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

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CLINICAL TRIAL PROTOCOL
LE PAGE
Document Number:
c02441868-07
EudraCT No.:
2014-005395-28
BI Trial No.:
1336.1
BI Investigational 
Product(s):
BI 836880
Title:
A First-in Human Phase I, non-randomized, open-label, multi-
center dose escalation trial of BI 836880 administered by 
repeated intravenous infusions in patients with solid tumors.
Brief Title:
Dose finding study of BI836880 in patients with solid tumors
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
Phone:
Fax :
Coordinating 
Investigator:
Phone:
Fax:
Status:
Final Protocol (revised protocol based on global amendment 5)
Version and Date:
Version:
Date:
6.0
08 March 2019
Page 1 of 103
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:
11 May 2015
Trial number:
1336.1
Revision date:
08 March2019
Title of trial:
A First-in Human Phase I, non-randomized, open-label, multi-center dose 
escalation trial of BI 836880 administered by repeated intravenous infusions 
in patients with solid tumors.
Coordinating
Investigator
Trial site(s):
Multi-centre trial conducted in 2 countries
Clinical phase:
Phase I; First In Human
Objective(s):
Objective of this trial is to determine the maximum tolerated dose (MTD) of 
BI 836880 and to provide preliminary safety data given as intravenous 
infusion and to determine recommended phase II dose. Further the PK-, 
immunogenicity and PD-profile, as well as primary signs of anti-tumor 
activity of BI 836880 should be assessed.
Methodology:
Non-randomized, uncontrolled, open-label, dose escalating study of 
BI 836880 administered intravenously
No. of patients: 
About 80 patients will be entered, including at least 12 patients treated at 
MTD with tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-
MRI.
total entered:
80
each treatment:
80 (all patients will receive trial drug, but on different dose levels)

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Name of company:
Boehringer Ingelheim 
Name of finished product:
not applicable
Name of active ingredient:
BI 836880
Protocol date:
11 May 2015
Trial number:
1336.1
Revision date:
08 March2019
Diagnosis :
Advanced or metastatic/refractory solid tumors
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. they 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

Signed written informed consent

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) sensory peripheral 
neuropathy CTCAE grade ≤ 2 or considered not clinically significant.
Test product(s):
BI 836880 and Diluent for BI 836880 drug product
dose:
Starting dose will be 40 mg every 3 weeks; 
the dose can be increased up to 1250 mg administered every 3 weeks.
mode of 
administration:
i.v.
Comparator products:
n/a
dose:
n/a
mode of 
administration:
n/a
Duration of treatment:
Administration of BI 836880 can be continued up to disease progression or until 
intolerable toxicities has been recorded.
Endpoints
1° endpoint:

assessment of the maximum tolerated dose (MTD) based on the number of 
patients presenting dose-limiting toxicities (DLTs) using CTCAE v4.03, started 
within 3 weeks after first administration of study treatment (i.e. within first 

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Name of company:
Boehringer Ingelheim 
Name of finished product:
not applicable
Name of active ingredient:
BI 836880
Protocol date:
11 May 2015
Trial number:
1336.1
Revision date:
08 March2019
cycle of treatment) and judged to be related to the study medication .
2° endpoints:

Exposure measures (AUC0-tz) after the first dose ;

Disposition kinetic measures (t1/2 ) after the first dose;

Drug related AEs leading to dose reduction or discontinuation during treatment 
period
Safety criteria:
Incidence and intensity of adverse events graded according to the common 
terminology criteria for adverse events (CTCAE, version 4.03), incidence of dose 
limiting toxicities; laboratory parameters, vital signs, ECG
Statistical methods:
Dose escalation guided by a Bayesian logistic regression model with over dose 
control

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FLOW CHART
Trial Periods
Screen
Treatment courses
EOT
EoR
FU /
EoFU
Course
1, 2, 3, 4
5, 6
718
ongoing
Week
w1
w2
w3
Imaging
w1
w2
Imaging
w1
Visit
Screen
V1
V2
V3
V4
V1
V2
V3
V1
Day; visit window [days]
-21 
to 
-1
d1
d2
d3; 
+1d
(1,2)*
d8; 
-1/+2d
d15; 
-1/+2d
d18;
+/-3d
(2,4)*
d1
d8;
-1d/
+2d
d18;
+/-3d
(6)*
d1
EoT 
(when 
defined)
Last 
admin
+42d;
-2/+3d
every 6 
weeks 
(+/-3d) 
until PD
Informed consent / IRT call
X
Demographics
X
Medical history
X
Review of in-/ exclusion criteria1
X
Height
X
Weight
X
X
X
X
X
ECOG performance status
X
X
X
X
X
body temperature 2
X
X
X (1,2)*
X
X
X
Blood pressure, heart rate 3
X
X (2x)**
X
X
X
X
X (2x)
X
X (2x)
X
X
12-lead ECG 4
X
X (2x)**
X (1,2)*
X (2x)
X (2x)
X
Echocardiography 5
X
if clinically indicated
X
General safety laboratory parameters 6
X
X
X
X
X
X
X
X
X
Serum pregnancy test 7
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
Physical examination 8
X
X
X
X
X
X
X
X
X
X
X
Adverse events 9
X
X
X
X
X
X
X
X
X
X
X
Eligibility for treatment / IRT call 10
X
X
X
Administration of BI 836880 11
X
X
X
Pharmacokinetics 13
X
X
X
X (1,2,4)*
X 
(1,2,4)*
X
X (7-12)*
X
X
X 
(FU1)*

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Trial Periods
Screen
Treatment courses
EOT
EoR
FU /
EoFU
Course *
1, 2, 3, 4
5, 6
718
ongoing
Week
w1
w2
w3
Imaging
w1
w2
Imagin
g
w1
Visit
Screen
V1
V2
V3
V4
V1
V2
V3
V1
Day; visit window [days]
-21 
to 
-1
d1
d2
d3; 
+1d
(1,2)*
d8; 
-1/+2d
d15; 
-1/+2d 
d18;
+/-3d
(2,4)
d1
d8;
-
1/+2d
d18;
+/-3d
(6)
d1
EoT 
(when 
defined)
EoT 
+42d;
-2/+3d
every 6 
weeks 
(+/-3d) 
until PD
Reason for treatment discontinuation
X
Patients status
X
X
Next line of anti-cancer therapy
X
X
* number in brackets indicate the course this visit/assessment is applicable  EoC = End of Course; FU1 = 1st Follow-up visit
** 2 timepoints to be evaluated at this visit; see detailed flowchart in Appendix 10.4
1
See section 3.3
2
See section 5.3.4
3
See section 5.3.4 and Appendix 10.2; for exact time points see detailed flowchart in Appendix 10.4
4
See section 5.3.6; for exact time points see detailed flowchart in Appendix 10.4
5
See section 5.3.7
6
See section 5.3.5
7
See section 5.3.5
8
See section 5.3.3
9
See section 5.3.8
10
See re-treatment criteria in section 4.1.4; for medication number allocation it’s possible to conduct IRT call ahead of the planned visit (= day of administration).
11
See section 4.1.4 and "Instruction for Pharmacist" which is filed in Investigator Site File;
see section 6.1 for hospitalization requirements
13, 
See detailed flowchart in Appendix 10.4. No samples will be collected after data base lock and trial completion (see section 6.2.3.5)
18
For the 2 ongoing patients, minimum set of procedures is mandatory. This includes safety lab, vital signs including blood pressure, adverse events, and pregnancy test if 
applicable. However, other assessments as indicated in the flowchart of the protocol or single lab values can be omitted according to investigator’s opinion.   

