An Open Label, Phase I Study of BI 836880 Monotherapy and Combination Therapy of BI 836880 and BI 754091 in Japanese Patients With Advanced Solid Tumours
Phase: PHASE1
Conditions: Neoplasms
Sponsor: Boehringer Ingelheim

001-MCS-40-106-RD-03 (16.0) / Saved on: 30 Aug 2018
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c25769893-03
BI Trial No.
1336-0012
BI Investigational
Medicinal Product(s)
BI 836880
BI 754091
Title
An open label, Phase I study of BI 836880 monotherapy and 
combination therapy of BI 836880 and BI 754091 in Japanese 
patients with advanced solid tumours
Lay Title
A study to find the best dose of BI 836880 alone and in 
combination with BI 754091 in Japanese patients with different 
types of advanced cancer
Clinical Phase
I
Clinical Trial Leader
Telephone: 
, Fax: 
Coordinating 
Investigator
Telephone: 
Status
Final Protocol / Revised Protocol (based on global amendment 2)
Version and Date
Version: 3.0
Date: 21 Aug 2019
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2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim 
Protocol date
20 Dec 2018
Revision date
21 Aug 2019
BI trial number
1336-0012
Title of trial
An open label, Phase I study of BI 836880 monotherapy and 
combination therapy of BI 836880 and BI 754091 in Japanese 
patients with advanced solid tumours
Coordinating 
Investigator
Telephone: 
Trial site(s)
Multi-centre trial conducted in Japan
Clinical phase
I
Trial rationale
The trial is required to define the maximum tolerated dose (MTD) 
and/or the recommended phase 2 dose (RP2D) of the BI 836880 
monotherapy and combination therapy of BI 836880 and BI 754091 
in Japanese patients to conduct the later phase clinical development in 
Asian populations.
Trial objective(s)
The main objectives of the trial are to investigate the following in 
patients with advanced solid tumours:

MTD and/or RP2D of BI 836880 monotherapy and the 
combination therapy of BI 836880 and BI 754091.

Safety, tolerability, pharmacokinetics (PK) and 
pharmacodynamics (Pd) of BI 836880 monotherapy.

Safety, tolerability, PK and Pd of combination therapy of BI 
836880 and BI 754091.
Trial endpoints
Part I (monotherapy part)
Primary:
-
Maximum tolerated dose (MTD).
-
Number of patients with DLTs in the MTD evaluation period.
Secondary:
-
PK parameters of BI 836880: Cmax and area under the curve 
(AUC)0-504h
Part II (combination therapy part)
Primary:
-
Maximum tolerated dose (MTD).
-
Number of patients with DLTs in the MTD evaluation period.

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Secondary:
-
PK parameters of BI 836880 and of BI 754091: Cmax and 
AUC0-504h
Trial design
Open label, uncontrolled, non-randomised, dose-escalation design
Total number of patients
treated
Approximately 24
Number of patients on 
each treatment
Approximately 24
Diagnosis
Patients with a confirmed diagnosis of advanced, unresectable, and/or 
metastatic solid tumours
Main in- and exclusion 
criteria
Main inclusion criteria:
•
Patients with a confirmed diagnosis of advanced, unresectable, 
and/or metastatic solid tumours (any type)
•
Patients with no therapy of proven efficacy, or who are not
amenable to standard therapies
•
Eastern Cooperative Oncology Group (ECOG) performance 
status ≤1
•
Adequate organ function defined with laboratory values
Main exclusion criteria:
•
Known hypersensitivity to the trial drugs or their excipients
•
Known HIV, HBV, or HCV infection
•
History of severe hypersensitivity reactions to other mAbs
•
Significant cardiovascular/cerebrovascular diseases, or 
uncontrolled hypertension
•
History of severe haemorrhagic or thromboembolic events in the 
past 12 months
•
Patients who require full-dose anticoagulation
•
Untreated brain metastasis(es) that may be considered active
•
Haematological malignancies
•
History (including current) of interstitial lung disease or 
pneumonitis within the last 5 years
•
Immunosuppressive corticosteroid doses (>10 mg prednisone 
daily or equivalent) within 4 weeks prior to the first dose of trial 
medication
Test product(s)
BI 836880
BI 754091 (Part 2 only)
dose
Part 1: 
BI 836880: starting dose 360 mg every three weeks
Part 2:
BI 836880: starting dose 120 mg every three weeks
BI 754091: starting dose 240 mg every three weeks
The starting dose of BI 836880 may be adapted via protocol 
amendment based on the most recent safety information from another 
ongoing trial, 1336-0011.
mode of 
administration
Intravenous infusion

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Comparator product(s)
Not applicable
dose
Not applicable
mode of
administration
Not applicable
Duration of treatment
Administration will continue until progressive disease (PD), 
unacceptable toxicity, or other withdrawal criteria.
Statistical methods
Part 1:
Dose escalation will be guided by Bayesian Logistic Regression
Models (BLRMs) with overdose control that will be fitted to binary
toxicity outcomes. The estimate of parameters will be updated as data
are accumulated using BLRM. At the end of dose escalation, the
toxicity probability at each dose (mono) level will be calculated to 
guide an estimate of the MTD and/or RP2D of BI 836880.
Part 2:
Dose escalation will be guided by Bayesian Logistic Regression
Models (BLRMs) with overdose control that will be fitted to binary
toxicity outcomes. The estimate of parameters will be updated as data
are accumulated using BLRM. At the end of dose escalation, the
toxicity probability at each dose (combination) level will be
calculated to guide an estimate of the MTD and/or RP2D of the
combination of BI 836880 plus BI 754091.

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FLOW CHART
Treatment Perioda
Cycle = 21 Days
Post-Treatment Period
Screening
Cycles 1, 2, 3, and 4l
Cycle 5
onwards
End-of-
Treatmentj
(EoT) Visit
Safety 
follow-up Visit
Visit
1k
2a
2b 
(C1,2 only)
3
4
1k
Day; visit window [days]
-14 to -1 unless 
otherwise 
specified
1k
2
3;
(+1d)
8;
(-1/+2d)
15;
(-1/+2d)
1k
Within 7 days 
of 
discontinuation
Last admin
+42d
(+3d)
Informed consent / IRT call
X
(-28 to -1)
Inclusion/Exclusion criteria
X
Medical history and Demographics
X
Physical Examination
X
X
X
X
X
ECOG performance status
X
X
X
X
Blood pressure, pulse rate, SpO2
c
X
X
X
X
X
X
X
X
X
Body temperaturec
X
X
X (C1,2)
X
X
12-lead ECG
X
X
X (C1,2)
X
X
Echocardiographyd
X
(-7 to -1)
X
General safety laboratory parametersb
X
(-10 to -1)
X
X
X
X
X
X
Pregnancy 
Test 
for 
Women 
of 
Child-Bearing Potentialb, f
X
X
X
X
Chest X-rayb
X
Xm
Xm
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X

