportion of patients to doses at, or close to, that dose (R13-4802, R13-4804, R13-4805). 
The trial can be expanded for early evaluation of antitumor activity of the drug in a specific 
tumor type and setting if signal of antitumor activity is observed during the dose escalation 
phase and/or RP2D confirmation phase. This expansion will take place after a protocol 
amendment.
SELECTION OF TRIAL POPULATION
3.3
It is estimated that approximately 40 patients will be enrolled at 2 study sites. The rate of 
enrolled patients may vary by study site, but it is expected to be approximately 20 patients 
per site. Among them approximately 25 patients will be treated in this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
Patients will be selected based on the eligibility criteria described below.
3.3.1
Main diagnosis for trial entry
All patients that will be included into the trial must have been diagnosed with histologically
or cytologically confirmed advanced or metastatic solid tumor, and either refractory after 
standard therapy for the disease or for which standard therapy is not reliably effective.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.

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3.3.2
Inclusion criteria
1.Age ≥18 years

2.Histologically confirmed malignancy which is locally advanced or metastatic solid 
tumor, and either refractory after standard therapy for the disease or for which 
standard therapy is not reliably effective e.g patients do not tolerate or have 
contraindications to otherwise available standard therapy and tumour lesions 
evaluable for Dynamic contrast-enhanced (DCE) MRI at MTD.
3.
ECOG performance status ≤ 2
4.
Adequate hepatic, renal and bone marrow functions as defined by the following 
criteria: 
a.
Total bilirubin within normal limits (≤ 1.5x ULN for patient with Gilberts   
syndrome)
b.ALT and AST ≤ 1.5x ULN (< 5xULN for patient known liver metastases)
c.Serum creatinine < 1.5x ULN
d.INR 0.8-1.2 or PTT < 1.5x ULN
e.ANC > 1.5 109/L
f.Platelet count > 100x109/ L.
g.Heamoglobin > 10 g/dl (without transfusion within previous week)
5.
Signed and dated written informed consent.
6.
Life expectancy ≥ 3 months in the opinion of the investigator
7.
Recovery from all reversible adverse events of previous anti-cancer therapies to 
baseline or CTCAE grade1, except for alopecia (any grade), sensory peripheral 
neuropathy CTCAE grade < 2 or considered by the investigator as clinically not 
significant.
8.
Male or female patients. Women of childbearing potential* must be ready and able to 
use highly effective methods of birth control per ICH M3(R2) in combination with
male condom as “double barrier”, during the trial and for at least 6 months after the 
end of treatment with BI 836880, that result in a low failure rate of less than 1% per
year when used consistently and correctly. A list of contraception methods meeting 
these criteria is provided in the patient information.
Male patient must always use condoms when sexually active during the trial and for 
at least 6 months after the end of treatment with BI 836880.
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for "women not 
of childbearing potential" as described below.
Women not of childbearing potential are defined as:

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Women who are postmenopausal (12 months with no menses without an alternative 
medical cause) or who are permanently sterilized (e.g., hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
3.3.3
Exclusion criteria
1. Known hypersensitivity to the trial drugs or their excipients or risk of allergic of 
anaphylactic reaction to the study drug according to the investigator judgement (e.g. 
patient with history of anaphylactic reaction or autoimmune disease that is not controlled 
by nonsteroidal anti-inflammatory drugs (NSAIDS), inhaled corticosteroids, or the 
equivalent of < 10 mg/day prednisone)
2. Current or prior treatment with any systemic anti-cancer therapy either within 28 days or 
a minimum of 5 half-lives, whichever is shorter at the start of study treatment.
3. Serious concomitant disease (based on investigator judgement), especially those affecting 
compliance with trial requirements or which are considered relevant for the evaluation of 
the endpoints of the trial drug, such as neurologic, psychiatric, infectious disease or active 
ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk 
associated with trial participation or trial drug administration, and in the judgment of the 
investigator would make the patient inappropriate for entry into the trial.
4. Major injuries and/or surgery (as judged by the investigator) or bone fracture within 4 
weeks of start of study treatment, or planned surgical procedures during the trial period.
5. Patients with personal or family history of QT prolongation and/or long QT syndrome, or 
prolonged QTcF at baseline (> 470 ms). QTcF will be calculated by Investigator as the 
mean of the 3 ECGs taken at screening.
6. Significant cardiovascular/ cerebrovascular disease (i.e uncontrolled hypertension, 
unstable angina, history of infarction within past 6 months, congestive heart failure > 
NYHA II). Uncontrolled hypertension defined as: blood pressure in tested and relaxed 
condition >= 140 mmHg, systolic or > 90 mmHg diastolic (with or without medication), 
measured according to Section 5.3.2 and Appendix 10.2.
7. History of severe haemorrhagic or thromboembolic event in the past 12 months 
(excluding central venous catheter thrombosis and peripheral deep vein thrombosis).
8. Known inherited predisposition to bleeding or to thrombosis in the opinion of the 
investigator.
9. Patient with brain metastases that are symptomatic and/or require therapy.
10. Patients who require full-dose anticoagulation (according to local guidelines). No vitamin 
K antagonist and other anticoagulation allowed; low-molecular-weight heparin (LMWH)
allowed only for prevention not for curative treatment.

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11. Use of alcohol or drug incompatible with patient participation in the study in the 
investigator opinion
12. Patient unable or unwilling to comply with protocol
13. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
14. Previous enrolment in this trial
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision.

Requiring concomitant drugs that interfere with the investigational product or other trial
medication (see Section 4.2.2) or patient who requires concomitant drugs, which in the 
opinion of the investigator may interfere with the investigational drug.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

The patient is no longer able to complete trial visit or trial-required procedures.

A DLT occurs which does not recover to a degree that allows continuation of treatment
(see Section 4.1.4) for re-treatment criteria and dose reduction scheme)

Progressive disease (except in cases with intra-patient dose escalation, (see Section
4.1.3) or start of any new anti-cancer therapy.
A patient can have withdrawn from the trial after discussion between the Investigator and the 
Sponsor if eligibility criteria are violated and/or the patient fails to comply with the protocol.
All withdrawals will be documented and the reason for withdrawal recorded and discussed, as
necessary, in the final Clinical Trial Report (CTR). As soon as a patient is withdrawn from 
the study treatment, the end of treatment visit (EoT) has to be performed if feasible. Every 
effort should be made to follow-up with patients in case an adverse event is still ongoing at 
the time of withdrawal. If a patient is withdrawn from the trial due to consent withdrawal, no 
further visit will be completed.
Patients who have not completed first course of BI 836880 treatment (3 weeks) for any other
reason than BI 836880 related toxicities will be considered not evaluable for MTD evaluation 
and should be replaced.
Patient who prematurely discontinue study drug for above mentioned reasons or any other 
reason, should have additional follow up visits until progression, lost to follow up, treatment 
with another anti-cancer treatment, death and /or end of the trial whichever comes first.

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Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the FC and Section 6.2.3.
Should the patient become pregnant during the trial, the treatment with BI 836880 must be 
stopped immediately, and this patient is not allowed to receive further trial medication from 
that point onward. The patient will be followed up until delivery or termination of pregnancy 
(see Section 5.3.6.2). The data of the patient will be collected and reported in the CTR until 
last patient last visit and any events occurring thereafter will be reported in BI drug safety 
database.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
(e)CRF. These data will be included in the trial database and reported.
3.3.5
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Violation of Good Clinical Practice (GCP), the CTP, or the contract 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).

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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1
Test product 1
Substance:
BI 836880
Pharmaceutical formulation:
solution for infusion after dilution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml (vials with 10 ml)
Posology
rate controlled infusion
Route of administration:
i.v.
Duration of use
until progression disease or unacceptable toxicity
Table 4.1.1: 2 
Diluent for Test product 1
Substance:
Diluent for BI 836880 drug product
Pharmaceutical formulation:
Diluent to prepare solution for infusion of BI 836880
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
50 ml/vial
Posology
rate controlled infusion
Route of administration:
i.v.
Duration of use
until progression disease or unacceptable toxicity

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4.1.2
Method of assigning patients to treatment groups
There is no randomisation, eligible patients will receive treatment.
Allocation to dose cohorts or expansion cohort will be done according to subject temporal 
availability and depending on dose cohort open for recruitment.
During Visit 1/Day 1 and after the patient’s eligibility has been confirmed, the treatment will 
be assigned via Interactive Response Technology (IRT). 
For medication number allocation at each visit, it’s possible to conduct IRT call ahead of the 
planned visit (= day of administration)
To facilitate the use of the IRT, the Investigator will receive all necessary instructions.
4.1.3
Selection of doses in the trial
Starting Dose 
Maximum safe starting dose was estimated using different methods taking in account all 
available nonclinical information, including PK/PD and toxicity data. The starting doses from 
these calculations were compared. The lowest dose derived from these calculations is 
recommended for the maximum safe starting dose (refer to Investigator’s Brochure for more 
details (c02353882)).
Based on the 13-week Good Laboratory Practice (GLP) toxicology trial in cynomolgus 
monkey, the Non-Observed-Adverse-Effect-Level (NOAEL) /Highest Non-Severely Toxic 
Dose (HNSTD) is defined as 60 mg/kg. According to this method and using a safety factor of 
6, the maximum starting dose is 10 mg/kg.
As a second approach, a mathematical PK/PD model was developed to predict the human 
therapeutic dose of BI 836880. The model was calibrated to data from a cynomolgus monkey 
PK/PD study and then scaled to human to perform simulations. The model is a two 
compartment in vivo model that includes the target ligands (VEGF-A and Ang2), their 
corresponding receptors (VEGFR2 and Tie2) and additional ligand/receptor pairs that share 
common receptors. Predictions were made for the minimum dose that maintains a high level 
of reduction in both VEGF:VEGFR2 and Ang2:Tie2 complexes by  BI 836880 at steady 
state. The VEGF-A:VEGFR2 complex and Ang2:Tie2 complex levels were considered 
surrogates of receptor signaling in silico.
The predicted human dose that according to this simulations achieves reduction in both 
VEGF:VEGFR2 and Ang2:Tie2 complexes at Cmin,ss is 0,67 mg/kg for a weekly dosing. At a 
dose level of 0.67 mg/ kg (dosed once every week) the fraction of VEGF-A:VEGFR2 
complex is predicted to be reduced to 35% - 55% of the pre-dose level, and the fraction of 
Ang2:Tie2 complex is predicted to be reduced to below 0.1 (90%) of the pre dose level.
Since the two methods resulted in different starting doses, and the dose based on the PK/PD 
modeling is expected to allow achieving reduction in both VEGF:VEGFR2 and Ang2:Tie2 
complexes, the lowest dose was selected as starting dose in this first in human trial.
The recommended starting dose is 0.67 mg/kg, correlates to a total dose of 40 mg.

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Dose escalation Scheme
Furthermore, the PK/PD modelling provided information on the number of doses needed to 
reach the targeted Cmin concentration in plasma that is supposed to maintain a continuous 
high suppression of VEGF-A:VEGFR2 and Ang2:Tie2 complex formation (>90%).
In a weekly dosing schedule, target Cmin plasma concentrations are expected to be achieved 
after 7 infusions of BI 836880 at dose of 2 mg/kg (120 mg), after 2 infusions at dose of 6 
mg/kg (360 mg) and after 1 infusion at dose of 12 mg/kg (720 mg).
To minimize the number of patients to be treated at a non-therapeutic dose (below targeted 
concentration) within an acceptable time to steady state, a maximum of 200% dose increment
will be applied for dose levels up to 40 mg. Dose escalation >120 mg will not exceed 100% 
dose increment. No dose adaptation to body weight or body surface will be made. All patients 
at the same dose level (DL) will be treated with the same total dose. Table 4.1.3: 1 shows 
potential dose levels to be tested.
Table 4.1.3: 1
Potential Dose levels
Dose level
Total dose (mg)
Approximate increment 
to next dose
Dose level 1 
( starting dose)
40
3x  (200%)
Dose level 2
120
1.25x (25%)
Dose level 3
150
1.20x (20 %)
Dose level 4
180
1.3x (30%)
Dose level 5
240
2x  (100%)
Dose level 6
480
1.5x (50%)
Dose level 7
720
1.3x (30%)
Dose level 8
960
1.7x (30%)
Dose level 9
1440 limited to 1250*
*Maximum dose that can be tested due to excipient limitation
Intermediate dose levels can be tested based on DSB decision.
Whenever a dose escalation step is to be performed (or a new cohort will be opened for 
recruitment), the data of previous dose cohorts with priority on DLTs will be reviewed and 
discussed within the DSB. DSB can decide to increase the dose, expand the tested cohort or 
to test an intermediate dose level.

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Patients, who received at least two treatment courses, deeming to have clinical benefit from 
treatment and tolerated BI 836880 well (i.e do not show any DLT) could be allowed to 
receive increased dose. Such decision will be taken in case by case manner on request by the 
investigator and confirmation by the DSB based on actual patient profile. Intra patient dose 
escalation can be repeated; however the dose can only be increased to the highest tested safe 
dose.
For patients with an intra-patient dose escalation(s) all assessments will be done according to 
instructions for the first cycle at start of treatment with BI 836880 and intensive PK-
sampling, sampling for ADA as well as sampling for biomarkers (Myriad panel and free/total 
VEGF-A/ Ang2) will be conducted (see flow chart and Appendix 10.4) and patients have to 
be closely followed for any adverse events. Therefore patients have to come to the clinic 
during the first course of intra-patient dose escalation every week. Additional visits are 
needed at day 2 and at day 3 of the 1st cycle of dose escalation. 
The above-mentioned procedures will be followed also in case of further intra-patient dose 
escalations.
4.1.4
Drug assignment and administration of doses for each patient
The study drug will be prepared according to “Instruction for Pharmacists” which will be 
filed in ISF. Upon notification of an entered patient in the study, the pharmacy will prepare 
the study drug in the assigned dosage for administration to the patient. 
BI 836880 will be given as weekly intra-venous infusion by authorised site staff in a 
specialized unit where emergency care can be provided (e.g. intensive care unit available, 
medical personal trained in advanced live support) according to “Instruction for 
Pharmacists”. The expected infusion time is 90 min. in case no relevant infusion reactions are 
observed, this may be shortened to about 30 min but should not be prolonged to more than 6 
hours even in case of technical issues. Appropriate drugs and medical equipment to treat 
anaphylactic reactions must be immediately available and study personal must be trained to 
recognize and treat anaphylaxis.
If symptoms of an infusion-related reaction CTCAE grade > 2 occur (that are not qualifying 
as DLT according to Section 5.3), the infusion should be temporarily stopped. Upon 
recovery, infusion should be resumed at 50% of the rate at which the reaction occurred. 
Depending on the time of occurrence and the severity of the reaction, the investigator may 
consider administrating additional supportive medication, e.g. corticosteroids for re-
introduction. Infusion rate and premedication for further treatment courses should be adapted 
according to Investigator decision, but adaptation of application scheme need to be agreed 
with sponsor.
BI 836880 will be administrated intravenously starting on course1 day1. In the event of delay 
or interruption of treatment due to adverse event, BI 836880 infusion should be skipped; and 
the next scheduled BI 836880 infusion should be administrated upon recovery to CTCAE 
Grade 1. 
Premedication: No premedication will be required for BI 836880 IV infusion.

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If a patient experienced sign of infusion reaction at any BI 836880 treatment, a premedication 
will be considered for all subsequent treatment infusions (dosage and schedule according to 
investigator’s decision) comparable to the following scheme:

Acetaminophen/paracetamol 650 mg-1000 mg p.o., or equivalent

Antihistamine p.o. or i.v., equivalent to Diphenhyldramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg
If infusion reaction and /or hypersensitivity reaction occurs in substantial amount of patients 
(about 30%) of treated patients without premedication, premedication, as described above, 
will be given to all treated patients. Such decision will be confirmed by the DSB; dosage and 
schedule should be aligned, and reflect institutional clinical standards.
Re-treatment criteria
4.1.4.1
Before initiating a new treatment course the actual health status will be assessed according to 
Flow Chart and described in Section 5.3. To continue treatment with further courses, all of 
the following criteria must be met:
QTcF < 470 ms (according to exclusion criterion #5)
No uncontrolled hypertension (according to exclusion criterion #6)
Acceptable tolerability (in case of an adverse event at the planned start of a treatment course 
patients may continue therapy only after recovery to a level which would allow further 
therapy; i.e. CTCAE grade 1 or pre-treatment value or considered not clinically significant).
In case one of the above mentioned criteria is not fulfilled the patient should be re-evaluated 
for up to 2 weeks. Any case of a delay in treatment course should be communicated to the 
Clinical Monitor at Boehringer Ingelheim. The investigator in agreement with the Clinical 
Monitor will decide about further treatment of individual patient, based on known risk/benefit 
of BI 836880. 
Dose reduction scheme
4.1.4.2
Administration of trial drug has to be stopped temporarily in case of a DLT (see Section 5.3). 
Patients may continue therapy only after recovery from DLT to at least fulfil re-treatment 
criteria. The future dose of BI 836880 must be finally agreed on between the sponsor and the 
investigator. A reduction of the dose will be allowed only once for an individual patient 
during the whole trial. Treatment has to be discontinued in case the DLT is not reversible.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Not applicable. In this open-label trial, treatment allocation will not be concealed throughout 
the trial. The CRF will contain information on allocated treatment.

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Unblinding and breaking the code
4.1.5.2
Not applicable
4.1.6
Packaging, labelling, and re-supply
BI 836880 will be supplied in 10 ml 10R vial containing 100 mg BI 836880 [10 mg/ml]
solution for infusion. The BI 836880 vials will be packed in one vial box. 
Diluent for BI 836880 drug product will be supplied in 50R vial containing 50 ml Diluent for 
BI 836880 drug product. The Diluent vials will be packed in one vial per box.
Boxes and vials will be labelled according to local regulations.
For details of packaging and the description of the label, refer to the ISF.
BI 836880 drug re-supply will be managed through IRT by the trial sites and BI
personnel.
4.1.7
Storage conditions
BI 836880 vials and Diluent vials, which will be provided by the sponsor and/or a CRO 
appointed by the sponsor must be kept in their original packaging and in secure limited 
access storage area according to the recommended storage conditions on the medication
label. The Investigator, the Pharmacist, or other personnel allowed to store and dispense.
The Investigator or pharmacist or investigational drug storage manager will be responsible 
for ensuring that the investigational product used in the study is securely maintained as 
specified by the sponsor and in accordance with the applicable regulatory requirements.
A temperature log must be maintained for documentation.
For details concerning the preparation of the infusion solution of BI 836880, please refer to 
the ‘instructions for pharmacists’ filed in the ISF.
4.1.8
Drug accountability
The Investigator or pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the principal Investigator.

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The Investigator or pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor after IRB / ethics committee approval of the 
trial and completion of a clinical trial contract between the Sponsor and the Head of Trial 
Center.
The Investigator or pharmacist or 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 patient, and 
the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. All remaining drug supplies
received at a respective study site will be destroyed at site. Partially used vials will be
destroyed after preparation infusion; unused medication and Diluent will be destroyed after
expiry or at the end of study before closing the site.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
Concomitant (non-oncological) therapies starting or changing during the course of the trial 
should be recorded in the electronic Case report Form (eCRF).
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication to reverse the action of BI 836880 is not available.
Potential side effects of BI 836880 have to be treated symptomatically. Symptomatic 
treatments of side effects or tumor-associated symptoms are allowed. Concomitant 
medications, or therapy to provide adequate care, may be given as clinically necessary. There 
are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Previous anti-cancer therapy must have been discontinued before first administration of BI 
836880 and the patient must have recovered from all clinical relevant reversible toxicities 
(see exclusion criteria in Section 3.3.3).
Concomitant anti-cancer therapy is not allowed.
Radiotherapy for local symptom control of non-target lesions can be allowed after discussion 
between the investigator and the sponsor. The irradiated area cannot be used for response 
assessment.

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Full-dose anticoagulation (according to local guidelines) with Vitamin K antagonist and other 
anticoagulation is not allowed during the trial conduct; LMWH is allowed only for 
prevention not for curative treatment.
Any planned surgeries are not allowed. Unplanned surgeries should be postponed whenever 
possible four weeks after stop of treatment. For urgent interventions patients should not be 
treated further and does require intense monitoring regarding wound healing and 
postoperative complications.
Restrictions on diet and life style
4.2.2.2
No restriction
4.3
TREATMENT COMPLIANCE
BI 836880 must be administered as an intravenous infusion under supervision of the 
investigator or dedicated clinical personnel. 
Compliance may be also be verified by pharmacokinetic assessment. Any discrepancies will 
be documented in the eCRF by the investigator or designee.

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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The primary endpoint to determine the maximum tolerated dose (MTD) based on the number 
of patients presenting dose limiting toxicity (DLT) using the National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) V4.03, during the first course
(i.e. over the first 3 weeks of treatment) and judged to be related to the study medication.
5.1.2
Secondary Endpoint(s)

Drug related AEs leading to dose reduction or discontinuation during treatment period
ASSESSMENT OF EFFICACY
5.2
The assessment by the investigator and the local radiologist will be the basis for continuation 
or discontinuation of the trial in an individual patient (in addition to safety). Tumor 
assessment will be performed every 6 weeks after start of treatment and at the time points 
specified in the Flow Chart. 
After the interim data base lock, frequency of tumor assessment may be adapted according to 
local standard of care and in agreement with the sponsor if the patient is deriving clinical 
benefit (e.g. CR, PR or SD > 6 months).   
CT images at baseline should be performed as close as possible to the treatment start and not 
older than 28 days at start of treatment.
At baseline, the investigator along with the radiologist will record the target (five target 
lesions maximum and maximum two per organ) and non-target lesions at baseline in the 
eCRF before the start of treatment. The same method of assessment and the same technique 
should be used to characterize each reported lesion at baseline and during follow up. Lesions 
in previously irradiated areas may not be considered measurable at baseline unless the lesions 
occurred after irradiation. Response will be evaluated according to the response evaluation 
criteria in solid tumors (RECIST version 1.1 (R09-0262). In the event of a delay, interruption 
or discontinuation of treatment, tumor assessment should continue to follow the original 
schedule. The schedule should be followed until progression is observed or until the patient 
commences further treatment for disease, whichever occurs first.

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Results of tumor-specific tumor markers which will be assessed routinely should be 
documented in the eCRF. 
After the interim data base lock, documentation of tumor markers in the e-CRF is no longer 
required.
ASSESSMENT OF SAFETY
5.3
Dose Limiting Toxicity (DLT)
The following drug-related adverse events will qualify as Dose-Limiting Toxicities:

CTCAE grade > 3 non haematological toxicity except:
Vomiting or diarrhea responding to supporting treatment
Fatigue lasting for less than 4 days
Transcient Grade 3 infusion reaction (i.e. if infusion- related reaction can be 
controlled by appropriate medication according to investigator’s decision and next 
infusion will not be delayed for more than two weeks).
Any laboratory abnormality, which is considered not clinically relevant by the 
investigator or resolves spontaneously or can be resolved with appropriate 
treatment. Clinically relevant abnormalities have to be documented as AE (see
Section 5.3.6)

CTCAE grade 4 neutropenia >7 days or complicated by infection (in case of 
neutropenia grade 4, close observation of patient is necessary.

CTCAE grade >3 febrile neutropenia 

CTCAE grade = 4 thrombocytopenia 

CTCAE grade > 3 thrombocytopenia with bleeding 

CTCAE grade > 3 proteinuria (urinary protein > 3.5 g/day)

Hypertension: increase of diastolic blood pressure (BP) by 15 mmHg confirmed by 
second measurement or ambulatory blood pressure measurement (when indicated; e.g. 
white coat effect) which cannot be controlled by hypertensive medication and requires
a dose reduction of BI 836880 for further treatment course.

All related AE leading to an interruption of BI 836880 for more than 14 days until 
recovery to baseline.
The MTD may be considered reached if the probability that the true DLT rate is in target 
interval (16%-33%) is sufficiently large (for details see Section 7). The DSB may recommend 
stopping the dose finding phase after the criterion for MTD is fulfilled. 
If the next dose level is recommended by the statistical model, however, the efficacy is 
considered sufficient at current dose level, the DSB may decide to include additional number
of patients at this dose level and declare this dose as RP2D and no further dose escalation will 
happen.
Based on the overall data after all patients on proposed RP2D have been treated for at least 1 
course, the DSB will make a final determination of RP2D.

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5.3.1
Physical examination
A complete physical examination including (height at screening only), cardiac, neurological, 
dermatological pulmological, weight and ECOG performance score, will be performed at 
screening and before the start of the treatment, EoT and EoR.  At further time points specified 
in the Flow Chart, not a complete physical examination will be performed, but at minimum 
the actual health status of the patient should be assessed (including, evaluation of blood 
pressure, ECG, lab safety parameters, AEs, concomitant therapies, ECOG as applicable).
During the physical examination, the patient should be assessed for possible AEs.
After the interim data base lock, physical examination, ECOG performance status, weight are 
no longer mandatory at the specific visits but will be performed at the investigator’s 
discretion. Findings will be documented in the eCRF only if qualifying as (S)AE. 
5.3.2
Vital Signs
Vital signs (blood pressure, heart rate and body temperature) will be recorded at every visit 
indicated in the flow chart.
At day of administration two time points will be evaluated:
1- At pre-dose (-60 minutes to – 5 minutes)
2- Shortly before the end of infusion 
In case of an infusion-related reaction, if deemed necessary, the investigator should decide 
for intensive monitoring of vital signs.
Blood pressure
Systolic and diastolic blood pressure as well as pulse rate (electronic or by palpation, count 
for 1 minute) will be measured after 5 minutes of rest in seated position. The blood pressure 
measurement should be performed three times at each time point and values of these 
measurement will be entered in the CRF (refer to Appendix 10.2 and Appendix 10.4)
After the interim data base lock blood pressure is no longer mandatory at specific visits but 
will be performed at the investigator’s discretion. Findings will be documented in the eCRF 
only if qualifying as (S)AE
Body temperature
Whenever possible the same method should be used for body temperature measurement in 
one patient. All methods used should deliver valid reproducible results according to common 
clinical practice.
Body temperature > 38°C must be re assessed 1 hour after, especially in cases of suspected 
febrile neutropenia (see CTCAE V.4.03).
After the interim data base lock body temperature is no longer mandatory at specific visits 
but will be performed at the investigator’s discretion. Findings will be documented in the 
eCRF only if qualifying as (S)AE

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5.3.3
Safety laboratory parameters
Blood sample for assessment of safety laboratory examinations have to be collected at the 
time points specified in the Flow Chart, but should be more frequent in case of relevant 
findings, e.g. in case of grade 4 neutropenia, as any non-proven recovery within 7 days will 
be counted as DLT or proteinurea, for which determination of CTCAE grade 2 versus grade 3 
needs to be done by quantitative measurement.
Safety laboratory examination will include haematology, biochemistry, coagulation, and 
urine analysis.

Haematology: Haemoglobin, red blood cell count (RBC), white blood cell count (WBC) 
and differential, platelets.

Biochemistry: glucose, sodium, potassium, calcium, magnesium, inorganic phosphate, 
creatinine, aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase, lactate deshydrogenase (LDH), bilirubin, urea, total protein, albumin, uric 
acid, CK, CK-MB. 
Serum immunoglobulin levels (IgG, IgM, IgA, IgE) and direct antiglobulin test have to be 
measured at screening and at occurrence of infusion related reactions.

Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT) or 
international normalised ratio (INR) where indicated (e.g. treatment with vitamin K 
antagonists)

Urinalysis: pH, glucose, leukocytes, erythrocytes, protein, nitrite will be analysed 
primarily qualitatively by dipstick. In case of pathological findings, further evaluation 
should be performed and the findings documented. A positive urine dipstick for protein of 
≥ 2+ has to be followed by a determination of urine protein to creatinine ratio (UPCR) in 
a morning spot urine sample. In case of a ratio ≥ 0.5, a 24-hour urine collection for 
protein loss has to be performed. The 24 hour urine collection will be repeated every time 
the UPCR is ≥ 0.5 as often as clinically indicated.
After the interim data base lock, safety laboratory tests (haematology, biochemistry, 
coagulation, urinalysis) will be performed at the investigator’s discretion based on the 
standard medical care. Findings will be recorded in the e-CRF only if qualifying for 
(S)AE/AESI.
Pregnancy test: a serum pregnancy test will be performed as outlined in the Flow Chart in 
women of childbearing potential.
Previous laboratory investigations performed within 72 hours prior to the first treatment 
administration visit are acceptable to confirm the patient eligibility.  
In case an administration is delayed due to an AE, the patient should visit the site at least 
once a week for assessment of safety laboratory and AEs. More frequent visits may be 
appropriate as assessed by the Investigator.

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5.3.4
Electrocardiogram (ECG)
12-lead ECGs will be digitally recorded in triplicate and performed for each patient at various 
time point according to the Flow Chart and Appendix 10.4.