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
MEDICAL BACKGROUND.............................................................................13
1.1
DRUG PROFILE................................................................................................13
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....16
RATIONALE FOR PERFORMING THE TRIAL.........................................16
2.1
TRIAL OBJECTIVES........................................................................................16
2.2
BENEFIT - RISK ASSESSMENT.....................................................................17
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................19
OVERALL TRIAL DESIGN AND PLAN .......................................................19
3.1
3.1.1
Administrative structure of the trial .................................................................20
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................21
SELECTION OF TRIAL POPULATION .......................................................22
3.3
3.3.1
Main diagnosis for trial entry ............................................................................22
3.3.2
Inclusion criteria .................................................................................................22
3.3.3
Exclusion criteria ................................................................................................23
3.3.4
Removal of patients from therapy or assessments...........................................24
3.3.4.1
Removal of individual patients .............................................................................24
3.3.4.2
Discontinuation of the trial by the sponsor...........................................................25
4.
TREATMENTS...................................................................................................27
TREATMENTS TO BE ADMINISTERED.....................................................27
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........27
4.1.2
Method of assigning patients to treatment groups...........................................27
4.1.3
Selection of doses in the trial..............................................................................28
4.1.4
Drug assignment and administration of doses for each patient......................29
4.1.5
Blinding and procedures for unblinding...........................................................31
4.1.5.1
Blinding.................................................................................................................31
4.1.5.2
Unblinding and breaking the code ........................................................................31
4.1.6
Packaging, labelling, and re-supply...................................................................31
4.1.7
Storage conditions...............................................................................................31
4.1.8
Drug accountability.............................................................................................32
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT.....................................................................................................32

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4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....33
4.2.2
Restrictions ..........................................................................................................33
4.2.2.1
Restrictions regarding concomitant treatment ......................................................33
4.2.2.2
Restrictions on diet and life style..........................................................................33
4.3
TREATMENT COMPLIANCE........................................................................33
5.
VARIABLES AND THEIR ASSESSMENT ....................................................34
TRIAL ENDPOINTS..........................................................................................34
5.1
5.1.1
Primary Endpoint(s)...........................................................................................34
5.1.2
Secondary Endpoint(s) .......................................................................................34
ASSESSMENT OF SAFETY.............................................................................35
5.3
5.3.1
Dose limiting Toxicity (DLT) .............................................................................35
5.3.2
Maximum Tolerated Dose (MTD).....................................................................35
5.3.3
Physical examination ..........................................................................................36
5.3.4
Vital Signs............................................................................................................36
5.3.5
Safety laboratory parameters ............................................................................37
5.3.6
Electrocardiogram (ECG)..................................................................................38
5.3.7
Echocardiography...............................................................................................38
5.3.8
Assessment of adverse events.............................................................................38
5.3.8.1
Definitions of AEs ................................................................................................38
5.3.9
Adverse event collection and reporting.............................................................41
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................43
5.4.1
Assessment of Pharmacokinetics.......................................................................43
5.4.2
Methods of sample collection .............................................................................44
OTHER ASSESSMENTS...................................................................................46
5.6
5.6.1
Demographics and history..................................................................................46
APPROPRIATENESS OF MEASUREMENTS..............................................47
5.7
6.
INVESTIGATIONAL PLAN.............................................................................48
VISIT SCHEDULE.............................................................................................48
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................48
6.2
6.2.1
Screening and run-in period(s)..........................................................................49
6.2.2
Treatment period(s)............................................................................................49
6.2.3
Follow Up Period and Trial Completion...........................................................50
6.2.3.1
End of treatment visit (EOT) ................................................................................50
6.2.3.2
Residual effect period (REP) ................................................................................50
6.2.3.3
Extended follow-up period....................................................................................50
6.2.3.3.1
Follow-up for progression.....................................................................................50

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6.2.3.3.2
Follow-up for Overall Survival.............................................................................51
6.2.3.4
Trial completion for an individual patient ............................................................51
6.2.3.5
Trial completion....................................................................................................51
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................52
STATISTICAL DESIGN – MODEL ................................................................52
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................56
7.2
PLANNED ANALYSES.....................................................................................56
7.3
7.3.1
Primary endpoint analyses.................................................................................56
7.3.2
Secondary endpoint analyses .............................................................................56
7.3.4
Safety analyses.....................................................................................................56
7.3.5
Pharmacokinetic analyses ..................................................................................58
INTERIM ANALYSES ......................................................................................60
7.4
HANDLING OF MISSING DATA ...................................................................60
7.5
RANDOMISATION ...........................................................................................61
7.6
DETERMINATION OF SAMPLE SIZE .........................................................61
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........62
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................62
DATA QUALITY ASSURANCE ......................................................................63
8.2
RECORDS...........................................................................................................63
8.3
8.3.1
Source documents ...............................................................................................63
8.3.2
Direct access to source data and documents.....................................................63
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS64
8.4
8.4.1
Listedness.............................................................................................................64
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................64
STATEMENT OF CONFIDENTIALITY........................................................64
8.5
END OF TRIAL..................................................................................................64
8.6
9.
REFERENCES....................................................................................................65
PUBLISHED REFERENCES............................................................................65
9.1
UNPUBLISHED REFERENCES......................................................................69
9.2
10.
APPENDICES.....................................................................................................70
INSTRUCTIONS FOR USE..............................................................................70
10.1
10.1.1
Instructions for Pharmacists..............................................................................70
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................70
10.2
PHARMACOKINETIC ANALYSES...............................................................71
10.3
BLOOD SAMPLING TIME POINTS FOR PK, 
 AND 
10.4
ECG RECORDING IN THE PHASE I PART OF THE STUDY (DOSE 
ESCALATION PHASE).....................................................................................73

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STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
10.6
AND DATA SCENARIOS .................................................................................76
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................80

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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine amino transferase
ANC
Absolute neutrophil count
Ang2
Angiopoietin2
AST
Aspartate amino transferase
BI
Boehringer Ingelheim
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
BLQ
Below the limit of quantification
BP
Blood Pressure
CA
Competent Authority
CI
Confidence Interval
CML
Local Clinical Monitor 
CPL
Clinical Program Leader
CPPL
Clinical Pharmacology Program Leader
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DCE-MRI
Dynamic Contrast-Enhanced Magnetic Resonance Imaging
DEDP
Drug Exposure During Pregnancy
DILI
Drug Induced Liver Injury
DL
Dose Level
DLT
Dose Limiting Toxicity
DSB
Data Safety Board
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDTA
Ethylendiaminetetraacetic Acid
EOT
End Of Treatment
EudraCT
European Clinical Trials Database
EWOC
Escalation with overdose control
FC
Flow Chart
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
i.v.
intravenous
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
INR
International Normalized Ratio

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IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LMWH
Low Molecular Weight Heparine
MedDRA
Medical Dictionary for Drug Regulatory Activities
MTD
Maximum Tolerated Dose
NC
Not calculated
NCA
Noncompartmental 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-Inflammaroty Drug
OPU
Operative Unit
p.o.
per os (oral)
PC
Patient Completion
PD
Pharmacodynamics
PD
Progressive Disease
PK
Pharmacokinetics
RDC
Remote Data Capture
RECIST
Response Evaluation Criteria In Solid Tumors
REP
Residual Effect Period
SAE
Serious Adverse Event
SD
Stable Disease
SOP
Standard Operation Procedure
SUSARs
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
Tie2
Receptor of the TIE Family
TME
Translational Medicine Expert
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
ULN
Upper Limit of Normal

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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, these 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, plays 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/Tie-e) 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
(c02353882-01)

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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 setting, 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 
Trebaninib in ovarian cancer. In a randomized Phase III trial in patient with recurrent ovarian 
cancer Trebaninib 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 blokers and Ang2 blockers is not durable and 
only a limited number of patient 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 
(Investigator’s Brochure).
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 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 weeks 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 (Trebaninib) in 
development is in Phase III in combination with chemotherapyR14-5440. 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 includes 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 study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´ 
safety see also section 5.3.8.1.
Because of the early stage of development of BI 836880 no reproduction toxicity or 
genotoxicity studies were performed. Because of the advanced stage of disease of phase I 
studies populations, women of childbearing potential can be included into the trials. To 
minimize the risk of unintentional exposure of an embryo or fetus to the investigational drug, 
women of childbearing potential must agree to the requirements for pregnancy testing and 
contraceptive methods described in this protocol.
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, 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 of 200% 
dose increment for dose up to 120 mg and a 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. Subsequent enrollment at all 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 cycle, then dose-escalation can occur based on these 2 patients. However, should one of 
these 2 patients experience a DLT in the first cycle, a third patient will be enrolled on the 
same dose level. After all patients in a cohort have either experienced a DLT or have been 
observed for at least one cycle (=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 dose 
escalation rules 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. Figure 3.1: 1 shows how the decision of dose escalation is 
made.