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Treatment Perioda
Cycle = 21 Days
Post-Treatment Period
Screening
Cycles 1, 2, 3, and 4l
Cycle 5
onwards
End-of-
Treatmentj
(EoT) Visit
Safety 
follow-up Visit
Visit
1k
2a
2b 
(C1,2 only)
3
4
1k
Day; visit window [days]
-14 to -1 unless 
otherwise 
specified
1k
2
3;
(+1d)
8;
(-1/+2d)
15;
(-1/+2d)
1k
Within 7 days 
of 
discontinuation
Last admin
+42d
(+3d)
Tumour assessmente
X
(-28 to -1)
Every 6 weeks ±3 days for 6 months (then every 9 weeks ±3 days thereafter)
Study drug administration
X
X
Pharmacokineticsg
X
X (C1-4 for 
Part I, C1 and 
4 for Part II)
X (Part I)
X (C1,2,4 for 
Part I, C1 and 4 
for Part II)
X (C1,2,4 for 
Part I, C1 and 
4 for Part II)
X (C5-12)
X
X
a
All cycles are 3 weeks (21 days) in duration. Patients will continue treatment with the study drugs until progressive disease (PD) by RECIST and/or iRECIST
(see Section 5.1.1), withdrawal of patient consent, or occurrence of unacceptable toxicity, whichever occurs first. Day 1 of Cycle 1 is defined as the day when 
the study medication is first administered.
b
Safety laboratory assessments including haematology, clinical biochemistry, and urinalysis will be performed locally. If screening laboratory assessments, 
pregnancy testing, and chest X-ray are performed within 3 days before initiation of treatment, they do not need to be repeated on Cycle 1 Day 1. Refer to 
Section 5.2 for additional details.
c
Vital signs include systolic and diastolic blood pressure, pulse rate, arterial oxygen saturation (SpO2), and body temperature. Details including the timing of 
assessment of blood pressure and pulse rate are provided in Section 5.2.3.

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d
Echocardiography should be performed at screening and EoT visits. During the treatment period, echocardiography should be performed if clinically indicated.
e
Screening tumour assessments (scans) should be performed ≤28 days prior to initiation of treatment. Scans obtained prior to study participation can be used for
the study as long as they are not older than 28 days at the day of first treatment. Tumour assessments should be done according to RECIST v1.1 and iRECIST
and should include computed tomography/positron emission tomography (CT/PET) scans of the chest and abdomen and, if clinically indicated, imaging of any 
other known or suspected sites of disease (e.g., pelvis, brain) using an appropriate method (CT/PET scan or magnetic resonance imaging [MRI]). The same 
radiographic procedure must be used throughout the trial. In case of suspected (but not confirmed) bone metastasis at screening, tumour assessment at 
screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or CT scan) should be 
performed. Correlative imaging should then be repeated at each tumour assessment. Assessments will be performed by the Investigator at screening and every 
2 cycles (meaning every 6 weeks ±3 days if there are no delays in cycles but as close as possible to the end of the second of the 2 cycles of treatment if there 
was a delay) for the first 6 months of treatment, once every 3 cycles (meaning every 9 weeks ±3 days if there are no delays in cycles but as close as possible to 
the end of the third of the 3 cycles of treatment if there was a delay), and at the discretion of the Investigator and copies will be collected by the sponsor or 
designee.
f
Women of child-bearing potential must have a serum beta human chorionic gonadotropin (βHCG) pregnancy test at screening. Thereafter, this test can be done 
in either serum or urine on Day 1 of each cycle, and at the EoT visit (see Section 5.2.4.5).
g
The detailed blood sampling time points for pharmacokinetics (PK), 
 are provided in Appendix 
10.4.
j
If the decision to permanently discontinue the study treatment is made during a scheduled visit, the EoT visit should be performed instead of the scheduled visit
assessments. In the combination treatment part (Part II), both BI 836880 and BI 754091 should be discontinued together if necessary.
k
Before initiating a new treatment cycle, the criteria to administer the study drug(s) should be checked (see Section 4.1.6)
l
Patients are required to be hospitalized under close surveillance with access to intensive care for at least 48 hours after the first administration of trial 
medication(s). Based on an individual risk assessment by investigator, the duration of surveillance may be shorten to 8 hours for cycles 2, 3, and 4, and at 
investigator's discretion for further cycles (see Section 6.1).
m
Chest X-ray is to be performed at Day 1 of every treatment cycle. Except for cycle 1, the chest X-ray examination for each cycle may be omitted if a chest CT 
scan is performed within 7 days prior to the drug administration on Day 1 for that cycle.

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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................17
1.2.1
BI 836880 .............................................................................................................17
1.2.2
BI 754091 .............................................................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................20
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................21
1.4.3
Discussion.............................................................................................................24
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........26
2.1.1
Main objectives....................................................................................................26
2.1.1.1
Primary objective:.................................................................................................26
2.1.1.2
Secondary objective..............................................................................................26
2.1.2
Primary endpoint(s)............................................................................................26
2.1.3
Secondary endpoint(s) ........................................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................29
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................29
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................30
3.3
SELECTION OF TRIAL POPULATION .......................................................30
3.3.1
Main diagnosis for trial entry ............................................................................30
3.3.2
Inclusion criteria .................................................................................................31
3.3.3
Exclusion criteria ................................................................................................32
3.3.4
Withdrawal of patients from treatment or assessments..................................33
3.3.4.1
Discontinuation of trial treatment .........................................................................34
3.3.4.2
Withdrawal of consent to trial participation .........................................................34
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................35
4.
TREATMENTS...................................................................................................36
4.1
INVESTIGATIONAL TREATMENTS ...........................................................36

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4.1.1
Identity of the Investigational Medicinal Products..........................................36
4.1.2
Selection of doses in the trial..............................................................................37
4.1.2.1
Selection of dose in Part I .....................................................................................37
4.1.2.2
Selection of dose in Part II....................................................................................38
4.1.3
Dose-finding scheme ...........................................................................................38
4.1.4
Method of assigning patients to treatment groups...........................................40
4.1.5
Drug assignment and administration of doses for each patient......................40
4.1.6
Dose modifications ..............................................................................................41
4.1.7
Dose limiting toxicities........................................................................................42
4.1.8
Definition of evaluable patient...........................................................................44
4.1.9
Blinding and procedures for unblinding...........................................................44
4.1.9.1
Blinding.................................................................................................................44
4.1.9.2
Unblinding and breaking the code ........................................................................44
4.1.10
Packaging, labelling, and re-supply...................................................................44
4.1.11
Storage conditions...............................................................................................44
4.1.12
Drug accountability.............................................................................................44
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................45
4.2.1
Other treatments and emergency procedures..................................................45
4.2.1.1
Permitted concomitant medications......................................................................45
4.2.2
Restrictions ..........................................................................................................46
4.2.2.1
Restrictions regarding concomitant treatment ......................................................46
4.2.2.2
Restrictions on diet and life style..........................................................................46
4.2.2.3
Contraception requirements..................................................................................47
4.3
TREATMENT COMPLIANCE........................................................................47
5.
ASSESSMENTS..................................................................................................48
5.1
ASSESSMENT OF EFFICACY........................................................................48
5.2
ASSESSMENT OF SAFETY.............................................................................48
5.2.1
Physical examination ..........................................................................................49
5.2.2
ECOG performance status.................................................................................49
5.2.3
Vital signs.............................................................................................................49
5.2.4
Safety laboratory parameters ............................................................................50
5.2.4.1
Hematology...........................................................................................................50
5.2.4.2
Biochemistry.........................................................................................................50
5.2.4.3
Coagulation...........................................................................................................51
5.2.4.4
Urinalysis ..............................................................................................................51
5.2.4.5
Pregnancy test .......................................................................................................51
5.2.5
Electrocardiogram ..............................................................................................51
5.2.6
Echocardiography...............................................................................................52
5.2.7
Chest X-ray..........................................................................................................52
5.2.8
Other safety parameters.....................................................................................52
5.2.9
Assessment of adverse events.............................................................................52
5.2.9.1
Definitions of AEs ................................................................................................52
5.2.9.2
Adverse event collection and reporting ................................................................56