At screening, visits between administrations of study treatment, and at EoT. Only one 
time point will be evaluated

At days of administration, two time points will be evaluated:
Pre-dose (-60 min. to -5 min.) and
Shortly before the end of the infusion
In case of drug-related ECG changes and whenever the investigator deems necessary,
additional ECG monitoring will be performed in the respective and later courses of treatment.
The ECGs will be recorded using dedicated equipment provided by the vendor.
The ECGs will be sent for evaluation by a central vendor, which will conduct the analysis in 
a blinded fashion. QTcF and other variables of interest will be described in a separate ECG 
plan. Data from this central review will be taken for retrospective data analysis.
In order not to confuse ECG recording, PK samples should be taken after performing the
ECG. The ECG recordings will be analysed and checked for pathological results by the
investigator; QTcF for each time point will be calculated as the mean of the 3 ECGs.
Decision on patient’s eligibility will be taken based on Investigator analysis of QTcF, based
on same recordings. Pathological ECG results will be recorded as AEs by the investigator.
After the interim data base lock, ECG will be performed as clinically indicated on local 
machine and the assessment will be done by the investigator. Shipment of ECGs to central 
vendor is no longer required.
Echocardiography
Echocardiography will be performed locally at screening (not older than 7 days before start of 
treatment) and at EoT. During treatment period, echocardiography will be conducted only if 
clinically indicated. 
After the interim data base lock findings related to echocardiography will be reported in the e
CRF only if qualifying as (S)AE
5.3.5
Other safety parameters
Not applicable
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.

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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe. 

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be reported as a serious event 
regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.

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The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

For patients with normal liver function at baseline:
an elevation of AST and/or ALT ≥ 3 fold ULN combined with an elevation of total
bilirubin ≥ 2 fold ULN measured in the same blood draw sample and/or.
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN

For patients with impaired function tests at baseline:
an elevation of AST and/or ALT ≥ 5 fold ULN combined with an elevation of 
bilirubin ≥ 2 fold ULN measured in the same blood draw sample.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” via eDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
DLT events
All DLT events (as defined in Section 5.3) in individual patients occurring at any time during 
the repeated treatment courses or follow-up period must be reported as adverse events of 
Special Interest (AESI).
Severity of AEs
The severity of adverse events should be classified and recorded in the (e)CRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (R12-2532).
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal

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relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
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.
Arguments that may suggest that there is a reasonable possibility of a causal 
relationship could be:
•
The event is consistent with the known pharmacology of the drug
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g.
pre- existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population 
not exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
• No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
• Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
• Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•Disappearance of the event even though the study drug treatment continues or remains 
unchanged
Adverse event collection and reporting
5.3.6.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
- From signing the informed consent onwards until the end of treatment (including the
Residual Effect Period, REP): all AEs (non-serious and serious) and all AESIs.

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- After the end of treatment (including the REP) until the individual patient’s end of trial: 
all related SAEs and all related AESIs.
- After the individual patient’s end of the trial: the Investigator does not need to actively
monitor the patient for AEs but should only report relevant SAEs and relevant AESIs of 
which the Investigator may become aware of. 
The rules for Adverse Event Reporting exemptions still apply.
Figure 5.3.6.2: 1AE collection
The REP is defined as 42 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment (please see Section 7.3.4). Events which occurred after the REP will be considered 
as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication.
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions. The rules for 
Adverse Event Reporting exemptions still apply
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.

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If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report 
immediately (within 24 hours) a potential drug exposure during pregnancy (DEDP) to 
the sponsor’s unique entry point (country-specific contact details will be provided in the 
ISF). The Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must
be followed up and reported to the sponsor’s unique entry point on the Pregnancy
Monitoring Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
Exemptions to (S)AE Reporting
Disease Progression in oncology trials is a study endpoint for analysis of efficacy and as such
is exempted from reporting as an (S)AE. Progression of the subject's underlying malignancy
will be recorded on the appropriate pages of the (e)CRF as part of efficacy data collection
only and will not be reported on the SAE Form. It will therefore not be entered in the safety
database (ARISg) and hence not get expeditiously reported. Death due to disease progression
is also to be recorded on the appropriate (e)CRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s)
and the progression of the underlying malignancy, the event must be reported as an (S)AE on
the SAE Form and on the (e)CRF.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics

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5.4.2
Methods of sample collection
5.4.3
Analytical determinations

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5.4.4
Pharmacokinetic - Pharmacodynamic Relationship
ASSESSMENT OF EXPLORATORY BIOMARKER(S)
5.5

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5.5.1
Imaging Pharmacodynamic endpoints

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OTHER ASSESSMENTS
5.6
5.6.1
Demographic and medical history
Demographics (sex, birth date, race if allowed by the local law), current medical condition
including relevant concomitant diagnosis will be collected during the screening visit.
Concomitant therapies present at the study entry and /or during the study will be recorded in 
the eCRF.
Medical history as follows:

Type of tumor

Date of the first histological diagnosis (month and year may be sufficient)

Primary tumor site

Differentiation grade (not specified, undifferentiated, poorly differentiated, 
moderately differentiated

Tumor stage according to the tumor

Number of metastatic sites at study entry will be provided

Previous surgeries an radiotherapy will be reported

Previous administrated chemotherapy, tyrosine kinase inhibitors, vaccine-therapy, 
antibodies therapy, immune-therapy, and hormone-therapy including start and end 
dates (month and year may be sufficient)

Previous neoadjuvant, adjuvant or palliative therapy

The date of tumor progression after  previous line (s) of therapy for advanced or 
metastatic disease

The start and end dates (month and year may be sufficient) of those previous therapies 
as well the number of courses (when applicable)

The best response obtained (complete response, partial response, stable disease, 
progressive disease, unknown

The reason for leading to treatment discontinuation (completion, PD, AE) 

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5.6.2
Immunogenicity assessment
APPROPRIATENESS OF MEASUREMENTS
5.7
Determination of the MTD is based on the toxicities grade according to CTCAE version 4.03
(R12-2532). The CTCAE criteria are commonly used in the assessment of adverse events in 
cancer patients. RECIST version 1.1 criteria (R09-0262) are used for evaluation of tumor 
response. These criteria are well established and scientifically accepted.

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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
The study Flow Chart describes all assessments which will be performed in patients treated 
with BI 836880.
All patients must provide written informed consent before any study related screening 
procedures can be performed. Time windows for visits are included in the Flow Chart.
Patient will visit the clinic at the time points specified in the Flow Chart. If a visit is missed
and the patient report to the Investigator between the missed visit and the next visit, the 
missed visit should be performed. The current date and the reason for delayed visit should be 
recorded in the source document. The next visit, however, should take place at the scheduled 
time after the first administration BI 836880.
To allow close monitoring for infusion-related reactions or other adverse events 
 
, patients are required to be hospitalised under 
close surveillance with access to intensive care for at least 48 hours after the first 
administration of BI 836880 at course 1 day 1and 24 hours after the second and third 
administrations of BI 836880 at course 1 day 8 and course 1 day 15 respectively.
After good tolerability of the first course of BI 836880 the investigator may evaluate the risk 
for an infusion-related reaction and other adverse events in view of relevant comorbidities or 
disease related symptoms, and as a result, shorten the duration of surveillance to 8 hours for 
courses 3 and 4
 and at investigator’s discretion for further courses.
If pathological laboratory values or other issues require an additional unscheduled visit, a
new eCRF page will be created for the unscheduled visit. At the unscheduled visit, it is
sufficient to record only the clinical relevant labs/examinations performed.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The investigations as outlined in the Flow Chart will be performed at the respective visits. 
Specific details to conduct of physical examination, collection of vital signs (including blood
pressure measurement), laboratory investigations, assessment of ECG and echocardiography
can be found in Section 5.3.

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After the interim data base lock, mandatory procedures/assessments and documentation in the 
eCRF will be adapted as described in the Flow Chart and the respective sections of this 
protocol.
6.2.1
Screening period
All Screening Visit procedures must be performed in the 21 days prior to the first 
administration of study medication except tumor assessments (CT/MRI) that may be used as 
screening exams if they were performed within 28 days prior to start of treatment.
Echocardiography must be obtained within 7 days before start of treatment.
Patients who meet the eligibility criteria will be allowed to take part to the study.
Refer to the Flow Chart for procedure details. Please review Sections 3.3.2 and 3.3.3 for 
specific eligibility criteria.
6.2.2
Treatment period(s)
All patients will receive continuous weekly treatment with BI 836880 until the criteria for 
stopping medication are met (see Section 3.3.4).
Treatment course is defined as 3-week treatment (21 days) in duration. During the treatment 
phase visits should be performed as scheduled wherever possible.
In the event of any study drug interruption or delay of treatment, the tumor assessment 
scheduled will not be changed.
After the interim data base lock, frequency of tumor assessment may be adapted according to 
local standard of care and in agreement with the sponsor if the patient is deriving clinical 
benefit (e.g. CR, PR or SD > 6 months).
 Additional visits are needed at day 2 for courses
1, 2 and 4. For course 3 and from course 5 onwards no additional visits, beside day 1 
including drug administration, are requested by protocol.
Refer to the Flow Chart for procedure details. 
6.2.3
Follow Up Period and Trial Completion
End of treatment visit
6.2.3.1
The EOT visit will be performed after permanent discontinuation of trial medication for any
Reason, as soon as possible, but no later than 21 days after permanent discontinuation of the
trial medication or when the investigator decided with the patient to permanently discontinue
the trial medication or became aware that the trial medication had been terminated.

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Residual effect period (REP)
6.2.3.2
The REP is defined in Section 5.3.6.2. The End of the Residual period visit (EoR) should not 
be performed earlier than 42 days after permanent discontinuation of the study drug. The
information collected at this visit should include all new AEs that occurred after EOT and a
follow-up of adverse events ongoing at EOT. Any subsequent anti-cancer therapy
administered between EOT and EoR should be reported.
Follow-up period for progression
6.2.3.3
For patients who progress according to RECIST criteria V1.1, one Follow up visit (FU1) will 
be performed after the EOT (i.e. at EoR, 42 calendar days after discontinuation of trial drug).
For patient who discontinue not due to progressive disease according to RECIST criteria 
V1.1, additional FU visits will be performed at 6-week intervals plus/minus 3 days, until
progression, start of another anticancer treatment, lost to follow up, death.
After the interim data base lock, frequency of tumor assessment may be adapted according to 
local standard of care and in agreement with the sponsor if the patient is deriving clinical 
benefit (e.g. CR, PR or SD > 6 months).   
During extended Follow up period (i.e. after the end of treatment, including  the REP and 
individual patient’s end of trial), all related SAEs or AESIs and Follow up AEs on going 
since the end of treatment have to be collected and documented  on the appropriate eCRF 
page and SAE form (if applicable). 
Refer to Flow Chart for details.
Trial completion for an individual patient
6.2.3.4
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up period (as defined in Section 6.2.3.3)

Lost to follow-up

Withdrawal to be followed-up

Death
At the earliest of the above criteria, the Patient Completion information should be
entered in the CRF.
Trial completion
6.2.3.5
The clinical trial will be considered completed when the last patient has completed the EoR 
visit. If patients are still on treatment at the time of interim data base lock and the Clinical 
Trial Report is written, these patients will be maintained in the trial as long as they are 
deriving clinical benefit (i.e. no disease progression, no drug-related AEs requiring drug 
discontinuation) or no new anti-cancer treatment started and there are willing to continue. For 
these patients, no blood sample will be collected for PK/PD and biomarker analysis, only 
(S)AEs and limited efficacy data will be collected. After the discontinuation of these patients, 
additional data collected after data base lock will be reported in separate listings and will not 

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lead to any further update of tables generated for section 15 of the CTR unless deemed 
necessary. These listings will be included in a revised CTR.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN – MODEL
7.1
This is phase I, open-label, dose-escalating trial to determine the MTD and RP2D for BI 
836880 in patients with solid tumors. MTD is defined as the highest dose with less than 25% 
risk of the true DLT probability being above 33%,and may be considered reached if the 
probability that the true DLT rate is in target interval (16%-33%) is sufficiently large. Dose 
escalation and determination of MTD will be guided by a Bayesian 2-parameter logistic 
regression model with overdose control (R13-4803, R13-4806). These designs have been 
shown to be superior regarding the precision of MTD determination compared to 3+3 designs 
and have been particularly endorsed by the FDA (R13-4881).
The model is formulated as follows:
logit(p(d)) = log(α) + β*log(d/d*),
where logit(p) = log(p/(1-p)). 
p(d) represents the probability of having a DLT in the first course at dose d, d* = 1250mg is 
the reference dose, allowing for the interpretation of α as the odds of a DLT at dose d*, and θ 
= (log(α), log(β)) with α, β > 0 is the parameter vector of the model.
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a mixture of three 
multivariate normal distributions, i.e.
π(θ) = φ1π1(θ) + φ2π2(θ) + φ3π3(θ)
with 
φi, i = 1, 2, 3 the prior mixture weights (φ1+ φ2+ φ3 = 1)
and 
πi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, with








2
22
,
22
,
11
,
22
,
11
,
2
11
,
i
i
i
i
i
i
i
i
i








Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
Prior derivation
For the current study, no relevant information in the form of human data was available, since 
no study in a comparable population has been conducted. Therefore, the three mixture 
components were established as follows:
1. A weakly informative prior was derived to reflect a priori assumption that the median 
DLT rate at the starting dose of 40mg would equal 0.1%, and the median DLT rate at 
the anticipated MTD of 480mg would equal 20%. This yields μ1 = (0.740, 0.798). The 
standard deviations were set such that large uncertainty about the parameter means is 

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reflected, and the correlation was set to 0, thus yielding σ1,11 = 2, σ1,22  = 1 and ρ1 = 0, 
respectively. The prior weight φ1 for the first component was chosen as 0.9.
2. A high-toxicity weakly informative prior was derived to reflect the case that the 
compound would be much more toxic than expected. For this prior component, it was 
assumed that the median DLT rate at the starting dose of 40mg would equal 10%, and 
the median DLT at the anticipated MTD of 480mg would equal 50%. These 
assumptions yield μ2 = (0.846, -0.123). The standard deviations and correlations were 
set identical to the weakly informative prior, i.e. σ2,11 = 2, σ2,22  = 1 and ρ2 = 0,
respectively. The prior weight φ2 for the second component was chosen as 0.05.
3. A low-toxicity weakly informative prior was derived to reflect the case that the 
compound would be much less toxic than expected. For this prior component, it was 
assumed that the median DLT rate at the starting dose of 40mg would equal 0.1%,
and the median DLT at the anticipated MTD of 480mg would equal 2%. These 
assumptions yield μ3 = (-2.731, 0.193), i.e. basically a flat curve. The standard 
deviations and correlations were set to σ3,11 = 5, σ3,22  = 0.01, therefore almost fixing 
the slope parameter to its mean. The correlation was set to 0, i.e. ρ3 = 0. The prior 
weight φ3 for the third component was chosen as 0.05.
A summary of the prior distribution is provided in Table 7.1:1. Additionally, the prior 
probabilities of DLT at different doses, as well as the corresponding probability of under-, 
targeted and overdosing, are shown in Table 7.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1:1. As can be seen from both, 
the Table and the Figure, the prior medians of the DLT probabilities are in-line with the prior 
medians derived from the weakly informative prior, and the uncertainty around the medians 
is large, showing the low amount of information this prior provides. This is also supported by 
the prior sample size, i.e. the information contained in the prior. This is approximately equal 
to1 patient, i.e. less than or around half of the weight the first cohort in the study will have.
Table 7.1: 1
Summary of prior distribution
Prior Component
Mixture Weight
Mean vector
SD vector
Correlation
1: Weakly inf.
0.900
0.740, 0.798
2.000, 1.000
0.000
2: High Tox
0.050
0.846, -0.123
2.000, 1.000
0.000
3: Low Tox
0.050
-2.731, 0.193
5.000, 0.010
0.000
Table 7.1: 2
Prior probabilities of DLT at selected doses
Dose
Probability of true DLT rate in
Quantiles
[0–0.16)
[0.16–0.33)
[0.33–1]
Mean
SD
2.5%
50%
97.5%
40
0.842
0.054
0.104
0.091
0.206
<.001
0.001
0.819
120
0.759
0.076
0.165
0.139
0.249
<.001
0.009
0.897
240
0.673
0.096
0.231
0.193
0.282
<.001
0.036
0.935
480
0.523
0.131
0.346
0.284
0.318
<.001
0.138
0.964
960
0.262
0.143
0.595
0.471
0.332
0.002
0.458
0.984
1250
0.142
0.114
0.744
0.594
0.316
0.012
0.659
0.991
Doses printed in bold face meet the overdose criterion (P(overdose) < 0.25))

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Figure 7.1: 1Prior medians and 95% credible intervals
The MTD may be considered reached if the following criteria are fulfilled:
1. At least 1 DLT on the trial and either
2. At least 6 patients haven been treated at the MTD and the posterior probability of the 
true DLT rate in the target interval (16%-33%) is above 50%, OR
3. At least 18 patients in the trial with 6 patients have been treated at MTD.
Statistical model assessment:
The model was assessed using two different metrics:
1. Hypothetical data scenarios: for various potential data constellations as they could 
occur in the actual trial, the maximal next doses as allowed by the model and by the 
100% escalation limit are investigated. Data scenarios thus provide a way to assess 
the “on-study” behaviour of the model.
2. Simulated operating characteristics: these illustrate for different assumed true dose-
toxicity relationships, how often a correct dose would be declared as MTD by the 
model. They are a way to assess the “long-run” behaviour of the model.

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In summary, the model showed very good behaviour as assessed by these metrics. More 
details can be found in Appendix 10.6. 
Based upon these design considerations, the trial will be analysed using general linear models 
which will include terms for centre and disease severity as covariates.
NULL AND ALTERNATIVE HYPOTHESES
7.2
No formal hypothesis testing is planned in this trial. All analyses in this trial are descriptive 
and exploratory by nature.
PLANNED ANALYSES
7.3
Only one analysis population will be considered for efficacy and safety analyses: the treated 
set. The treated set (TS) will consist of all patients who were treated with at least one single 
dose of BI 836880.
The primary analysis will be based on the treated set population excluding patients that have 
to be replaced for analysis of the MTD, see Section 3.3.4.1 for further details.
No per protocol population will be used for analyses; however protocol violations will be 
identified and listed.
7.3.1
Primary endpoint analyses
In order to determine the MTD the occurrence of a DLT in the first course will be assessed on 
an individual patient level. The MTD will be determined as described in Section 7.1.
Based on the data observed in the trial other models might be considered either additionally 
or replacing the primary model. For feasibility or other reasons a different dose might be 
considered as the recommended dose for Phase II.
7.3.2
Secondary endpoint analyses
Please refer to Section 7.3.4 for safety related secondary endpoint.
7.3.4
Safety analyses
All patients of the treated set will be included in the safety analyses. Two analyses will be 
performed. The first analysis of safety will be performed for the first part of the trial 

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(determination of the MTD, first course only, treatment regimen = initial dose at the start of 
the treatment, treated set). This descriptive analysis will evaluate the MTD for the 
monotherapy of BI 836880. The second analysis will be performed with respect to all courses 
and will act as a support for the determination of the MTD (treated set).
Events that started between the first administration of the treatment until 6 weeks (42 days) 
after the last administration of treatment will be considered as having occurred on treatment.
Events that started after 42 days since last administration of treatment will be considered as 
having occurred post-treatment and will be presented separately. 
Adverse events will be graded according to CTCAE Version 4.03 (R12-2532) and reported 
according to BI standards. Frequency, severity, and causal relationship of adverse events will 
be tabulated by system organ class and preferred term after coding according to the current 
version of the Medical Dictionary for Drug Regulatory Activities (MedDRA).
Serious adverse events will be tabulated. In addition, events leading to dose reduction or 
treatment discontinuation will be examined, but may not be reported as individual tables, 
depending upon the extent of overlap. Descriptive statistics will be used to describe changes 
in laboratory tests over time. In addition, all abnormalities of potential clinical significance 
will be reported. In general, potential clinical significance is defined as at least CTCAE
Grade 2 and an increase in CTCAE classification from baseline. The incidence and severity
of the more important adverse events (as determined from the analyses above) will be 
correlated descriptively with pharmacokinetic data, if possible.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 42 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’.  The residual effect 
period is defined as 42 days after the last trial medication application. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 

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reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.

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INTERIM ANALYSES
7.4
Interim safety evaluations will be performed as considered necessary. In particular safety 
evaluations will be performed after each dose cohort by the DSB consisting of the 
investigators and representatives of the sponsor (refer to Section 3.1.1). Based on this the 
DSB will recommend the next dose level as well as the corresponding cohort size. DSB
meeting minutes and outputs provided for these DSB meetings will be documented and 
archived in the clinical trial master file (CTMF).
If considered necessary, as soon as the MTD is determined an evaluation of the safety aspects 
will be performed. Results of this evaluation will be documented and archived. If applicable
such an analysis will be defined in more detail in the TSAP.
HANDLING OF MISSING DATA
7.5
No imputation will be performed on missing efficacy data.
Missing baseline laboratory values will be imputed by the respective values from the
screening visit. No other imputations will be performed on missing data although every effort 

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will be made to obtain complete information on all adverse events and to follow-up the 
patients for efficacy data.
RANDOMISATION
7.6
Patients will be assigned, not randomised, into escalating dosage cohorts by order of 
admission into the trial. Doses will be assigned based on the decision made by the DSB (see 
Section 7.3.4).
DETERMINATION OF SAMPLE SIZE
7.7
About 25-30 patients will be expected for the dose finding part and confirmation of RP2D. 
Fewer patients might be needed based on the recommendation of the DSB and the criteria 
specified (see Section 7.1). 

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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonized standards for Medical Devices (ISO 14155-01 and ISO 14155-02).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs),
and relevant regulations.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.

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RECORDS
8.3
Electronic Case Report Forms (e)CRF for individual patients will be provided by the 
Sponsor. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRF/eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRF / eCRF, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
END OF TRIAL
8.6
The trial will end when the last patient has completed the last follow up visit as specified in 
Section 6.2.3.4  
After the interim data base lock the trial will end when the last patient has completed the EoR 
visit as specified in Section 6.2.3.4  and 6.2.3.5

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The IEC / competent authority in each participating EU member state will be notified about 
the end of the trial or early termination of the trial.
PROTOCOL VIOLATIONS
8.7
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.

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9.
REFERENCES
PUBLISHED REFERENCES
9.1
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R13-5295
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Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou
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Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib
versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized 
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with regard to the safe and effective use of the medicinal product, 
labelling and package leaflet, last updated: 15/08/2014).
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Product_Information/ human/000582/WC500029271.pdf (access date: 1
September 2014) 2014.
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fluorouracil, leucovorin, and irinotecan improves survival in a phase III 
randomized trial in patients with metastatic colorectal cancer previously 
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Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ.
Improved survival with bevacizumab in advanced cervical cancer. N 
Engl J Med 2014. 370(8):734-743.

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Martinez Garcia M. Results from the first-in-human (FIH) phase I study 
of RO5520985 (RG7221), a novel bispecific human anti-ANG-2/anti-
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DiCioccio AT, Trail P, Siu LL. A phase 1b study of combined 
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with advanced solid malignancies. 50th Ann Mtg of the American 
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(pts) with advanced solid tumors. 50th Ann Mtg of the American Society 
of Clinical Oncology (ASCO), Chicago, 30 May - 3 Jun 2014 J Clin 
Oncol 2014. 32(15)(Suppl) Abstr 2542.
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Muyldermands S. Nanobodies and their potential applications.
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UNPUBLISHED REFERENCES
9.2
c02353882
Investigator’s Brochure: BI 836880 in solid tumors.Version 1. 11 June 
2015.
001-MCS-36-472 
Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics.

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10.
APPENDICES
INSTRUCTIONS FOR USE
10.1
10.1.1
Instruction for Pharmacists
Refer to the ISF
BLOOD PRESSURE MEASUREMENT PROCEDURE
10.2
The preferred method of blood pressure measurement is by a standard mercury
sphygmomanometer. If a standard mercury sphygmomanometer is not available, alternative
devices according to website dableducational.org may be used. At screening, blood pressure
should be taken in both arms. If the pressures differ by more than 10 mmHg (as in the
presence of a subclavian steal syndrome), the arm with the higher pressure (either systolic or
- if needed to decide - diastolic) should be used for subsequent measurements. Blood pressure
measurements should be performed on the same arm and, if possible, by the same person.
The same method and device must be used throughout the trial for a patient i.e. if a patient
receives the first blood pressure measurement for example with an electronic device, the
same method and device should be used throughout the study for this patient (without
switching to manual blood pressure measurement). On the other hand, inter-patient variability
is acceptable, i.e. a study site is allowed to consistently use an electronic device to measure
the blood pressure in a given patient throughout the study and a manual technique in another
patient. After patients have rested quietly, in the seated position for five minutes, three blood
pressure measurements will be taken two minutes apart and all three results have to be
entered in the eCRF. The seated pulse rate will be taken during the two-minute interval
between the second and third blood pressure reading. Blood pressure measurements should
be recorded to the nearest 2 mmHg only when measured with a manual sphygmomanometer;
when digital devices are used the value from the device should be rounded to the nearest 1
mmHg. For calculation of mean values, decimal places should be rounded to integers (e.g. a
DBP of 94.5 would be rounded to 95 mmHg and a DBP of 109.4 would be rounded to 109
mmHg). The above mentioned procedure is considered as standardised conventional blood
pressure measurement (CBPM).
In case of a suspected “white coat effect” it is recommended to repeat the measurement in a
pleasant condition after sufficient rest. Ambulatory blood pressure measurement (ABPM) can
be an option in specific cases to observe BP profiles over a longer period (e.g. during infusion
and thereafter) and even outside the hospital in private surrounding. However treatment
decisions should be based whenever possible on CBPM as described above and ABPM 
should be used for observation only. In case BP values from ABPM should be used for 
treatment related decisions, this has to be taken from appropriate time points and validated
ABPM devices according to website dableducational.org should be used. Values from self 
blood pressure measurement (SBPM) communicated from patient to investigator is not 
considered valuable for study related decisions.

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STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
10.6
DATA SCENARIOS
The model was assessed by two different metrics: hypothetical on-study data scenarios and 
long-run operating characteristics. 
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.6:1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model and the 200% 
escalation limit or doses of interest. For each scenario, the probability of overdose for the 

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current dose, as well as the next potential dose and related probabilities of under-dosing, 
target dose and over-dosing are shown. A new cohort will be open for enrolment after the 
review on data from the previous cohort is completed by the DSB.
For example, scenario 1 represents the case that no DLT is observed in two patients at the 
starting dose of 40mg. In this case, the next dose permitted by the model and by the 200% 
escalation rule is 120 mg. Scenario 4 represents the case that no DLTs are observed in the 
first cohort of two patients at 40mg, and 1 DLT is observed in the second cohort of three 
patients at 120mg. In this case, the model requires to re-enroll at the current dose level of 
120mg. Scenario 5 shows the case that 2 DLTs are observed in the second cohort of three 
patients at 120mg. The model then allows a de-escalation.
Scenario 6 and 7 illustrate the case where no DLTs are seen in the first three cohorts. In 
scenario 6, no DLT is observed at 480mg, either. However, the model does not allow the 
escalation to 960mg for safety concerns despite the fact that no DLTs are observed in the first 
four cohorts. On the other hand, scenario 7 presents the case that 1 DLT is seen at 480mg. In 
this case, no escalation to 1250mg is allowed as well. These two cases illustrate the adaptive 
behaviour of the model even in extreme situations. In scenario 8, no DLs are seen in the first 
three cohorts. Dose was escalated to 960mg after 6 patients were tested on 480mg without 
DLT. De-escalation occurred as a result of one out of the three patients treated on dose 
960mg had DLT.

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Table 10.6: 1
Hypothetical data scenarios 
Scenario
Cohort
Dose 
(mg)
# DLT
# Pat
Current 
Dose: 
P(OD)
Next 
Dose
Next Dose
P(UD)
P(TD)
P(OD)
1
1
40
0
2
0.019
120
0.862
0.076
0.062
2
1
40
1
3
0.318
N/A
N/A
N/A
N/A
3
1
40
0
2
2
120
0
2
0.018
240
0.841
0.093
0.066
4
1
40
0
2
2
120
1
3
0.231
120
0.451
0.318
0.231
5
1
40
0
2
2
120
2
3
0.623
40
0.455
0.308
0.237
6
1
40
0
2
2
120
0
2
3
240
0
3
4
480
0
3
0.02
480
0.903
0.077
0.020
7
1
40
0
2
2
120
0
2
3
240
0
3
4
480
1
3
0.229
480
0.424
0.347
0.229
8
1
40
0
2
2
120
0
2
3
240
0
3
4
480
0
6
5
960
1
3
0.353
480
0.943
0.054
0.003
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose 
with true DLT rate in the target interval can be approximated via simulation. Table 10.6: 2
describes 5 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases as 
follows:

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
- Scenario 1: aligned with prior medians

- Scenario 2: high-toxicity scenario

- Scenario 3: low-toxicity scenario

- Scenario 4: low-tox followed by high-tox

- Scenario 5: non-logistic dose-toxicity scenario
Table 10.6: 2
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
40
120
240
480
960
1250
1 (Prior)
P(DLT)
0.091
0.139
0.193
0.284
0.471
0.594
2 (High Tox)
0.100
0.227
0.351
0.500
0.649
0.700
3 (Low Tox)
0.001
0.007
0.022
0.180
0.250
0.350
4 (Non-Logistic)
0.040
0.100
0.180
0.280
0.360
0.380
5 (Low-High)
0.001
0.011
0.047
0.181
0.500
0.640
For each of these scenarios, 1000 trials were simulated. It was then assessed how often a dose 
was declared as MTD with true DLT rate in the under-, targeted or over-dose range. 
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.6: 3.
Table 10.6: 3
Simulated operating characteristics 
Scenario
% of trials declaring an MTD with true DLT rate in
# Patients
# DLT
underdose
target dose
overdose
STOPPED
Mean
(Min-Max)
Mean
(Min- Max)
1
23.1
56.4
0.1
20.4
16.45
(3 – 34)
2.982
(1 – 10)
2
18.1
38.3
19.6
24.0
16.01
(3 – 36)
3.73
(1 – 11)
3
20.2
79.6
0.2
0
20.42
(17 – 38)
2.248
(1 – 6)
4
19.4
71.4
0.6
8.6
18.42
(3 – 35)
3.09
(1 – 10)
5
25.6
74.0
0.3
0
20.11
(16 – 40)
2.43
(1- 6)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior medians, 
56.4% of the simulated trials declared a dose as MTD with true DLT rate in the targeted dose 
range. Note that 20.4% of the simulated trials stop because of high toxicity. This is mostly 
due to the cases that 1 DLT is observed out of 3 patients at the starting dose 40mg. In reality, 

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this situation would rarely happen as the safety profile of starting dose is expected to be good. 
In addition, dose escalation could still happen after the discussion within DSB.
In scenario 2 (high-toxicity scenario), the starting dose has already >10% probability of 
observing at least 2 DLTs out of 3 patients or 1 DLT out of 2 patients in the first cohort. This 
contributes to the high percentage (24.0%) of all simulated trials for which the trial is stopped 
since none of the doses is considered tolerable anymore. This is an expected situation for a 
high-toxicity scenario.
In scenarios 3, 4 and 5, more than 50% of the simulated trials declared a dose as MTD with 
true DLT rate in the targeted dose range. 
The mean patient numbers range from 16.0 patients (high-toxicity scenario) to 20.4 patients 
(low-toxicity scenario) and the maximum number of patients was 40. Therefore, the patient 
numbers are as expected and increase when moving away from the high-toxicity scenario. 
In summary, the considered data scenarios show a reasonable behavior of the model and the 
operating characteristics demonstrate a good precision of MTD determination. 