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Figure 3.1: 1: Escalation Decision – Combination of clinical and statistical expertise
BI 836880 infusion will be repeated every 3 weeks. In the case the patient shows a stable 
disease or even a response, the administration of BI 836880 can be continued up to disease 
progression or until intolerable toxicity has been recorded. In specific cases an intra-patient 
dose escalation can be granted (see section 4.1.3).
Once a MTD has been reached it is foreseen to enroll up to 12 patients on this dose level to 
enlarge the group of patients treated on proposed RP2D. A minimum of 12 patients must 
have tumour lesions evaluable for Dynamic contrast-enhanced (DCE)-MRI to allow a better 
interpretation of a pharmacodynamics (vascular) effect of BI 836880. Confirmation of the 
RP2D will be made based on all available safety, PK and Pharmacodynamics (PD) data at all 
treatment cycles and all dose levels.
In case of anti-tumor activity signals in a given tumor type, DSB can take the decision for a 
trial expansion to recruit patients with the same tumor type with the aim to generate safety 
and preliminary efficacy data specific to such disease. 2-3 tumor type expansion cohorts are 
planned. Up to a total of 20 patients may be recruited in each tumor type expansion cohort
and will be treated according to same Flow Chart as patient in previous cohorts. This is to 
confirm RP2D in patient with specific tumor type according to study objective and to prepare 
further Phase II studies. This change will be implemented with a further amendment to this
protocol. 
3.1.1
Administrative structure of the trial
The coordinating investigator is an investigator participating in the trial that has experience of 
this type of trial and investigations. The coordinating investigator has been designated by 
Boehringer Ingelheim and will sign the clinical trial report.
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 
recommended Phase II dose as well as the decision for a tumor type expansion cohort. 
Members of this DSB will be investigators of participating trial sites, Trial Statistician

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(TSTAT), Clinical Program Leader (CPL) and Trial Clinical Monitor (TCM); Clinical 
Pharmacology Program Leader (CPPL) and Translational Medicine Expert (TME) can be 
invited as needed, especially for discussion of PK/PD data and discussion of biomarker. 
Minimum needed data for dose escalation decision is explained in the DSB charter.
On-site monitoring will be performed by BI or a CRO authorized by Boehringer Ingelheim.
Pharmacokinetic analyses will be performed by Boehringer Ingelheim or a CRO authorized 
by Boehringer Ingelheim.
Routine safety laboratory exams will be performed by local laboratories.
All trial relevant documentation will be stored in the Trial Master File (TMF) at BI. In 
addition each site will have an ISF containing all trial documents relevant for the site.
Boehringer Ingelheim has appointed a TCM, responsible for coordinating all required
activities, in order to 

manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (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 monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
An IRT system from an external vendor will be used for trial medication supply and re-
supplies.
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 (as 
protocol reference, if applicable) can be found in the ISF and BIRDS.
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 BIRDS.
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 

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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 anti-tumor effect 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.
SELECTION OF TRIAL POPULATION
3.3
Patients with advanced/metastatic solid malignant tumors who are either refractory after 
standard therapy for the disease or for which standard therapy is not reliably effective will be 
eligible. This study is planned to be conducted in at least 2 sites in Germany and France. 
Approximately 80 patients will be enrolled.
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.
3.3.1
Main diagnosis for trial entry
All patients who 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.
3.3.2
Inclusion criteria
1. Age ≥18 years
2. 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. they 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: 
a. Total bilirubin within normal limits 
(≤ 1.5x ULN for patient with Gilberts syndrome) and
b. ALT and AST ≤ 1.5x ULN 
(<5x ULN for patients with known liver metastases) and
c. Serum creatinine < 1.5x ULN and 

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d. INR 0,8-1,2 or PTT < 1.5x ULN;
e. ANC > 1,5x 109/L and 
f.
Platelets > 100x109/ L.
g. Hb > 10 g/dl (without transfusion within previous week)
5. Signed 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 grade 1, except for alopecia (any grade), sensory peripheral neuropathy 
CTCAE grade <=2 or considered not clinically 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:
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 drug product according to 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 before start of treatment. 
3. Serious concomitant disease, 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 

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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 or bone fracture within 4 weeks of start of 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 diseases (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 rested and relaxed condition >= 
140 mmHg, systolic or >= 90 mmHg diastolic (with or without medication), measured 
according to section 5.3.4 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;
LMWH allowed only for prevention not for curative treatment
11. Active alcohol or drug abuse in the opinion of the investigator.
12. Patients who are under judicial protection and patients who are legally institutionalized
13. Patients unable or unwilling to comply with protocol
14. Women who are pregnant, breast-feeding, or who plan to become pregnant while in the 
trial
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent, without the need to justify the decision.

The patient needs to take drugs that interfere with the investigational product or other trial 
medication (see also section 4.2.2) or patient require concomitant drugs, which in the 
opinion of the Investigator may interfere with the investigational drug.

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
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases or pregnancy).

The Investigator may also stop a patient’s participation if the patient is no longer able to 
complete trial visits or trial-required procedures.
A patient can be 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 report of the trial. As soon as a patient is withdrawn from the trial 
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.
A patient has to discontinue trial drug administration in case:

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 guidelines)

Progressive disease (PD; except in cases with intra-patient dose escalation, see section
4.1.3) or start of any new anti-cancer therapy.
Patients who have not completed one cycle of BI 836880 treatment (3 weeks) will be 
replaced. Patient who terminated treatment due to DLT will not be replaced.
Patient who discontinue study drug for above mentioned reasons or any other reason 
prematurely should continue Follow up visits until study end (e.g. progressive disease). Study 
assessments may be omitted if a patient is willing to return to the pre-defined study visits and 
may stay on treatment, with the exception of following assessments which are considered 
mandatory for each Follow up visit: collection of adverse events, patient status, concomitant 
therapy, safety lab tests including pregnancy test (if applicable), vital signs.
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
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
Electronic Case Report Form (eCRF). These data will be included in the trial database and 
reported.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of Good Clinical Practice (GCP), the Clinical Trial Protocol (CTP), or the 
contract disturbing the appropriate conduct of the trial

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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)
In this trial, the IMP BI836880 will be switched to a new pharmaceutical formulation which 
is to be diluted in a standard 5% Glucose/dextrose solution. The New formulation will be 
made available in this trial at the latest before expiry of the old formulation prepared with a 
drug specific diluent. Details of the trial medication BI836880 and respective diluent are 
presented in the table below, in the IB’s for BI836880 as well as in the instructions for the 
pharmacist (filed in ISF)
Table 4.1.1: 1
Test product 1
Substance:
BI 836880
Pharmaceutical formulation:
Solution for infusion 
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml (vials with 10ml)
Posology
rate controlled infusion 
Route of administration:
i.v.
Duration of use:
until progression or unacceptable toxicity
4.1.2
Method of assigning patients to treatment groups
No randomiation, all patient will receive investigational product.
Allocation to dose cohorts or expansion groups will be done according to subjects’ temporal 
availability and depending on dose cohort open for recruitment.
Medication will be assigned via Interactive Response Technology (IRT) for each treatment 
course. Each medication box does have a unique medication number. To facilitate the use of 
the IRT, the Investigator will receive all necessary instructions.

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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 (see Investigator’s Brochure for more 
details (c02353882-01)).
The recommended starting dose is 0.67 mg/kg, correlates to a total dose of 40 mg. 
Dose escalation Scheme
Furthermore, the PK/PD modelling provided information on the number of doses needed to 
reach a steady state the targeted concentration that allow a continuous high level target 
coverage ( ≥ 90%). In an every 3 weeks schedule, Ctrough plasma concentrations at steady 
state above the targeted Cmin are expected be achieved after 3 infusions of BI 836880 at dose 
of 6 mg/kg (360 mg) and1 infusion of BI 836880 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 120 mg. Dose escalation ≥120mg will not exceed 100% 
dose increment. No dose adaptation to body weight or body surface will be made. All patients 

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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)
Maximum dose 
increment
DL 1
40
200%
DL 2
120
200%
DL3
360
100%
DL4
720
100%
DL5
1000
100%
DL6
1440 Limited to 1250*
Intermediate dose levels can be tested based on DSB decision.
*Maximum dose that can be tested due to excipient limitation
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.
Patients, who received at least two treatment cycles, deeming to have clinical benefit from 
treatment and tolerated the drug BI 836880 well (i.e. do not show any DLT) could be allowed 
to receive increased dose. Such decision will be taken in a case by case manner on request by 
Investigator and confirmation by DSB based on actual patient profile. Intra-patient dose 
escalation can be repeated; however the dose can only be increased to 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,
 
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 and handled according to “Instruction for Pharmacists” 
which will be filed in ISF. Upon notification a patient entered the study; the pharmacy will 
prepare the study drug in the assigned dosage for administration to the patient.