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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................58
5.3.1
Assessment of pharmacokinetics .......................................................................58
5.3.2
Methods of sample collection .............................................................................58
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................62
6.
INVESTIGATIONAL PLAN.............................................................................63
6.1
VISIT SCHEDULE.............................................................................................63
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................63
6.2.1
Screening and run-in period(s)..........................................................................64
6.2.2
Treatment period(s)............................................................................................64
6.2.3
Follow-up period and trial completion..............................................................65
6.2.3.1
End of treatment (EoT) visit .................................................................................65
6.2.3.2
Safety follow-up visit............................................................................................65
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................66
7.1
STATISTICAL DESIGN - MODEL.................................................................66
7.1.1
Statistical design – Part I (BI 836880 monotherapy dose finding part).........66
7.1.2
Statistical design – Part II (BI 836880 and BI 754091 combination dose 
finding).................................................................................................................68
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................72
7.3
PLANNED ANALYSES.....................................................................................72
7.3.1
General considerations .......................................................................................73
7.3.2
Primary endpoint analyses.................................................................................73
7.3.3
Secondary endpoint analyses .............................................................................73
7.3.5
Safety analyses.....................................................................................................73
7.3.6
Interim Analyses .................................................................................................74
7.4
HANDLING OF MISSING DATA ...................................................................74
7.5
RANDOMISATION ...........................................................................................74
7.6
DETERMINATION OF SAMPLE SIZE .........................................................74

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........76
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................76
8.2
DATA QUALITY ASSURANCE ......................................................................77
8.3
RECORDS...........................................................................................................77
8.3.1
Source documents ...............................................................................................77
8.3.2
Direct access to source data and documents.....................................................78
8.3.3
Storage period of records ...................................................................................78
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................79
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........79
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................79
8.6
TRIAL MILESTONES.......................................................................................79
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................80
9.
REFERENCES....................................................................................................82
9.1
PUBLISHED REFERENCES............................................................................82
9.2
UNPUBLISHED REFERENCES......................................................................84
10.
APPENDICES.....................................................................................................85
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST .....85
10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS (PART 
II ONLY)..............................................................................................................88
10.3
BLOOD PRESSURE MEASUREMENT PROCEDURE...............................91
10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK), 
 
 BLOOD SAMPLING...............................................................92
10.5
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE 
AND DATA SCENARIOS .................................................................................96
10.5.1
Part I (BI 836880 monotherapy dose finding part)..........................................96
10.5.2
Part II (BI 836880 and BI 754091 combination dose finding) ........................99
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................102
11.1
GLOBAL AMENDMENT 1 ............................................................................102
11.2
GLOBAL AMENDMENT 2 ............................................................................107

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ABBREVIATIONS
ADA
Anti-Drug Antibodies
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, and Accurate
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
Ang2
Angiopoietin-2
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BLRM
Bayesian Logistics Regression Model
BUN
Blood Urea Nitrogen
CA
Competent Authority
CKD-EPI
Chronic Kidney Disease Epidemiology
Cmax
Maximum Concentration
CRA
Clinical Research Associate
CK
Creatine Kinase
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CR
Complete Response
CRO
Contract Research Organisation
CTCAE
Common Terminology Criteria for Adverse Events
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
DCE-MRI
Dynamic Contrast-Enhanced Magnetic Resonance Imaging
DILI
Drug Induced Liver Injury
DLT
Dose Limiting Toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group

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eGFR
Estimated Glomerular Filtration Rate
EMA
European Medicines Agency
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoT
End of Treatment
EWOC
Escalation With Overdose Control
FDA
(United States) Food and Drug Administration
FGF
Fibroblast Growth Factor
GCP
Good Clinical Practice
GEP
Gene-Expression Profile
GMP
Good Manufacturing Practice
HBc
Hepatitis B core
HBs
Hepatitis B surface
HBV
Hepatitis B Virus
HIV
Human Immunodeficiency Virus
irAE
Immune related Adverse Event
i.v.
intravenous
IB
Investigator’s Brochure
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
INR
International Normalised Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LDH
Lactate Dehydrogenase
LMWH
Low Molecular Weight Heparin
LPLT
Last Patient Last Treatment
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal Antibody
MAP
Meta-Analytic Predictive
MedDRA
Medical Dictionary for Drug Regulatory Activities

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MDSC
Myelo-derived suppressor cell
MRI
Magnetic Resonance Imaging
MSI
Microsatellite Instability
MTD
Maximum Tolerated Dose
NK
Natural Killer
NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
NSCLC
Non-Small Cell Lung Cancer
NYHA
New York Heart Association
OPU
Operative Unit
OR
Objective Response
p.o.
per os (oral)
Pd
Pharmacodynamics
PD
Progressive disease
PD-1
Programmed-cell-death-protein-1
PD-L1
Programmed-cell-death ligand-1
PD-L2
Programmed-cell-death ligand-2
PK
Pharmacokinetics
PR
Partial Response
PT
Prothrombin Time
QTcF
Corrected QT interval by Fredericia
RECIST
Response Evaluation Criteria In Solid Tumours
REP
Residual Effect Period
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SD
Stable Disease
SMC
Safety Monitoring Committee
SOP
Standard Operating Procedure
SpO2
Arterial oxygen saturation
SUSAR
Suspected Unexpected Serious Adverse Reactions
t1/2
Half Life Time
tmax
Timepoint of Maximum Plasma Concentration
TMB
Tumour Mutation Burden

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TNM
Tumour, Node, Metastasis
Treg
Regulatory T-cell
TSAP
Trial Statistical Analysis Plan
ULN
Upper Level of Normal
UPCR
Ration of Urine Protein to Creatinine
VEGF
Vascular Endothelial Growth Factor
VEGFR
Vascular Endothelial Growth Factor Receptor
WHO
World Health Organisation
WOCBP
Woman of childbearing potential