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of 
global 
amendment
I
Date of CTP 
revision
24 Mar 2017
EudraCT 
number
2015-001132-38
BI Trial 
number
1336.6
BI 
Investigationa
l Product(s)
BI 836880
Title of 
protocol
Phase I, non-randomized, open-label, multi-center dose escalation trial of 
BI 836880 administered by weekly repeated intravenous infusions in 
patients with advanced solid tumors.
To be 
implemented 
only after 
approval of 
the IRB / IEC
/ Competent 
Authorities
To be 
implemented 
immediately 
in order to 
eliminate 
hazard –
IRB / IEC / 
Competent 
Authority to 
be notified of 
change with 
request for 
approval
Can be 
implemented 
without IRB /
IEC / 
Competent 
Authority 
approval as 

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changes 
involve 
logistical or 
administrativ
e aspects only
Section to be 
changed
Synopsis: total entered
Description of 
change
Approximately 40 patients
Was changed to:
Approximately 40 patients, including at least 12 patients treated at MTD 
with tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-
MRI
Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
Synopsis
Description of 
change

Histologically or cytologically confirmed malignancy which is 
locally advanced or metastatic solid tumor, and either refractory 
after standard therapy for the disease or for which standard 
therapy is not reliably effective, e.g. patients do not tolerate or
have contraindications to otherwise available 
Was changed to:

Histologically or cytologically confirmed malignancy which is 
locally advanced or metastatic solid tumor, and either refractory 
after standard therapy for the disease or for which standard 
therapy is not reliably effective, e.g. patients do not tolerate or
have contraindications to otherwise available standard therapy
and tumour lesions evaluable for Dynamic-enhanced (DCE)-MRI 
at MTD
Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
Flow chart: footnote #3; section 5.3.2
Description of 
change
Footnote #3
3Body Temperature: whenever possible the same method should be used for body temperature 
measurement in one patient.  Acceptable methods could be: oral, rectal measurement with 
thermometer (digital, mercury, or other fluid). Not acceptable: infrared measurement in ear, 
forehead or temple. Body temperature > 38°C must be re assessed 1 hour after.
Section 5.3.2 body temperature
Whenever possible the same method should be used for body temperature 
measurement in one patient. All methods used should deliver valid 
reproducible results according to common clinical practice.  Acceptable 

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methods could be, but not limited to: oral, rectal measurement with 
thermometer (digital, mercury, or other fluid). Not acceptable/preferred 
methods include: infrared measurement in ear, forehead or temple.
Was changed to
Footnote #3
3Body Temperature: whenever possible the same method should be used for body temperature 
measurement in one patient. Body temperature > 38°C   must be re assessed 1 hour after.
Section 5.3.2 body temperature
Whenever possible the same method should be used for body temperature 
measurement in one patient. All methods used should deliver valid 
reproducible results according to common clinical practice.  
Rationale for 
change
- To allow some flexibility to the sites to measure body temperature 
according to common clinical practice. 
-To be consistent with the wording (> 38°C) elsewhere in the protocol
Section to be 
changed
Footnote #5 and section #5.3.3 
Description of 
change
Footnote #5
5Haematology, biochemistry and coagulation parameters will be performed locally. Previous 
safety lab: investigations are acceptable if performed within 72 hours prior to the screening visit.
For details see Section 5.3.3
Section #5.3.3
Previous laboratory investigations performed within 72 hours prior to the 
screening visit are acceptable to confirm the eligibility at for the 
screening.  
Was changed to 
Footnote #5
5Haematology, biochemistry and coagulation parameters will be performed locally. Previous 
safety lab: investigations are acceptable if performed within 72 hours prior to the first treatment 
administration. For details see Section 5.3.3
Section #5.3.3
Previous laboratory investigations performed within 72 hours prior to the 
first treatment administration visit are acceptable to confirm the patient 
eligibility.  
Rationale for 
change
To confirm patient eligibility before start of  study treatment
Section to be 
changed
3.1
Description of 
change
Was added:
Once a MTD has been reached, a minimum of 12 patients must have 
tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-MRI to 
allow a better interpretation of pharmacodynamics (vascular) effect of BI 
836880

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Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
3.1.1
Description of 
change
Members of the DSB will be investigators of participating trial sites, Trial 
Statistician (TSTAT), Clinical Program Leader (CPL) and Trial Clinical 
Monitor (TCM).
Was changed to:
Members of the DSB will be investigators of participating trial sites, Trial 
Statistician (TSTAT), Clinical Program Leader (CPL), Trial Clinical 
Monitor (TCM) and BI Lead Risk Management Physician
Rationale for 
change
Addition of one Data Safety Board member that was omitted  in the 
previous version of the protocol
Section to be 
changed
3.3.2
Description of 
change
Histologically confirmed malignancy which is locally advanced or 
metastatic solid tumor, and either refractory after standard therapy for the 
disease or for which standard therapy is not reliably effective e.g patients 
do not tolerate or have contraindications to otherwise available standard 
therapy
Was changed to:
Histologically confirmed malignancy which is locally advanced or 
metastatic solid tumor, and either refractory after standard therapy for the 
disease or for which standard therapy is not reliably effective e.g patients 
do not tolerate or have contraindications to otherwise available standard 
therapy and tumour lesions evaluable for Dynamic contrast-enhanced 
(DCE) MRI at MTD
Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
3.3.2
Description of 
change
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an 
alternative medical cause) or who are permanently sterilized (e.g., tubal 
occlusion, hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy).
Was changed to:
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an 
alternative medical cause) or who are permanently sterilized (e.g.,  
hysterectomy, bilateral oophorectomy or bilateral salpingectomy).

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Rationale for 
change
Tubal ligation is no longer considered a highly effective method of 
contraception and no longer a method of permanent sterilisation
Section to be 
changed
Section 4.1.2
Description of 
change
Was added:
“..For medication number allocation at each visit it’s possible to conduct 
IRT call ahead of the planned visit (= day of administration)..”
Rationale for 
change
Clarification for logistical reasons
Section to be 
changed
Table 4.1.3:1
Description of 
change
Dose level
Total dose (mg)
Approximate 
increment to next 
dose
Dose level 1 
( starting dose)
40
3x (200%)
Dose level 2
120
2x (100%)
Dose level 3
240
2x (100%)
Dose level 4
480
1.5x (50%)
Dose level 5
720
1.3x (30%)
Dose level 6
960
1.7x (30%)
Dose level 7
1440 limited to 
1250*
Intermediate dose level of “720 mg” was added and potential dose levels 
were adapted
Rationale for 
change
Intermediate dose level of “720 mg” was added in the table as requested 
by the Spanish authority during the approval  process
Section to be
changed
4.1.3
Description of 
change
was added:
For patients with an intra-patient dose escalation(s) all assessments will 
be done according to instructions for the first cycle at start of treatment 
with BI 836880 and intensive PK-sampling, sampling for ADA as well as 
sampling for biomarkers (Myriad panel and free/total VEGF-A/ Ang2) 
will be conducted (see flow chart and Appendix 10.4) and patients have 

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to be closely followed for any adverse events. Therefore patients have to 
come to the clinic during the first course of intra-patient dose escalation 
every week. Additional visits are needed at day 2 and at day 3 of the 1st
course of dose escalation. 
The above-mentioned procedures will be followed also in case of further 
intra-patient dose escalations.
Rationale for 
change
Specific guidance for patients with an intra-patient dose escalation is 
provided for assessments to be done within the first course with the 
escalated dose
Section to be 
changed
5.2
Description of 
change
Was added:
Results of tumor-specific tumor markers which will be assessed routinely 
should be documented in the eCRF
Rationale for 
change
To better assess tumour response in tumors for which tumour marker 
testing is performed routinely
Section to be 
changed
5.5
Description of 
change
Additional assays may be added if new data suggests relevance to the 
study drug mechanism of action. Furthermore, the collected samples may 
be used for testing of other disease related
biomarkers that may be of scientific interest for understanding 
mechanisms of the disease (i.e. cancer) after initiation/completion of this 
trial
Was changed to 
Additional assays may be added if new data suggests relevance to the 
study drug mechanism of action. 
Rationale for 
change
For clarification, deletion of the sentence suggesting  unspecified 
investigations to be done, also to comply with Spanish authority request 
during approval process
Section to be 
changed
5.6.2
Description of 
change
Was removed:
After completion of the study the plasma samples may be used for further 
ADA characterization or methodological investigations, e.g., for stability 
testing or isotyping. Any additional characterization data will be reported 
separately
Rationale for 
change
For clarification, deletion of the sentence suggesting  unspecified 
investigations to be done, also to comply with Spanish authority request 
during approval process
Section to be 
6.1 

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changed
Description of 
change
To allow close monitoring for infusion-related reactions or other adverse 
events and availability of patients for PK visits, after administration of BI 
836880, patients are required to be hospitalised under close surveillance 
with access to intensive care for at least 48 hours and 24 hours after the
first and the second administration of  BI 836880, respectively.
Was changed to 
To allow close monitoring for infusion-related reactions or other adverse 
events and availability of patients for PK visits at course 1, patients are 
required to be hospitalised under close surveillance with access to 
intensive care for at least 48 hours after the first administration of BI 
836880 at course 1 day 1 and 24 hours after the second and third 
administrations of BI 836880 at course 1 day 8 and course 1 day 15
respectively.
Rationale for 
change
To clarify patient monitoring during first course
Section to be 
changed
Table 10.4
Description of 
change
Blood sampling scheme for PK, ADA and biomarkers
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time / 
planned 
time
PK: 
BI 
836880***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-A/ 
Ang2
ECG
BP
1
V1
3
48:00
x
x
x
x 
(3x)
V3
15
Before end of  
infusion
337:30**
x (3)
x 
(3x)
Immediately 
after the end 
of infusion*
337:30**
x
Correction of typo errors  at time points C1V1; C1V3
Course
Visit
Day
Time Point 
(hh:min)
CRF Time 
/ planned 
time
PK: 
BI 
836880***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-A/ 
Ang2
ECG
BP
2
V2
8
Before start of 
BI 836880 
infusion
167:55
x
x
x 
(3x)
x 
(3x)
Immediately 
after end of 
infusion*
169:30**
x
V3
15
Before start of 
BI 836880 
infusion
335:55
x
x
x 
(3x)
x
(3x)

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Start of BI 
836880 infusion
336:00
Before end of 
infusion
337:30**
x 
(3x)
x 
(3x)
Immediately 
after end of 
infusion*
337:30**
x
Correction of typo errors at C2V2; and PK time point was added at 
C2V3 (337:30)
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time / 
planned 
time
PK: 
BI 
836880***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-A/ 
Ang2
ECG
BP
4
V1
2
24:00
x
x
x (3x)
x(3x)
V3
15
Immediately 
after  end of 
infusion*
337:30**
x
One PK time point was added at C4V3, ECG and BP time points were 
added at C4V1D2
Rationale for 
change
Corrections of typo errors and PK, ECG and BP time points were added 
as they were omitted in error in the previous version of the protocol
Section to be 
changed
Table 10.4 appendices
Description of 
change
The following footnote was added:
In case of an intra-patient dose escalation the 1st course with the higher dose will follow course 
one at the start of treatment with BI 836880 with regards to sampling PK, ADA as well as 
Biomarkers (Myriad panel and free/total VEGF-A/ Ang2)
Rationale for 
change
To provide guidance for patients with an intra-patient dose escalation 
with regards to assessments to be done within first course with escalated 
dose

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Number of global 
amendment
2
Date of CTP revision
28 Sep 2017
EudraCT number
2015-001132-38
BI Trial number
1336.6
BI Investigational 
Product(s)
BI 836880
Title of protocol
Phase I, non-randomized, open-label, multi-center dose 
escalation trial of BI 836880 administered by weekly 
repeated intravenous infusions in patients with 
advanced solid tumors.
To be implemented only 
after approval of the IRB / 
IEC / Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
5.5.1 Imaging Pharmacodynamic endpoints
Description of change
Methods of sample collection
…..DCE-MRI will be performed on a coronal slice 
through one or more representative lesions
selected and identified by the responsible radiologist 
from the morphological scans. For
DCE-MRI, a T1-weighted inversion recovery-gradient 
echo sequence is used, for which the
patient will receive an intravenous bolus application of 
the gadolinium contrast agent
Multihance®. Detailed parameter settings are given in 
the MR-Protocol.
Was changed to :

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Methods of sample collection
….DCE-MRI will be performed on a coronal slice 
through one or more representative lesions selected and 
identified by the responsible radiologist from the 
morphological scans. For DCE-MRI, a T1-weighted 
inversion recovery-gradient echo sequence is used, for 
which the patient will receive an intravenous bolus 
application of the gadolinium contrast agent. Detailed 
parameter settings are given in the MR-Protocol.
Rationale for change
A risk of brain deposits with repeated use of
gadolinium-based contrast agents for magnetic
resonance imaging (MRI) like Multihance
previously recommend within this protocol has
been reported and radiologists therefore prefer the
use of gadolinium-based contrast agents for which
this risk has not been reported.
Section to be changed
Section 4.1.3 table 4.1.3:1 potential dose level
Description of change
Was added: dose level  of 180 mg 
Rationale for change
This intermediate dose level was tested based on Data 
Safety Board decision
Number of global 
amendment
3
Date of CTP revision
13 Mar 2019
EudraCT number
2015-001132-38
BI Trial number
1336.6
BI Investigational 
Product(s)
BI 836880
Title of protocol
Phase I, non-randomized, open-label, multi-center dose 
escalation trial of BI 836880 administered by weekly 
repeated intravenous infusions in patients with 
advanced solid tumors.
To be implemented only 
after approval of the IRB / 
IEC / Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented 
without IRB / IEC / 
Competent Authority 

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approval as changes involve 
logistical or administrative 
aspects only
Section to be changed

Title page

Abbreviation

Section 3.1.1- administration of the trial
Description of change
Trial Clinical Monitor (TCM) was changed to Clinical 
Trial Leader (CTL) and Clinical Monitor Local (CML) 
was changed to Clinical Trial Manager (CTM)
Rationale for change
Administrative changes
Section to be changed
Synopis- methodology
Description of change
Non randomized, uncontrolled, open-label, dose 
escalation followed by an expansion cohort
Was changed to
Non randomized, uncontrolled, open-label, dose 
escalation 
Rational for change
Expansion cohort is no longer planned for this trial
Section to be changed
Synopsis- N° of patients
Description of change
Approximately 50 patients to be enrolled
Was changed to
Approximately 40 patients to be enrolled
Rational for change
To adapt the sample size since expansion cohort is no 
longer planned for this trial
Section to be changed
Synopis
Description of change
Approximately 40 patients, including at least 12 
patients treated at MTD with tumour lesions evaluable 
for Dynamic contrast-enhanced (DCE)-MRI.
40 patients will receive study treatment
Was changed to
Approximately 25 patients.
Approximately 25 patients will receive study treatment
Rationale for change
It is no longer required to enroll 12 patients with DCE-
MRI to be treated at MTD, and to adapt the sample size 
since expansion cohort is no longer planned for this 
trial
Section to be changed
Flow chart
Description of change
Change s have been made in the following footnotes 
and sections: 
Footnote numbers and sections in the protocol:
**: no additional follow up visits required after the interim data 
base lock
- 2: change to frequency of physical examination and ECOG 
Performance

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- 3: change to frequency of body temperature, following the 
interim data base lock (refer to section 5.3.2)
- 4: change to frequency of blood pressure, following the interim 
data base lock (refer to section 5.3.2)
- 5: change to frequency of laboratory tests, following the interim 
data base lock (refer to section 5.3.3)
- 6: change to frequency of tumor assessment, following the 
interim data base lock
- 7: change to frequency and assessment of ECG and no 
requirement to send ECGs to central vendor, following the interim 
data base lock (refer to section 5.3.4)
- 8: clarification about echocardiography data entry in the eCRF ( 
refer to section 5.3.4)
- 9: no blood samples for PK analysis will be taken following the 
interim data base lock (refer to appendix 10.4)
- 10: no blood samples for ADA analysis will be taken following
the interim data base lock (refer to appendix 10.4)
- 11; 12: no blood samples for biomarker analysis will be taken 
following the interim data base lock (refer to appendix 10.4)
-14: DCE-MRI measurement is no longer mandatory following the 
interim data base lock
Rationale for change
At the time of interim data base lock, sufficient data 
will have been collected for PK, ADA and biomarker 
analyses, therefore no longer required. 
Also to provide more flexibility to trial procedures
Section to be changed
Section 3.1 overall trial design and plan
Description of change
Was deleted:
Once a MTD has been reached, a minimum of 12 
patients must have tumour lesions evaluable for 
Dynamic contrast-enhanced (DCE)-MRI to allow a 
better interpretation of pharmacodynamics (vascular) 
effect of BI 836880.
Once the RP2D has been determined and in case of 
anti-tumor activity signals is reported in given tumor 
type(s), DSB can take the decision for a trial expansion 
to recruit patients with the same tumor type(s) with the 
aim to generate safety and preliminary efficacy data 
specific to such disease. Approximately 10-15 
additional patients will be treated in the expansion 
cohort, sample size will be re evaluated when the 
expansion cohort is open. 
Rationale for change
-Since the Prof of Pharmacological Principal (PoPP)
has been determined with the sister trial 1336.1 (3-
weekly dosing), enrollment of 12 patients with DCE-
MRI in this trial is no longer mandatory.
-To reflect the fact that expansion cohort is no longer 
planned for this trial

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Section to be changed
Section 3.1 overall trial design and plan
Description of change
Was added:
After the interim data base lock, the study is 
considered completed when the last patient in the 
study has discontinued the study treatment and 
completed the EoR visit (see Section 6.2.3.5).
Rationale for change
Clarification on the definition of trial completion after 
the interim data base lock
Section to be changed
Section 3.3 selection of trial population
Description of change
It is estimated that approximately 50 patients will be 
enrolled at 2 study sites. The rate of enrolled patients 
may vary by study site, but it is expected to be 
approximately 25 patients per site. Among them 40 
patients will be enrolled and treated in this trial.
Was changed to 
It is estimated that approximately 40 patients will be 
enrolled at 2 study sites. The rate of enrolled patients 
may vary by study site, but it is expected to be 
approximately 20 patients per site. Among them 
approximately 25 patients will be treated in this trial.
Rationale for change
To adapt the sample size since expansion cohort is no 
longer planned for this trial
Section to be changed
Section 4.1.3 table 4.1.3:1 potential dose level
Description of change
Was added: dose level  of 150 mg 
Rationale for change
This intermediate dose level was tested based on Data 
Safety Board decision
Section to be changed
5.2 assessment of efficacy
Description of change
Was added:
After the interim data base lock, frequency of tumor 
assessment may be adapted according to local 
standard of care and in agreement with the sponsor 
if the patient is deriving clinical benefit (e.g. CR, PR 
or SD > 6 months).   
Rationale for change
To reduce imaging assessment frequency
Section to be changed
5.2 assessment of efficacy
Description of change
Was added:
After the interim data base lock, collection of tumor 
markers in the e-CRF is no longer required.
Rationale for change
Following data the interim data base lock there is no 
longer requirement to enter tumor maker data in e-CRF
Section to be changed
Abbreviation and section 5.3.6.1 Definition of AEs
Description of change
Remote Data Capture (RDC) was changed to 
Electronic Data Capture (eDC)
Rationale for change
Administrative

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Section to be changed
6.2 - Details of trial procedures at selected visits
Description of change
Was added:
After the interim data base lock, mandatory 
procedures/assessments and documentation in the 
eCRF will be adapted as described in the flow chart 
and the respective sections of this protocol
Rationale for change
To reflect the changes to trial  procedures/assessments 
following the interim data base lock
Section to be changed
6.2.2 treatment period(s)
6.2.3.3 Follow-up period for progression
Description of change
Was added:
After the interim data base lock, frequency of tumor 
assessment may be adapted according to local 
standard of care and in agreement with the sponsor 
if the patient is deriving clinical benefit (e.g. CR, PR 
or SD > 6 months).
Rationale for change
To reduce imaging assessment frequency
Section to be changed
Section 6.2.3.5 trial completion
Description of change
Section 6.2.3.5 was added:
The clinical trial will be considered completed when 
the last patient has completed the EoR visit.
If patients are still on treatment at the time of 
interim data base lock and the Clinical Trial Report 
is written, these patients will be maintained in the 
trial as long as they are deriving clinical benefit (i.e. 
no disease progression, no drug-related AEs 
requiring drug discontinuation) or no new anti-
cancer treatment started and there are willing to 
continue. For these patients, no blood sample will be 
collected for PK/PD and biomarker analysis, only 
(S)AEs and limited efficacy data will be collected. 
After the discontinuation of these patients, 
additional data collected after interim data base 
lock will be reported in separate listings and will not 
lead to any further update of tables generated for 
section 15 of the CTR unless deemed necessary. 
These listings will be included in a revised CTR.
Rationale for change
Clarification for the definition of trial completion 
following the interim data base lock
Section to be changed
Section 7.7 determination of sample size
Description of change
Was deleted
Additional 10-15 patients will be included in the 
expansion cohorts, in case one or more tumor types will 
be selected for further evaluation. Sample size will be 
reevaluated when the expansion cohort is open.

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Rationale for change
Expansion cohort is no longer planned for this trial
Section to be changed
8.6 End of Trial
Description of change
The trial will end when the last patient has completed 
the last follow up visit as specified in Section 6.2.3.4
Was changed to:
After the interim data base lock the trial will end 
when the last patient has completed the EoR visit as 
specified in Section 6.2.3.4 and 6.2.3.5
Rationale for change
Clarification for the definition of end of trial, following 
the interim data base lock

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03124055
6.0
clinical-trial-protocol-version-04
Phase I non-randomized open-label multi-center dose escalation trial of BI 836880
administered by weekly repeated intravenous infusions in patients with advanced
solid tumors
Author-Clinical Trial Leader
13 Mar 2019 16:46 CET
Approval-Therapeutic Area 
13 Mar 2019 17:48 CET
Author-Trial Clinical
Pharmacokineticist
14 Mar 2019 07:44 CET
Approval-Clinical Program 
14 Mar 2019 11:29 CET
Author-Trial Statistician
15 Mar 2019 14:16 CET
Verification-Paper Signature
Completion
18 Mar 2019 09:37 CET

Boehringer Ingelheim 
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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Clinical Trial Protocol
TITLE PAGE
Document Number:
c03124055-06
EudraCT No.:
2015-001132-38
BI Trial No.:
1336.6
BI Investigational 
Product(s):
BI 836880
Title:
Phase I, non-randomized, open-label, multi-center dose escalation 
trial of BI 836880 administered by weekly repeated intravenous 
infusions in patients with advanced solid tumors.
Brief Title:
Weekly BI 836880 in patients with advanced solid tumors
Clinical Phase:
I
Clinical Trial Leader:
Phone: 
Fax: 
Coordinating 
Investigator:
Principal 
Investigator:
Phone: 
Fax: 
Tel 
Fax 
Status:
Final Protocol (Revised Protocol based on global amendment 3)
Version and Date:
Version:
Date:
Revised Protocol
4.0
13 Mar 2019
Page 1 of 99
Proprietary confidential information.
2019 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.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 836880
Protocol date:
10 Dec 2015
Trial number:
1336.6
Revision date:
13 Mar 2019
Title of trial:
Phase I, non-randomized, open-label, multi-center dose escalation trial of BI 
836880 administered by weekly repeated intravenous infusions in patients with 
advanced solid tumors
Coordinating
Investigator:
Principal Investigator
Phone: 
Fax:
Tel 
Fax 
Trial site(s):
Multicentre-trial conducted in 2 countries
Clinical phase:
I
Objective(s):
To determine the maximum tolerated dose (MTD) and provide preliminary safety 
data of BI 836880 given as intravenous infusion and to determine recommended 
phase II dose. Further the PK, immunogenicity and PD-profile, as well as primary 
signs of antitumor activity of BI 836880 should be assessed
Methodology:
Non randomized, uncontrolled, open-label, dose escalation
No. of patients:
Approximately 40 patients to be enrolled
total entered:
Approximately 25 patients
each treatment:
Approximately 25 patients will receive study treatment
Diagnosis :
Advanced or metastatic/ refractory solid tumors

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Name of company:
Boehringer Ingelheim 
Name of finished product:
Not applicable
Name of active ingredient:
BI 836880
Protocol date:
10 Dec 2015
Trial number:
1336.6
Revision date:
13 Mar 2019
Main criteria
for inclusion:

Age > 18 years

Histologically or cytologically confirmed malignancy which is locally 
advanced or metastatic solid tumor, and either refractory after standard 
therapy for the disease or for which standard therapy is not reliably 
effective, e.g. patients do not tolerate or have contraindications to 
otherwise available standard therapy and tumour lesions evaluable for 
Dynamic contrast-enhanced (DCE) MRI at MTD

ECOG performance status < 2

Adequate hepatic, renal and bone marrow functions

Life expectancy > 3 months in the opinion of the investigator

Recovery from all reversible adverse events of previous anti-cancer 
therapies to baseline or CTCAE grade 1, except for alopecia (any grade) 
and sensory peripheral neuropathy CTCAE grade < 2
Test product(s):
BI 836880 and Diluent for BI 836880
dose:
Starting dose of 40 mg weekly infusion
mode of 
administration:
Intravenous weekly in a 21-day treatment course
Comparator products:
Not applicable
dose:
Not applicable
mode of 
administration:
Not applicable 
Duration of treatment:
Continuous treatment in the absence of disease progression or unacceptable
toxicity
Endpoints
Primary endpoint

Maximum Tolerated Dose (MTD)
Secondary endpoint

Drug related AEs leading to dose reduction or discontinuation during 
treatment period
Safety criteria:
Adverse events according to Common Terminology Criteria (CTCAE version  
4.03), incidence of dose limiting toxicities, physical examination, vital signs, safety 
laboratory parameters, ECOG
Statistical methods:
Descriptive and exploratory statistics analyses. Dose escalation guided by a 
Bayesian logistic regression model with over dose control

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FLOW CHART COURSE 1
Trial periods
Screening
Treatment course***
EOT*
EoR*
FU**
Course
1
Visit
Screen
V1
V2
V3
Day
-21 to -1
1
2
3
8 +2
15+2
EoT+42 d
Informed consent 1
x
Demographics
x
Medical  history
x
Inclusion/exclusion criteria
x
x
Physical examination2
x
x
x
x
x
x
x
x
Height
x
Weight
x
x
x
Body temperature3
x
x
x
x
x
x
Blood pressure4,  heart rate
x
x
x
x
x
x
x
x
ECOG performance status
x
x
x
Administration of BI 836880 infusion
x
x
x
Safety Lab parameters5
x
x
x
x
x
Pregnancy test
x
x
x
Tumor assessment6
x
x
x
12-lead ECG7
x
x
x
x
x
x
Echocardiography8
x
x
Pharmacokinetics9
x
x
x
x
x
x
x
x (FU1)
Anti-drug antibodies10
x
x
x
x (FU1)

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Trial periods
Screening
Treatment course***
EOT*
EoR*
FU**
Course
1
Visit
Screen
V1
V2
V3
Day
-21 to -1
1
2
3
8+2
15+2
EoT+42 d
Biomarker : Myriad  Ang MAP panel11
x
x
x
Biomarker: free/total VEGF-A, Ang212
x
x
x
x
x
x
x
x (FU1)
Concomitant therapy
x
x
x
x
x
x
x
x
x
Adverse events13
x
x
x
x
x
x
x
x
x
DCE-MRI14
x
x
x
Completion of  trial medication
x
Completion of patient participation
x