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BI 836880 will be given as 3 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 minutes. In case no relevant infusion 
reactions are observed, this can be shorten to about 30 minutes but should not be prolonged to 
more than 6 hours, also 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 or higher, but not qualifying as 
DLT according to section 5.3.1 occur, the infusion should be temporarily stopped. Upon 
recovery, it should be infused 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 
administering 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 adaption of application scheme need to be agreed with sponsor. 
An every 2 week application scheme with comparable visit schedule to every 3 week 
application is optional in case there are no concerns from every 3 week schedule and can only 
be started with approval by DSB.
Premedication: No premedication will be required for BI 836880 IV infusion. If a patient 
expressed sign of infusion reaction at any BI 836880 treatment, a premedication will be 
considered for all subsequent treatment infusions (dosage and schedule according 
investigator’s decision) comparable to following scheme:

Acetaminophen/Paracetamol 650 mg - 1000 mg p.o., or equivalent

Antihistamine p.o. or i.v., equivalent to Diphenhydramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg
If infusion reaction and/or hypersensitivity reaction occurred in a substantial amount of 
patient (about 30%) of treated patients without premedication, premedication (as described
above) prior to BI 836880 infusion will be given to all patients to be treated in the study. 
Such decision will be confirmed by the DSB; dosage and schedule should be aligned, but also 
should reflect local clinical standards.
Re-treatment criteria:
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:

No uncontrolled hypertension (according to Exclusion-Criterion #6)

QTcF <=470 ms (according to Exclusion-Criterion #5)

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
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 guidelines
Administration of trial drug has to be stopped temporarily in case of a DLT (see section 
5.3.1). 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
4.1.5.1
Blinding
Not applicable, as this is an open-label single arm study.
The trial will be handled in an open fashion, i.e. also for the purpose of data cleaning and 
preparation of the analysis.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
BI 836880 will be supplied in 10ml 10R vial containing 100mg BI 836880 [10mg/ml] 
solution for infusion. The BI 836880 vials will be packed in one vial per box.
Boxes and vials will be labelled according to local regulations. Re-supply to sites will be 
triggered by IRT, depending on available medication, recruitment and current dose level.
For further details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
BI 836880 vials must be stored in their original packaging. The study product must be stored 
according to the instructions on the label. The Investigator, the Pharmacist, or other personnel
is allowed to store and dispense investigational product. They will be responsible for ensuring 

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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 to make certain that the drug supplies are stored at the 
correct temperature.
In-use-stability of ready to use solution refers to “Instructions for Pharmacists” as described 
in section 4.1.4.
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation 
If the storage conditions are found to be outside the specified range, the CML (as provided in 
the list of contacts) must be contacted immediately.
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
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).

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4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
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
4.2.2.1
Restrictions regarding concomitant treatment
Previous anti-cancer therapy must have been discontinued before first administration of trial 
drug and the patient must have recovered from all clinically relevant reversible toxicities (see 
Exclusion Criteria section 3.3.3 for further details).
Concomitant anti-cancer therapy is not allowed.
Radiotherapy for local symptom control of non-target lesions can be allowed after consulting 
the investigator and sponsor.
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 (see Exclusion Criteria section 3.3.3 for further 
details). Unplanned surgeries should be postponed whenever possible four weeks after stop of 
treatment. For urgent interventions patients should not be further treated and should be 
intensely monitored regarding wound healing and post-operative complications.
4.2.2.2
Restrictions on diet and life style
No restriction.
4.3
TREATMENT COMPLIANCE
BI 836880 will be administered as an intravenous infusion under supervision of the 
Investigator or dedicated clinical personnel. Compliance may 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 assess the maximum tolerated dose (MTD) is based on the number 
of patients presenting dose-limiting toxicities (DLTs) using the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE)v4.03, started within 3 
weeks after first administration of study treatment (i.e. within first cycle of treatment) and
judged to be related to the study medication .
5.1.2
Secondary Endpoint(s)

Exposure measures (AUC0-tz) after the first dose ;

Disposition kinetic measures (t1/2 ) after the first dose;

Drug related AEs leading to dose reduction or discontinuation during treatment period;

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ASSESSMENT OF SAFETY
5.3
5.3.1
Dose limiting Toxicity (DLT)
The DLT is defined as follows:

Drug related CTCAE grade ≥ 3 non hematological toxicity with the following exceptions:

Vomiting or diarrhea responding to supportive treatment

Fatigue shorter than 4 days

Transient Grade 3 infusion reaction; i.e. if infusion-related reaction IRR 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 recovered with appropriate 
treatment (e.g.: ALK-P, GGT, Amylase, Lipase)
Clinically relevant abnormalities have to be documented as AE (see section 5.3.8)

CTCAE grade 4 neutropenia > 7 days or complicated by infection (please note, that in 
case of grade 4 neutropenia a more frequent follow up of patient is necessary as planned 
according to Flow Chart), or 

febrile neutropenia CTCAE grade ≥3 or 

CTCAE Grade 4 thrombocytopenia or CTCAE Grade thrombocytopenia ≥3 with bleeding

Treatment delay for > 2 weeks due to unresolved drug-related adverse events, started 
within 3 weeks after first treatment.

Hypertension: increase of diastolic blood pressure (BP) by 15mmHg confirmed by a
second measurement or by ambulatory blood pressure measurement (when indicated; e.g. 
white coat effect) which can’t be controlled by hypertensive medication and requests a
dose reduction of BI 836880 for further treatment cycle.

Proteinuria: urinary protein >= 3.5 g/day (CTCAE grade 3)
5.3.2
Maximum Tolerated Dose (MTD)
The MTD may be considered reached if the probability that the true DLT rate is in target 
interval (16% - 33%) is sufficiently large. For detailed definition see statistical part 
(section 7). The DSB may recommend stopping the dose finding phase after the criterion for 
MTD is fulfilled. Further patients may be included to confirm the MTD.
If 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, declare this dose as RP2D and no further dose escalation will 
happen.
Decision on next steps (dose escalation, de-escalation or cohort expansion) will be made by a 
Data Safety Board (DSB) based on all available safety data, including DLT information from 

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last cohort as described above but also findings from subsequent courses as well as other data 
(e.g. PK/PD data) when available.
Based on the overall data after all patients on proposed RP2D have been treated for at least 1 
cycle, the DSB will make a final determination of RP2D. 
Before the conclusion of the dose escalation phase and prior to the start of the expansion 
cohort, up to 12 patients should have been treated on the proposed RP2D.
After determination of RP2D, 2-3 expansion cohorts could be started to treat a specified 
patient population based on preliminary efficacy data and according to DSB decision.
All DSB decisions of dose escalation, and to open a new cohort for recruitment will be 
communicated to Investigators. Once MTD and RP2D is defined this information will be 
send to authorities.
5.3.3
Physical examination
A complete physical examination (including cardiac, neurological, dermatological, 
pulmological etc.), record of height, weight and ECOG performance score will be performed 
at screening and before start of treatment and EoT and EoR. At further time points specified 
in the FC not a complete PE must be done, but at minimum the actual health status of the 
patient should be assessed (incl. evaluation of BP, ECG, lab values, AE, CT, ECOG as 
applicable). During the physical examination, the patient should be assessed for possible 
AEs.
5.3.4
Vital Signs
Vital signs (blood pressure, heart rate and body temperature) will be recorded at every visit 
indicated in the FC.
At days of administration blood pressure and heart rate will be evaluated at two time points: 
1. pre-dose (-60 min. to -5 min.), 
2. shortly before the end of the infusion.
In case of an infusion-related reaction, the Investigator should decide whether to intensify or 
prolong monitoring of vital signs of the patient.
Blood pressure
Systolic and diastolic blood pressure as well as pulse rate (electronically or by palpation, 
count for 1 minute) will be measured after 5 minutes of rest in the seated position. The blood 
pressure measurement should be performed three times at each time point and the values of 
these measurements will be entered in the eCRF. Further details on the procedure for blood 
pressure measurements are given in Appendix 10.2.
Body temperature
Whenever possible the same method should be used for body temperature measurement in 
one patient. All methods used should deliver valid and reproducible results according to 

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common clinical practice. Acceptable methods could be, but are not limited to: oral, rectal 
measurement with thermometer (digital, mercury or other fluid). Not acceptable/preferred 
methods include: IR-measurement in ear, forehead or temple. 
Body temperature measurements >= 38°C must be re-assesed after 1 hour, especially in cases 
suspective for febrile neutropenia (see CTCAE v. 4.03).
5.3.5
Safety laboratory parameters
Blood and urine samples for assessment of general 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 vs. 
grade 3 need to be done by quantitative measurement. Laboratory values planned for V1d1 
(=day of administration) must be available before start of infusion in order to evaluate 
eligibility of patient to receive treatment. Therefore it’s possible to take blood sample a 
valuable time ahead (usually the day before treatment). Safety laboratory examinations will 
include hematology, biochemistry, coagulation and urine analysis:
Hematology
Hemoglobin, white blood cell count (WBC) with differential, 
platelets (PLT)
Biochemistry
Glucose, sodium, potassium, calcium, magnesium, inorganic 
phosphate, creatinine, AST, ALT, alkaline phosphatase (AP), 
lactate dehydrogenase (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)
Urine
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be 
analysed primarily qualitatively by dipstick..
In case of clinically relevant findings, further evaluation 
should be performed and the findings documented. A positive 
urine dipstick for protein of  ≥ 2+ (CTCAE gr 2) has to be 
followed by a determination of the ratio of urine protein to 
creatinine (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 ratio is ≥ 0.5 as often as clinically 
indicated.
Pregnancy test
A serum pregnancy test needs to be obtained at the time 

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points indicated in the Flow Chart in patients of childbearing 
potential. 
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.
5.3.6
Electrocardiogram (ECG)
Triplicate 12-lead ECGs (3 ECGs taken approximately 2-3 minutes apart) will be performed 
in all patients at various time points according to Study Flow:

At Screening, visits between administration and at EoT:
only one time point will be evaluated.