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Despite the recent advancements in cancer treatment, cancer remains a leading cause of death
globally. In 2018, the estimated number of new cancer cases was approximately 18 million, 
and 9.5 million cancer-related deaths worldwide (R18-3204). In the majority of cases, the 
disease is diagnosed in late stages and the vast majority of patients progress on available 
treatment and succumb to their disease. These statistics clearly highlight the urgent need for 
novel therapeutic agents and treatment strategies to improve the treatment outcome for cancer
patients.
Studies in mice have shown that Angiopoietin-2 (Ang2), a ligand of a tyrosine kinase 
receptor called Tie2 receptor, controls vascular remodelling by enabling the functions of 
other angiogenic factors, such as Vascular Endothelial Growth Factor (VEGF) (R12-3593).
Ang2 is primarily expressed by endothelial cells, strongly induced by hypoxia and other
angiogenic factors and has been demonstrated to regulate tumour vessel plasticity, allowing
vessels to respond to VEGF and Fibroblast Growth Factor 2 (FGF2) (R12-3834).
The normal role of the immune system is to protect the body against the invasion of foreign 
agents such as bacteria, viruses and parasites as well as the body’s own malfunctioning cells. 
Once a mounted immune response (adaptive or innate) completes its task of eliminating the 
threat, the immune system deploys the immune system checkpoint program to dampen the 
immune response and minimize collateral immune-mediated damage to healthy tissue. The 
programmed-cell-death-protein-1 (PD-1) receptor and its ligands, programmed-cell-death 
ligand-1 (PD-L1) and programmed-cell-death ligand-2 (PD-L2) are the major immune 
checkpoint master switches. The expression of PD-1 on immune cells, including T and B 
lymphocytes, natural killer (NK) cells and antigen presenting cells is upregulated in response 
to inflammation in peripheral tissue. As with PD-1 level, the expression of PD-L1 is also 
induced as a result of peripheral tissue inflammation. The interaction of PD-1 and PD-L1
results in an inhibitory signal that interferes with antigen receptor signalling, marked changes 
in the cytokine profile decreased T-cell activation, increased activation of regulatory T-cells 
(Tregs) and increase in cytotoxic T-cell apoptosis. Collectively, these events lead to an 
immune suppressive environment and dampening of the immune response. Tumour immune 
evasion is achieved when PD-L1 within the tumour microenvironment engages PD-1 
expressed on activated tumour infiltration T-cells and initiates the immune suppressive 
tumour microenvironment in which activated cytotoxic T-cells are inactivated and some are 
sent down an apoptotic pathway.
Angiogenesis is the formation of new blood vessels from pre-existing vasculature and is a
key process in tumour growth. The Ang2/Tie2 and the VEGF/VEGFR2 pathways have been
identified as key pathways mediating tumour 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 mAb 
(monoclonal antibody) bevacizumab has demonstrated anti-tumour activity in clinical trials 
and is currently approved for several indications and setting, mainly in combination with 

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standard chemotherapy regimens (R15-1222). High circulation level of Ang2 was observed in 
several tumour type and correlate with poor prognosis. Anti-tumour activity was reported 
with Ang2 inhibition in Phase I trials. 
VEGF-A induces accumulation of Myelo-derived suppressor cells (MDSCs), immature DC, 
Treg and tumour-associated macrophage. MDSCs are able to control activation of T-cell and 
NK cells. Anti-VEGF treatment significantly enhances dendritic cell maturation (R17-4036,
R17-4037), decrease Treg either by inhibiting the accumulation of MDSCs and immature 
dendritic cells (DC) in tumour environment, or directly through VEGF/ Vascular Endothelial 
Growth Factor Receptor (VEGFR) pathway inhibition of Treg (R17-4038, R17-4039). Ang2 
Blockade facilitates the extravasation and perivascular accumulation of activated interferon 
alpha-expressing CD-8 cytotoxic T lymphocytes. 
Preclinical evidence of interaction between these 2 pathways was shown as well as 
encouraging anti-tumour activity of the combination of VEGF blockade and PD-1/PD-L1 
blockade (c02353883).
1.2
DRUG PROFILE
1.2.1
BI 836880
The 
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. The 
cloned and isolated VHH domain is a stable polypeptide harbouring the full 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, 
). 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
(c02353883).
BI 836880 is highly potent and showed in vivo monotherapy efficacy (tumour growth
inhibition) in several tumour xenograft representing colon cancer (CXF 243), non-small cell
lung cancer (LXFE 211, LXFE 1422), mammary cancer (MAXF 401), ovarian cancer
(OVXF 1353), pancreatic cancer (PAXF 546) and renal cell cancer (RXF 1220) .
A 13-week repeat dose administration of BI 836880 was performed in cynomolgus monkeys. 
BI 836880 was well tolerated up to the highest dose of 60 mg/kg. No mortality was attributed 
directly to BI 836880 administration. BI 836880 did not demonstrate any effects on 
neurological, renal, or cardiovascular functions including electrocardiograms (ECGs). In a 
monkey presenting the immunogenic reaction, membrano-proliferative glomerulopathy in the 
kidney was observed. This finding was considered a secondary response to immune complex 
deposition in the glomeruli and not directly related to BI 836880 administration.