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FLOW CHART COURSES 2 ONWARDS
Trial periods
Repeated treatment courses***
EOT*
EoR*
FU**
Course
2,3,4,5 onwards
Visit
V1
V2
V3
Day
1
2
3
8 +2
15+2
EoT+42 d
Physical examination2
x
x
x
x
x
Weight
x
x
Body temperature3
x
x
x
x
Blood pressure4,  heart rate
x
x(C2,C4)
x
x
x
x
ECOG performance status
x
x
Administration of  
BI 836880 infusion
x
x
x
Safety Lab parameters5
x
x
x
x
Pregnancy test
x
x
Tumor assessment6
x
x
x
12-lead ECG7
x
x (C2,C4)
x (C2,C4)
x (C2,C4)
x
Echocardiography8
x
x
Pharmacokinetics9
x
x (C2,C4)
x (C2,C4)
x (C2,C4)
x
x
x (FU1)
Anti-drug antibodies10
x
x
x
x (FU1)
Biomarker : Myriad Ang MAP panel11
x (C2, C4)
x
Biomarker: free/total VEGF-A, Ang212
x 
x (C2, C4)
x (C2, C4)
x (C2, C4)
x
x
x (FU1)
Concomitant therapy
x
x
x
x
x
x
x
Adverse events13
x
x
x
x
x
x
x
DCE-MRI14
x ( C3, C5)
x
Completion of  trial medication
x
Completion of patient participation
x

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(C2, C3, C4, C5) = (courses 2, 3, 4 and 5)
FU1= first follow up visit
*End Of Treatment (EOT) must be performed within 21 days of the last administration of study drug. If last administration of the study drug occurs during a scheduled visit, 
examinations as defined for EOT should be performed instead of examinations for the scheduled visit.
EoR*= End of Residual Effect Period
**One Follow-up visit (FU1) should be performed 42 calendar days after the discontinuation of study drug for all patients. For patients who discontinue not due to progressive 
disease, additional FU visits will be performed at 6-week intervals plus /minus 3 days, until progression, lost to follow-up, start of another anti-cancer treatment, death.
After the interim data base lock additional FU visits are no longer required
***Treatment courses are 3 weeks in duration (21 days). All subsequent visit dates should be calculated based on Course 1 Visit 1 date. If one visit is skipped in case of treatment 
interruption patients may continue on treatment until the criteria for stopping medication are met (see Section 3.3.4)
1Written informed consent must be obtained before any trial specific screening assessments are performed.
2A complete physical examination (including cardiac, neurological, dermatological pulmological etc..) at screening and before the start of the treatment, EoT and End of Residual 
Effect Period (EoR). At further time points specified in the Flow Chart, physical examination should be limited to the assessment of the actual health status (including, evaluation 
of blood pressure, ECG, lab safety parameters, AEs, concomitant therapies, ECOG, as applicable). After the interim data base lock, physical examination, ECOG performance 
status are no longer mandatory at the specific visits but will be performed at the investigator’s discretion. Findings will be documented in the eCRF only if qualifying as (S)AE 
3Body Temperature: whenever possible the same method should be used for body temperature measurement in one patient. Body temperature > 38°C  must be re assessed 1 hour 
after. After the interim data base lock body temperature is no longer mandatory at specific visits but will be performed at the investigator’s discretion. Findings will be documented 
in the eCRF only if qualifying as (S)AE
4Blood Pressure : Systolic and diastolic blood pressure as well as pulse rate (electronic or by palpation, count for 1 minute) will be measured after 5 minutes of rest in seated 
position. The blood pressure measurement should be performed three times at each time point (refer to Appendix 10.2 and Appendix 10.4 for detailed time points). After the 
interim data base lock blood pressure is no longer mandatory at specific visits but will be performed at the investigator’s discretion. Findings will be documented in the eCRF only 
if qualifying as (S)AE
5Haematology, biochemistry and coagulation parameters will be performed locally. Previous safety lab: investigations are acceptable if performed within 72 hours prior to the first 
treatment administration. For details see Section 5.3.3 After the interim data base lock safety laboratory tests will be performed at investigator’s discretion based on the standard 
medical care. Findings will be documented in the eCRF only if qualifying as (S)AE
6Tumor assessment will be performed every 6 weeks after start of treatment with BI 836880 (in the week preceding the start of treatment course 3, 5, 7, 9, 11...) and should include 
CT scans or MRI. Imaging not older than 28 days at start of treatment will suffice as screening images and don’t have to be repeated. The EOT tumor assessment is optional if 
performed in the previous 4 weeks. In the event of any treatment interruption or treatment delay, the tumor assessment should follow the original schedule
After the interim data base lock, frequency of tumor assessment may be adapted according to local standard of care and in agreement with the sponsor if the patient is deriving 
clinical benefit (e.g. CR, PR or SD > 6 months).   

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7Triplicate 12-Lead resting digital electrocardiogram (3xECG taken approximately 2-3 minutes apart) will be performed at screening and will be repeated at visits (refer to 
Section 5.3.4 and Appendix 10.4 for detailed time point).
After the interim data base lock, ECG will be performed as clinically indicated on local machine and the assessment will be done by the investigator. Shipment of ECGs to central 
vendor is no longer required
8Echocardiography will be performed locally at screening (not older than 7 days before start of treatment) and at EoT. During treatment period, echocardiography will be 
conducted only if clinically indicated. After the interim data base lock findings related to echocardiography will be reported in the eCRF only if qualifying as (S)AE
9Pharmacokinetics: For detailed information about pharmacokinetic (PK) sampling time points and handling procedures refer to Appendix 10.4. The last blood samples for PK, 
ADA and Biomarkers (myriad ANG Map Panel, free/total VEGF-A, Ang2) will be taken in this trial when the last patient has discontinued the trial treatment and performed the 
EoT visit. After the interim data base lock no blood sample will be taken for PK analysis
10Immunogenicity assessment (ADA): for detailed sampling schedule refer to Appendix 10.4. After the interim data base lock no blood sample will be taken for ADA analysis
11Biomarker: myriad Ang Map Panel: for detailed sampling schedule refer to Appendix 10.4. After the interim data base lock no blood sample will be taken for Myriad Ang Map 
panel analysis
12Biomarker: free/total VEGF-A, Ang2: for detailed sampling schedule refer to Appendix 10.4. After the interim data base lock no blood sample will be taken for free/total VEGF-
A, Ang2 analysis
13AEs must be collected and reported from signing the informed consent onwards through the end of treatment (including Residual Effect Period, REP): all AEs (serious and non-
serious) and all AESIs must be collected and reported from signing the informed consent onwards through the end of treatment (including Residual Effect Period, REP). After the 
end of treatment (including the REP) during the extended follow-up period until the individual patient’s end of trial: all related SAEs and all related AESIs must be collected and 
reported.  After the individual patient’s end of trial: the investigator does not need to actively monitor the patient for AEs but should only report relevant SAEs and relevant AESIs 
of which the Investigator may become aware of (Please refer to Section 5.3.6 and Section 6.2.3.3)
14DCE-MRI measurements will be done only for suitable patients with preferably liver metastases > 2cm. DCE-MRI measurement will be done during the screening period, 1 
week after first administration of BI 836880 (C1V2), after the 2nd treatment course (C3V1) and after the 4th treatment course (C5 V1) in absence of progressive disease. In case 
patient stopped treatment for other reasons than progressive disease, DCE-MRI should still be conducted as long as patient is in Follow up for progression. Time points for 3rd and 
4th imaging, depending on when patient stopped treatment, have to be adapted as 6 weeks and 12 weeks after 1st infusion
(refer to Section 5.5.1)
After the interim data base lock, DCE-MRI measurement is no longer mandatory

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART COURSE 1 ...................................................................................................4
FLOW CHART COURSES 2 ONWARDS...........................................................................6
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................15
MEDICAL BACKGROUND.............................................................................15
1.1
DRUG PROFILE................................................................................................15
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....18
RATIONALE FOR PERFORMING THE TRIAL.........................................18
2.1
TRIAL OBJECTIVES........................................................................................18
2.2
BENEFIT-RISK ASSESSMENT.......................................................................19
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................21
OVERALL TRIAL DESIGN AND PLAN .......................................................21
3.1
3.1.1
Administrative structure of the trial .................................................................23
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................24
SELECTION OF TRIAL POPULATION .......................................................24
3.3
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria .................................................................................................25
3.3.3
Exclusion criteria ................................................................................................26
3.3.4
Removal of patients from therapy or assessments...........................................27
Removal of individual patients .............................................................................27
3.3.4.1
3.3.5
Discontinuation of the trial by the sponsor.......................................................28
4.
TREATMENTS...................................................................................................29
TREATMENTS TO BE ADMINISTERED.....................................................29
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........29
4.1.2
Method of assigning patients to treatment groups...........................................30
4.1.3
Selection of doses in the trial..............................................................................30
4.1.4
Drug assignment and administration of doses for each patient......................32
Re-treatment criteria .............................................................................................33
4.1.4.1
Dose reduction scheme .........................................................................................33
4.1.4.2
4.1.5
Blinding and procedures for unblinding...........................................................33
Blinding.................................................................................................................33
4.1.5.1
Unblinding and breaking the code ........................................................................34
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................34
4.1.7
Storage conditions...............................................................................................34
4.1.8
Drug accountability.............................................................................................34

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CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....35
4.2.2
Restrictions ..........................................................................................................35
Restrictions regarding concomitant treatment ......................................................35
4.2.2.1
Restrictions on diet and life style..........................................................................36
4.2.2.2
4.3
TREATMENT COMPLIANCE........................................................................36
5.
VARIABLES AND THEIR ASSESSMENT ....................................................37
TRIAL ENDPOINTS..........................................................................................37
5.1
5.1.1
Primary Endpoint(s)...........................................................................................37
5.1.2
Secondary Endpoint(s) .......................................................................................37
ASSESSMENT OF EFFICACY........................................................................37
5.2
ASSESSMENT OF SAFETY.............................................................................38
5.3
5.3.1
Physical examination ..........................................................................................39
5.3.2
Vital Signs............................................................................................................39
5.3.3
Safety laboratory parameters ............................................................................40
5.3.4
Electrocardiogram (ECG)..................................................................................41
5.3.5
Other safety parameters.....................................................................................41
5.3.6
Assessment of adverse events.............................................................................41
Definitions of AEs ................................................................................................41
5.3.6.1
Adverse event collection and reporting ................................................................44
5.3.6.2
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................46
5.4.1
Assessment of Pharmacokinetics.......................................................................46
5.4.2
Methods of sample collection .............................................................................47
5.4.3
Analytical determinations ..................................................................................47
5.4.4
Pharmacokinetic - Pharmacodynamic Relationship .......................................48
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................48
5.5
5.5.1
Imaging Pharmacodynamic endpoints..............................................................49
OTHER ASSESSMENTS...................................................................................50
5.6
5.6.1
Demographic and medical history.....................................................................50
5.6.2
Immunogenicity assessment...............................................................................51
APPROPRIATENESS OF MEASUREMENTS..............................................51
5.7
6.
INVESTIGATIONAL PLAN.............................................................................52
VISIT SCHEDULE.............................................................................................52
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................52
6.2
6.2.1
Screening period..................................................................................................53
6.2.2
Treatment period(s)............................................................................................53
6.2.3
Follow Up Period and Trial Completion...........................................................53
End of treatment visit............................................................................................53
6.2.3.1
Residual effect period (REP) ................................................................................54
6.2.3.2
Follow-up period for progression .........................................................................54
6.2.3.3
Trial completion for an individual patient ............................................................54
6.2.3.4
54
6.2.3.5
Trial completion....................................................................................................

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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................56
STATISTICAL DESIGN – MODEL ................................................................56
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................59
7.2
PLANNED ANALYSES.....................................................................................59
7.3
7.3.1
Primary endpoint analyses.................................................................................59
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................59
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................61
Phamacokinetic analyses.......................................................................................61
7.3.5.1
Pharmacodynamic analyses ..................................................................................63
7.3.5.2
Biomarker analyses...............................................................................................63
7.3.5.3
INTERIM ANALYSES ......................................................................................63
7.4
HANDLING OF MISSING DATA ...................................................................63
7.5
RANDOMISATION ...........................................................................................64
7.6
DETERMINATION OF SAMPLE SIZE .........................................................64
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........65
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................65
DATA QUALITY ASSURANCE ......................................................................65
8.2
RECORDS...........................................................................................................66
8.3
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................66
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................66
8.4
STATEMENT OF CONFIDENTIALITY........................................................66
8.5
END OF TRIAL..................................................................................................66
8.6
PROTOCOL VIOLATIONS .............................................................................67
8.7
9.
REFERENCES....................................................................................................68
PUBLISHED REFERENCES............................................................................68
9.1
UNPUBLISHED REFERENCES......................................................................72
9.2
10.
APPENDICES.....................................................................................................73
INSTRUCTIONS FOR USE..............................................................................73
10.1
10.1.1
Instruction for Pharmacists ...............................................................................73
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................73
10.2
PHARMACOKINETIC ANALYSES...............................................................74
10.3
BLOOD SAMPLING TIME POINTS FOR PK,ADA, BIOMARKER AND 
10.4
ECG RECORDING IN THE PHASE I PART OF THE STUDY(DOSE 
ESCALATION PHASE).....................................................................................76
TRIAL BIOMARKER PLAN............................................................................80
10.5
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.6
AND DATA SCENARIOS .................................................................................80
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................85

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ABBREVIATIONS
ABPM
Ambulatory Blood Pressure Measurement 
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine amino transferase
ANC
Absolute neutrophil count
Ang2
Angiopoeitin2
AST
Aspartate amino transferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BLQ
Below the limit of quantification
BP
Blood Pressure
CA
Competent Authority
CBPM
Conventional Blood Pressure Measurement
CI
Confidence Interval
CPL
Clinical Program Leader
CPPL
Clinical Pharmacology Program Leader
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organisation
CTMF 
Clinical Trial Master File 
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Clinical Trial Leader
CTM
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DCE-MRI
Dynamic Contrast-Enhanced Magnetic Resonance Imaging
DEDP
Drug Exposure During Pregnancy
DBP
Diastolic Blood Pressure
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DSB
Data Safety Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDTA
Ethylenediaminetetraacetic Acid
EoR
End of Residual effect period
EOT
End of Treatment
EudraCT
European Clinical Trials Database
EWOC
Escalation with overdose control
FC
Flow Chart
FU
Follow up
FDA
Food and Drug Administration

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GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HNSTD
Highest No-Severely Toxic Dose
IB
Investigator’s Brochure
IC
Informed Consent
ICH 
International Conference on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
Ktrans
Volume transfer constant obtained from DCE-MRI data
LMWH
Low Molecular Weight Heparin
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTD
Maximum Tolerated Dose
NCA
Non Compartmental Analysis
NCI
National Cancer Institute
NOA
Not Analysed
NOAEL
No Observed Adverse Effect Level
NOP
No Peak detectable
NOR
No valid Result
NOS
No Sample
NSAID
Nonsteroidal Anti-Inflammatory Drug
NYHA
New York Heart Association
OPU
Operative Unit
p.o
Per os (oral)
PD
Progressive Disease
PLGF
Placenta Growth Factor
PK/PD
Pharmacokinetics/Pharmacodynamics
PR
Partial Response
QT
QT interval corrected for heart rate
QTcf
QT interval corrected for heart rate according to Fridericia’s formula
eDC
Electronic Data Capture
RECIST
Response Evaluation Criteria In Solid Tumors
REP
Residual Effect Period
RP2D
Recommended Phase II Dose 
SAE
Serious Adverse Event
SD
Stable Disease
SBPM
Self-Blood Pressure Measurement
SOP
Standard Operation Procedure
SUSAR
Suspect Unexpected Serious Adverse Event
TDMAP
Trial Data Management and Analysis Plan
Tie2
Receptor of the TIE Family

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TME
Translational Medicine Expert 
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSE
Turbo Spin Echo
TSTAT
Trial Statistician
ULN
Upper Limit of Normal
UPCR
Urine Protein to Creatinine Ratio
VEGF
Vascular Endothelial Growth Factor

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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Cancer remains an important health problem with 14.1 million new cancer cases, 8.2 million
cancer deaths and 32.6 million people living with cancer (within 5 years of diagnosis) in 2012
worldwide (R14-2220). Most patients with locally advanced and/or metastatic tumors are not
curable and died due to their disease. There is therefore a substantial need for novel
therapeutic strategies to improve the outcome of patients with advanced or metastatic
malignancies who have failed conventional therapies, or for whom no therapy of proven
efficacy exists. In the last decade, several novel compounds targeting specific cellular
components or tumor environment, including tumor vasculature and angiogenesis have been
developed based on increasing understanding of cancer biology and cell regulation.
Angiogenesis is considered as a key process in tumor growth (R12-2552). Once a certain
tumor size is reached, existing blood vessels are no longer sufficient and new blood vessels 
are required to continue growth. Acquisition of the angiogenic phenotype can result from 
genetic changes or local environmental changes that lead to the activation of endothelial cells. 
One way for a tumor to activate endothelial cells is through the secretion of pro-angiogenic
growth factors (e.g. vascular endothelial growth factor, angiopoietin2, etc.) which then bind
to receptors on nearby dormant endothelial cells that line the interior of vessels.
Vascular endothelial growth factor plays a major role in angiogenesis. Blockade of VEGF
axis has proven to represent an efficacious treatment for patients with advanced malignancies
when given in combination with cytotoxic “backbone” therapy.
Angiopoietin2 (Ang2), a ligand of the Tie2 receptor, play an important role in angiogenesis
and it’s in vivo inhibition results in tumor growth inhibition and vasculature changes (R12-
3593).
Both pro-angiogenic pathways (VEGF/VEGF-R and Ang-2/Tie2) have been reported to
synergize and to crosstalk (R14-5320, R14-5323). The anticipated clinical benefit of
VEGFxAng2 dual inhibition would be the modulation of tumor angiogenesis and reduced
tumor growth rate.
Developement of anti-angiogenic agents targeting pro-angiogenic factors is a valid concept
which showed clinical efficacy in monotherapy (mainly with tyrosine kinase inhibitors: TKI)
and/or in combination with standard treatment (chemotherapies) (R05-2504, R09-5764,
R12-5190, R14-5143, R14-5142, R14-3261, R13-5295, R14-5374, R12-0021, R14-5318).
DRUG PROFILE
1.2
The Nanobody® technology was originally developed following the discovery that camelidae
(camels and llamas) possess fully functional antibodies that lack light chains. These heavy
chain antibodies contain a single variable domain (VHH) and two constant domains (CH2 
and CH3). The cloned and isolated VHH domain is a stable polypeptide harbouring the full

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antigen-binding capacity of the original heavy-chain antibody. These newly discovered VHH
domains form the basis of a new generation of therapeutic antibodies named Nanobodies
(R15-1719).
BI 836880 is a genetic fusion protein of one VEGF-A-binding and one Ang2-binding
single domain antibodies (VHH, Nanobody®). The two single domain antibody moieties are
linked via a human serum albumin-binding Alb11 domain, serving as half-life extension, and
glycine-serine linkers between the domains. The protein has a molecular mass of 40.7 kDa
(c02353882).
BI 836880 potently binds to both hVEGF165 and hVEGF121 with similar affinity in the low
nanomolar to sub-nanomolar range and completely inhibits binding of hVEGF165 to
VEGFR. BI 836880 potently binds to human Ang2 with an affinity constant estimated to be
KD=16pM and potently inhibited and fully blocked human Ang2 binding to Tie2 with an
IC50 of 50pM in the presence of human serum albumin (c02353882).
BI 836880 is highly potent and showed in vivo monotherapy efficacy (tumor growth
inhibition) in several tumor xenograft representing colon cancer (CXF 243), non-small cell
lung cancer (LXFE 211, LXFE 1422), mammary cancer (MAXF 401), ovarian cancer
(OVXF 1353), pancreatic cancer (PAXF 546) and renal cell cancer (RXF 1220)
(c02353882).
BI 836880 cross-reacts to cynomolgus VEGF, as well as mouse, rat and cynomolgus Ang2
which points to cynomolgus monkey as the most suitable species for toxicology assessment.
Based on this, a 13-week repeat dose administration of BI 836880 was performed in
cynomolgus monkeys. Animals received weekly BI 836880 intravenous doses by a 5-minute
infusion at doses of 0 (vehicle only), 1, 10 and 60 mg/kg for a total of 14 doses followed by a
13-week recovery period. BI 836880 was well tolerated up to the highest dose of 60 mg/kg.
No mortality was attributed directly to BI 836880 administration. But one monkey in the
10 mg /kg dose tier had to be euthanized due to an important immunogenic reaction.
BI 836880 did not demonstrate any effects on neurological, renal, or cardiovascular functions
including electrocardiograms (ECGs). In the monkey presenting the immunogenic reaction,
membranoproliferative glomerulopathy in the kidney was observed. This finding was 
considered as a secondary response to immune complex deposition in the glomeruli and not 
directly related to BI 836880 administration.
No BI 836880 related adverse changes in body weight, food consumption or clinical
observations were noted. BI 836880 did not result in ocular changes, changes in physical
examination parameters.
No adverse or BI 836880-related changes in hematology, chemistry, coagulation or urinalysis
were observed (c02353882).
BI 836880 administration resulted in a microscopic growth plate cartilage change (increased
zone of hypertrophy) in the sternum of the males in the ≥10 mg/kg dose groups. This change
was of minimal in severity and was considered not adverse since it was not expected to

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negatively affect bone growth. Increased thickness of the growth plate zone of hypertrophy is
a known effect of angiogenesis inhibitors such as Bevacizumab.
The pharmacokinetics (PK) and immunogenicity of BI 836880 were investigated in
cynomolgus monkeys following a single intravenous (i.v.) at 3 dose levels. BI 836880
demonstrated an unexpected dose-dependent clearance and a supra-proportionally AUC0-∞
increase with the increase of dose. Among the nine monkeys in this study, six monkeys were
ADA positive post-dose at one or more of the sampling time points. In the 13-week toxicity
and toxicokinetics, BI 836880 exposure (Cmax and AUC0-168) increased approximately dose-
proportionally from 1 to 60 mg/kg in weeks 1, 4 and 13. There was a moderate (~ 2-fold)
accumulation of BI 836880 after repeated dosing. The Cmax and AUC0-168 values were similar
between the male and female monkeys at the same dose level in each sampling week. The
discrepancy in dose proportionality between these two studies is likely due to the difference
in sampling. More sampling time points (up to 42 days post dosing) in the single dose PK
study allowed better characterization of the later portion of the concentration-time profiles
(after ~ 240 h), where dose-dependent clearance was more pronounced.
No clinical experience has been gained in humans so far.
For a more detailed description of the drug profile refer to the current Investigator’s Brochure
(IB) which is included in the Investigator Site File (ISF)

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Angiogenesis is the formation of new blood vessels from pre-existing vasculature and is a
key process in tumor growth. The Ang2/Tie2 and the VEGF/VEGFR2 pathways have been
identified as key pathways mediating tumor angiogenesis (R13-0448). Multiple studies have 
described increased VEGF levels in a variety of human cancers and the VEGF expression 
levels have been correlated with poor survival (R15-1720). The VEGF neutralizing 
monoclonal antibody bevacizumab has demonstrated anti-tumor activity in clinical trials and 
is currently approved for several indications and settings, mainly in combination with 
standard chemotherapy regimens (R15-1222).
Studies in mice have shown that Ang2, a ligand of the Tie2 receptor, controls vascular
remodeling by enabling the functions of other angiogenic factors, such as VEGF (R12-3593).
Ang2 is primarily expressed by endothelial cells, strongly induced by hypoxia and other
angiogenic factors and has been demonstrated to regulate tumor vessel plasticity, allowing
vessels to respond to VEGF and FGF2 (R12-3834).
The inhibition of Ang2 is currently being tested in Phase II/III trials of the peptibody
Trebananib in ovarian cancer. In a randomized Phase III trial in patient with recurrent ovarian
cancer Trebananib was tested in combination with paclitaxel compared to chemotherapy
alone and demonstrated improvement in PFS (7.2 month vs 5.4 months, HR 0.66 95% CI
0.57-0.77, p< 0.0001) (R14-5440).
Unfortunately, the anti-tumor activity of VEGF blockers and Ang2 blockers is not durable 
and only a limited number of patients benefit from such therapies. New therapeutic strategies 
are needed to improve outcome of metastatic/advanced cancer patients.
Pre-clinical data demonstrate that improved efficacy can be achieved by combined inhibition
of VEGF and Ang2 (R14-5320, R14-5323). This observation was confirmed by internal data
(c02353882).
This supports testing BI 836880 in human with the objective to improve patients’ outcome.
First step for this clinical development is to define the safety profile of BI 836880 and the
recommended dose for further development.
TRIAL OBJECTIVES
2.2
Primary objective:

To determine the maximum tolerated dose (MTD) of BI 836880 given as weekly
intravenous infusion and to determine recommended phase II dose.
Secondary objective:

To provide preliminary safety data

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BENEFIT-RISK ASSESSMENT
2.3
BI 836880 has not been tested in human so far. In the 13-week toxicology study in
cynomolgus monkeys, BI 836880 was well tolerated up to the highest tested dose of
60 mg/kg.
Anti-VEGF or anti-VEGF-R antibodies have been largely tested in clinic with a well-defined
safety profile. Most commonly reported adverse events with such compounds are fatigue,
hypertension, proteinuria, diarrhea and bleeding (epistaxis). Severe adverse events include
gastrointestinal perforations, tumor haemorrhage and arterial thromboembolism (R14-3588,
R14-3261).
There is less clinical experience with anti-Ang2 compared to VEGF pathway blockade
clinical experience. The most advanced anti-angiopoietin compound (Trebananib) in
development is in Phase III in combination with chemotherapy (R14-5440). Other anti-Ang2
compounds are currently in early stage of clinical development (R15-1645, R15-1646, R15-
1648). From this clinical experience the most commonly reported side effects are fatigue and 
gastro-intestinal symptoms (diarrhea, nausea and vomiting). No bleeding or thromboembolic 
events were reported with this class of compound. Of note, almost all tested anti-Ang2 
molecules failed to define a MTD (R15-1646, R15-1648).
Limited clinical experience of dual blockade is available. Recently, Phase I data of the
bispecific human anti-Ang2/anti VEGF-A antibody (RG7221) were reported. MTD was not
reached with only one dose limiting toxicity (DLT) reported (fatal pulmonary hemorrhage).
Hypertension was the most common observed adverse event (R15-1644).
Based on this clinical available data it is expected that blockade of both targets will result in
similar side effects as anti-VEGF and anti-Ang2 blockade. Based on the phase I trial results
of RG7221 no increase in side effect severity is anticipated with BI 836880. It is anticipated
that the safety profile of BI 836880 will most likely include fatigue, hypertension,
proteinuria, gastro-intestinal side effects and bleeding.
Previous clinical experience with nanobodies in different disease showed acceptable safety
profile with no specific side effect related to this technology (R13-2303).
Because additional adverse event not previously observed with anti-VEGF and anti-Ang2
may also occur in humans, and taking in consideration BI 836880 toxicology study results,
patients will be closely monitored for the development of adverse events that may results
from BI 836880 administration, with a special attention to renal function and immunogenic
side effect.

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Although rare, a potential for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´
safety (see also Section 5.3.6.1)
Because of the early stage of development of BI 836880 no reproduction toxicity or 
genotoxicity studies were performed. Because of advanced stage of the disease of phase I 
studies populations, women of childbearing potential can be included in this study. To 
minimize the risk of unintentional exposure of an embryo or foetus to the investigational 
drug, women of childbearing potential must agree to the requirements for pregnancy testing 
and contraceptive methods described in this protocol.
A Data Safety Board (DSB) will be appointed to periodically review and monitor data from 
the trial (refer to Section 3.1.1).
Overall, BI 836880 is expected to have an acceptable safety profile and an adequate
risk/benefit in patients with locally advanced or metastatic solid tumor who are either
refractory after standard therapy for the disease or for which standard therapy is not reliably
effective.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a Phase I, multi-centre, non-randomized, uncontrolled, open-label, dose escalating 
study of BI 836880 administered intravenously. The eligible patient population will be 
patients with advanced solid tumors. Dose escalation will be guided by a Bayesian logistic 
regression model with over dose control (details refer to Section 7), restricted to a maximum 
200% dose increment for the first dose escalation and maximum of 100% dose increment for 
dose >120 mg. At any time during the trial, it will not be permitted to escalate to a dose 
which does not fulfil the escalation with overdose control (EWOC) criterion (refer to Section 
7). 
For any dose-escalation cohort, at least 2 patients will be required. At first dose level, first 
patient will be treated and observed for at least 2 weeks before allowing the second patient to 
receive BI 836880 infusion. For subsequent dose levels within dose escalation, each patient 
in a given cohort (dose level) will be observed for a minimum of 48 hours after first BI 
836880 application before allowing treatment for subsequent patient in the same cohort .
In case only 2 patients are evaluable and neither has experienced a DLT within the first 
course, then dose-escalation can occur based on these 2 patients. However, should one of 
these 2 patients experience a DLT in the first course, a third patient will be enrolled at the 
same dose level. After all patients in a cohort have either experienced a DLT or have been 
observed for at least one course (3 weeks) without a DLT, the Bayesian model will be 
updated with the newly accumulated data. The overdose risk will then be calculated for each 
dose, and escalation will be permitted to all doses which fulfil the EWOC criterion and the 
dose escalation scheme according to Section 4.1.3. Decision on further recruitment (dose
escalation, de-escalation or cohort expansion) will be made by a Data Safety Board (DSB)
based on the collected safety data as well as other data (e.g. PK/PD data) when available. 
If DLTs are observed in the first two consecutive patients of a previously untested dose level, 
subsequent enrolment to that cohort will be stopped. The Bayesian logistic regression model 
will be re-run to confirm that the dose-level still fulfils the EWOC criterion. Decision will be 
made whether the next patients will be enrolled on the same dose level, or if they will be 
enrolled to a lower dose level.