At days of administration two time points will be evaluated: 
1. pre-dose (-60 min. to -5 min.), 
2. 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 cycles of treatment. 
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 patients’ 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.
5.3.7
Echocardiography
Echocardiography have to be conducted at screening (not older than 7 days) and at EoT-visit.
During treatment phase it has only to be done when clinically indicated.
5.3.8
Assessment of adverse events
5.3.8.1
Definitions of AEs
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.
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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

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
results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

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.
Life-threatening in this context 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.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the Remote Data Capture (RDC)
system. These events should always be reported as SAEs as described in section 5.3.9.
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. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see section 5.3.9.
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 the RDC-system.

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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.
Dose Limiting Toxicities:
Any medical event fulfilling the criteria of DLT (see section 5.3.1) should be reported by 
Investigator as AESI.
Intensity of AEs
The intensity of the AE should be judged based on the following:
The intensity of adverse events should be classified and recorded in the (e)CRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 (v4.03: 
June 14, 2010) (R12-2532).
Causal relationship of AEs
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.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
The causal relationship must be provided by the Investigator for all potential trial drugs, i.e. 
the BI trial drug and for all other trial drugs (such as any active comparator or placebo).
The reason for the decision on causal relationship needs to be provided in the (e)CRF and on 
the SAE form (if applicable).

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5.3.9
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate / eCRF by the 
Investigator:

From signing the informed consent onwards until the end of the REP all AEs (non-serious 
and serious), and AESIs.

After the end of the REP until trial completion, all related SAEs and related AESIs.

If in an individual patient only vital status information is collected from a certain time
point on, no further AEs or AESIs will be reported for this patient.
The REP is defined as 42 days (6 weeks) 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.
After the last per protocol contact the Investigator does not need to actively monitor patients 
for AEs. However, if the Investigator becomes aware of SAEs or AESIs that occurred after 
the last per protocol contact, the SAEs and AESIs should be reported by the Investigator to 
the Sponsor if considered relevant by the Investigator.
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). 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.

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Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication.
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of the underlying disease (if not recorded as study endpoint, see exemption 
below) or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be 
obtained.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
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). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
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.

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Examples of exempted events of PD may be:

Progression of underlying malignancy (Progressive disease [PD]):  if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 

Hospitalization/Procedures due solely to the progression of underlying malignancy (PD)

Clinical symptoms and/or signs of progression (without confirmation by objective criteria 
e.g. imaging, clinical measurement): if the symptom can exclusively be determined to be 
due to the progression of the underlying malignancy and does meet the expected pattern 
of progression for the disease under study.
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.
Exempted events are collected and tracked following a protocol-specified monitoring plan. 
Exempted events are monitored at appropriate intervals preferably by an independent 
committee such as a Data Safety Board.
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.
Pharmacokinetic data may additionally be analysed using 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 interim 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 interim 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 interim 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 10.2 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 interim 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 interim
analyses, and the outputs will not be validated. Minor discrepancies between interim and final
results may therefore occur.

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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 an 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 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, 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.

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OTHER ASSESSMENTS
5.6
5.6.1
Demographics and history
Demographics including gender, year of birth and race/ethnicity, as well as detailed 
oncologic disease history will be obtained, which include date of first diagnosis of 
malignancy, history of previous treatment lines, as well as staging and grading information.

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APPROPRIATENESS OF MEASUREMENTS
5.7
Determination of MTD is based on toxicities graded according to CTCAE version 4.03 (R12-
2532). The CTCAE criteria are commonly used in the assessment of AEs in cancer patients. 
 These criteria are well 
established and scientifically accepted. 

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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Patients must comply with all inclusion and exclusion criteria prior to the patient enters the 
study (see Section 3.3).
All patients should adhere to the visit schedule as specified in the Flow Chart. In case a 
patient misses a visit within one treatment course and the patient belatedly reports to the 
investigator between the missed and the next scheduled visit, the delayed visit should be 
scheduled as soon as possible and documented with the actual date and the reason for the 
delayed visit. The next visit, should still take place at the time it was originally scheduled in 
this treatment course. Some flexibility is allowed in scheduling the visits according to the 
time window specified in the Flow Chart.
However, in case the day of treatment administration (visit 1 day 1 of a course) is delayed, all 
subsequent visits of a course will be recalculated based on the actual date of treatment of the 
delayed course.
During the treatment phase, after administration of BI 836880, patients are required to be 
hospitalized under close surveillance with access to intensive care for at least 48 hours after 
administration of BI 836880 to allow close monitoring for infusion-related reactions or other 
adverse events and availability of patients for PK visits. After good tolerability of the first 
two courses 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 cycles.
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, 
 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 (incl 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, 
 are given 
in section 5.4 and 5.5.

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6.2.1
Screening and run-in period(s)
Screening Period
The examinations required for the screening visit may be conducted within a time interval of 
21 days prior to the first study drug administration. Prior to any other study related procedure, 
written informed consent must be obtained from the patient.
CT/MRI images obtained prior to study participation can be used within the study as long as 
they are not older than 28 days at day of first treatment.
Echocardiography must be obtained within 7 days before start of treatment.
If for administrative or medical reasons, the patient is not entered within the defined 
screening period, it is allowed to re screen a patient. There is no maximum time period 
defined for re-screening. The same Pat-ID will be used for the patient throughout the re-
screening as assigned during first screening.
If the patient has been determined eligible by the investigator to enter the trial (refer to 
Section 3.3), the investigator will assign one or more medication number(s) to the patient 
through the IRT system at Visit 1 (Section 4.1.3). First dose of BI 836880 will be 
administered at the beginning of Visit 1 at the trial site (Day 1, cycle 1).
6.2.2
Treatment period(s)
A treatment cycle is defined as 3 weeks of duration. If initiation of a subsequent cycle is 
delayed due to medical reasons, additional visits beyond Day 21 may be necessary and may 
be performed at investigator’s discretion, and should be recorded in the eCRF.
Patients may continue treatment as long as they have clinical benefit (no PD, no toxicities, no 
new anti-cancer treatment started) and patient is willing to continue.
During cycle 1, 2 and 4 intensive PK-sampling will be conducted and patients have to be 
observed closely for any adverse events. Therefore patients have to come to the clinic during 
the first four courses every week to the clinic. Additional visits are needed at day 2 for cycles 
1, 2 and 4 and at day 3 for cycle 1. In course 5 and 6 the patient is requested to come to the 
clinic on day 8 after administration of study drug. From cycle 7 onwards no additional visits, 
beside day 1 including drug administration, are requested by protocol.
For the 2 ongoing patients, minimum set of procedures is mandatory. This includes safety 
lab, vital signs including blood pressure, adverse events, and pregnancy test if applicable. 
However, other assessments as indicated in the flowchart of the protocol or single lab values 
can be omitted according to investigator’s opinion.   

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6.2.3
Follow Up Period and Trial Completion
6.2.3.1
End of treatment visit (EOT)
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason as soon as possible but no later than 3 weeks 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.
6.2.3.2
Residual effect period (REP)
The REP is defined in Section 5.3.9 (6 weeks). The End of REP (EoR) visit should not be 
performed earlier than 42 days after permanent discontinuation of the trial medication. 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
6.2.3.3
Extended follow-up period
6.2.3.3.1
Follow-up for progression
For patients who did not progress, additional follow-up visits after the EoR visit will be 
performed every 6 weeks plus/minus 3 days.
The follow-up for progression period will end at the earliest of the following events:

Lost to follow-up

Disease progression 

Start of a new anti–cancer therapy 

Death

End of whole trial as specified in Section 8.6
At the end of the follow-up period, the EoFU (End of Follow-Up) visit has to be performed. 
The following will be obtained and / or performed during the follow-up visits and the EoFU 
visit.