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The pharmacokinetics (PK) and immunogenicity of BI 836880 were investigated in
cynomolgus monkeys following a single intravenous (i.v.) at 3 dose levels. BI 836880
demonstrated an unexpected dose-dependent clearance and a supra-proportionally AUC0-∞
increase with the increase of dose. Among the nine monkeys in this study, six monkeys were
anti-drug antibodies (ADA) positive post-dose at one or more of the sampling time points. No 
Changes in pharmacokinetic parameters were observed in these animals. In the 13-week 
toxicity and toxicokinetics, BI 836880 exposure (maximum concentration [Cmax] and area 
under the curve [AUC]0-168) increased approximately dose proportionally from 1 to 60 mg/kg 
in weeks 1, 4 and 13. There was a moderate accumulation (~ 2-fold). BI 836880 is currently 
tested in monotherapy in 2 phase I trials. 
BI 836880 monotherapy is currently tested in two phase I trials, trial 1336-0001 for every 3 
week administration schedule and trial 1336-0006 for weekly administration schedule, both 
conducted in Europe. 29 and 18 patients received BI 836880 in trial 1336-0001 and in trial 
1336-0006 respectively. Dose levels between 40 mg and 1000 mg of BI 836880 are tested. In 
trial 1336-0001, the dose of 720 mg was defined as MTD and recommended phase 2 dose
(RP2D).
In these two trials, the most commonly reported adverse events (AEs) are hypertension, 
asthenia, nausea, vomiting, diarrhoea and constipation. Other relevant AEs (mode of action 
related) include, peripheral oedema, bleeding (epistaxis), and proteinuria. The Safety profile 
of BI 836880 is as expected based on its mode of action. New antihypertensive treatment or 
change in previous antihypertensive treatment was needed in very few patients.
An exploratory, preliminary biomarker analysis performed in these two trials has shown that 
systemic VEGF levels are completely blocked already at the lowest dose of 40 mg i.v., while 
systemic ANG2 levels were blocked dose-dependently showing complete inhibition at 
dosages starting at 360 mg 3-weekly or 120 mg weekly. At these dosages both, systemic 
VEGF and ANG2, remain below limit of quantitation even before start of next treatment. 
From exploratory, preliminary PK analysis, plasma concentrations of BI 836880 increased 
dose-dependently (based on Cmax and AUC), over the dose ranges 40-1000 mg (1336-0001 
q3w) and 40-180 mg (1336-0006 qw). A slight accumulation could be observed over 
treatment cycles 1, 2 and 4 based on Cmax and partial AUCs in both trials (accumulation ratios 
were up to 1.5) while the elimination seemed dose-independent. In 1336-0001 (q3w), the 
gmean half-life over all dose groups was 197 hours (cycle 1, n=12), 238 hours (cycle 2, n=7), 
and 343 hours (cycle 4, n=4). It seems as if the required trough values of 20 mg/L (according 
to preclinical experiments) could be achieved at dosages starting from 720 mg q3w. 
Furthermore, to assess the vascular pharmacodynamics (Pd) effect of BI 836880, dynamic 
contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed in 1336-0001
trial at the two highest dose level (7 patients at 750 mg and 1 patient at 1000 mg). DCE-MRI 
imaging were performed at baseline and 1 week after dosing. Changes in Ktrans (compared 
to basline value) were evaluated for vascular perfusion changes. Amongst the 8 patients, 
Ktrans decrease was observed in 7 patient (> 40% in 4 patients, 20-40% in 2 patient and 
10-20% in 1 patient).

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Objective responses (ORs) were reported in 3 patients in trial 1336-0001 and 2 patients in 
trial 1336-0006. Those patient had ovarian cancer (two patients), endometrial cancer, breast 
cancer and nasopharyngeal cancer (one patient each tumour type)
The combination therapy of BI 836880 and BI 754091 is being investigated in patients with 
non small cell lung cancer (NSCLC) as well as other indications in Boehringer Ingelheim 
(BI) trial 1336-0011, which is being conducted in Western countries. The planned dose levels 
of BI 836880 in trial 1336-0011 are 360, 500, and 720 mg once every three weeks, combined 
with BI 754091 dose of 240 mg once every three weeks.
The Residual Effect Period (REP) of BI 836880 is 42 days. 
For a more detailed description of the drug profile refer to the current Investigator’s Brochure
(IB) (c02353883).
1.2.2
BI 754091
BI 754091 is a humanized IgG4 pro-monocolonal antibody showing potent and selective 
binding to human PD-1. BI 754091 has highly human frameworks and a low predicted 
immunogenicity score. The BI 754091 molecule has a molecular weight approximately 148 
kilodaltons. The antibody is composed of 2 heavy chains (446 amino acids each) and 2 light 
chains (218 amino acids each). The 4 polypeptide chains of the antibody are linked together 
by disulfide bonds. Each heavy chain contains one consensus sequence for N-linked 
glycosylation.
BI 754091 shows anti-tumour effects in vivo several mice model including in the syngenic 
MC-38 mouse model. 
A 13-week repeat dose administration of BI 754091 was performed in cynomolgus monkeys. 
BI 754091 was well tolerated and no related mortality or clinical signs, or changes to body 
weight, food consumption, respiratory rate or electrocardiogram were observed. 
BI 754091 exposure increased dose-proportionally and accumulated with repeat dosing for all 
tested dose levels. BI 754091 was still detectable after 4 week recovery period in the highest 
dose level (100 mg/kg). Engagement of BI 754091 with target was assessed by measuring 
available BI 754091-free PD-1 on CD3+/CD95+ T cells. After 13 weeks of dosing BI 754091 
resulted in in vivo target engagement at all dose levels. After 4 week recovery period; 
available PD-1 remained decreased in the 100 mg dose group demonstrating sustained target 
engagement throughout the recovery period.
BI 754091 is currently being tested in patients in several BI clinical trials either in 
monotherapy or in combination with other treatments. 
Trial 1381-0001 is a phase I clinical trial of BI 754091 monotherapy, conducted in Western 
countries. In the dose-escalation cohorts, 80 mg, 240 mg, and 400 mg dose levels
administered once every three weeks were investigated and 3 patients were dosed at each 
dose level. No dose limiting toxicities (DLTs) or protocol defined immune-related AEs

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(irAEs) were reported and the maximum tolerated dose (MTD) was not reached in the dose 
escalation cohorts. The recommended dose for further investigation was determined to be
240 mg. An exploratory analysis of biomarker performed in the 9 patients treated at 80 mg, 
240 mg and 400 mg shows 100% PD-1 receptor occupancy in peripheral blood in all 
on-treatment patient samples compared to baseline throughout one treatment cycle. Plasma 
concentration of BI 754091 appears to increase linearly (based on AUC0-504h, Cmax and Cpre). 
Trial 1381-0004 is a phase I clinical trial of BI 754091 monotherapy, conducted in Asian
countries. In the dose-finding part, 6 Japanese patients were treated with 240 mg dose level
administered once every three weeks and no DLTs or protocol defined irAEs were reported. 
MTD was not reached and the RP2D was determined to be 240 mg.
The Residual Effect Period (REP) of the combination therapy of BI 836880 and BI 754091 is
42 days.
For a more detailed description of the drug profile refer to the current IB (c07895879).
1.3
RATIONALE FOR PERFORMING THE TRIAL
Most patients with locally advanced or metastatic tumours will succumb to their disease,
justifying the substantial need for novel therapeutic strategies to improve the outcome for
patients with advanced or metastatic malignancies.
It is well established that pro-angiogenic factors (e.g. VEGF-A) have an immunosuppressive 
effect in the tumour microenvironment. Preclinical data showed modulation of 
immunosuppressive cells by an anti-VEGF treatment and enhancement of anti-tumour effect 
with the combination of VEGF and PD-1 inhibition. Furthermore, internal BI preclinical data 
showed an additive effect of the angiopoietin inhibition on the top of the dual VEGF and 
PD-1 inhibition. (see BI 836880 IB, c02353883). Ang2 Blockade facilitates the extravasation 
and perivascular accumulation of activated interferon alpha-expressing CD-8 cytotoxic T 
lymphocytes. Combination of VEGF and Ang2 blockade promote perivascular T cell 
accumulation. 
This scientific rationale and preclinical data support a combination trial of the triple 
inhibition of VEGF, Ang-2 and PD-1 inhibition. 
This trial is intended to assess the safety, efficacy and pharmacokinetics (PK) and 
pharmacodynamics (Pd) of BI 836880 monotherapy and combination of BI 836880 and BI 
754091 in Japanese patients to establish a safe combination dose that will enable Asian 
patients to be included in global clinical trials with this same combination. 
In order to be able to address future scientific questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see Section 5.5). If the patient agrees, banked 
samples may be used for future biomarker research and drug development projects, e.g. to 
identify patients that are more likely to benefit from a treatment or experience an AE, or to 
gain a mechanistic or genetic understanding of drug effects and thereby better match patients 
with therapies.