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Figure 3.1: 1Study design
All patients eligible after the screening will be administrated with BI 836880 weekly 
infusion. In case the patient shows a stable disease or even a response, the study treatment 
will continue until one of the withdrawal criteria listed in Section 3.3.4 is met.
An estimated of about 25-30 patients will be necessary to establish MTD and confirm RP2D.
Confirmation of the RP2D will be made based on all available safety, PK and 
Pharmacodynamics (PD) data at all treatment courses and all dose levels.
All patients will have regular evaluations for assessment of safety parameters as detailed in 
the Flow Chart.
An End of trial (EOT) evaluation is to be completed when a patient permanently discontinues 
the study drug, for any reason listed in Section 3.3.4.
A Follow-up evaluation will be completed 42 days after permanent discontinuation of the 
study drug. Refer to the Flow Chart for details. This visit will be defined as the last visit in 
the on-study period for the trial.
For adverse event collection, please refer to Section 5.3.6.
Further PK/PD 
Further safety assessment
Anti-tumor activity
Dose escalation
Screening: Up to 21 
days before treatment 
start
(28 days for tumor 
imaging imaging)
Treatment starting dose BI 
836880 
at  40 mg
Qw dosing 
Bayesian model with EWOC: 
Dose recommendation after every 
dose cohort
At least 2 patients per cohort
Data Safety Board:
Determination of MTD and RP2D
EOT within 21
days of the last 
administration 
of study drug 
1 Follow 
up visit
Or
Additional 
Follow up 
visits every 
6 weeks for 
patients 
who 
discontinue 
not due to 
Progressive 
disease, 
until PD or 
lost to 
follow up 
or start of 
anti-cancer 
therapy, 
death
Residual period = EOT + 42 days

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After the interim data base lock, the study is considered completed when the last patient in 
the study has discontinued the study treatment and completed the EoR visit (see Section 
6.2.3.5).
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim and will be conducted in two (2) sites. 
Additional sites may be added to boost the recruitment and recruitment may vary between 
sites. 
The study will be performed by investigators specialized in the treatment of advanced cancers 
and experienced in phase I trials in oncology.
A DSB will be appointed to evaluate DLT, overall safety and other available data (e.g. PK 
data) and confirm dose escalation steps. DSB will also evaluate all available data to confirm 
the Recommended Phase II dose, as well as the decision for a tumor type expansion cohort.
Members of the DSB will be investigators of participating trial sites, Trial Statistician
(TSTAT), Clinical Program Leader (CPL), Clinical Trial Leader (CTL) and BI Lead Risk 
Management Physician. Clinical Pharmacology Program Leader (CPPL) and Translational 
Medicine Expert (TME) can be invited as needed, especially for discussion of PK/PD and 
biomarker.
Minimum data for dose escalation decision will be described in the DSB charter. 
On-site monitoring will be performed by BI or by CRO authorized by Boehringer Ingelheim. 
Pharmacokinetic analyses will be performed by Boehringer Ingelheim or a CRO authorized 
by Boehringer Ingelheim. 
Exploratory biomarker analyses will be performed by BI and/or a dedicated CRO/ laboratory 
authorized by Boehringer Ingelheim.
Routine safety laboratory exams will be performed by local laboratories.
All relevant trial documentation will be stored in Boehringer Ingelheim Trial Master File 
(TMF) at BI. In addition, each site will have an Investigator Site File (ISF) containing all trial 
documents relevant for the site.
Boehringer Ingelheim has appointed a Trial Clinical Leader (CTL), responsible for 
coordinating all required activities, in order to:
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial,
-
ensure appropriate training and information of local Clinical Trial Manager (CTM),
Clinical Research Associates (CRAs), and Investigators of participating countries.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information
can be found in the ISF.

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A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and 
responsibilities will be defined in a contract. Relevant documentation on the participating 
(Principal) Investigators and other important participants, including their curricula vitae, will 
be filed in ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
This open label, single arm, dose-escalation trial is designed to determine the MTD and 
Recommended Phase II dose of BI 836880 monotherapy. No control group is planned. Dose 
escalation and cohort size will be determined based on a Bayesian logistic regression model 
with overdose control. An escalation with overdose control design will increase the chance of 
treating patients at efficacious doses while reducing the risk of overdosing. This design is 
based on practical experience and is a preferable algorithmic method due to its superior 
ability to identify the dose with the desired toxicity rate and its allocation of a greater 
proportion of patients to doses at, or close to, that dose (R13-4802, R13-4804, R13-4805). 
The trial can be expanded for early evaluation of antitumor activity of the drug in a specific 
tumor type and setting if signal of antitumor activity is observed during the dose escalation 
phase and/or RP2D confirmation phase. This expansion will take place after a protocol 
amendment.
SELECTION OF TRIAL POPULATION
3.3
It is estimated that approximately 40 patients will be enrolled at 2 study sites. The rate of 
enrolled patients may vary by study site, but it is expected to be approximately 20 patients 
per site. Among them approximately 25 patients will be treated in this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
Patients will be selected based on the eligibility criteria described below.
3.3.1
Main diagnosis for trial entry
All patients that will be included into the trial must have been diagnosed with histologically
or cytologically confirmed advanced or metastatic solid tumor, and either refractory after 
standard therapy for the disease or for which standard therapy is not reliably effective.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.

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3.3.2
Inclusion criteria
1.Age ≥18 years

2.Histologically confirmed malignancy which is locally advanced or metastatic solid 
tumor, and either refractory after standard therapy for the disease or for which 
standard therapy is not reliably effective e.g patients do not tolerate or have 
contraindications to otherwise available standard therapy and tumour lesions 
evaluable for Dynamic contrast-enhanced (DCE) MRI at MTD.
3.
ECOG performance status ≤ 2
4.
Adequate hepatic, renal and bone marrow functions as defined by the following 
criteria: 
a.
Total bilirubin within normal limits (≤ 1.5x ULN for patient with Gilberts   
syndrome)
b.ALT and AST ≤ 1.5x ULN (< 5xULN for patient known liver metastases)
c.Serum creatinine < 1.5x ULN
d.INR 0.8-1.2 or PTT < 1.5x ULN
e.ANC > 1.5 109/L
f.Platelet count > 100x109/ L.
g.Heamoglobin > 10 g/dl (without transfusion within previous week)
5.
Signed and dated written informed consent.
6.
Life expectancy ≥ 3 months in the opinion of the investigator
7.
Recovery from all reversible adverse events of previous anti-cancer therapies to 
baseline or CTCAE grade1, except for alopecia (any grade), sensory peripheral 
neuropathy CTCAE grade < 2 or considered by the investigator as clinically not 
significant.
8.
Male or female patients. Women of childbearing potential* must be ready and able to 
use highly effective methods of birth control per ICH M3(R2) in combination with
male condom as “double barrier”, during the trial and for at least 6 months after the 
end of treatment with BI 836880, that result in a low failure rate of less than 1% per
year when used consistently and correctly. A list of contraception methods meeting 
these criteria is provided in the patient information.
Male patient must always use condoms when sexually active during the trial and for 
at least 6 months after the end of treatment with BI 836880.
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for "women not 
of childbearing potential" as described below.
Women not of childbearing potential are defined as:

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Women who are postmenopausal (12 months with no menses without an alternative 
medical cause) or who are permanently sterilized (e.g., hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
3.3.3
Exclusion criteria
1. Known hypersensitivity to the trial drugs or their excipients or risk of allergic of 
anaphylactic reaction to the study drug according to the investigator judgement (e.g. 
patient with history of anaphylactic reaction or autoimmune disease that is not controlled 
by nonsteroidal anti-inflammatory drugs (NSAIDS), inhaled corticosteroids, or the 
equivalent of < 10 mg/day prednisone)
2. Current or prior treatment with any systemic anti-cancer therapy either within 28 days or 
a minimum of 5 half-lives, whichever is shorter at the start of study treatment.
3. Serious concomitant disease (based on investigator judgement), especially those affecting 
compliance with trial requirements or which are considered relevant for the evaluation of 
the endpoints of the trial drug, such as neurologic, psychiatric, infectious disease or active 
ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk 
associated with trial participation or trial drug administration, and in the judgment of the 
investigator would make the patient inappropriate for entry into the trial.
4. Major injuries and/or surgery (as judged by the investigator) or bone fracture within 4 
weeks of start of study treatment, or planned surgical procedures during the trial period.
5. Patients with personal or family history of QT prolongation and/or long QT syndrome, or 
prolonged QTcF at baseline (> 470 ms). QTcF will be calculated by Investigator as the 
mean of the 3 ECGs taken at screening.
6. Significant cardiovascular/ cerebrovascular disease (i.e uncontrolled hypertension, 
unstable angina, history of infarction within past 6 months, congestive heart failure > 
NYHA II). Uncontrolled hypertension defined as: blood pressure in tested and relaxed 
condition >= 140 mmHg, systolic or > 90 mmHg diastolic (with or without medication), 
measured according to Section 5.3.2 and Appendix 10.2.
7. History of severe haemorrhagic or thromboembolic event in the past 12 months 
(excluding central venous catheter thrombosis and peripheral deep vein thrombosis).
8. Known inherited predisposition to bleeding or to thrombosis in the opinion of the 
investigator.
9. Patient with brain metastases that are symptomatic and/or require therapy.
10. Patients who require full-dose anticoagulation (according to local guidelines). No vitamin 
K antagonist and other anticoagulation allowed; low-molecular-weight heparin (LMWH)
allowed only for prevention not for curative treatment.

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11. Use of alcohol or drug incompatible with patient participation in the study in the 
investigator opinion
12. Patient unable or unwilling to comply with protocol
13. Women who are pregnant, nursing, or who plan to become pregnant while in the trial
14. Previous enrolment in this trial
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision.

Requiring concomitant drugs that interfere with the investigational product or other trial
medication (see Section 4.2.2) or patient who requires concomitant drugs, which in the 
opinion of the investigator may interfere with the investigational drug.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

The patient is no longer able to complete trial visit or trial-required procedures.

A DLT occurs which does not recover to a degree that allows continuation of treatment
(see Section 4.1.4) for re-treatment criteria and dose reduction scheme)

Progressive disease (except in cases with intra-patient dose escalation, (see Section
4.1.3) or start of any new anti-cancer therapy.
A patient can have withdrawn from the trial after discussion between the Investigator and the 
Sponsor if eligibility criteria are violated and/or the patient fails to comply with the protocol.
All withdrawals will be documented and the reason for withdrawal recorded and discussed, as
necessary, in the final Clinical Trial Report (CTR). As soon as a patient is withdrawn from 
the study treatment, the end of treatment visit (EoT) has to be performed if feasible. Every 
effort should be made to follow-up with patients in case an adverse event is still ongoing at 
the time of withdrawal. If a patient is withdrawn from the trial due to consent withdrawal, no 
further visit will be completed.
Patients who have not completed first course of BI 836880 treatment (3 weeks) for any other
reason than BI 836880 related toxicities will be considered not evaluable for MTD evaluation 
and should be replaced.
Patient who prematurely discontinue study drug for above mentioned reasons or any other 
reason, should have additional follow up visits until progression, lost to follow up, treatment 
with another anti-cancer treatment, death and /or end of the trial whichever comes first.

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Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the FC and Section 6.2.3.
Should the patient become pregnant during the trial, the treatment with BI 836880 must be 
stopped immediately, and this patient is not allowed to receive further trial medication from 
that point onward. The patient will be followed up until delivery or termination of pregnancy 
(see Section 5.3.6.2). The data of the patient will be collected and reported in the CTR until 
last patient last visit and any events occurring thereafter will be reported in BI drug safety 
database.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
(e)CRF. These data will be included in the trial database and reported.
3.3.5
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Violation of Good Clinical Practice (GCP), the CTP, or the contract 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).

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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1
Test product 1
Substance:
BI 836880
Pharmaceutical formulation:
solution for infusion after dilution
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml (vials with 10 ml)
Posology
rate controlled infusion
Route of administration:
i.v.
Duration of use
until progression disease or unacceptable toxicity
Table 4.1.1: 2 
Diluent for Test product 1
Substance:
Diluent for BI 836880 drug product
Pharmaceutical formulation:
Diluent to prepare solution for infusion of BI 836880
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
50 ml/vial
Posology
rate controlled infusion
Route of administration:
i.v.
Duration of use
until progression disease or unacceptable toxicity

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4.1.2
Method of assigning patients to treatment groups
There is no randomisation, eligible patients will receive treatment.
Allocation to dose cohorts or expansion cohort will be done according to subject temporal 
availability and depending on dose cohort open for recruitment.
During Visit 1/Day 1 and after the patient’s eligibility has been confirmed, the treatment will 
be assigned via Interactive Response Technology (IRT). 
For medication number allocation at each visit, it’s possible to conduct IRT call ahead of the 
planned visit (= day of administration)
To facilitate the use of the IRT, the Investigator will receive all necessary instructions.
4.1.3
Selection of doses in the trial
Starting Dose 
Maximum safe starting dose was estimated using different methods taking in account all 
available nonclinical information, including PK/PD and toxicity data. The starting doses from 
these calculations were compared. The lowest dose derived from these calculations is 
recommended for the maximum safe starting dose (refer to Investigator’s Brochure for more 
details (c02353882)).
Based on the 13-week Good Laboratory Practice (GLP) toxicology trial in cynomolgus 
monkey, the Non-Observed-Adverse-Effect-Level (NOAEL) /Highest Non-Severely Toxic 
Dose (HNSTD) is defined as 60 mg/kg. According to this method and using a safety factor of 
6, the maximum starting dose is 10 mg/kg.
As a second approach, a mathematical PK/PD model was developed to predict the human 
therapeutic dose of BI 836880. The model was calibrated to data from a cynomolgus monkey 
PK/PD study and then scaled to human to perform simulations. The model is a two 
compartment in vivo model that includes the target ligands (VEGF-A and Ang2), their 
corresponding receptors (VEGFR2 and Tie2) and additional ligand/receptor pairs that share 
common receptors. Predictions were made for the minimum dose that maintains a high level 
of reduction in both VEGF:VEGFR2 and Ang2:Tie2 complexes by  BI 836880 at steady 
state. The VEGF-A:VEGFR2 complex and Ang2:Tie2 complex levels were considered 
surrogates of receptor signaling in silico.
The predicted human dose that according to this simulations achieves reduction in both 
VEGF:VEGFR2 and Ang2:Tie2 complexes at Cmin,ss is 0,67 mg/kg for a weekly dosing. At a 
dose level of 0.67 mg/ kg (dosed once every week) the fraction of VEGF-A:VEGFR2 
complex is predicted to be reduced to 35% - 55% of the pre-dose level, and the fraction of 
Ang2:Tie2 complex is predicted to be reduced to below 0.1 (90%) of the pre dose level.
Since the two methods resulted in different starting doses, and the dose based on the PK/PD 
modeling is expected to allow achieving reduction in both VEGF:VEGFR2 and Ang2:Tie2 
complexes, the lowest dose was selected as starting dose in this first in human trial.
The recommended starting dose is 0.67 mg/kg, correlates to a total dose of 40 mg.

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Dose escalation Scheme
Furthermore, the PK/PD modelling provided information on the number of doses needed to 
reach the targeted Cmin concentration in plasma that is supposed to maintain a continuous 
high suppression of VEGF-A:VEGFR2 and Ang2:Tie2 complex formation (>90%).
In a weekly dosing schedule, target Cmin plasma concentrations are expected to be achieved 
after 7 infusions of BI 836880 at dose of 2 mg/kg (120 mg), after 2 infusions at dose of 6 
mg/kg (360 mg) and after 1 infusion at dose of 12 mg/kg (720 mg).
To minimize the number of patients to be treated at a non-therapeutic dose (below targeted 
concentration) within an acceptable time to steady state, a maximum of 200% dose increment
will be applied for dose levels up to 40 mg. Dose escalation >120 mg will not exceed 100% 
dose increment. No dose adaptation to body weight or body surface will be made. All patients 
at the same dose level (DL) will be treated with the same total dose. Table 4.1.3: 1 shows 
potential dose levels to be tested.
Table 4.1.3: 1
Potential Dose levels
Dose level
Total dose (mg)
Approximate increment 
to next dose
Dose level 1 
( starting dose)
40
3x  (200%)
Dose level 2
120
1.25x (25%)
Dose level 3
150
1.20x (20 %)
Dose level 4
180
1.3x (30%)
Dose level 5
240
2x  (100%)
Dose level 6
480
1.5x (50%)
Dose level 7
720
1.3x (30%)
Dose level 8
960
1.7x (30%)
Dose level 9
1440 limited to 1250*
*Maximum dose that can be tested due to excipient limitation
Intermediate dose levels can be tested based on DSB decision.
Whenever a dose escalation step is to be performed (or a new cohort will be opened for 
recruitment), the data of previous dose cohorts with priority on DLTs will be reviewed and 
discussed within the DSB. DSB can decide to increase the dose, expand the tested cohort or 
to test an intermediate dose level.

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Patients, who received at least two treatment courses, deeming to have clinical benefit from 
treatment and tolerated BI 836880 well (i.e do not show any DLT) could be allowed to 
receive increased dose. Such decision will be taken in case by case manner on request by the 
investigator and confirmation by the DSB based on actual patient profile. Intra patient dose 
escalation can be repeated; however the dose can only be increased to the highest tested safe 
dose.
For patients with an intra-patient dose escalation(s) all assessments will be done according to 
instructions for the first cycle at start of treatment with BI 836880 and intensive PK-
sampling, sampling for ADA as well as sampling for biomarkers (Myriad panel and free/total 
VEGF-A/ Ang2) will be conducted (see flow chart and Appendix 10.4) and patients have to 
be closely followed for any adverse events. Therefore patients have to come to the clinic 
during the first course of intra-patient dose escalation every week. Additional visits are 
needed at day 2 and at day 3 of the 1st cycle of dose escalation. 
The above-mentioned procedures will be followed also in case of further intra-patient dose 
escalations.
4.1.4
Drug assignment and administration of doses for each patient
The study drug will be prepared according to “Instruction for Pharmacists” which will be 
filed in ISF. Upon notification of an entered patient in the study, the pharmacy will prepare 
the study drug in the assigned dosage for administration to the patient. 
BI 836880 will be given as weekly intra-venous infusion by authorised site staff in a 
specialized unit where emergency care can be provided (e.g. intensive care unit available, 
medical personal trained in advanced live support) according to “Instruction for 
Pharmacists”. The expected infusion time is 90 min. in case no relevant infusion reactions are 
observed, this may be shortened to about 30 min but should not be prolonged to more than 6 
hours even in case of technical issues. Appropriate drugs and medical equipment to treat 
anaphylactic reactions must be immediately available and study personal must be trained to 
recognize and treat anaphylaxis.
If symptoms of an infusion-related reaction CTCAE grade > 2 occur (that are not qualifying 
as DLT according to Section 5.3), the infusion should be temporarily stopped. Upon 
recovery, infusion should be resumed at 50% of the rate at which the reaction occurred. 
Depending on the time of occurrence and the severity of the reaction, the investigator may 
consider administrating additional supportive medication, e.g. corticosteroids for re-
introduction. Infusion rate and premedication for further treatment courses should be adapted 
according to Investigator decision, but adaptation of application scheme need to be agreed 
with sponsor.
BI 836880 will be administrated intravenously starting on course1 day1. In the event of delay 
or interruption of treatment due to adverse event, BI 836880 infusion should be skipped; and 
the next scheduled BI 836880 infusion should be administrated upon recovery to CTCAE 
Grade 1. 
Premedication: No premedication will be required for BI 836880 IV infusion.

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If a patient experienced sign of infusion reaction at any BI 836880 treatment, a premedication 
will be considered for all subsequent treatment infusions (dosage and schedule according to 
investigator’s decision) comparable to the following scheme:

Acetaminophen/paracetamol 650 mg-1000 mg p.o., or equivalent

Antihistamine p.o. or i.v., equivalent to Diphenhyldramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg
If infusion reaction and /or hypersensitivity reaction occurs in substantial amount of patients 
(about 30%) of treated patients without premedication, premedication, as described above, 
will be given to all treated patients. Such decision will be confirmed by the DSB; dosage and 
schedule should be aligned, and reflect institutional clinical standards.
Re-treatment criteria
4.1.4.1
Before initiating a new treatment course the actual health status will be assessed according to 
Flow Chart and described in Section 5.3. To continue treatment with further courses, all of 
the following criteria must be met:
QTcF < 470 ms (according to exclusion criterion #5)
No uncontrolled hypertension (according to exclusion criterion #6)
Acceptable tolerability (in case of an adverse event at the planned start of a treatment course 
patients may continue therapy only after recovery to a level which would allow further 
therapy; i.e. CTCAE grade 1 or pre-treatment value or considered not clinically significant).
In case one of the above mentioned criteria is not fulfilled the patient should be re-evaluated 
for up to 2 weeks. Any case of a delay in treatment course should be communicated to the 
Clinical Monitor at Boehringer Ingelheim. The investigator in agreement with the Clinical 
Monitor will decide about further treatment of individual patient, based on known risk/benefit 
of BI 836880. 
Dose reduction scheme
4.1.4.2
Administration of trial drug has to be stopped temporarily in case of a DLT (see Section 5.3). 
Patients may continue therapy only after recovery from DLT to at least fulfil re-treatment 
criteria. The future dose of BI 836880 must be finally agreed on between the sponsor and the 
investigator. A reduction of the dose will be allowed only once for an individual patient 
during the whole trial. Treatment has to be discontinued in case the DLT is not reversible.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Not applicable. In this open-label trial, treatment allocation will not be concealed throughout 
the trial. The CRF will contain information on allocated treatment.

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Unblinding and breaking the code
4.1.5.2
Not applicable
4.1.6
Packaging, labelling, and re-supply
BI 836880 will be supplied in 10 ml 10R vial containing 100 mg BI 836880 [10 mg/ml]
solution for infusion. The BI 836880 vials will be packed in one vial box. 
Diluent for BI 836880 drug product will be supplied in 50R vial containing 50 ml Diluent for 
BI 836880 drug product. The Diluent vials will be packed in one vial per box.
Boxes and vials will be labelled according to local regulations.
For details of packaging and the description of the label, refer to the ISF.
BI 836880 drug re-supply will be managed through IRT by the trial sites and BI
personnel.
4.1.7
Storage conditions
BI 836880 vials and Diluent vials, which will be provided by the sponsor and/or a CRO 
appointed by the sponsor must be kept in their original packaging and in secure limited 
access storage area according to the recommended storage conditions on the medication
label. The Investigator, the Pharmacist, or other personnel allowed to store and dispense.
The Investigator or pharmacist or investigational drug storage manager will be responsible 
for ensuring that the investigational product used in the study is securely maintained as 
specified by the sponsor and in accordance with the applicable regulatory requirements.
A temperature log must be maintained for documentation.
For details concerning the preparation of the infusion solution of BI 836880, please refer to 
the ‘instructions for pharmacists’ filed in the ISF.
4.1.8
Drug accountability
The Investigator or pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol,

Availability of the proof of a medical license for the principal Investigator.

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The Investigator or pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor after IRB / ethics committee approval of the 
trial and completion of a clinical trial contract between the Sponsor and the Head of Trial 
Center.
The Investigator or pharmacist or 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 patient, and 
the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. All remaining drug supplies
received at a respective study site will be destroyed at site. Partially used vials will be
destroyed after preparation infusion; unused medication and Diluent will be destroyed after
expiry or at the end of study before closing the site.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
Concomitant (non-oncological) therapies starting or changing during the course of the trial 
should be recorded in the electronic Case report Form (eCRF).
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication to reverse the action of BI 836880 is not available.
Potential side effects of BI 836880 have to be treated symptomatically. Symptomatic 
treatments of side effects or tumor-associated symptoms are allowed. Concomitant 
medications, or therapy to provide adequate care, may be given as clinically necessary. There 
are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Previous anti-cancer therapy must have been discontinued before first administration of BI 
836880 and the patient must have recovered from all clinical relevant reversible toxicities 
(see exclusion criteria in Section 3.3.3).
Concomitant anti-cancer therapy is not allowed.
Radiotherapy for local symptom control of non-target lesions can be allowed after discussion 
between the investigator and the sponsor. The irradiated area cannot be used for response 
assessment.

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Full-dose anticoagulation (according to local guidelines) with Vitamin K antagonist and other 
anticoagulation is not allowed during the trial conduct; LMWH is allowed only for 
prevention not for curative treatment.
Any planned surgeries are not allowed. Unplanned surgeries should be postponed whenever 
possible four weeks after stop of treatment. For urgent interventions patients should not be 
treated further and does require intense monitoring regarding wound healing and 
postoperative complications.
Restrictions on diet and life style
4.2.2.2
No restriction
4.3
TREATMENT COMPLIANCE
BI 836880 must be administered as an intravenous infusion under supervision of the 
investigator or dedicated clinical personnel. 
Compliance may be also be verified by pharmacokinetic assessment. Any discrepancies will 
be documented in the eCRF by the investigator or designee.

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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint(s)
The primary endpoint to determine the maximum tolerated dose (MTD) based on the number 
of patients presenting dose limiting toxicity (DLT) using the National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) V4.03, during the first course
(i.e. over the first 3 weeks of treatment) and judged to be related to the study medication.
5.1.2
Secondary Endpoint(s)

Drug related AEs leading to dose reduction or discontinuation during treatment period
ASSESSMENT OF EFFICACY
5.2
The assessment by the investigator and the local radiologist will be the basis for continuation 
or discontinuation of the trial in an individual patient (in addition to safety). Tumor 
assessment will be performed every 6 weeks after start of treatment and at the time points 
specified in the Flow Chart. 
After the interim data base lock, frequency of tumor assessment may be adapted according to 
local standard of care and in agreement with the sponsor if the patient is deriving clinical 
benefit (e.g. CR, PR or SD > 6 months).   
CT images at baseline should be performed as close as possible to the treatment start and not 
older than 28 days at start of treatment.
At baseline, the investigator along with the radiologist will record the target (five target 
lesions maximum and maximum two per organ) and non-target lesions at baseline in the 
eCRF before the start of treatment. The same method of assessment and the same technique 
should be used to characterize each reported lesion at baseline and during follow up. Lesions 
in previously irradiated areas may not be considered measurable at baseline unless the lesions 
occurred after irradiation. Response will be evaluated according to the response evaluation 
criteria in solid tumors (RECIST version 1.1 (R09-0262). In the event of a delay, interruption 
or discontinuation of treatment, tumor assessment should continue to follow the original 
schedule. The schedule should be followed until progression is observed or until the patient 
commences further treatment for disease, whichever occurs first.

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Results of tumor-specific tumor markers which will be assessed routinely should be 
documented in the eCRF. 
After the interim data base lock, documentation of tumor markers in the e-CRF is no longer 
required.
ASSESSMENT OF SAFETY
5.3
Dose Limiting Toxicity (DLT)
The following drug-related adverse events will qualify as Dose-Limiting Toxicities:

CTCAE grade > 3 non haematological toxicity except:
Vomiting or diarrhea responding to supporting treatment
Fatigue lasting for less than 4 days
Transcient Grade 3 infusion reaction (i.e. if infusion- related reaction can be 
controlled by appropriate medication according to investigator’s decision and next 
infusion will not be delayed for more than two weeks).
Any laboratory abnormality, which is considered not clinically relevant by the 
investigator or resolves spontaneously or can be resolved with appropriate 
treatment. Clinically relevant abnormalities have to be documented as AE (see
Section 5.3.6)

CTCAE grade 4 neutropenia >7 days or complicated by infection (in case of 
neutropenia grade 4, close observation of patient is necessary.

CTCAE grade >3 febrile neutropenia 

CTCAE grade = 4 thrombocytopenia 

CTCAE grade > 3 thrombocytopenia with bleeding 

CTCAE grade > 3 proteinuria (urinary protein > 3.5 g/day)

Hypertension: increase of diastolic blood pressure (BP) by 15 mmHg confirmed by 
second measurement or ambulatory blood pressure measurement (when indicated; e.g. 
white coat effect) which cannot be controlled by hypertensive medication and requires
a dose reduction of BI 836880 for further treatment course.

All related AE leading to an interruption of BI 836880 for more than 14 days until 
recovery to baseline.
The MTD may be considered reached if the probability that the true DLT rate is in target 
interval (16%-33%) is sufficiently large (for details see Section 7). The DSB may recommend 
stopping the dose finding phase after the criterion for MTD is fulfilled. 
If the next dose level is recommended by the statistical model, however, the efficacy is 
considered sufficient at current dose level, the DSB may decide to include additional number
of patients at this dose level and declare this dose as RP2D and no further dose escalation will 
happen.
Based on the overall data after all patients on proposed RP2D have been treated for at least 1 
course, the DSB will make a final determination of RP2D.