Record all related SAEs and all related AESI and a follow-up of adverse events ongoing 
since End of REP to EoFU as entered in source data 

Concomitant medications for treatment of an adverse event reported in the (e)CRF 
including trade name, indication and dates of administration

Perform tumour assessment and imaging  

Treatment and date with any other anti-cancer  drug including the name and type of the 
anti-cancer drug and/or best supportive care 

Outcome (date of and reason for death, in case the patient had PD the actual date of PD 
shall be recorded)

Samples for PK, 
 at first Follw-up (FU1)

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6.2.3.3.2
Follow-up for Overall Survival
Not applicable.
6.2.3.4
Trial completion for an individual patient
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up period 

Lost to follow-up

Withdrawal to be followed-up

Death
At the earliest of the above criteria, the Patient Completion (PC) information should be 
entered in the CRF.
6.2.3.5
Trial completion
The end of the trial will occur when the last patient completes his/her REP. In case patients
would be still on treatment when data base is locked and the Clinical Trial Report (CTR) is 
being drafted, these patients will be maintained in the trial and may continue treatment as 
long as they have clinical benefit (no PD, no drug-related adverse events requiring 
discontinuation, no new anti-cancer treatment started) and patient is willing to continue. For 
these patients, no blood sample will be collected for PK 
analysis. After the 
discontinuation of these patients, the data collected after the database lock (DBL) will be
provided as separate listings and will not lead to any further updating of tables produced 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 tumor. The MTD 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 Bayesion 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 cycle at dose d, d* = 720mg 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. 

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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 720mg would equal 20%. This yields μ1 = (-0.333, 0.647). The 
standard deviations were set such that large uncertainty about the parameter means is 
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 720mg would equal 50%. These assumptions 
yield μ2 = (0.419, -0.274). 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 720mg would equal 2%. These assumptions yield 
μ3 = (-3.316, 0.042), 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 
to 1.2 patients, 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
-0.333 0.647
2.000, 1.000
0.000
2: High Tox
0.050
0.419 -0.274
2.000, 1.000
0.000
3: Low Tox
0.050
-3.316 0.042
5.000, 0.010
0.000

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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
0.877
0.049
0.074
0.069
0.172
<.001
0.001
0.703
120
0.813
0.071
0.116
0.104
0.208
<.001
0.006
0.812
360
0.685
0.110
0.205
0.176
0.258
<.001
0.043
0.899
720
0.515
0.153
0.332
0.274
0.295
<.001
0.148
0.944
1250
0.269
0.164
0.566
0.444
0.318
0.005
0.410
0.975
Doses printed in bold face meet the overdose criterion (P(overdose) < 0.25))

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Figure 7.1: 1 Prior medians and 95% credible intervals
The MTD may be considered reached if the following criteria is 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 cycle 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 endpoints and section 7.3.5 for PK 
related endpoints.
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 cycle 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 cycles 
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. 
In general, later events will be attributed to the post-study period and will be presented 
separately. However, post-study events will be examined to determine whether they need to 
be combined with on-treatment events in an additional table.
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 intensity 
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.
Adverse events that start before first drug intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’.
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 
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.

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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 analyses
Refer to section 5.4.1 for pharmacokinetic parameters to be calculated using non-
compartmental analysis (NCA).
 
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. Phoenix 
WinNonlin. Only concentrations within the validated concentration range will be used for the 
calculation of pharmacokinetic parameters. For pre-dose samples, the actual sampling time 
will be set to zero.
Plasma concentrations will be plotted graphically versus time for all evaluable subjects as 
listed in the drug plasma concentration-time tables. For the presentation of the mean profiles, 
the geometric and arithmetic mean and the planned blood sampling times will be used. If the 
actual sampling time deviates significantly from the planned time, the corresponding plasma 
concentration will be excluded from the calculation of descriptive statistics.
The following descriptive statistics will be calculated for analyte concentrations as well as for 
all pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, 
maximum, 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 

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values as well as the descriptive statistics will be reported with three significant digits in the 
clinical trial report.

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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 
will be made to obtain complete information on all adverse events and to follow-up the 
patients for efficacy data.

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Pharmacokinetics:
Drug concentration-time profiles: Concentration data identified with NOS (no sample), NOR 
(no valid result), NOA (not analyzed), BLQ (below the limit of quantification) and NOP (no 
peak detectable) will be ignored and not replaced by zero at any time point (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 7.4.).
DETERMINATION OF SAMPLE SIZE
7.7
About 40 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). Additional 40 patients will be included in the expansion cohorts, 
in case two (or three) tumor types will be selected for further evaluation.

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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report unless there is public interest to 
publish before the end of the trial. In this event the Sponsor and the investigator(s) will agree 
on the publication strategy
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
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).
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
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 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 according to ICH GCP and to the regulatory and legal requirements of the 

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participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional patient-information form retained by the investigator as 
part of the trial records. A signed copy of the informed consent and any additional patient 
information must be given to each patient or the patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.
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.
RECORDS
8.3
Case Report Forms (e)CRF for individual patients will be provided by the Sponsor. See 
section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / 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. Food and Drug Administration 
(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.

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LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For the BI 836880 this is the current version of the Investigator’s Brochure (c02353882-01).
The current version of this reference document is to be provided in the ISF. No AEs are 
classified as listed for study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited safety reporting (7/15 days reports) at a site will end 30 days after the trial drug 
was permanently discontinued for the last patient at that site.
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 EoR visit as specified in Section 
6.2.3.4  and 6.2.3.5. The IEC / competent authority in each participating EU member state 
needs to be notified about the end of the trial or early termination of the trial.

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9.
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Jain RK, Duda DG, Willett CG, Sahani DV, Zhu AX, Loeffler JS, 
Batchelor TT, Sorensen AG. Biomarkers of response and resistance to 
antiangiogenic therapy. Nat Rev Clin Oncol 2009. 6(6):327-338.
UNPUBLISHED REFERENCES
9.2
c02353882-01
. Investigator’s Brochure BI 836880 Version 1.0. 11 Jun 2015.

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10.
APPENDICES
INSTRUCTIONS FOR USE
10.1
10.1.1
Instructions for Pharmacists
Available in 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 an 
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 decribed 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 timepoints 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, the following pharmacokinetic parameters of BI 836880 will be evaluated using 
noncompartmental analysis methods according to the internal BI 
After the first dose:

AUC0-168 (area under the plasma concentration-time curve over the time interval from 0 to 
168h). 

t1/2 (terminal half-life).

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Pharmacokinetic parameters will be calculated using noncompartmental analyis (NCA). The 
derivation of pharmacokinetic parameters is described in detail in 

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BLOOD SAMPLING TIME POINTS FOR PK, 
 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, 
 in courses 1, 2, 
3 and from course 4 onwards
Course
Visit
Day
Time Point 
(hh:min)
CRF 
Time / 
planned 
time
PK:
BI 
836880
ECG
BP
1***
V1
1
Before start of 
BI 836880 infusion
-0:05
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
2
24:00
x
X (3x)
X (3x)
3
48h after the end of 
infusion
48:00
x
X (3x)
V2
8
168:00
x
X (3x)
V3
15
336:00
x
X (3x)

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Table 10.4: 1(cont’d)
Blood sampling scheme for PK, 
 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
ECG
BP
2
V1
1
Before start of 
BI 836880 infusion
-0:05
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
2
24:00
x
X 
(3x)
X 
(3x)
3
48h after the end of 
infusion
48:00
x
X 
(3x)
V2
8
168:00
x
X 
(3x)
V3
15
336:00
x
X 
(3x)
3
V1
1
Before start of BI 
836880 infusion
-0:05
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
2
24:00
x
X 
(3x)

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Table 10.4: 1(cont’d)
Blood sampling scheme for PK, 
 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
ECG
BP
4
V1
1
Before start of 
BI 836880 infusion
-0:05
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
2
24:00
x
X 
(3x)
V2
8
168:00
x
X 
(3x)
V3
15
336:00
x
X 
(3x)
5-12
V1
1
Before start of 
BI 836880 infusion
-0:05
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
(3x)
X 
(3x)
EoR****
x
X 
(3x)
FU1****
x
*
within 5 min after the end of infusion
**
PTM 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.
***
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, 
****          No samples will be collected after data base lock and the trial is completed (see Section 6.2.3.5)

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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 
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 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 120mg. 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.
Finally, 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 720mg, either. However, the model does not allow the 
escalation to 1250mg 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 
720mg. 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.