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In summary, the unmet medical need in patients with advanced solid tumours, the 
manageable anticipated safety profiles of BI 836880 and BI 754091 and scientific and 
clinical rationale for increased benefit from this combination warrant its evaluation in a 
global population including Asian (Japanese) patients. While safety and tolerability as well as 
early signs of activity in Western population will be investigated in separate ongoing trials, 
this study will provide supporting evidence for mono- and combination therapy in the 
Japanese population.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
This trial is for patients with advanced cancer and for whom there are no therapy options of 
proven efficacy, or who are not amenable to currently available standard therapies. BI 
836880 is an investigational antiangiogenic agent and BI 754091 is an investigational 
immune checkpoint inhibitor. There are many antiangiogenic agents already approved to treat 
various types of cancer. Similarly there are many immune checkpoint inhibitors approved in 
various types of cancers. By participating in this trial and receiving study medication(s) either 
as monotherapy or in combination, patients with advanced cancer may have a better chance 
to delay tumour progression, compared with no anti-cancer treatment.
Based on the mode of action of BI 836880 and BI 754091, published and internal preclinical 
data, and available clinical data,  it is anticipated that treatment with this combination will 
potentially improve response rate with prolonged duration of response as compared to each 
monotherapy.
1.4.2
Risks
Both BI 836880 and BI 754091 are investigational agents. Table 1.4.2: 1 displays the 
anticipated side effects of the study drugs, based on the mechanism of action, observed 
clinical data from ongoing studies, and published clinical data for drugs targeting VEGF, 
Ang2, and PD-1.
Table 1.4.2: 1
Potential risks, their rationale, and mitigation strategy
Potential risks of clinical 
relevance for this trial
Summary of data, rationale 
for the risk
Mitigation strategy
Investigational Medicinal Product BI 836880 (monotherapy)
Hypertension
This is a class effect and has 
been identified as an
expected AE in this trial. In 
Phase I trials, Grade 1 or 2 
hypertension has occurred in 
31.0% of patients and Grade 
3 hypertension in 27.6% of 
patients. All hypertensive 
Patients with uncontrolled 
hypertension are excluded. 
Frequent blood pressure 
monitoring is implemented.

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episodes were transient 
requiring no treatment or 
resolved with the initiation 
or intensification of 
anti-hypertensive agents.
Thromboembolic events 
(e.g. pulmonary embolism, 
deep vein thrombosis)
This is a class effect and 
expected AE with 
antiangiogenics. 
Patients with history of 
severe thromboembolic 
event in the past 12 months 
are excluded.
Bleeding
This is a class effect and 
expected AE with 
antiangiogenics.
Patients with history of 
severe haemorrhagic event 
in the past 12 months are 
excluded. Full-dose 
anticoagulation (according 
to local guidelines) with 
Vitamin K antagonist and 
other anticoagulation are not 
allowed during the trial 
conduct.
Infusion related reactions
As with any mAb, allergic 
reactions to study 
medication administration is 
possible and they are 
potentially severe.
Patients with history of 
severe hypersensitivity 
reactions to other mAbs are 
excluded. A 48-hour 
hospitalisation with access 
to intensive care is 
mandated for all patients
after the first study drug 
administration to secure the 
patient safety.
Drug-induced liver injury 
(DILI)
Rare but can be a 
potentially severe event, 
thus under constant 
surveillance by sponsors 
and regulators for all drugs 
in development.
Timely detection, 
evaluation, and follow-up 
of laboratory alterations in 
selected liver laboratory 
parameters to ensure 
patients' safety.
Investigational Medicinal Product BI 754091 (monotherapy)
Immune-related adverse 
events (irAEs)
irAEs are associated with 
immune mediated mode of 
action and can be 
potentially severe.
Recommendations for the 
management of irAEs are 
provided. Investigators 
involved in this trial have 
experience in managing 
irAE and sites have 
facilities. A 48-hour 

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hospitalisation with access 
to intensive care is 
mandated for all patients 
after the first study drug 
administration to secure the 
patient safety.
Infusion related reactions
As with any mAb, allergic 
reactions to study 
medication administration 
is possible and they are 
potentially severe
Patients with history of 
severe hypersensitivity 
reactions to other mAbs are 
excluded. A 48-hour 
hospitalisation with access 
to intensive care is 
mandated to secure the 
patient safety.
Drug-induced liver injury 
(DILI)
Rare but can be a 
potentially severe event, 
thus under constant 
surveillance by sponsors 
and regulators for all drugs 
in development.
Timely detection, 
evaluation, and follow-up 
of laboratory alterations in 
selected liver laboratory 
parameters to ensure 
patients' safety.
Trial procedures
Biopsies
Biopsies are mandatory for 
Part II. Patients may 
experience biopsy related 
AEs such as pain or 
bleeding.
The risks are clearly 
explained in the informed 
consent document.
Dose escalation/DLT 
assessment
Assessment of DLT may be 
difficult if any safety 
assessments specified in 
cycle 1 are missing or not 
evaluable.
The Safety Monitoring 
Committee (SMC) will 
assess the data from all 
patients, and discuss if a 
patient is evaluable for DLT 
or any replacement is 
required.
Other risks
NA