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5.3.1
Physical examination
A complete physical examination including (height at screening only), cardiac, neurological, 
dermatological pulmological, weight and ECOG performance score, will be performed at 
screening and before the start of the treatment, EoT and EoR.  At further time points specified 
in the Flow Chart, not a complete physical examination will be performed, but at minimum 
the actual health status of the patient should be assessed (including, evaluation of blood 
pressure, ECG, lab safety parameters, AEs, concomitant therapies, ECOG as applicable).
During the physical examination, the patient should be assessed for possible AEs.
After the interim data base lock, physical examination, ECOG performance status, weight are 
no longer mandatory at the specific visits but will be performed at the investigator’s 
discretion. Findings will be documented in the eCRF only if qualifying as (S)AE. 
5.3.2
Vital Signs
Vital signs (blood pressure, heart rate and body temperature) will be recorded at every visit 
indicated in the flow chart.
At day of administration two time points will be evaluated:
1- At pre-dose (-60 minutes to – 5 minutes)
2- Shortly before the end of infusion 
In case of an infusion-related reaction, if deemed necessary, the investigator should decide 
for intensive monitoring of vital signs.
Blood pressure
Systolic and diastolic blood pressure as well as pulse rate (electronic or by palpation, count 
for 1 minute) will be measured after 5 minutes of rest in seated position. The blood pressure 
measurement should be performed three times at each time point and values of these 
measurement will be entered in the CRF (refer to Appendix 10.2 and Appendix 10.4)
After the interim data base lock blood pressure is no longer mandatory at specific visits but 
will be performed at the investigator’s discretion. Findings will be documented in the eCRF 
only if qualifying as (S)AE
Body temperature
Whenever possible the same method should be used for body temperature measurement in 
one patient. All methods used should deliver valid reproducible results according to common 
clinical practice.
Body temperature > 38°C must be re assessed 1 hour after, especially in cases of suspected 
febrile neutropenia (see CTCAE V.4.03).
After the interim data base lock body temperature is no longer mandatory at specific visits 
but will be performed at the investigator’s discretion. Findings will be documented in the 
eCRF only if qualifying as (S)AE

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5.3.3
Safety laboratory parameters
Blood sample for assessment of safety laboratory examinations have to be collected at the 
time points specified in the Flow Chart, but should be more frequent in case of relevant 
findings, e.g. in case of grade 4 neutropenia, as any non-proven recovery within 7 days will 
be counted as DLT or proteinurea, for which determination of CTCAE grade 2 versus grade 3 
needs to be done by quantitative measurement.
Safety laboratory examination will include haematology, biochemistry, coagulation, and 
urine analysis.

Haematology: Haemoglobin, red blood cell count (RBC), white blood cell count (WBC) 
and differential, platelets.

Biochemistry: glucose, sodium, potassium, calcium, magnesium, inorganic phosphate, 
creatinine, aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase, lactate deshydrogenase (LDH), bilirubin, urea, total protein, albumin, uric 
acid, CK, CK-MB. 
Serum immunoglobulin levels (IgG, IgM, IgA, IgE) and direct antiglobulin test have to be 
measured at screening and at occurrence of infusion related reactions.

Coagulation: activated partial thromboplastin time (aPTT), prothrombin time (PT) or 
international normalised ratio (INR) where indicated (e.g. treatment with vitamin K 
antagonists)

Urinalysis: pH, glucose, leukocytes, erythrocytes, protein, nitrite will be analysed 
primarily qualitatively by dipstick. In case of pathological findings, further evaluation 
should be performed and the findings documented. A positive urine dipstick for protein of 
≥ 2+ has to be followed by a determination of urine protein to creatinine ratio (UPCR) in 
a morning spot urine sample. In case of a ratio ≥ 0.5, a 24-hour urine collection for 
protein loss has to be performed. The 24 hour urine collection will be repeated every time 
the UPCR is ≥ 0.5 as often as clinically indicated.
After the interim data base lock, safety laboratory tests (haematology, biochemistry, 
coagulation, urinalysis) will be performed at the investigator’s discretion based on the 
standard medical care. Findings will be recorded in the e-CRF only if qualifying for 
(S)AE/AESI.
Pregnancy test: a serum pregnancy test will be performed as outlined in the Flow Chart in 
women of childbearing potential.
Previous laboratory investigations performed within 72 hours prior to the first treatment 
administration visit are acceptable to confirm the patient eligibility.  
In case an administration is delayed due to an AE, the patient should visit the site at least 
once a week for assessment of safety laboratory and AEs. More frequent visits may be 
appropriate as assessed by the Investigator.

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5.3.4
Electrocardiogram (ECG)
12-lead ECGs will be digitally recorded in triplicate and performed for each patient at various 
time point according to the Flow Chart and Appendix 10.4.

At screening, visits between administrations of study treatment, and at EoT. Only one 
time point will be evaluated

At days of administration, two time points will be evaluated:
Pre-dose (-60 min. to -5 min.) and
Shortly before the end of the infusion
In case of drug-related ECG changes and whenever the investigator deems necessary,
additional ECG monitoring will be performed in the respective and later courses of treatment.
The ECGs will be recorded using dedicated equipment provided by the vendor.
The ECGs will be sent for evaluation by a central vendor, which will conduct the analysis in 
a blinded fashion. QTcF and other variables of interest will be described in a separate ECG 
plan. Data from this central review will be taken for retrospective data analysis.
In order not to confuse ECG recording, PK samples should be taken after performing the
ECG. The ECG recordings will be analysed and checked for pathological results by the
investigator; QTcF for each time point will be calculated as the mean of the 3 ECGs.
Decision on patient’s eligibility will be taken based on Investigator analysis of QTcF, based
on same recordings. Pathological ECG results will be recorded as AEs by the investigator.
After the interim data base lock, ECG will be performed as clinically indicated on local 
machine and the assessment will be done by the investigator. Shipment of ECGs to central 
vendor is no longer required.
Echocardiography
Echocardiography will be performed locally at screening (not older than 7 days before start of 
treatment) and at EoT. During treatment period, echocardiography will be conducted only if 
clinically indicated. 
After the interim data base lock findings related to echocardiography will be reported in the e
CRF only if qualifying as (S)AE
5.3.5
Other safety parameters
Not applicable
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.

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An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe. 

requires inpatient hospitalisation or 

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be reported as a serious event 
regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.

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The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. 
AESIs need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

For patients with normal liver function at baseline:
an elevation of AST and/or ALT ≥ 3 fold ULN combined with an elevation of total
bilirubin ≥ 2 fold ULN measured in the same blood draw sample and/or.
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN

For patients with impaired function tests at baseline:
an elevation of AST and/or ALT ≥ 5 fold ULN combined with an elevation of 
bilirubin ≥ 2 fold ULN measured in the same blood draw sample.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” via eDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
DLT events
All DLT events (as defined in Section 5.3) in individual patients occurring at any time during 
the repeated treatment courses or follow-up period must be reported as adverse events of 
Special Interest (AESI).
Severity of AEs
The severity of adverse events should be classified and recorded in the (e)CRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (R12-2532).
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal

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relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
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.
Arguments that may suggest that there is a reasonable possibility of a causal 
relationship could be:
•
The event is consistent with the known pharmacology of the drug
•
The event is known to be caused by or attributed to the drug class.
•
A plausible time to onset of the event relative to the time of drug exposure.
•
Evidence that the event is reproducible when the drug is re-introduced
•
No medically sound alternative aetiologies that could explain the event (e.g.
pre- existing or concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population 
not exposed to drugs (e.g. Stevens-Johnson syndrome).
•
An indication of dose-response (i.e. greater effect size if the dose is increased, 
smaller effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal
relationship could be:
• No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)
• Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
• Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
•Disappearance of the event even though the study drug treatment continues or remains 
unchanged
Adverse event collection and reporting
5.3.6.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
- From signing the informed consent onwards until the end of treatment (including the
Residual Effect Period, REP): all AEs (non-serious and serious) and all AESIs.

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- After the end of treatment (including the REP) until the individual patient’s end of trial: 
all related SAEs and all related AESIs.
- After the individual patient’s end of the trial: the Investigator does not need to actively
monitor the patient for AEs but should only report relevant SAEs and relevant AESIs of 
which the Investigator may become aware of. 
The rules for Adverse Event Reporting exemptions still apply.
Figure 5.3.6.2: 1AE collection
The REP is defined as 42 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment (please see Section 7.3.4). Events which occurred after the REP will be considered 
as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication.
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions. The rules for 
Adverse Event Reporting exemptions still apply
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.

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If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report 
immediately (within 24 hours) a potential drug exposure during pregnancy (DEDP) to 
the sponsor’s unique entry point (country-specific contact details will be provided in the 
ISF). The Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must
be followed up and reported to the sponsor’s unique entry point on the Pregnancy
Monitoring Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
Exemptions to (S)AE Reporting
Disease Progression in oncology trials is a study endpoint for analysis of efficacy and as such
is exempted from reporting as an (S)AE. Progression of the subject's underlying malignancy
will be recorded on the appropriate pages of the (e)CRF as part of efficacy data collection
only and will not be reported on the SAE Form. It will therefore not be entered in the safety
database (ARISg) and hence not get expeditiously reported. Death due to disease progression
is also to be recorded on the appropriate (e)CRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s)
and the progression of the underlying malignancy, the event must be reported as an (S)AE on
the SAE Form and on the (e)CRF.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Pharmacokinetic profiles of BI 836880 in plasma will be investigated after the first and after
repeated doses. Standard plasma PK parameters as listed in Appendix 10.3 will be calculated, 
if data allow and if scientifically reasonable.

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Pharmacokinetic data may additionally be analysed using a population pharmacokinetic
approach. For this purpose data may also be combined with data from other trials. Modelling
activities will be planned and documented separately according to internal and external
guidelines and SOP.
Exploratory pharmacokinetic analyses can be performed as necessary for DSB
decisions, but are not expected to be done more frequently than every other DSB and do
require sufficient lead time to collect samples, measure BI 836880 plasma concentrations,
analyse data and prepare meaningful outputs. The final exploratory analysis will be
performed after the cohort at MTD in the dose finding phase completed the first treatment 
course. 
For the purpose of these exploratory analyses, PK plasma samples obtained up to at least 24 
hours after drug administration will be used. A scientifically sound subset of the PK
parameters listed in Appendix 10.3 will be calculated which may include Cmax, AUC and t1/2,
if these parameters can be reliably determined from the available samples and plasma
concentration time profiles. In contrast to the final PK analysis, the exploratory analyses will 
be based on planned sampling times rather than on actual times; no supplementary subject
information, e.g. on adverse events or concomitant medication, will be used in these analyses, 
and the outputs will not be validated. Minor discrepancies between exploratory and final
results may therefore occur.
5.4.2
Methods of sample collection
For the quantification of BI 836880 plasma concentrations, at least 2 mL blood will be taken
from a forearm vein in a K2 EDTA (ethylenediaminetetraacetic acid) anticoagulant blood
drawing tube at time points specified in the Flow Chart and in Appendix 10.4. Plasma will be
divided into duplicate aliquots and stored frozen at about -70°C or below at the participating 
sites or logistics CRO until shipment on dry ice to the bioanalytical laboratory of Boehringer
Ingelheim or a Boehringer Ingelheim selected and authorized CRO.
Details about sample collection, K2 EDTA plasma preparation, required tubes, labelling of 
tubes, storage and shipment (frequency and addresses) will be provided in a separate 
laboratory manual.
After completion of the study the plasma samples may be used for further methodological
investigations, e.g., for stability testing. However, only data related to the analyte will be
generated by these additional investigations, and such data will be reported separately.
The study samples will be discarded no later than 3 years after the final study report has been
generated.
5.4.3
Analytical determinations
BI 836880 will be quantified using a validated bioanalytical assay.
After completion of the PK analysis, remaining plasma samples may be used for additional
angiogenesis-related biomarker analyses as described in Section 5.5.

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5.4.4
Pharmacokinetic - Pharmacodynamic Relationship
No formal analysis of a pharmacokinetic/pharmacodynamic relationship is planned.
Correlation between drug concentration and response may be made if adequate data are
available. In addition, exploratory correlation will also be made between drug concentration
and AEs.
Data may also be used to develop pharmacokinetic/pharmacodynamic models using nonlinear
mixed effect modelling techniques, if feasible. For this purpose data may also be combined
with data from other trials. Modelling activities will be planned and documented separately
according to internal and external guidelines and SOP.
ASSESSMENT OF EXPLORATORY BIOMARKER(S)
5.5
This section refers to exploratory biomarkers. 
Plasma derived protein biomarkers
The biomarkers described below are exploratory in nature and to be seen as hypothesis
generating studies, which will be used to expand our understanding of the study drug. The
analyses will be performed if considered clinically and/or scientifically justified at the time of
the planned analysis. Participation in the biomarker test is mandatory.
Plasma biomarker studies will focus on exploring pharmacodynamic effects. In a screening
assay circulating angiogenic factors such as but not limited to angiopoietin-2 (Ang2), sTie2,
vascular endothelial growth factor A (VEGF A), sVEGFR1, sVEGFR2, sVEGFR3 and
placenta growth factor (PLGF) will be analyzed in plasma (Appendix 10.5).
In addition to the screening assay mentioned above soluble targets such as free and/or total
VEGF as well as free and/or total Ang2 will be examined in plasma samples.
Exploratory pharmacodynamic analyses can be performed as necessary for DSB
decisions, but are not expected to be done more frequently than every other DSB and do
require sufficient lead time to collect samples, measure analyte plasma concentrations,
analyse data and prepare meaningful outputs. The final exploratory analysis will be
performed after the cohort at MTD in the dose finding phase completed the first two
treatment courses.
For the purpose of these exploratory analyses, PD plasma samples obtained up to at least 24 
hours after drug administration will be used. In contrast to the final PK analysis, the
exploratory analyses will be based on planned sampling times rather than on actual times; no
supplementary subject information, e.g. on adverse events or concomitant medication, will be
used in these analyses, and the outputs will not be validated. Minor discrepancies between 
exploratory and final results may therefore occur.
Methods of sample collection 
For circulating angiogenic biomarkers (Myriad panel) such as Ang2, sTie2, VEGF A,
sVEGFR1, sVEGFR2, sVEGFR3 and PLGF 3 ml of blood will be taken from the forearm
vein at those time points specified in the Flow chart and Appendix 10.4. For quantification of
free/total VEGF and free/total Ang2 another 6 ml blood will be taken from the forearm vein

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at those time points specified in the Flow chart and in Appendix 10.5.
Plasma samples for protein biomarkers need to be stored at ≤-70 °C. Detailed instructions for
sampling, handling, storage, and shipment of the biomarker samples will be provided in the
ISF/lab manual. Date and time of sampling will be recorded in the eCRF.
Details about blood sample collection, plasma preparation, required tubes, labelling of tubes, 
storage and shipment (frequency and addresses) will be provided in the lab manual.
The samples will be stored for a maximum period of 15 years (under consideration of local
legislation) after study termination.
Analytical determinations
Plasma biomarker analysis will be performed using immunoassays.
Additional assays may be added if new data suggests relevance to the study drug mechanism
of action. 
The analysis will be performed at Boehringer Ingelheim or a CRO with given authorization
by BI.
5.5.1
Imaging Pharmacodynamic endpoints
Dynamic contrast-enhanced (DCE)-MRI described below is exploratory in nature and to be
seen as hypothesis-generating evaluation, which will be used to expand understanding of
mode of action of the study drug. The analyses will be used for the non-invasive
quantification of microvascular structure and function properties (vascular permeability,
vascular density, regional flow) in solid tumors and be performed in all dose groups to
potentially allow for a PK/PD analysis. From the analysis of DCE-MRI data the parameters
Ktrans and IAUC60 or more specifically their relative, intra-individual change from baseline
after the first and the second treatment course are obtained as measures for treatment-induced
changes in tumor vessel permeability and perfusion. Morphological changes (tumor
volume, RECIST) can also be quantified from MRI data.
Methods of sample collection
DCE-MRI measurement will be done during the screening period, 1 week (C1V2) after first 
administration of BI 836880, after the 2nd treatment course (C3V1) and after the 4th
treatment course (C5 V1) in absence of progressive disease. 
During treatment period, DCE-MRI measurements will be done before study drug 
administration at the scheduled time points. If not possible then DCE-MRI can be performed 
one day earlier to the study drug administration.
In case patient stopped treatment for other reasons than progressive disease, DCE-MRI 
should still be conducted as long as patient is in Follow up period. Time points for 3rd and 4th
imaging, depending on when patient stopped treatment, have to be adapted as 6 weeks and 12 
weeks after 1st infusion. The exact time points for DCE-MRI have to be calculated according 
to Flow Chart and can be chosen to coincide with the radiological assessment in a scheduled
follow-up visit.
With the objective to minimize methodological variability only patients with lesions
considered suitable for DCE-MRI by a radiologist’s assessment of the morphological MRI

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data (preferably liver metastases > 2cm; other lesions may only be included after consultation
with the sponsor) will be included in this evaluation. For certain tumor types suitable lesions
will not be available and such patients will not be examined by DCE-MRI. For assessment of
the morphological changes of lesions the following sequences are used: T1-weigthed
multislice breath-hold FLASH and T2-weigthed multislice breath-hold TSE (Turbo Spin
Echo). Slice orientation is preferably axial, other orthograde (but no tilted) orientations can
be used when suitable. T1 and T2-scans are acquired at identical slice position, the same
orientation and position is used for scans at subsequent time points.
DCE-MRI will be performed on a coronal slice through one or more representative lesions
selected and identified by the responsible radiologist from the morphological scans. For
DCE-MRI, a T1-weighted inversion recovery-gradient echo sequence is used, for which the
patient will receive an intravenous bolus application of the gadolinium contrast agent.
Detailed parameter settings are given in the MR-Protocol.
OTHER ASSESSMENTS
5.6
5.6.1
Demographic and medical history
Demographics (sex, birth date, race if allowed by the local law), current medical condition
including relevant concomitant diagnosis will be collected during the screening visit.
Concomitant therapies present at the study entry and /or during the study will be recorded in 
the eCRF.
Medical history as follows:

Type of tumor

Date of the first histological diagnosis (month and year may be sufficient)

Primary tumor site

Differentiation grade (not specified, undifferentiated, poorly differentiated,
moderately differentiated

Tumor stage according to the tumor

Number of metastatic sites at study entry will be provided

Previous surgeries an radiotherapy will be reported

Previous administrated chemotherapy, tyrosine kinase inhibitors, vaccine-therapy,
antibodies therapy, immune-therapy, and hormone-therapy including start and end
dates (month and year may be sufficient)

Previous neoadjuvant, adjuvant or palliative therapy

The date of tumor progression after  previous line (s) of therapy for advanced or
metastatic disease

The start and end dates (month and year may be sufficient) of those previous therapies
as well the number of courses (when applicable)

The best response obtained (complete response, partial response, stable disease,
progressive disease, unknown

The reason for leading to treatment discontinuation (completion, PD, AE)

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5.6.2
Immunogenicity assessment
Methods of ADA sample collection
For the determination of anti-drug antibodies (ADA), approximately 3 mL of blood will be
taken from a forearm vein in a K2 EDTA (ethylendiaminetetraacetic acid) anticoagulant 
blood drawing tube at those time points specified in the Flow Chart and in Appendix 10.4.
EDTA plasma will be divided into duplicate aliquots into 2 mL cryovials and stored frozen at 
approximately -70oC or below at the investigator sites or logistics CRO until shipment on dry 
ice to the bioanalytical laboratory. The second aliquot will be shipped only after the 
acknowledgement of receipt of the first aliquot.
Details about sample collection, preparation, storage and shipment are described in the
laboratory manual.
Analytical Determination of ADA in Human Plasma Samples
After receipt at the analytical laboratory, plasma samples will be stored at approximately
-70°C or below until analysis. The presence of ADA to BI 836880 will be assessed via a
tiered approach using a validated electrochemiluminescence assay (screening, confirmatory,
and titration analysis as appropriate).
Analyses will be performed preferably at the analytical laboratory listed as follow or at 
another CRO with given authorisation by Boehringer Ingelheim.

ICON Development Solutions

Whitesboro, NY
The study samples will be discarded no later than 15 years after the final study report has 
been generated.
A detailed description of the assay will be available prior to the start of sample analysis in the
validation report.
APPROPRIATENESS OF MEASUREMENTS
5.7
Determination of the MTD is based on the toxicities grade according to CTCAE version 4.03
(R12-2532). The CTCAE criteria are commonly used in the assessment of adverse events in 
cancer patients. RECIST version 1.1 criteria (R09-0262) are used for evaluation of tumor 
response. These criteria are well established and scientifically accepted.

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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
The study Flow Chart describes all assessments which will be performed in patients treated 
with BI 836880.
All patients must provide written informed consent before any study related screening 
procedures can be performed. Time windows for visits are included in the Flow Chart.
Patient will visit the clinic at the time points specified in the Flow Chart. If a visit is missed
and the patient report to the Investigator between the missed visit and the next visit, the 
missed visit should be performed. The current date and the reason for delayed visit should be 
recorded in the source document. The next visit, however, should take place at the scheduled 
time after the first administration BI 836880.
To allow close monitoring for infusion-related reactions or other adverse events and 
availability of patients for PK visits at course 1, patients are required to be hospitalised under 
close surveillance with access to intensive care for at least 48 hours after the first 
administration of BI 836880 at course 1 day 1and 24 hours after the second and third 
administrations of BI 836880 at course 1 day 8 and course 1 day 15 respectively.
After good tolerability of the first course of BI 836880 the investigator may evaluate the risk 
for an infusion-related reaction and other adverse events in view of relevant comorbidities or 
disease related symptoms, and as a result, shorten the duration of surveillance to 8 hours for 
courses 3 and 4 (PK samples included) and at investigator’s discretion for further courses.
If pathological laboratory values or other issues require an additional unscheduled visit, a
new eCRF page will be created for the unscheduled visit. At the unscheduled visit, it is
sufficient to record only the clinical relevant labs/examinations performed.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The investigations as outlined in the Flow Chart will be performed at the respective visits. A
more detailed overview of collection of blood samples for PK, PD and circulating
biomarkers, as well as ECG assessment and BP measurements are given in Appendix 10.4.
Specific details to conduct of physical examination, collection of vital signs (including blood
pressure measurement), laboratory investigations, assessment of ECG and echocardiography
can be found in Section 5.3.
Procedure for collection of blood samples for PK, ADA and circulating biomarkers are given
in Sections 5.4 and 5.5.
DCE-MRI will only be performed in patients having suitable lesions. Details are described in
Section 5.5.1.

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After the interim data base lock, mandatory procedures/assessments and documentation in the 
eCRF will be adapted as described in the Flow Chart and the respective sections of this 
protocol.
6.2.1
Screening period
All Screening Visit procedures must be performed in the 21 days prior to the first 
administration of study medication except tumor assessments (CT/MRI) that may be used as 
screening exams if they were performed within 28 days prior to start of treatment.
Echocardiography must be obtained within 7 days before start of treatment.
Patients who meet the eligibility criteria will be allowed to take part to the study.
Refer to the Flow Chart for procedure details. Please review Sections 3.3.2 and 3.3.3 for 
specific eligibility criteria.
6.2.2
Treatment period(s)
All patients will receive continuous weekly treatment with BI 836880 until the criteria for 
stopping medication are met (see Section 3.3.4).
Treatment course is defined as 3-week treatment (21 days) in duration. During the treatment 
phase visits should be performed as scheduled wherever possible.
In the event of any study drug interruption or delay of treatment, the tumor assessment 
scheduled will not be changed.
After the interim data base lock, frequency of tumor assessment may be adapted according to 
local standard of care and in agreement with the sponsor if the patient is deriving clinical 
benefit (e.g. CR, PR or SD > 6 months).
During course 1, 2 and 4 intensive PK-sampling will be conducted and patients have to be
observed closely for any adverse events. Additional visits are needed at day 2 for courses
1, 2 and 4. For course 3 and from course 5 onwards no additional visits, beside day 1 
including drug administration, are requested by protocol.
Refer to the Flow Chart for procedure details. 
6.2.3
Follow Up Period and Trial Completion
End of treatment visit
6.2.3.1
The EOT visit will be performed after permanent discontinuation of trial medication for any
Reason, as soon as possible, but no later than 21 days after permanent discontinuation of the
trial medication or when the investigator decided with the patient to permanently discontinue
the trial medication or became aware that the trial medication had been terminated.

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Residual effect period (REP)
6.2.3.2
The REP is defined in Section 5.3.6.2. The End of the Residual period visit (EoR) should not 
be performed earlier than 42 days after permanent discontinuation of the study drug. The
information collected at this visit should include all new AEs that occurred after EOT and a
follow-up of adverse events ongoing at EOT. Any subsequent anti-cancer therapy
administered between EOT and EoR should be reported.
Follow-up period for progression
6.2.3.3
For patients who progress according to RECIST criteria V1.1, one Follow up visit (FU1) will 
be performed after the EOT (i.e. at EoR, 42 calendar days after discontinuation of trial drug).
For patient who discontinue not due to progressive disease according to RECIST criteria 
V1.1, additional FU visits will be performed at 6-week intervals plus/minus 3 days, until
progression, start of another anticancer treatment, lost to follow up, death.
After the interim data base lock, frequency of tumor assessment may be adapted according to 
local standard of care and in agreement with the sponsor if the patient is deriving clinical 
benefit (e.g. CR, PR or SD > 6 months).   
During extended Follow up period (i.e. after the end of treatment, including  the REP and 
individual patient’s end of trial), all related SAEs or AESIs and Follow up AEs on going 
since the end of treatment have to be collected and documented  on the appropriate eCRF 
page and SAE form (if applicable). 
Refer to Flow Chart for details.
Trial completion for an individual patient
6.2.3.4
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up period (as defined in Section 6.2.3.3)

Lost to follow-up

Withdrawal to be followed-up

Death
At the earliest of the above criteria, the Patient Completion information should be
entered in the CRF.
Trial completion
6.2.3.5
The clinical trial will be considered completed when the last patient has completed the EoR 
visit. If patients are still on treatment at the time of interim data base lock and the Clinical 
Trial Report is written, these patients will be maintained in the trial as long as they are 
deriving clinical benefit (i.e. no disease progression, no drug-related AEs requiring drug 
discontinuation) or no new anti-cancer treatment started and there are willing to continue. For 
these patients, no blood sample will be collected for PK/PD and biomarker analysis, only 
(S)AEs and limited efficacy data will be collected. After the discontinuation of these patients, 
additional data collected after data base lock will be reported in separate listings and will not 

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lead to any further update of tables generated for section 15 of the CTR unless deemed 
necessary. These listings will be included in a revised CTR.