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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
0.013
120
0.894
0.062
0.044
2
1
40
1
3
0.278
N/A
N/A
N/A
N/A
3
1
40
0
2
2
120
0
2
0.013
360
0.816
0.103
0.081
4
1
40
0
2
2
120
1
3
0.194
120
0.497
0.309
0.194
5
1
40
0
2
2
120
2
3
0.575
40
0.434
0.330
0.236
6
1
40
0
2
2
120
0
2
3
360
0
3
4
720
0
3
0.025
720
0.878
0.097
0.025
7
1
40
0
2
2
120
0
2
3
360
0
3
4
720
1
3
0.224
720
0.436
0.340
0.224
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:

- 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

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Table 10.6: 2
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
40
120
360
720
1250
1 (Prior)
P(DLT)
0.069
0.104
0.176
0.274
0.444
2 (High Tox)
0.100
0.204
0.371
0.500
0.603
3 (Low Tox)
0.001
0.006
0.039
0.180
0.250
4 (Non-Logistic)
0.040
0.180
0.280
0.360
0.380
5 (Low-High)
0.001
0.010
0.180
0.317
0.600
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
22.7
61.6
0.2
15.5
17.05
(3 – 34)
2.896
(1 – 10)
2
9.5
52.0
14.8
23.7
15.38
(3 – 30)
3.642
(1 – 10)
3
26.2
73.8
0
0
19.77
(16 – 36)
2.236
(1 – 6)
4
5.5
79.2
5.7
9.6
17.78
(3 – 35)
3.664
(1 – 10)
5
14.4
85.4
0.2
0
19.60
(15 – 40)
3.303
(1- 8)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior medians, 
61.6% of the simulated trials declared a dose as MTD with true DLT rate in the targeted dose 
range. Note that 15.5% 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, 
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 (23.7%) of all simulated trials for which the trial is stopped 

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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 15.4 patients (high-toxicity scenario) to 19.8 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
1
Date of CTP revision
19 Oct 2015
EudraCT number
2014-005395-28
BI Trial number
1336.1
BI Investigational Product(s)
BI 836880
Title of protocol
A First-in Human Phase I, non-randomized, open-
label, multi-center dose escalation trial of BI 
836880 administered by repeated intravenous 
infusions in patients with solid tumors.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Synopsis
Description of change
Change of one of the main inclusion criteria
Rationale for change
Adapted in synopsis according to change in 
section 3.3.2
Section to be changed
Flow Chart
Description of change
a) BP measurement added whenever AE 
assessment foreseen
b) IRT call can be made ahead of study visit
Rationale for change
a) To have complete assessment of AESI at each 
visit
b) Clarification for logistical reasons
Section to be changed
Section 3.1
Description of change
Sequential start of treatment added; 
1.
2 weeks between 1st and 2nd patient in first 
dose cohort, 
2.
48 hours between first administration to 

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different subjects during dose escalation, 
3.
At least 3 week observation (=1 cycle) 
between subsequent cohorts
Further description of extension of MTD cohort 
and objective of expansion cohort
Rationale for change
a) Added to CTP for safety reasons
b) Further clarification
Section to be changed
Section 3.3.2
Description of change
a) Incl.-Crit. #2 reworded
b) Incl.-Crit. #8: contraception period extended
c) Excl.-Crit. #12 added
Rationale for change
a) More precise description of study population
b) Safety reasons
c) Added according to German drug law
Section to be changed
Section 4.1.3
Description of change
Added “clinical” benefit
Rationale for change
As continuation of treatment could be considered 
in best interest of patient even in case of objective 
progression according to RECIST. Any decision to 
continue treatment need to be confirmed by DSB.
Section to be changed
Section 4.1.4
Description of change
Added more detailed description of medical 
requirements at study site
Rationale for change
More detailed site description as pre-requisit 
according to CTP
Section to be changed
Section 5.3.5
Description of change
Added time window for blood drawing
Rationale for change
Blood drawing allowed ahead of study visit for 
logistical reasons
Section to be changed
Section 6.1

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Description of change
Prolonged hospitalization time after admin from 
24 h to 48 h
Rationale for change
Increase of close observation time for safety 
reasons in first-in-human trial
Section to be changed
Section 8.1
Description of change
Deleted “patient’s legally accepted representative”
Rationale for change
According to ethics request
Section to be changed
Section 10.6
Description of change
Text and table of statistical appendix updated
Rationale for change
To better illustrate possible dose escalation 
scenarios according to Bayesian design

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Number of global amendment
2
Date of CTP revision
14 February 2017
EudraCT number
2014-005395-28
BI Trial number
1336.1
BI Investigational Product(s)
BI 836880
Title of protocol
A First-in Human Phase I, non-randomized, open-
label, multi-center dose escalation trial of BI 
836880 administered by repeated intravenous 
infusions in patients with solid tumors.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Titel page
Description of change
Change of TCM
Was changed to
Phone:
Fax:
Rationale for change
Previous TCM has taken over another position
Section to be changed
Synopsis
Description of change
No. of patients:
The following:
About 80 patients will be entered
Was changed to:
About 80 patients will be entered, including at least 
12 patients treated at MTD with tumour lesions 
evaluable for Dynamic contrast-enhanced (DCE)-

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MRI
Rationale for change
Change was implemented to make sure that a 
pharmacodynamics effect can be documented
Section to be changed
Synopsis
Description of change
Main criteria for inclusion
The following:
…..
•
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. they do not 
tolerate or have contraindications to otherwise 
available standard 
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. they 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 
pharmacodynamics effect can be documented
Section to be changed
3.1 OVERALL TRIAL DESIGN AND PLAN
Description of change
The following:
Once a MTD has been reached it is foreseen to 
enroll up to 12 patients Confirmation of the RP2D 
will be made based on all available safety, PK and 
Pharmacodynamics (PD) data at all treatment 
cycles and all dose levels.
In case of anti-tumor activity signals in a given 
tumor type, DSB can take the decision for a trial 
expansion to recruit patients with the same tumor 
type with the aim to generate safety and 
preliminary efficacy data specific to such disease. 
2-3 tumor type expansion cohorts are planned. Up 
to a total of 20 patients may be recruited in each 
tumor type expansion cohort and will be treated 

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according to same Flow Chart as patient in 
previous cohorts. This is to confirm RP2D in 
patient with specific tumor type according to study 
objective and to prepare further Phase II studies. 
This change will be implemented with a further 
amendment to this protocol.
Was changed to:
Once a MTD has been reached it is foreseen to 
enroll up to 12 patients on this dose level to enlarge 
the group of patients treated on proposed RP2D. A 
minimum of 12 patients must have tumour lesions 
evaluable for Dynamic contrast-enhanced (DCE)-
MRI to allow a better interpretation of a 
pharmacodynamics (vascular) effect of BI 836880. 
on this dose level to enlarge the group of patient 
treated on proposed RP2D. Confirmation of the 
RP2D will be made based on all available safety, 
PK and Pharmacodynamics (PD) data at all 
treatment cycles and all dose levels.
In case of anti-tumor activity signals in a given 
tumor type, DSB can take the decision for a trial 
expansion to recruit patients with the same tumor 
type with the aim to generate safety and 
preliminary efficacy data specific to such disease. 
2-3 tumor type expansion cohorts are planned. Up 
to a total of 20 patients may be recruited in each 
tumor type expansion cohort and will be treated 
according to same Flow Chart as patient in 
previous cohorts. This is to confirm RP2D in 
patient with specific tumor type according to study 
objective and to prepare further Phase II studies. 
This change will be implemented with a further 
amendment to this protocol.
Rationale for change
Change was implemented to make sure that a 
pharmacodynamics effect can be documented.
Administrative change
Section to be changed
3.3.2 Inclusion criteria
Description of change
The following:
…..
2.
Histologically or cytologically confirmed 
malignancy which is locally advanced or metastatic 
solid tumor, and either refractory after standard 

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therapy for the disease or for which standard 
therapy is not reliably effective, e.g. they do not 
tolerate or have contraindications to otherwise 
available standard therapy 
Was changed to:
2.
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. they 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 
pharmacodynamics effect can be documented.
Section to be changed
3.3.2 Inclusion criteria
Description of change
The following:
…..
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).
Rationale for change
Tubal occlusion is no longer defined as “not of 
childbearing potential”
Section to be changed
4.1.3 Selection of doses in the trial
Description of change
The following:
Table 4.1.3: 1 Potential dose levels

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Dose level
Total dose 
(mg)
Maximum dose 
increment
DL 1
40
200%
DL 2
120
200%
DL3
360
100%
DL4
720
100%
DL5
1440 Limited 
to 1250*
Was changed to:
Dose level
Total dose 
(mg)
Maximum dose 
increment
DL 1
40
200%
DL 2
120
200%
DL3
360
100%
DL4
720
100%
DL5
1000
100%
DL6
1440 Limited 
to 1250*
Rationale for change
Data Safety Board decided on introduction of this 
additional dose level
Section to be changed
4.1.3 Selection of doses in the trial
Description of change
The following 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, 
 
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 

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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 cycle with the escalated dose. 