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1.4.3
Discussion
Both BI 836880 and BI 754091 are currently tested in early phase clinical trials as 
monotherapy and as a combination.
The observed clinical data from the on-going BI 836880 phase I trials (1336-0001 and 
1336-0006) have been consistent with the anticipated possible side effects of VEGF and 
Ang2 inhibition, with hypertension, asthenia, nausea, vomiting, diarrhoea and constipation
being the most commonly reported AEs. Most of these reported AEs were grade 1-2 
(Common Terminology Criteria for Adverse Events [CTCAE] version 4.03) (See BI 836880 
IB, c02353883). In trial 1336-0001, utilizing q3 week administration, a DLT (pulmonary 
embolism) was observed in 1 patient receiving BI 836880 at 1000 mg. In trial 1336-0006, 
utilizing weekly administration, 4 patients experienced DLT(s). These DLTs consisted of 
proteinuria (1 patient treated at 120 mg dose level, proteinuria and hypertension (1 patient 
treated at 240 mg), LVEF decrease (1 patient treated at 240 mg) and hypertension (1 patient 
treated at 180 mg). Dose level of BI 836880 given at 180 mg is currently expanded to 
confirm the MTD. In trial 1336-0011, two patients were treated at the dose level of BI 
836880 360 mg and BI 754091 240 mg by 15 October 2018, and DLT (pulmonary embolism) 
was observed in one patient. The MTD information from trial 1336-0011 is expected in Jun 
2019.
BI 754091 is tested in monotherapy and in combination with other compounds. In the first 
phase I trial (1381-0001), three doses of BI 754091 (80, 240 and 400 mg) were tested in the 
dose escalation part, and no DLTs or protocol defined irAEs were reported during the MTD 
evaluation period at any dose level. The most common AEs were nausea, fatigue, decrease 
appetite, constipation and arthralgia. Based on this dose escalation data, the dose of 240 mg 
was recommended for further development in monotherapy or as a starting dose in 
combination trials. In trial 1381-0004, 6 Japanese patients received BI 754091 at 240 mg and 
and no DLTs or protocol defined irAEs were reported.
The combination of an immune checkpoint inhibitor with a VEGF blocker has previously 
been tested in a phase I and II trials combining atezolizumab with bevacizumab in patients 
with renal cell carcinoma (R18-3778). This combination was well tolerated with most 
reported AEs as mild or moderate in severity. The only grade 3-4 reported events were 
hypertension. Reported AEs included check-point inhibitor related events such as fatigue, 
chills, diarrhoea, rash and pruritus and other AEs related to VEGF blockade (fatigue, 
hypertension, and epistaxis). 
Patients should be advised and carefully monitored for the potential risk of side effects from 
these investigational drugs. Due to the potential for severe hypertension and potential 
infusion reactions, a 48 hours hospitalization is required after the first administration of trial 
medication(s) for closer observation with access to intensive care for ensuring patient safety. 
Patients with uncontrolled hypertension, with history of severe haemorrhage or 
thromboembolism are not allowed to participate in this trial. The clinical trial sites qualified 
to participate in this trial will be comprehensive cancer centres with good experience in 
treating patients with investigational drugs and have the necessary infrastructure. The 
investigators and sponsor will form a Safety Monitoring Committee (SMC). The SMC will 

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meet regularly and at minimum after all patients in each dose cohort have completed cycle 1. 
The sponsor will continuously assess risk benefit based on accumulating clinical data from all 
clinical trials with these two investigational agents. Any significant change in risk-benefit 
will be communicated to investigator and patients. 
There is a guidance from health authorities to carefully monitor a potential for drug-induced 
liver injury (DILI). Although rare, a potential for DILI is under constant surveillance by 
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.9.1.4, adverse events of special interest (AESI).
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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
2.1.1.1
Primary objective:
The primary objective of this trial is:
Part I

To determine Maximum tolerated dose (MTD) and/or recommended Phase 2 dose 
(RP2D) of BI 836880 monotherapy
Part II

To determine MTD and/or RP2D of the combination therapy of BI 836880 and BI 
754091
The definition of MTD and RP2D are as follows:

MTD: the highest dose with less than 25% risk of the true DLT rate being equal or above 
33% during the MTD evaluation period

RP2D: RP2D is determined by SMC and it may be any dose which fulfils the escalation 
with overdose control (EWOC) criterion. The SMC may decide to declare a dose as 
RP2D without determining the MTD, in consideration of all available data including the 
one from preceding trials.
The MTD will be determined based on the frequency of patients experiencing DLTs during 
the MTD evaluation period. The MTD evaluation period is defined as first treatment cycle.
2.1.1.2
Secondary objective
The secondary objectives are:
Part I

To document the safety and tolerability, and characterise pharmacokinetics (PK) of BI 
836880 as monotherapy
Part II

To document the safety and tolerability, and characterise PK of the combination therapy 
of BI 836880 and BI 754091
2.1.2
Primary endpoint(s)
Part I and II:

Maximum tolerated dose (MTD). 

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
Number of patients with DLTs in the MTD evaluation period. 
For definition of DLTs, refer to Section 4.1.7.
A BLRM (Bayesian Logistics Regression Model) employing the escalation with overdose 
control (EWOC) principle will be used during the escalation phase for selection of doses and 
for estimation of the MTD. Cohorts of patients will receive escalating doses of BI 836880 
single agent or combination of BI 836880 and BI 754091 until the MTD is reached, or RP2D 
is determined. Each cohort will consist of newly enrolled patients. Estimation of the MTD 
during the escalation phase of the trial will be based upon the estimation of the probability of 
a DLT in the MTD evaluation period in the set of evaluable patients for MTD. The 
corresponding methodology is described in Section 7 and Appendix 10.5.
2.1.3
Secondary endpoint(s)
Part I

The following PK parameters of BI 836880 will be calculated in cycles 1, 2 and 4:

Cmax: maximum measured concentration of BI 836880 in plasma

AUC0-504h: area under the concentration-time curve of BI 836880 in plasma over the 
time interval from 0 to 504 hours
Part II

The following PK parameters of BI 836880 and BI 754091 will be calculated in cycles 1 
and 4:

Cmax: maximum measured concentration of BI 836880 and BI 754091 in plasma

AUC0-504h: area under the concentration-time curve of BI 836880 and BI 754091 in 
plasma over the time interval from 0 to 504 hours

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a Phase I, non-randomized, uncontrolled, open-label, dose escalation trial of
BI 836880 monotherapy and combination therapy of BI 836880 and BI 754091, which are 
administered intravenously every 3 weeks. The eligible patient population will be advanced 
solid tumours. The trial consists of two Parts; Part I (monotherapy part) and Part II 
(combination therapy part). Part II will commence after completion of Part I.
The data obtained from the trial will determine the MTD estimate based on a Bayesian 
logistic regression model with overdose control (R13-4803). The BLRM estimates the MTD 
by updating estimates of the probability of observing a DLT in the MTD evaluation period 
for each dose level in the trial as patient information becomes available. At any time in the 
trial, it will not be permitted to escalate to a dose which does not fulfil the escalation with 
overdose control (EWOC) principle (refer to Section 7).
Successive cohorts of patients will receive increasing doses of BI 836880 single agent or 
combination of BI 836880 and BI 754091 until the MTD is reached or RP2D is determined. 
For any dose-escalation cohort, at least 3 patients will be required (refer to Section 7). 
However, in the case that only 2 patients are evaluable and neither has experienced a DLT 
within the MTD evaluation period, then dose-escalation can occur based on these 2 patients.
Doses may be de-escalated based on the occurrence of DLT and overall safety data. For the 
first cohort, 3 patients are planned to be treated. A cohort size of at least 3 patients will be 
treated at each subsequent cohorts. After all patients in a cohort have either experienced a 
DLT or have been observed for at least the MTD evaluation period without experiencing a 
DLT, the Bayesian model will be updated with the newly accumulated data. The overdose 
risk will then be calculated for each dose, and dose 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 the Safety Monitoring Committee (SMC) based on the collected safety data as well 
as other data when available. The doses will not exceed the RP2D established in the 
preceding trials in Western patients.
If DLTs are observed in the first 2 consecutive patients of a previously untested dose level,
subsequent enrolment to that cohort will be stopped. The BLRM will be re-run to confirm 
that the dose-level still fulfils the EWOC principle. Based on this information, the SMC will 
evaluate whether the next patients will be enrolled at the same dose level, or if they will be 
enrolled at a lower dose level.
The SMC may recommend stopping the dose escalation phase after the criterion for MTD 
(Section 7.1) is fulfilled. Further patients may be included to confirm this MTD estimate, i.e. 
to confirm that the EWOC criterion is still fulfilled. If no DLT is observed at a dose of which 
the efficacy is considered sufficient, the SMC may decide to include an additional number of 