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN – MODEL
7.1
This is phase I, open-label, dose-escalating trial to determine the MTD and RP2D for BI 
836880 in patients with solid tumors. MTD is defined as the highest dose with less than 25% 
risk of the true DLT probability being above 33%,and may be considered reached if the 
probability that the true DLT rate is in target interval (16%-33%) is sufficiently large. Dose 
escalation and determination of MTD will be guided by a Bayesian 2-parameter logistic 
regression model with overdose control (R13-4803, R13-4806). These designs have been 
shown to be superior regarding the precision of MTD determination compared to 3+3 designs 
and have been particularly endorsed by the FDA (R13-4881).
The model is formulated as follows:
logit(p(d)) = log(α) + β*log(d/d*),
where logit(p) = log(p/(1-p)). 
p(d) represents the probability of having a DLT in the first course at dose d, d* = 1250mg is 
the reference dose, allowing for the interpretation of α as the odds of a DLT at dose d*, and θ 
= (log(α), log(β)) with α, β > 0 is the parameter vector of the model.
Since a Bayesian approach is applied, a prior distribution π(θ) for the unknown parameter 
vector θ needs to be specified. This prior distribution will be specified as a mixture of three 
multivariate normal distributions, i.e.
π(θ) = φ1π1(θ) + φ2π2(θ) + φ3π3(θ)
with 
φi, i = 1, 2, 3 the prior mixture weights (φ1+ φ2+ φ3 = 1)
and 
πi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, with








2
22
,
22
,
11
,
22
,
11
,
2
11
,
i
i
i
i
i
i
i
i
i








Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
Prior derivation
For the current study, no relevant information in the form of human data was available, since 
no study in a comparable population has been conducted. Therefore, the three mixture 
components were established as follows:
1. A weakly informative prior was derived to reflect a priori assumption that the median 
DLT rate at the starting dose of 40mg would equal 0.1%, and the median DLT rate at 
the anticipated MTD of 480mg would equal 20%. This yields μ1 = (0.740, 0.798). The 
standard deviations were set such that large uncertainty about the parameter means is 

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reflected, and the correlation was set to 0, thus yielding σ1,11 = 2, σ1,22  = 1 and ρ1 = 0, 
respectively. The prior weight φ1 for the first component was chosen as 0.9.
2. A high-toxicity weakly informative prior was derived to reflect the case that the 
compound would be much more toxic than expected. For this prior component, it was 
assumed that the median DLT rate at the starting dose of 40mg would equal 10%, and 
the median DLT at the anticipated MTD of 480mg would equal 50%. These 
assumptions yield μ2 = (0.846, -0.123). The standard deviations and correlations were 
set identical to the weakly informative prior, i.e. σ2,11 = 2, σ2,22  = 1 and ρ2 = 0,
respectively. The prior weight φ2 for the second component was chosen as 0.05.
3. A low-toxicity weakly informative prior was derived to reflect the case that the 
compound would be much less toxic than expected. For this prior component, it was 
assumed that the median DLT rate at the starting dose of 40mg would equal 0.1%,
and the median DLT at the anticipated MTD of 480mg would equal 2%. These 
assumptions yield μ3 = (-2.731, 0.193), i.e. basically a flat curve. The standard 
deviations and correlations were set to σ3,11 = 5, σ3,22  = 0.01, therefore almost fixing 
the slope parameter to its mean. The correlation was set to 0, i.e. ρ3 = 0. The prior 
weight φ3 for the third component was chosen as 0.05.
A summary of the prior distribution is provided in Table 7.1:1. Additionally, the prior 
probabilities of DLT at different doses, as well as the corresponding probability of under-, 
targeted and overdosing, are shown in Table 7.1: 2. Graphically, the prior medians with 
accompanying 95% credible intervals are shown in Figure 7.1:1. As can be seen from both, 
the Table and the Figure, the prior medians of the DLT probabilities are in-line with the prior 
medians derived from the weakly informative prior, and the uncertainty around the medians 
is large, showing the low amount of information this prior provides. This is also supported by 
the prior sample size, i.e. the information contained in the prior. This is approximately equal 
to1 patient, i.e. less than or around half of the weight the first cohort in the study will have.
Table 7.1: 1
Summary of prior distribution
Prior Component
Mixture Weight
Mean vector
SD vector
Correlation
1: Weakly inf.
0.900
0.740, 0.798
2.000, 1.000
0.000
2: High Tox
0.050
0.846, -0.123
2.000, 1.000
0.000
3: Low Tox
0.050
-2.731, 0.193
5.000, 0.010
0.000
Table 7.1: 2
Prior probabilities of DLT at selected doses
Dose
Probability of true DLT rate in
Quantiles
[0–0.16)
[0.16–0.33)
[0.33–1]
Mean
SD
2.5%
50%
97.5%
40
0.842
0.054
0.104
0.091
0.206
<.001
0.001
0.819
120
0.759
0.076
0.165
0.139
0.249
<.001
0.009
0.897
240
0.673
0.096
0.231
0.193
0.282
<.001
0.036
0.935
480
0.523
0.131
0.346
0.284
0.318
<.001
0.138
0.964
960
0.262
0.143
0.595
0.471
0.332
0.002
0.458
0.984
1250
0.142
0.114
0.744
0.594
0.316
0.012
0.659
0.991
Doses printed in bold face meet the overdose criterion (P(overdose) < 0.25))

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Figure 7.1: 1Prior medians and 95% credible intervals
The MTD may be considered reached if the following criteria are fulfilled:
1. At least 1 DLT on the trial and either
2. At least 6 patients haven been treated at the MTD and the posterior probability of the 
true DLT rate in the target interval (16%-33%) is above 50%, OR
3. At least 18 patients in the trial with 6 patients have been treated at MTD.
Statistical model assessment:
The model was assessed using two different metrics:
1. Hypothetical data scenarios: for various potential data constellations as they could 
occur in the actual trial, the maximal next doses as allowed by the model and by the 
100% escalation limit are investigated. Data scenarios thus provide a way to assess 
the “on-study” behaviour of the model.
2. Simulated operating characteristics: these illustrate for different assumed true dose-
toxicity relationships, how often a correct dose would be declared as MTD by the 
model. They are a way to assess the “long-run” behaviour of the model.

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In summary, the model showed very good behaviour as assessed by these metrics. More 
details can be found in Appendix 10.6. 
Based upon these design considerations, the trial will be analysed using general linear models 
which will include terms for centre and disease severity as covariates.
NULL AND ALTERNATIVE HYPOTHESES
7.2
No formal hypothesis testing is planned in this trial. All analyses in this trial are descriptive 
and exploratory by nature.
PLANNED ANALYSES
7.3
Only one analysis population will be considered for efficacy and safety analyses: the treated 
set. The treated set (TS) will consist of all patients who were treated with at least one single 
dose of BI 836880.
The primary analysis will be based on the treated set population excluding patients that have 
to be replaced for analysis of the MTD, see Section 3.3.4.1 for further details.
No per protocol population will be used for analyses; however protocol violations will be 
identified and listed.
7.3.1
Primary endpoint analyses
In order to determine the MTD the occurrence of a DLT in the first course will be assessed on 
an individual patient level. The MTD will be determined as described in Section 7.1.
Based on the data observed in the trial other models might be considered either additionally 
or replacing the primary model. For feasibility or other reasons a different dose might be 
considered as the recommended dose for Phase II.
7.3.2
Secondary endpoint analyses
Please refer to Section 7.3.4 for safety related secondary endpoint.
7.3.4
Safety analyses
All patients of the treated set will be included in the safety analyses. Two analyses will be 
performed. The first analysis of safety will be performed for the first part of the trial 

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(determination of the MTD, first course only, treatment regimen = initial dose at the start of 
the treatment, treated set). This descriptive analysis will evaluate the MTD for the 
monotherapy of BI 836880. The second analysis will be performed with respect to all courses 
and will act as a support for the determination of the MTD (treated set).
Events that started between the first administration of the treatment until 6 weeks (42 days) 
after the last administration of treatment will be considered as having occurred on treatment.
Events that started after 42 days since last administration of treatment will be considered as 
having occurred post-treatment and will be presented separately. 
Adverse events will be graded according to CTCAE Version 4.03 (R12-2532) and reported 
according to BI standards. Frequency, severity, and causal relationship of adverse events will 
be tabulated by system organ class and preferred term after coding according to the current 
version of the Medical Dictionary for Drug Regulatory Activities (MedDRA).
Serious adverse events will be tabulated. In addition, events leading to dose reduction or 
treatment discontinuation will be examined, but may not be reported as individual tables, 
depending upon the extent of overlap. Descriptive statistics will be used to describe changes 
in laboratory tests over time. In addition, all abnormalities of potential clinical significance 
will be reported. In general, potential clinical significance is defined as at least CTCAE
Grade 2 and an increase in CTCAE classification from baseline. The incidence and severity
of the more important adverse events (as determined from the analyses above) will be 
correlated descriptively with pharmacokinetic data, if possible.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 42 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’.  The residual effect 
period is defined as 42 days after the last trial medication application. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 

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reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
Phamacokinetic analyses
7.3.5.1
Refer to Section 5.5.1 for pharmacokinetic parameters to be calculated using non-
compartmental analysis (NCA). The derivation of pharmacokinetic parameters is described in 
detail in the BI SOP 001-MCS-36-472.
All evaluable subjects who received at least one dose of BI 836880 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.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis. 

If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the clinical trial 
report associated with an appropriate flag.
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Noncompartmental pharmacokinetic analyses of the plasma 
concentration-time data will be performed using a validated software program, e.g. 
WinNonlin Version 5.2. Only concentrations within the validated concentration range will be 
used for the calculation of pharmacokinetic parameters. For pre-dose samples, the actual 
sampling time will be set to zero.
Plasma concentrations will be plotted graphically versus time for all evaluable subjects as 
listed in the drug plasma concentration-time tables. For the presentation of the mean profiles, 
the geometric and arithmetic mean and the planned blood sampling times will be used. If the 
actual sampling time deviates significantly from the planned time, the corresponding plasma 
concentration will be excluded from the calculation of descriptive statistics.
The following descriptive statistics will be calculated for analyte concentrations as well as for 
all pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, 

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maximum, P10, Q1, Q3, P90, arithmetic coefficient of variation, geometric mean, and 
geometric coefficient of variation. The data format for descriptive statistics of concentrations 
will be identical with the data format of the respective concentrations. The descriptive 
statistics of pharmacokinetic parameters will be calculated using the individual values with 
the number of decimal places as provided by the evaluation program. Then the individual 
values as well as the descriptive statistics will be reported with three significant digits in the 
clinical trial report.
Dose proportionality of BI 836880 will be assessed based on Cmax,ss, AUCτ,ss and Cmax, AUC0-
. The attainment of steady state will be explored by plotting trough concentrations (Cpre, 
Cpre,N) against time.
Assessment of dose proportionality:
Dose proportionality will be explored using the power model that describes the functional 
relationship between the dose and PK endpoints, Cmax, AUC0-∞, Cmax,ss, AUCτ,ss. The basic 
model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. Based on the estimate for 
the slope parameter , a two sided 95% confidence interval for the slope will be computed. 
Perfect dose proportionality would correspond to a slope of 1. The assumption of a linear 
relationship between the log-transformed pharmacokinetic endpoint and the log-transformed 
dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed. The 
model for dose proportionality analysis will be detailed in Trial Statistical Analysis Plan 
(TSAP).
Attainment of steady state:
The statistical model to explore the attainment of steady state using the trough concentrations 
described above for each dose level will be a repeated measures linear model on the 
logarithmic scale including 'subject' as a fixed effect and 'time' as a repeated effect. The 
corresponding model, if all dose levels are analysed simultaneously, will include the log-
transformed 'dose' as a covariate. Both models allow modelling the covariance structure of 
the data. The structure of the covariance matrix generally is not known in advance and will 
therefore be determined on a data-driven basis. The strategy/criteria to determine the final 
structure will be described in the TSAP.
Subsequently, adjusted least square means and two sided 95% confidence intervals will be 
calculated and back transformed by exponentiation. Furthermore pairwise comparisons of the 
log-transformed differences between all subsequent  time points (log(Cpre,i/Cpre,j) = log(Cpre,i) 
- log(Cpre,j) where j>i) will be performed including the calculation of two sided 95% 
confidence intervals using t tests. Comparisons which reveal small p-values will be inspected 
to determine if the relevant differences between time points are resulting from not yet 
attaining steady state. In general, all dose levels will be analysed separately. If there is 
evidence that the patterns (or trend) of the trough concentration profiles are comparable 
across dose levels they will be analysed simultaneously if this is justified. Other analyses, 
such as regression over time may be considered as post-hoc analyses.

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To support the analyses of dose proportionality, and attainment of steady state, graphical 
representations of the data might be created. These might include (but are not limited to) 
individual time-courses of trough plasma concentrations and the (geometric) mean plasma 
concentration time profiles.
Pharmacodynamic analyses
7.3.5.2
DCE-MRI
Modulation of vascular characteristics and size of suitable tumor lesions (preferably liver 
lesions) will be assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-
MRI) before and after treatment with BI 836880. All subjects who received at least two DCE-
MRI measurements will be included in the analysis. 
The temporal evolution of contrast medium-induced signal intensity within tumor lesions will 
be acquired quantitatively and be related to the vascular parameters, such as vascular 
permeability, vascular density, and regional vascular flow. 
DCE-MRI images will be analyzed using software designed to allow for the visualization of 
dynamic enhancement parameters. Quantitative modelling of the tissue gadolinium 
concentration time curve using a multi-compartmental model will yield the parameters 
transfer constant (Ktrans) and IAUC60 (Initial Area Under Curve at 60 seconds) for each 
imaging time point. Time profiles of Ktrans and IAUC60 and their changes from baseline 
will be summarized by descriptive statistics and visualized by treatment group. Changes in 
Ktrans and IAUC60 values will be related to dose of BI 836880 and parameters of clinical 
efficacy. DCE-MRI parameters will be derived at University Medical Center Freiburg, 
Department of Radiology. Statistical analyses will be done at BI.
Biomarker analyses
7.3.5.3
The exploratory statistical analyses of the biomarker data will be performed separately and 
results will be covered in a separate report.
INTERIM ANALYSES
7.4
Interim safety evaluations will be performed as considered necessary. In particular safety 
evaluations will be performed after each dose cohort by the DSB consisting of the 
investigators and representatives of the sponsor (refer to Section 3.1.1). Based on this the 
DSB will recommend the next dose level as well as the corresponding cohort size. DSB
meeting minutes and outputs provided for these DSB meetings will be documented and 
archived in the clinical trial master file (CTMF).
If considered necessary, as soon as the MTD is determined an evaluation of the safety aspects 
will be performed. Results of this evaluation will be documented and archived. If applicable
such an analysis will be defined in more detail in the TSAP.
HANDLING OF MISSING DATA
7.5
No imputation will be performed on missing efficacy data.
Missing baseline laboratory values will be imputed by the respective values from the
screening visit. No other imputations will be performed on missing data although every effort 

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will be made to obtain complete information on all adverse events and to follow-up the 
patients for efficacy data.
Pharmacokinetics:
Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR 
(no valid result), NOA (not analysed), BLQ (below the limit of quantification) and NOP (no 
peak detectable) will be ignored and not replaced by zero at any time point (including the lag
phase). Descriptive statistics of concentrations at specific time points will be calculated only 
when at least 2/3 of the individuals have concentrations within the validated concentration 
range.
Pharmacokinetic parameters:
In the non-compartmental analysis, concentration data identified with NOS, NOR and NOA 
will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag 
phase is defined as the period between time 0 and the first time point with a concentration 
above the quantification limit. All other BLQ and NOP values of the profile will be ignored. 
Descriptive statistics of parameters will be calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. Pharmacokinetic parameters which 
cannot be determined will be identified by "not calculated" (NC).
RANDOMISATION
7.6
Patients will be assigned, not randomised, into escalating dosage cohorts by order of 
admission into the trial. Doses will be assigned based on the decision made by the DSB (see 
Section 7.3.4).
DETERMINATION OF SAMPLE SIZE
7.7
About 25-30 patients will be expected for the dose finding part and confirmation of RP2D. 
Fewer patients might be needed based on the recommendation of the DSB and the criteria 
specified (see Section 7.1). 

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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonized standards for Medical Devices (ISO 14155-01 and ISO 14155-02).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs),
and relevant regulations.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.

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RECORDS
8.3
Electronic Case Report Forms (e)CRF for individual patients will be provided by the 
Sponsor. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRF/eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRF / eCRF, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
END OF TRIAL
8.6
The trial will end when the last patient has completed the last follow up visit as specified in 
Section 6.2.3.4  
After the interim data base lock the trial will end when the last patient has completed the EoR 
visit as specified in Section 6.2.3.4  and 6.2.3.5

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The IEC / competent authority in each participating EU member state will be notified about 
the end of the trial or early termination of the trial.
PROTOCOL VIOLATIONS
8.7
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.

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9.
REFERENCES
PUBLISHED REFERENCES
9.1
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Liang SX, Gynecologic Oncology Group. Incorporation of bevacizumab 
in the primary treatment of ovarian cancer. N Engl J Med 2011. 
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of angiogenesis. Nature 2011. 473:298-307.
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methotrexate. ACR/ARHP Sci Mtg 2011, 75th Ann Sci Mtg of the
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Tourneau C le, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose
escalation designs in dose-finding phase I trials of molecularly targeted
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Babb J, Rogatko A, Zacks S. Cancer phase I clinical trials: efficient dose
escalation with overdose control. Stat Med 1998. 17:1103-1120.
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Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE,
Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou
YC, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C,
Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of axitinib
versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized 
phase 3 trial. Lancet 2011. 378:1931-1939.
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worldwide in 2012: online analysis: incidence/mortality > rates: 
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Agency for Research on Cancer 2012.
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Garon EB, et al. Ramucirumab plus docetaxel versus placebo plus
docetaxel for second-line treatment of stage IV non-small-cell lung 
cancer after disease progression on platinum-based therapy (REVEL): a
multicentre, double-blind, randomised phase 3 trial. Lancet, Published
online June 2, 2014, doi: 10.1016/S0140-6736(14)60845-X Lancet 2014.
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Avastin 25 mg/ml concentrate for solution for infusion (Roche Pharma)
(summary of product characteristics, manufacturers of the biological 
active substance and manufacturers responsible for batch release, 
conditions or restrictions regarding supply and use, other conditions and 
requirements of the marketing authorisation, conditions or restrictions 
with regard to the safe and effective use of the medicinal product, 
labelling and package leaflet, last updated: 15/08/2014).
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Product_Information/ human/000582/WC500029271.pdf (access date: 1
September 2014) 2014.
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T, Ruff P, Hazel GA van, Moiseyenko V, Ferry D, McKendrick J, 
Polikoff J, Tellier A, Castan R, Allegra C. Addition of aflibercept to 
fluorouracil, leucovorin, and irinotecan improves survival in a phase III 
randomized trial in patients with metastatic colorectal cancer previously 
treated with an oxaliplatin-based regimen. J Clin Oncol 2012. 
30(28):3499-3506.
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Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ.
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Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C,
Valle J, Metrakos P, Smith D, Vinik A, Chen JS, Hoersch D, Hammel P,
Wiedenmann B, Cutsem E van, Patyna S, Lu DR, Blanckmeister C, 
Chao R, Ruszniewski P. Sunitinib malate for the treatment of pancreatic
neuroendocrine tumors. N Engl J Med 2011. 364(6):501-513.
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Brown JL, Cao ZA, Pinzon-Ortiz M, Kendrew J, Reimer C, Wen S, 
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to broad antitumor activity in combination with VEGF inhibitors and 
chemotherapy agents in preclinical models. Mol Cancer Ther 2010. 
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JV, Oliner JD, McDonald DM. Complementary actions of inhibitors of
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Res 2010. 70(6):2213-2223.
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Sternberg CN, Davis ID, Mardiak J, Szcylik C, Lee E, Wagstaff J, 
Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, 
McCann L, Pandite L, Roychowdhury DF, Hawkins RE. Pazopanib in 
locally advanced or metastatic renal cell carcinoma: results of a 
randomized phase III trial. Clin Oncol 2010. 28(6):1061-1068.
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Monk BJ, et al. Anti-angiopoietin therapy with trebananib for recurrent:
ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind,
placebo-controlled phase 3 trial. Lancet Oncol 2014. 15(8):799-808.
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(U.S. prescribing information, revised: 11/2014). 2014.
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Hidalgo M, Tourneau C le, Massard C, Boni V, Calvo E, Albanell J, 
Taus A, Sablin MP, Varga A, Bahleda R, Krieter O, Markovtsova L, 
Carlile D, Lahr A, Nayak T, Lechner K, Koehler A, Uffelen I van, 
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of RO5520985 (RG7221), a novel bispecific human anti-ANG-2/anti-
VEGF-A antibody, administered as an intravenous infusion to patients 
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Papadopoulos KP, Graham DM, Tolcher AW, Razak RAR, Patnaik A,
Bedard PL, Rasco DW, Amaya A, Moore KN, Konner JA, Matei D, 
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DiCioccio AT, Trail P, Siu LL. A phase 1b study of combined 
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antibody (MAb) to angiopoietin-2 (Ang2) and ziv-aflibercept in patients 
with advanced solid malignancies. 50th Ann Mtg of the American 
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Clin Oncol 2014. 32(15)(Suppl) Abstr 2522.
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Gao B, DiCioccio AT, Trail P, Siu LL. A phase I first-in-human study of
REGN910 (SAR307746), a fully human and selective angiopoietin-2
(Ang2) monoclonal antibody (MAb), in patients with advanced solid 
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31(15)(Suppl) Abstr 2517.
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(pts) with advanced solid tumors. 50th Ann Mtg of the American Society 
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UNPUBLISHED REFERENCES
9.2
c02353882
Investigator’s Brochure: BI 836880 in solid tumors.Version 1. 11 June 
2015.
001-MCS-36-472 
Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics.

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10.
APPENDICES
INSTRUCTIONS FOR USE
10.1
10.1.1
Instruction for Pharmacists
Refer to the ISF
BLOOD PRESSURE MEASUREMENT PROCEDURE
10.2
The preferred method of blood pressure measurement is by a standard mercury
sphygmomanometer. If a standard mercury sphygmomanometer is not available, alternative
devices according to website dableducational.org may be used. At screening, blood pressure
should be taken in both arms. If the pressures differ by more than 10 mmHg (as in the
presence of a subclavian steal syndrome), the arm with the higher pressure (either systolic or
- if needed to decide - diastolic) should be used for subsequent measurements. Blood pressure
measurements should be performed on the same arm and, if possible, by the same person.
The same method and device must be used throughout the trial for a patient i.e. if a patient
receives the first blood pressure measurement for example with an electronic device, the
same method and device should be used throughout the study for this patient (without
switching to manual blood pressure measurement). On the other hand, inter-patient variability
is acceptable, i.e. a study site is allowed to consistently use an electronic device to measure
the blood pressure in a given patient throughout the study and a manual technique in another
patient. After patients have rested quietly, in the seated position for five minutes, three blood
pressure measurements will be taken two minutes apart and all three results have to be
entered in the eCRF. The seated pulse rate will be taken during the two-minute interval
between the second and third blood pressure reading. Blood pressure measurements should
be recorded to the nearest 2 mmHg only when measured with a manual sphygmomanometer;
when digital devices are used the value from the device should be rounded to the nearest 1
mmHg. For calculation of mean values, decimal places should be rounded to integers (e.g. a
DBP of 94.5 would be rounded to 95 mmHg and a DBP of 109.4 would be rounded to 109
mmHg). The above mentioned procedure is considered as standardised conventional blood
pressure measurement (CBPM).
In case of a suspected “white coat effect” it is recommended to repeat the measurement in a
pleasant condition after sufficient rest. Ambulatory blood pressure measurement (ABPM) can
be an option in specific cases to observe BP profiles over a longer period (e.g. during infusion
and thereafter) and even outside the hospital in private surrounding. However treatment
decisions should be based whenever possible on CBPM as described above and ABPM 
should be used for observation only. In case BP values from ABPM should be used for 
treatment related decisions, this has to be taken from appropriate time points and validated
ABPM devices according to website dableducational.org should be used. Values from self 
blood pressure measurement (SBPM) communicated from patient to investigator is not 
considered valuable for study related decisions.

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PHARMACOKINETIC ANALYSES
10.3
If data allow and if scientifically reasonable, the following pharmacokinetic parameters of BI 
836880 will be evaluated using non compartmental analysis methods according to the internal 
BI SOP 001-MCS-36-472.
After the first dose:

Cmax (maximum measured plasma concentration of BI 836880 in plasma).

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

AUC0-∞(area under the plasma concentration-time curve of the analyte over the time
interval from zero extrapolated to infinity).

AUC0-tz (area under the plasma concentration-time curve of the analyte over the time
interval from 0 up to the last quantifiable data point).

AUC0-168 (area under the plasma concentration-time curve over the time interval from 
0 to 168 h).

%AUCtz-∞(the percentage of the AUC0-∞that is obtained by extrapolation)

AUCt1-t2 (area under the concentration time curve of the analyte in plasma over the 
time interval t1 to t2)

tmax (time from dosing to the maximum measured plasma concentration).

λz (terminal rate constant in plasma)

t1/2 (terminal half-life).

MRTinf (mean residence time after intravenous infusion).

CL (total clearance of the analyte in plasma).

Vz (apparent volume of distribution during the terminal phase).

Vss (volume of distribution after intravenous infusion at steady state).
After repeated doses (steady state parameters will be calculated only, if steady state has 
been achieved):

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)

Cmin,ss (minimum concentration of the analyte in plasma at steady state over a uniform

dosing interval τ)

tmin,ss (time to reach minimum plasma concentration during the dosing interval τ at 
steady state)

Cavg (average concentration of the analyte in plasma at steady state)

Cpre,ss (predose concentration of the analyte in plasma at steady state immediately 
before administration of the next dose)

Cpre,N (The predose concentration immediately before administration of the Nth dose 
over the dosing interval τ is taken directly from the observed drug plasma 
concentration-time data)

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

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
AUCt1-t2,ss (area under the concentration time curve of the analyte in plasma over the 
time interval t1 to t2 at steady state)

tmax,ss (time from last dosing to maximum concentration of the analyte in plasma at 
steady state)

λz,ss (terminal rate constant in plasma at steady state)

t1/2,ss (terminal half-life of the analyte in plasma at steady state)

MRTinf,ss (mean residence time of the analyte in the body after intravenous infusion at

steady state)

CLss (total clearance of the analyte in plasma at steady state)

Vz,ss (volume of distribution during the terminal phase after multiple intravascular
administrations at steady)

Vss,ss (volume of distribution after multiple intravascular administrations at steady 
state).

RA, Cmax (accumulation ratio based on Cmax)

RA, AUC (accumulation ratio based on AUC0-τ)

Linearity index

PTF (Peak-Trough Fluctuation)
If deemed necessary, further appropriate pharmacokinetic parameters might be calculated.
Pharmacokinetic parameters will be calculated using non compartmental analysis (NCA). 
The derivation of pharmacokinetic parameters is described in detail in BI SOP. Blood 
sampling time points for PK, ADA, biomarker and ECG recording in the phase I part of 
the study (dose escalation phase)

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BLOOD SAMPLING TIME POINTS FOR PK,ADA, BIOMARKER AND 
10.4
ECG RECORDING IN THE PHASE I PART OF THE STUDY(DOSE 
ESCALATION PHASE)
Table 10.4: 1
Blood sampling scheme for PK, ADA and biomarker in courses 1, 2, 
3 and from course 4 onwards
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time /
planned 
time
PK: 
BI 
836880
***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-
A/ Ang2
ECG
BP
1
V1
1
Before start of 
BI 836880 infusion
-0:05
x
x
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
0:00
Before end of infusion
1:30**
x (3x)
x (3x)
Immediately after end 
of infusion*
1:30**
x
0.5h after the end of 
infusion
2:00
x
1.5h after the end of 
infusion
3:00
x
3.5h after the end of 
infusion
5:00
x
6.5h after the end of 
infusion
8:00
x
x
2
24:00
x
x
x (3x)
x (3x)
3
48:00
x
x
x
x (3x)
V2
8
Before start of 
BI 836880 infusion
167:55
x
x
x (3)
x (3x)
Start of  BI 836880  
infusion
168:00
Before end of infusion
169:30**
x(3)
x (3x)
Immediately after the 
end of infusion*
169:30**
x
V3
15
Before start of 
BI 836880 infusion
335:55
x
x
x(3)
x (3x)
Start of  BI 836880  
infusion
336:00
Before end of  infusion
337:30**
x (3)
x (3x)
Immediately after the 
end of infusion*
337:30**
x

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Table 10.4: 1(cont’d)
Blood sampling scheme for PK, ADA and biomarker in courses 1, 2, 
3 and from course 4 onwards (cont.)
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time /
planned 
time
PK: 
BI 
836880
***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-
A/ Ang2
ECG
BP
2
V1
1
Before start of 
BI 836880 infusion
-0:05
x
x
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
0:00
Before end of infusion
1:30**
x (3x)
x (3x)
Immediately after end 
of infusion*
1:30**
x
0.5h after the end of 
infusion
2:00
x
1.5h after the end of 
infusion
3:00
x
3.5h after the end of 
infusion
5:00
x
6.5h after the end of 
infusion
8:00
x
x
2
24:00
x
x
x (3x)
x (3x)
V2
8
Before start of 
BI 836880 infusion
167:55
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
168:00
Before end of infusion
169:30**
x (3x)
x (3x)
Immediately after end 
of infusion*
169:30**
x
V3
15
Before start of 
BI 836880 infusion
335:55
x
x
x (3x)
x(3x)
Start of BI 836880 
infusion
336:00
Before end of infusion
337:30**
x (3x)
x (3x)
Immediately after end 
of infusion*
337:30**
x

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Table 10.4: 1(cont’d)
Blood sampling scheme for PK, ADA and biomarker in courses 1, 2, 
3 and from course 4 onwards (cont.)
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time /
planned 
time
PK: 
BI 
836880
***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-
A/ Ang2
ECG
BP
3
V1
1
Before start of  BI 
836880 infusion
-0:05
x
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
0:00
Before end of infusion
1:30**
x (3x)
x (3x)
Immediately after end 
of infusion*
1:30**
x

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Table 10.4: 1(cont’d)
Blood sampling scheme for PK, ADA and biomarker in courses 1, 2, 
3 and from course 4 onwards (cont.)
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time /
planned 
time
PK: 
BI 
836880
***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-
A/ Ang2
ECG
BP
4
V1
1
Before start of 
BI 836880 infusion
-0:05
x
x
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
0:00
Before end of infusion
1:30**
x (3x)
x (3x)
Immediately after end 
of infusion*
1:30**
x
0.5h after the end of 
infusion
2:00
x
1.5h after the end of 
infusion
3:00
x
3.5h after the end of 
infusion
5:00
x
6.5h after the end of 
infusion
8:00
x
x
2
24:00
x
x
x(3x)
x(3x)
V2
8
Before start of 
BI 836880 infusion
167:55
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
168:00
Before end of 
BI 836880 infusion
169:30**
x (3x)
x (3x)
Immediately after end 
of infusion*
169:30**
x
V3
15
Before start of 
BI 836880 infusion
335:55
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
336:00
Before end of 
BI 836880 infusion
337:30**
x (3x)
x (3x)
Immediately after  end 
of infusion*
337:30**
x

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Table 10.4: 1(cont’d)
Blood sampling scheme for PK, ADA and biomarker in courses 1, 2, 
3 and from course 4 onwards (cont.)
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time /
planned 
time
PK: 
BI 
836880
***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-
A/ Ang2
ECG
BP
5-12
V1
1
Before start of BI 
836880 infusion
-0:05
x
x
x
x (3x)
x (3x)
Start of BI 836880 
infusion
0:00
Before end of infusion
1:30**
x (3x)
x (3x)
EOT
x
x
x
x (3x)
x (3x)
EoR
x
x
x
x
x (3x)
FU1
x
x
x
*       within 5 min after the end of infusion
**     Planned time point of 1:30 according to an infusion duration of 90 min. If the infusion duration should be shorter (or 
longer), the PK sample has to be taken in any case immediately after the end of the infusion/the ECG has to be 
conducted shortly before end of infusion and the actual sampling time needs to be recorded in the eCRF. 
Subsequent PK samples (in C1, C2 and C4) have to be taken 0.5h, 1.5h, 3.5h and 6.5h after the end of the
infusion.
***
The last blood samples for PK, ADA and Biomarkers (myriad Ang Map Panel, free/total VEGF-A, Ang2) will be 
taken in this trial when the last patient has discontinued the trial treatment and performed the EoT visit.
After the interim data base lock (see Section 6.2.3.5), no blood samples will be collected for PK, ADA and biomarker
analyses
**** In case of an intra-patient dose escalation the 1st cycle with the higher dose will follow cycle one at the start of 
treatment with BI 836880 with regards to sampling PK, ADA as well as Biomarkers (Myriad panel and free/total 
VEGF-A/ Ang2)
TRIAL BIOMARKER PLAN
10.5
Time profiles of plasma derived protein biomarkers and their changes from baseline will be 
summarized by descriptive statistics and visualized by line plots per dose group to identify 
treatment related changes. The correlation between the biomarkers and potential associations 
to clinical endpoints, if applicable, will be investigated and visualized as well.
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
10.6
DATA SCENARIOS
The model was assessed by two different metrics: hypothetical on-study data scenarios and 
long-run operating characteristics. 
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.6:1. These scenarios reflect potential on-
study data constellations and related escalation as allowed by the model and the 200% 
escalation limit or doses of interest. For each scenario, the probability of overdose for the 

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current dose, as well as the next potential dose and related probabilities of under-dosing, 
target dose and over-dosing are shown. A new cohort will be open for enrolment after the 
review on data from the previous cohort is completed by the DSB.
For example, scenario 1 represents the case that no DLT is observed in two patients at the 
starting dose of 40mg. In this case, the next dose permitted by the model and by the 200% 
escalation rule is 120 mg. Scenario 4 represents the case that no DLTs are observed in the 
first cohort of two patients at 40mg, and 1 DLT is observed in the second cohort of three 
patients at 120mg. In this case, the model requires to re-enroll at the current dose level of 
120mg. Scenario 5 shows the case that 2 DLTs are observed in the second cohort of three 
patients at 120mg. The model then allows a de-escalation.
Scenario 6 and 7 illustrate the case where no DLTs are seen in the first three cohorts. In 
scenario 6, no DLT is observed at 480mg, either. However, the model does not allow the 
escalation to 960mg for safety concerns despite the fact that no DLTs are observed in the first 
four cohorts. On the other hand, scenario 7 presents the case that 1 DLT is seen at 480mg. In 
this case, no escalation to 1250mg is allowed as well. These two cases illustrate the adaptive 
behaviour of the model even in extreme situations. In scenario 8, no DLs are seen in the first 
three cohorts. Dose was escalated to 960mg after 6 patients were tested on 480mg without 
DLT. De-escalation occurred as a result of one out of the three patients treated on dose 
960mg had DLT.