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Section to be changed
10 APPENDICES
10.4
BLOOD SAMPLING TIME POINTS FOR 
PK, 
 AND ECG 
RECORDING IN THE PHASE I PART OF THE 
STUDY (DOSE ESCALATION PHASE)
Table 10.4: 1 Blood sampling scheme for PK, 
 in courses 1, 2, 3 and from 
course 4 onwards
Description of change
The following footnote was added:
..
***
in case of an intra-patient dose escalation 

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the 1st cycle with the higher dose will follow cycle 
one at the start of treatment with BI 836880 with 
regards to sampling, (PK, 
 
Rationale for change
Specific guidance for patients with an intra-patient 
dose escalation is provided for assessments to be 
done within the first cycle with the escalated dose.
Section to be changed
Minor changes within the following sections:
-
Synopsis
-
Abbreviations
-
3.3 SELECTION OF TRIAL 
POPULATION
-
7.3.5
Pharmacokinetic analyses
-
Table 10.4: 1 Blood sampling scheme for 
PK, 
 in courses 1, 2, 3 
and from course 4 onwards
Description of change
Typos as well as minor inconsistencies between 
sections have been corrected
Rationale for change
See above

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Number of global amendment
3
Date of CTP revision
12 May 2017
EudraCT number
2014-005395-28
BI Trial number
1336.1
BI Investigational Product(s)
BI 836880
Title of protocol
A First-in Human Phase I, non-randomized, open-
label, multi-center dose escalation trial of BI 
836880 administered by repeated intravenous 
infusions in patients with solid tumors.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only

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Number of global amendment
4
Date of CTP revision
10 July 2018
EudraCT number
2014-005395-28
BI Trial number
1336.1
BI Investigational Product(s)
BI 836880
Title of protocol
A First-in Human Phase I, non-randomized, open-
label, multi-center dose escalation trial of BI 
836880 administered by repeated intravenous 
infusions in patients with solid tumors.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Synopsis
Description of change
Change of TCM
Was changed to:
Phone:
Fax : 

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Section to be changed
6.2.3 Follow Up Period and Trial Completion
Description of change
Section 6.2.3.3.1 was changed
The following:
For patients who did not progress, additional 
follow-up visits after the EoR visit will be 
performed every 6 weeks plus/minus 3 days.
Was changed to:
For patients who did not progress, additional 
follow-up visits after the EoR visit will be 
performed every 6 weeks plus/minus 3 days.
 
Section 6.2.3.5 was added :
6.2.3.5 Trial completion
The end of the trial will occur when the last patient 
completes his/her REP. In case patients would be 
still on treatment when data base is locked and the 
Clinical Trial Report (CTR) is being drafted, these 
patients will be maintained in the trial and may
continue treatment as long as they have clinical 
benefit (no PD, no drug-related adverse events 
requiring discontinuation, no new anti-cancer 
treatment started) and patient is willing to continue. 
For these patients, no blood sample will be 
collected for PK 
 analysis. After 
the discontinuation of these patients, the data 
collected after the database lock (DBL) will be 
provided as separate listings and will not lead to 
any further updating of tables produced for section 
15 of the CTR unless deemed necessary. These 
listings will be included in a revised CTR.
Rationale for change

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
Clarification about trial completion and 
planned procedures about ongoing patients 
at DBL and additional data collected after 
DBL.
Section to be changed
Appendix 10.4
Table 10.4  : 1(cont’d) Blood sampling scheme for 
PK, 
 in courses 1, 2, 3 and 
from course 4 onwards (cont.)
Description of change
This footnote was added:
**** No samples will be collected after data base lock 
and the trial is completed (see Section 6.2.3.5)
Rationale for change
footnote added to be in line with section 6.2.3.5

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Number of global amendment
5
Date of CTP revision
08 March 2019
EudraCT number
2014-005395-28
BI Trial number
1336.1
BI Investigational Product(s)
BI 836880
Title of protocol
A First-in Human Phase I, non-randomized, open-
label, multi-center dose escalation trial of BI 
836880 administered by repeated intravenous 
infusions in patients with solid tumors.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
X
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
Flow Chart
Description of change
Footnote N°18 was added about the 2 ongoing 
patients and procedures to be performed:
For the 2 ongoing patients, minimum set of 
procedures is mandatory. This includes safety lab, 
vital signs including blood pressure, adverse 
events, and pregnancy test if applicable. However, 
other assessments as indicated in the flowchart of 
the protocol or single lab values can be omitted 
according to investigator’s opinion.   
Rationale for change
Clarification provided about mandatory procedures  
to be performed for the 2 ongoing patients based on 
flow chart and medical opinion of the investigator
Section to be changed
4.1.1 Identity of BI Investigational product(s) and 
comparator product(s)
Description of change

Explanation is provided about the change in 
BI836880 formulation, the following 
paragraph was added:  
In this trial, the IMP BI836880 will be switched to 
a new pharmaceutical formulation which is to be 
diluted in a standard 5% Glucose/dextrose solution. 

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The New formulation will be made available in this 
trial at the latest before expiry of the old 
formulation prepared with a drug specific diluent. 
Details of the trial medication BI836880 and 
respective diluent are presented in the table below, 
in the IB’s for BI836880 as well as in the 
instructions for the pharmacist (filed in ISF)

Table 4.1.1: 2 was deleted as this diluent 
will not be used.
Rationale for change
Clarification about the new pharmaceutical 
formulation of BI836880 and new diluent (standard 
5% Glucose /dextrose)
Section to be changed
4.1.6 Packaging, labelling, and re-supply
Description of change
The following text:
BI 836880 will be supplied in 10ml 10R vial 
containing 100mg BI 836880 [10mg/ml] solution 
for infusion. The BI 836880 vials will be packed in 
one vial per box.
Diluent for BI 836880 drug product will be 
supplied in 50R vial containing 50ml Diluent for 
BI 836880 drug product. The Diluent vials will be 
packed in one vial per box.
Was changed to:
BI 836880 will be supplied in 10ml 10R vial 
containing 100mg BI 836880 [10mg/ml] solution 
for infusion. The BI 836880 vials will be packed in 
one vial per box.
Diluent for BI 836880 drug product will be 
supplied in 50R vial containing 50ml Diluent for 
BI 836880 drug product. The Diluent vials will be 
packed in one vial per box.
Rationale for change
Section adapted according to change in the new 
pharmaceutical formulation of BI836880 which 
will be diluted with a standard 5% 
Glucose/dextrose.
Section to be changed
4.1.7 Storage conditions
Description of change
The following text:
BI 836880 vials and Diluent Buffer vials must be 
stored in their original packaging. The study 
product must be stored according to the 

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instructions on the label. The Investigator, the 
Pharmacist, or other personnel is allowed to store 
and dispense investigational product. They 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.
Was changed to:
BI 836880 vials and Diluent Buffer vials must be 
stored in their original packaging. The study 
product must be stored according to the 
instructions on the label. The Investigator, the 
Pharmacist, or other personnel is allowed to store 
and dispense investigational product. They 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.
Rationale for change
Section adapted according to change in the new 
pharmaceutical formulation of BI836880 which 
will be diluted with a standard 5% 
Section to be changed
5.3.6 Electrocardiogram (ECG)
Description of change
The following text:
…..
In case of drug-related ECG changes and whenever 
the investigator deems necessary, additional ECG 
monitoring will be performed in the respective and 
later cycles of treatment. 
The ECGs will be recorded by a digital ECG 
machine and send 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.
Was changed to:
In case of drug-related ECG changes and whenever 
the investigator deems necessary, additional ECG 
monitoring will be performed in the respective and 
later cycles of treatment. 

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The ECGs will be recorded by a digital ECG 
machine and send 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.
Rationale for change
Centralized ECG will not be used anymore for the 
2 ongoing patients. Standard ECG will be 
performed and any significant finding based on 
medical opinion of the investigator should be 
reported in the eCRF.

 
 
 
 
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clinical-trial-protocol-version-06
A First-in Human Phase I, non-randomized, open-label, multi-center dose escalation
trial of BI 836880 administered by repeated intravenous infusions in patients with
solid tumors.
Approval-Clinical Trial Leader
11 Mar 2019 16:51 CET
Approval-Therapeutic Area 
11 Mar 2019 17:06 CET
Author-Trial Statistician
11 Mar 2019 18:04 CET
Author-Trial Clinical
Pharmacokineticist
12 Mar 2019 07:17 CET
Approval-Clinical Program 
12 Mar 2019 10:22 CET
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Expert
12 Mar 2019 19:21 CET
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13 Mar 2019 09:17 CET

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