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Table 10.6: 1
Hypothetical data scenarios 
Scenario
Cohort
Dose 
(mg)
# DLT
# Pat
Current 
Dose: 
P(OD)
Next 
Dose
Next Dose
P(UD)
P(TD)
P(OD)
1
1
40
0
2
0.019
120
0.862
0.076
0.062
2
1
40
1
3
0.318
N/A
N/A
N/A
N/A
3
1
40
0
2
2
120
0
2
0.018
240
0.841
0.093
0.066
4
1
40
0
2
2
120
1
3
0.231
120
0.451
0.318
0.231
5
1
40
0
2
2
120
2
3
0.623
40
0.455
0.308
0.237
6
1
40
0
2
2
120
0
2
3
240
0
3
4
480
0
3
0.02
480
0.903
0.077
0.020
7
1
40
0
2
2
120
0
2
3
240
0
3
4
480
1
3
0.229
480
0.424
0.347
0.229
8
1
40
0
2
2
120
0
2
3
240
0
3
4
480
0
6
5
960
1
3
0.353
480
0.943
0.054
0.003
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model. Under an 
assumed true dose-toxicity curve, metrics such as the probability of recommending a dose 
with true DLT rate in the target interval can be approximated via simulation. Table 10.6: 2
describes 5 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the model. These scenarios reflect a wide range of possible cases as 
follows:

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
- Scenario 1: aligned with prior medians

- Scenario 2: high-toxicity scenario

- Scenario 3: low-toxicity scenario

- Scenario 4: low-tox followed by high-tox

- Scenario 5: non-logistic dose-toxicity scenario
Table 10.6: 2
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
40
120
240
480
960
1250
1 (Prior)
P(DLT)
0.091
0.139
0.193
0.284
0.471
0.594
2 (High Tox)
0.100
0.227
0.351
0.500
0.649
0.700
3 (Low Tox)
0.001
0.007
0.022
0.180
0.250
0.350
4 (Non-Logistic)
0.040
0.100
0.180
0.280
0.360
0.380
5 (Low-High)
0.001
0.011
0.047
0.181
0.500
0.640
For each of these scenarios, 1000 trials were simulated. It was then assessed how often a dose 
was declared as MTD with true DLT rate in the under-, targeted or over-dose range. 
Furthermore, the average, minimum and maximum number of patients per trial and the 
average number of DLTs per trial are reported. Results are shown in Table 10.6: 3.
Table 10.6: 3
Simulated operating characteristics 
Scenario
% of trials declaring an MTD with true DLT rate in
# Patients
# DLT
underdose
target dose
overdose
STOPPED
Mean
(Min-Max)
Mean
(Min- Max)
1
23.1
56.4
0.1
20.4
16.45
(3 – 34)
2.982
(1 – 10)
2
18.1
38.3
19.6
24.0
16.01
(3 – 36)
3.73
(1 – 11)
3
20.2
79.6
0.2
0
20.42
(17 – 38)
2.248
(1 – 6)
4
19.4
71.4
0.6
8.6
18.42
(3 – 35)
3.09
(1 – 10)
5
25.6
74.0
0.3
0
20.11
(16 – 40)
2.43
(1- 6)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior medians, 
56.4% of the simulated trials declared a dose as MTD with true DLT rate in the targeted dose 
range. Note that 20.4% of the simulated trials stop because of high toxicity. This is mostly 
due to the cases that 1 DLT is observed out of 3 patients at the starting dose 40mg. In reality, 

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this situation would rarely happen as the safety profile of starting dose is expected to be good. 
In addition, dose escalation could still happen after the discussion within DSB.
In scenario 2 (high-toxicity scenario), the starting dose has already >10% probability of 
observing at least 2 DLTs out of 3 patients or 1 DLT out of 2 patients in the first cohort. This 
contributes to the high percentage (24.0%) of all simulated trials for which the trial is stopped 
since none of the doses is considered tolerable anymore. This is an expected situation for a 
high-toxicity scenario.
In scenarios 3, 4 and 5, more than 50% of the simulated trials declared a dose as MTD with 
true DLT rate in the targeted dose range. 
The mean patient numbers range from 16.0 patients (high-toxicity scenario) to 20.4 patients 
(low-toxicity scenario) and the maximum number of patients was 40. Therefore, the patient 
numbers are as expected and increase when moving away from the high-toxicity scenario. 
In summary, the considered data scenarios show a reasonable behavior of the model and the 
operating characteristics demonstrate a good precision of MTD determination. 

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of 
global 
amendment
I
Date of CTP 
revision
24 Mar 2017
EudraCT 
number
2015-001132-38
BI Trial 
number
1336.6
BI 
Investigationa
l Product(s)
BI 836880
Title of 
protocol
Phase I, non-randomized, open-label, multi-center dose escalation trial of 
BI 836880 administered by weekly repeated intravenous infusions in 
patients with advanced solid tumors.
To be 
implemented 
only after 
approval of 
the IRB / IEC
/ Competent 
Authorities
To be 
implemented 
immediately 
in order to 
eliminate 
hazard –
IRB / IEC / 
Competent 
Authority to 
be notified of 
change with 
request for 
approval
Can be 
implemented 
without IRB /
IEC / 
Competent 
Authority 
approval as 

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changes 
involve 
logistical or 
administrativ
e aspects only
Section to be 
changed
Synopsis: total entered
Description of 
change
Approximately 40 patients
Was changed to:
Approximately 40 patients, including at least 12 patients treated at MTD 
with tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-
MRI
Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
Synopsis
Description of 
change

Histologically or cytologically confirmed malignancy which is 
locally advanced or metastatic solid tumor, and either refractory 
after standard therapy for the disease or for which standard 
therapy is not reliably effective, e.g. patients do not tolerate or
have contraindications to otherwise available 
Was changed to:

Histologically or cytologically confirmed malignancy which is 
locally advanced or metastatic solid tumor, and either refractory 
after standard therapy for the disease or for which standard 
therapy is not reliably effective, e.g. patients do not tolerate or
have contraindications to otherwise available standard therapy
and tumour lesions evaluable for Dynamic-enhanced (DCE)-MRI 
at MTD
Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
Flow chart: footnote #3; section 5.3.2
Description of 
change
Footnote #3
3Body Temperature: whenever possible the same method should be used for body temperature 
measurement in one patient.  Acceptable methods could be: oral, rectal measurement with 
thermometer (digital, mercury, or other fluid). Not acceptable: infrared measurement in ear, 
forehead or temple. Body temperature > 38°C must be re assessed 1 hour after.
Section 5.3.2 body temperature
Whenever possible the same method should be used for body temperature 
measurement in one patient. All methods used should deliver valid 
reproducible results according to common clinical practice.  Acceptable 

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methods could be, but not limited to: oral, rectal measurement with 
thermometer (digital, mercury, or other fluid). Not acceptable/preferred 
methods include: infrared measurement in ear, forehead or temple.
Was changed to
Footnote #3
3Body Temperature: whenever possible the same method should be used for body temperature 
measurement in one patient. Body temperature > 38°C   must be re assessed 1 hour after.
Section 5.3.2 body temperature
Whenever possible the same method should be used for body temperature 
measurement in one patient. All methods used should deliver valid 
reproducible results according to common clinical practice.  
Rationale for 
change
- To allow some flexibility to the sites to measure body temperature 
according to common clinical practice. 
-To be consistent with the wording (> 38°C) elsewhere in the protocol
Section to be 
changed
Footnote #5 and section #5.3.3 
Description of 
change
Footnote #5
5Haematology, biochemistry and coagulation parameters will be performed locally. Previous 
safety lab: investigations are acceptable if performed within 72 hours prior to the screening visit.
For details see Section 5.3.3
Section #5.3.3
Previous laboratory investigations performed within 72 hours prior to the 
screening visit are acceptable to confirm the eligibility at for the 
screening.  
Was changed to 
Footnote #5
5Haematology, biochemistry and coagulation parameters will be performed locally. Previous 
safety lab: investigations are acceptable if performed within 72 hours prior to the first treatment 
administration. For details see Section 5.3.3
Section #5.3.3
Previous laboratory investigations performed within 72 hours prior to the 
first treatment administration visit are acceptable to confirm the patient 
eligibility.  
Rationale for 
change
To confirm patient eligibility before start of  study treatment
Section to be 
changed
3.1
Description of 
change
Was added:
Once a MTD has been reached, a minimum of 12 patients must have 
tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-MRI to 
allow a better interpretation of pharmacodynamics (vascular) effect of BI 
836880

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Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
3.1.1
Description of 
change
Members of the DSB will be investigators of participating trial sites, Trial 
Statistician (TSTAT), Clinical Program Leader (CPL) and Trial Clinical 
Monitor (TCM).
Was changed to:
Members of the DSB will be investigators of participating trial sites, Trial 
Statistician (TSTAT), Clinical Program Leader (CPL), Trial Clinical 
Monitor (TCM) and BI Lead Risk Management Physician
Rationale for 
change
Addition of one Data Safety Board member that was omitted  in the 
previous version of the protocol
Section to be 
changed
3.3.2
Description of 
change
Histologically confirmed malignancy which is locally advanced or 
metastatic solid tumor, and either refractory after standard therapy for the 
disease or for which standard therapy is not reliably effective e.g patients 
do not tolerate or have contraindications to otherwise available standard 
therapy
Was changed to:
Histologically confirmed malignancy which is locally advanced or 
metastatic solid tumor, and either refractory after standard therapy for the 
disease or for which standard therapy is not reliably effective e.g patients 
do not tolerate or have contraindications to otherwise available standard 
therapy and tumour lesions evaluable for Dynamic contrast-enhanced 
(DCE) MRI at MTD
Rationale for 
change
Change was implemented to make sure that a pharmacodynamic effect 
can be documented
Section to be 
changed
3.3.2
Description of 
change
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an 
alternative medical cause) or who are permanently sterilized (e.g., tubal 
occlusion, hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy).
Was changed to:
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an 
alternative medical cause) or who are permanently sterilized (e.g.,  
hysterectomy, bilateral oophorectomy or bilateral salpingectomy).

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Rationale for 
change
Tubal ligation is no longer considered a highly effective method of 
contraception and no longer a method of permanent sterilisation
Section to be 
changed
Section 4.1.2
Description of 
change
Was added:
“..For medication number allocation at each visit it’s possible to conduct 
IRT call ahead of the planned visit (= day of administration)..”
Rationale for 
change
Clarification for logistical reasons
Section to be 
changed
Table 4.1.3:1
Description of 
change
Dose level
Total dose (mg)
Approximate 
increment to next 
dose
Dose level 1 
( starting dose)
40
3x (200%)
Dose level 2
120
2x (100%)
Dose level 3
240
2x (100%)
Dose level 4
480
1.5x (50%)
Dose level 5
720
1.3x (30%)
Dose level 6
960
1.7x (30%)
Dose level 7
1440 limited to 
1250*
Intermediate dose level of “720 mg” was added and potential dose levels 
were adapted
Rationale for 
change
Intermediate dose level of “720 mg” was added in the table as requested 
by the Spanish authority during the approval  process
Section to be
changed
4.1.3
Description of 
change
was added:
For patients with an intra-patient dose escalation(s) all assessments will 
be done according to instructions for the first cycle at start of treatment 
with BI 836880 and intensive PK-sampling, sampling for ADA as well as 
sampling for biomarkers (Myriad panel and free/total VEGF-A/ Ang2) 
will be conducted (see flow chart and Appendix 10.4) and patients have 

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to be closely followed for any adverse events. Therefore patients have to 
come to the clinic during the first course of intra-patient dose escalation 
every week. Additional visits are needed at day 2 and at day 3 of the 1st
course of dose escalation. 
The above-mentioned procedures will be followed also in case of further 
intra-patient dose escalations.
Rationale for 
change
Specific guidance for patients with an intra-patient dose escalation is 
provided for assessments to be done within the first course with the 
escalated dose
Section to be 
changed
5.2
Description of 
change
Was added:
Results of tumor-specific tumor markers which will be assessed routinely 
should be documented in the eCRF
Rationale for 
change
To better assess tumour response in tumors for which tumour marker 
testing is performed routinely
Section to be 
changed
5.5
Description of 
change
Additional assays may be added if new data suggests relevance to the 
study drug mechanism of action. Furthermore, the collected samples may 
be used for testing of other disease related
biomarkers that may be of scientific interest for understanding 
mechanisms of the disease (i.e. cancer) after initiation/completion of this 
trial
Was changed to 
Additional assays may be added if new data suggests relevance to the 
study drug mechanism of action. 
Rationale for 
change
For clarification, deletion of the sentence suggesting  unspecified 
investigations to be done, also to comply with Spanish authority request 
during approval process
Section to be 
changed
5.6.2
Description of 
change
Was removed:
After completion of the study the plasma samples may be used for further 
ADA characterization or methodological investigations, e.g., for stability 
testing or isotyping. Any additional characterization data will be reported 
separately
Rationale for 
change
For clarification, deletion of the sentence suggesting  unspecified 
investigations to be done, also to comply with Spanish authority request 
during approval process
Section to be 
6.1 

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changed
Description of 
change
To allow close monitoring for infusion-related reactions or other adverse 
events and availability of patients for PK visits, after administration of BI 
836880, patients are required to be hospitalised under close surveillance 
with access to intensive care for at least 48 hours and 24 hours after the
first and the second administration of  BI 836880, respectively.
Was changed to 
To allow close monitoring for infusion-related reactions or other adverse 
events and availability of patients for PK visits at course 1, patients are 
required to be hospitalised under close surveillance with access to 
intensive care for at least 48 hours after the first administration of BI 
836880 at course 1 day 1 and 24 hours after the second and third 
administrations of BI 836880 at course 1 day 8 and course 1 day 15
respectively.
Rationale for 
change
To clarify patient monitoring during first course
Section to be 
changed
Table 10.4
Description of 
change
Blood sampling scheme for PK, ADA and biomarkers
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time / 
planned 
time
PK: 
BI 
836880***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-A/ 
Ang2
ECG
BP
1
V1
3
48:00
x
x
x
x 
(3x)
V3
15
Before end of  
infusion
337:30**
x (3)
x 
(3x)
Immediately 
after the end 
of infusion*
337:30**
x
Correction of typo errors  at time points C1V1; C1V3
Course
Visit
Day
Time Point 
(hh:min)
CRF Time 
/ planned 
time
PK: 
BI 
836880***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-A/ 
Ang2
ECG
BP
2
V2
8
Before start of 
BI 836880 
infusion
167:55
x
x
x 
(3x)
x 
(3x)
Immediately 
after end of 
infusion*
169:30**
x
V3
15
Before start of 
BI 836880 
infusion
335:55
x
x
x 
(3x)
x
(3x)

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Start of BI 
836880 infusion
336:00
Before end of 
infusion
337:30**
x 
(3x)
x 
(3x)
Immediately 
after end of 
infusion*
337:30**
x
Correction of typo errors at C2V2; and PK time point was added at 
C2V3 (337:30)
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time / 
planned 
time
PK: 
BI 
836880***
ADA***
Bio-
marker:
Myriad 
panel
Bio-
marker:
free/total 
VEGF-A/ 
Ang2
ECG
BP
4
V1
2
24:00
x
x
x (3x)
x(3x)
V3
15
Immediately 
after  end of 
infusion*
337:30**
x
One PK time point was added at C4V3, ECG and BP time points were 
added at C4V1D2
Rationale for 
change
Corrections of typo errors and PK, ECG and BP time points were added 
as they were omitted in error in the previous version of the protocol
Section to be 
changed
Table 10.4 appendices
Description of 
change
The following footnote was added:
In case of an intra-patient dose escalation the 1st course with the higher dose will follow course 
one at the start of treatment with BI 836880 with regards to sampling PK, ADA as well as 
Biomarkers (Myriad panel and free/total VEGF-A/ Ang2)
Rationale for 
change
To provide guidance for patients with an intra-patient dose escalation 
with regards to assessments to be done within first course with escalated 
dose

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Number of global 
amendment
2
Date of CTP revision
28 Sep 2017
EudraCT number
2015-001132-38
BI Trial number
1336.6
BI Investigational 
Product(s)
BI 836880
Title of protocol
Phase I, non-randomized, open-label, multi-center dose 
escalation trial of BI 836880 administered by weekly 
repeated intravenous infusions in patients with 
advanced solid tumors.
To be implemented only 
after approval of the IRB / 
IEC / Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented 
without IRB / IEC / 
Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Section to be changed
5.5.1 Imaging Pharmacodynamic endpoints
Description of change
Methods of sample collection
…..DCE-MRI will be performed on a coronal slice 
through one or more representative lesions
selected and identified by the responsible radiologist 
from the morphological scans. For
DCE-MRI, a T1-weighted inversion recovery-gradient 
echo sequence is used, for which the
patient will receive an intravenous bolus application of 
the gadolinium contrast agent
Multihance®. Detailed parameter settings are given in 
the MR-Protocol.
Was changed to :

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Methods of sample collection
….DCE-MRI will be performed on a coronal slice 
through one or more representative lesions selected and 
identified by the responsible radiologist from the 
morphological scans. For DCE-MRI, a T1-weighted 
inversion recovery-gradient echo sequence is used, for 
which the patient will receive an intravenous bolus 
application of the gadolinium contrast agent. Detailed 
parameter settings are given in the MR-Protocol.
Rationale for change
A risk of brain deposits with repeated use of
gadolinium-based contrast agents for magnetic
resonance imaging (MRI) like Multihance
previously recommend within this protocol has
been reported and radiologists therefore prefer the
use of gadolinium-based contrast agents for which
this risk has not been reported.
Section to be changed
Section 4.1.3 table 4.1.3:1 potential dose level
Description of change
Was added: dose level  of 180 mg 
Rationale for change
This intermediate dose level was tested based on Data 
Safety Board decision
Number of global 
amendment
3
Date of CTP revision
13 Mar 2019
EudraCT number
2015-001132-38
BI Trial number
1336.6
BI Investigational 
Product(s)
BI 836880
Title of protocol
Phase I, non-randomized, open-label, multi-center dose 
escalation trial of BI 836880 administered by weekly 
repeated intravenous infusions in patients with 
advanced solid tumors.
To be implemented only 
after approval of the IRB / 
IEC / Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented 
without IRB / IEC / 
Competent Authority 

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approval as changes involve 
logistical or administrative 
aspects only
Section to be changed

Title page

Abbreviation

Section 3.1.1- administration of the trial
Description of change
Trial Clinical Monitor (TCM) was changed to Clinical 
Trial Leader (CTL) and Clinical Monitor Local (CML) 
was changed to Clinical Trial Manager (CTM)
Rationale for change
Administrative changes
Section to be changed
Synopis- methodology
Description of change
Non randomized, uncontrolled, open-label, dose 
escalation followed by an expansion cohort
Was changed to
Non randomized, uncontrolled, open-label, dose 
escalation 
Rational for change
Expansion cohort is no longer planned for this trial
Section to be changed
Synopsis- N° of patients
Description of change
Approximately 50 patients to be enrolled
Was changed to
Approximately 40 patients to be enrolled
Rational for change
To adapt the sample size since expansion cohort is no 
longer planned for this trial
Section to be changed
Synopis
Description of change
Approximately 40 patients, including at least 12 
patients treated at MTD with tumour lesions evaluable 
for Dynamic contrast-enhanced (DCE)-MRI.
40 patients will receive study treatment
Was changed to
Approximately 25 patients.
Approximately 25 patients will receive study treatment
Rationale for change
It is no longer required to enroll 12 patients with DCE-
MRI to be treated at MTD, and to adapt the sample size 
since expansion cohort is no longer planned for this 
trial
Section to be changed
Flow chart
Description of change
Change s have been made in the following footnotes 
and sections: 
Footnote numbers and sections in the protocol:
**: no additional follow up visits required after the interim data 
base lock
- 2: change to frequency of physical examination and ECOG 
Performance

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- 3: change to frequency of body temperature, following the 
interim data base lock (refer to section 5.3.2)
- 4: change to frequency of blood pressure, following the interim 
data base lock (refer to section 5.3.2)
- 5: change to frequency of laboratory tests, following the interim 
data base lock (refer to section 5.3.3)
- 6: change to frequency of tumor assessment, following the 
interim data base lock
- 7: change to frequency and assessment of ECG and no 
requirement to send ECGs to central vendor, following the interim 
data base lock (refer to section 5.3.4)
- 8: clarification about echocardiography data entry in the eCRF ( 
refer to section 5.3.4)
- 9: no blood samples for PK analysis will be taken following the 
interim data base lock (refer to appendix 10.4)
- 10: no blood samples for ADA analysis will be taken following
the interim data base lock (refer to appendix 10.4)
- 11; 12: no blood samples for biomarker analysis will be taken 
following the interim data base lock (refer to appendix 10.4)
-14: DCE-MRI measurement is no longer mandatory following the 
interim data base lock
Rationale for change
At the time of interim data base lock, sufficient data 
will have been collected for PK, ADA and biomarker 
analyses, therefore no longer required. 
Also to provide more flexibility to trial procedures
Section to be changed
Section 3.1 overall trial design and plan
Description of change
Was deleted:
Once a MTD has been reached, a minimum of 12 
patients must have tumour lesions evaluable for 
Dynamic contrast-enhanced (DCE)-MRI to allow a 
better interpretation of pharmacodynamics (vascular) 
effect of BI 836880.
Once the RP2D has been determined and in case of 
anti-tumor activity signals is reported in given tumor 
type(s), DSB can take the decision for a trial expansion 
to recruit patients with the same tumor type(s) with the 
aim to generate safety and preliminary efficacy data 
specific to such disease. Approximately 10-15 
additional patients will be treated in the expansion 
cohort, sample size will be re evaluated when the 
expansion cohort is open. 
Rationale for change
-Since the Prof of Pharmacological Principal (PoPP)
has been determined with the sister trial 1336.1 (3-
weekly dosing), enrollment of 12 patients with DCE-
MRI in this trial is no longer mandatory.
-To reflect the fact that expansion cohort is no longer 
planned for this trial

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Section to be changed
Section 3.1 overall trial design and plan
Description of change
Was added:
After the interim data base lock, the study is 
considered completed when the last patient in the 
study has discontinued the study treatment and 
completed the EoR visit (see Section 6.2.3.5).
Rationale for change
Clarification on the definition of trial completion after 
the interim data base lock
Section to be changed
Section 3.3 selection of trial population
Description of change
It is estimated that approximately 50 patients will be 
enrolled at 2 study sites. The rate of enrolled patients 
may vary by study site, but it is expected to be 
approximately 25 patients per site. Among them 40 
patients will be enrolled and treated in this trial.
Was changed to 
It is estimated that approximately 40 patients will be 
enrolled at 2 study sites. The rate of enrolled patients 
may vary by study site, but it is expected to be 
approximately 20 patients per site. Among them 
approximately 25 patients will be treated in this trial.
Rationale for change
To adapt the sample size since expansion cohort is no 
longer planned for this trial
Section to be changed
Section 4.1.3 table 4.1.3:1 potential dose level
Description of change
Was added: dose level  of 150 mg 
Rationale for change
This intermediate dose level was tested based on Data 
Safety Board decision
Section to be changed
5.2 assessment of efficacy
Description of change
Was added:
After the interim data base lock, frequency of tumor 
assessment may be adapted according to local 
standard of care and in agreement with the sponsor 
if the patient is deriving clinical benefit (e.g. CR, PR 
or SD > 6 months).   
Rationale for change
To reduce imaging assessment frequency
Section to be changed
5.2 assessment of efficacy
Description of change
Was added:
After the interim data base lock, collection of tumor 
markers in the e-CRF is no longer required.
Rationale for change
Following data the interim data base lock there is no 
longer requirement to enter tumor maker data in e-CRF
Section to be changed
Abbreviation and section 5.3.6.1 Definition of AEs
Description of change
Remote Data Capture (RDC) was changed to 
Electronic Data Capture (eDC)
Rationale for change
Administrative

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Section to be changed
6.2 - Details of trial procedures at selected visits
Description of change
Was added:
After the interim data base lock, mandatory 
procedures/assessments and documentation in the 
eCRF will be adapted as described in the flow chart 
and the respective sections of this protocol
Rationale for change
To reflect the changes to trial  procedures/assessments 
following the interim data base lock
Section to be changed
6.2.2 treatment period(s)
6.2.3.3 Follow-up period for progression
Description of change
Was added:
After the interim data base lock, frequency of tumor 
assessment may be adapted according to local 
standard of care and in agreement with the sponsor 
if the patient is deriving clinical benefit (e.g. CR, PR 
or SD > 6 months).
Rationale for change
To reduce imaging assessment frequency
Section to be changed
Section 6.2.3.5 trial completion
Description of change
Section 6.2.3.5 was added:
The clinical trial will be considered completed when 
the last patient has completed the EoR visit.
If patients are still on treatment at the time of 
interim data base lock and the Clinical Trial Report 
is written, these patients will be maintained in the 
trial as long as they are deriving clinical benefit (i.e. 
no disease progression, no drug-related AEs 
requiring drug discontinuation) or no new anti-
cancer treatment started and there are willing to 
continue. For these patients, no blood sample will be 
collected for PK/PD and biomarker analysis, only 
(S)AEs and limited efficacy data will be collected. 
After the discontinuation of these patients, 
additional data collected after interim data base 
lock will be reported in separate listings and will not 
lead to any further update of tables generated for 
section 15 of the CTR unless deemed necessary. 
These listings will be included in a revised CTR.
Rationale for change
Clarification for the definition of trial completion 
following the interim data base lock
Section to be changed
Section 7.7 determination of sample size
Description of change
Was deleted
Additional 10-15 patients will be included in the 
expansion cohorts, in case one or more tumor types will 
be selected for further evaluation. Sample size will be 
reevaluated when the expansion cohort is open.

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Rationale for change
Expansion cohort is no longer planned for this trial
Section to be changed
8.6 End of Trial
Description of change
The trial will end when the last patient has completed 
the last follow up visit as specified in Section 6.2.3.4
Was changed to:
After the interim data base lock the trial will end 
when the last patient has completed the EoR visit as 
specified in Section 6.2.3.4 and 6.2.3.5
Rationale for change
Clarification for the definition of end of trial, following 
the interim data base lock

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03124055
6.0
clinical-trial-protocol-version-04
Phase I non-randomized open-label multi-center dose escalation trial of BI 836880
administered by weekly repeated intravenous infusions in patients with advanced
solid tumors
Author-Clinical Trial Leader
13 Mar 2019 16:46 CET
Approval-Therapeutic Area 
13 Mar 2019 17:48 CET
Author-Trial Clinical
Pharmacokineticist
14 Mar 2019 07:44 CET
Approval-Clinical Program 
14 Mar 2019 11:29 CET
Author-Trial Statistician
15 Mar 2019 14:16 CET
Verification-Paper Signature
Completion
18 Mar 2019 09:37 CET

Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03124055
6.0