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patients at the same dose level and/or to declare this dose as the recommended dose for 
further development (RP2D). 
The SMC can declare any dose fulfilling the EWOC criterion as RP2D, independent of the 
MTD estimate.
BI 836880 and BI 754091 will be administered every 3 weeks. The study treatment can be 
continued until progressive disease, unacceptable toxicity, or other withdrawal criteria are
observed.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Dose levels and cohort size will be determined based on the recommendation of the SMC, 
guided by a BLRM with overdose control. An EWOC 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 an efficient method due to its ability to identify the dose 
with a desired toxicity rate and its allocation of a greater proportion of patients to doses at or 
close to that desired dose (R13-4802; R13-4804; R13-4805). The use of Bayesian models for 
Phase I studies has also been advocated by the European Medicines Agency (EMA) guideline 
on small populations (R07-4856) and by the United States Food and Drug Administration 
(FDA) (R13-4881).
The results from this trial will form the basis for decisions for future studies.
3.3
SELECTION OF TRIAL POPULATION
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
3.3.1
Main diagnosis for trial entry
Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic solid tumour
are the target population of this trial.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.

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3.3.2
Inclusion criteria
1. Of legal age (according to local legislation) at screening. No upper limit.
2. Signed and dated written informed consent in accordance with International Council on 
Harmonisation (ICH) Good Clinical Practice (GCP) and local legislation prior to 
admission to the trial.
3. Male or female patients. Women of childbearing potential (WOCBP)1 and men able to 
father a child must be ready and able to use highly effective methods of birth control per 
ICH M3 (R2) that result in a low failure rate of less than 1% per year when used 
consistently and correctly, starting with the screening visit and through 6 months after the 
last dose of study treatment. A list of contraception methods meeting these criteria is 
provided in the patient information. The requirement of contraception does not apply to 
women of no childbearing potential and men not able to father a child, but they must have 
an evidence of such at screening.
4. Patients with a confirmed diagnosis of advanced, unresectable, and/or metastatic solid 
tumours (any type). Measurable lesion not mandatory for participation in this trial. 
5. Patients with no therapy of proven efficacy, or who are not amenable to standard 
therapies
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
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, must 
be ≤ CTCAE grade 2 or considered not clinically significant.
8. Adequate organ function defined as all of the following (all screening labs should be 
performed at local lab within 10 days prior to treatment initiation):
Table 3.3.2: 1
Definition of adequate organ function
System
Laboratory Value
Hematological
Absolute neutrophil count 
(ANC)
≥1.5 x 109/L (≥1500/mm3)
Platelets
≥75 x 109/L (≥75,000/mm3)
Haemoglobin
≥9.0 g/dL
Renal
Serum creatinine OR
estimated glomerular filtration 
rate (eGFR) (Chronic Kidney 
Disease Epidemiology 
[CKD-EPI] Collaboration 
equation)
≤ 1.5 x upper limit of normal (ULN) OR
≥50 mL/min for patients with creatinine levels >1.5x ULN
(confirmation of eGFR is only required when creatinine is >1.5 X 
ULN)
Hepatic
Total bilirubin
≤1.5 times the upper limit of normal (ULN).
Aspartate aminotransferase 
(AST) and alanine 
aminotransferase (ALT)
≤2.5 x ULN OR ≤5 x ULN for patients with liver metastases.
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming 
post-menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.

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Coagulation

International Normalised Ratio 
(INR) or Prothrombin Time 
(PT)

≤1.5xULN. If the patient is receiving anticoagulant therapy, a 
prolonged INR or PT is acceptable as long as it is within 
therapeutic range of intended use of anticoagulants.

Activated Partial 
Thromboplastin Time (aPTT)

≤1.5xULN. If the patient is receiving anticoagulant therapy, a 
prolonged aPTT is acceptable as long as it is within therapeutic 
range of intended use of anticoagulants.
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. Known history of human immunodeficiency virus (HIV) infection. Test results obtained 
in routine diagnostics are acceptable if done within 14 days before the informed consent 
date.
3. Any of the following laboratory evidence of hepatitis virus infection. 
o
Positive results of hepatitis B surface (HBs) antigen
o
Presence of hepatitis B core (HBc) antibody together with hepatitis virus B (HBV) 
Deoxyribonucleic acid (DNA)
o
Presence of hepatitis virus C (HCV) Ribonucleic acid (RNA)
Test results obtained in routine diagnostics are acceptable if done within 14 days before 
the informed consent date.
4. History of severe known hypersensitivity reactions to other mAbs.
5. Immunosuppressive corticosteroid doses (>10 mg prednisone daily or equivalent) within 
4 weeks prior to the first dose of trial medication.
6. Any investigational or anti-tumour treatment within 4 weeks or 5 half-life periods 
(whichever is shorter) prior to the initiation of trial treatment.
7. 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 
(gastrointestinal tract, skin) or laboratory abnormality that may increase the risk 
associated with trial participation or trial drug administration, and in the judgment of the 
investigator would make the patient inappropriate for entry into the trial.
8. Major injuries and/or surgery or bone fracture within 4 weeks of start of treatment, or 
planned surgical procedures during the trial period.
9. Patients with personal or family history of QT prolongation and/or long QT syndrome, or 
prolonged QTcF (Corrected QT interval by Fredericia) at screening (>470 ms).
10. Significant cardiovascular/cerebrovascular diseases (i.e. uncontrolled hypertension, 
unstable angina, history of infarction within past 6 months, congestive heart failure >
NYHA [New York Heart Association] class II).
Uncontrolled hypertension is defined as follows: Blood pressure in rested and relaxed 
condition ≥140 mmHg, systolic or ≥90 mmHg diastolic (with or without medication), 
measured according to Appendix 10.3.
11. Left Ventricular Ejection Fraction (LVEF) <50% measured locally by echocardiography

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12. History of severe haemorrhagic or thromboembolic event in the past 12 months
(excluding central venous catheter thrombosis and peripheral deep vein thrombosis).
13. Known inherited predisposition to bleeding or to thrombosis in the opinion of the 
investigator.
14. Untreated brain metastasis(es) that may be considered active. Patients with previously
treated brain metastases may participate provided they are stable (i.e., without evidence of 
PD by imaging for at least 4 weeks prior to the first dose of trial treatment, and any
neurologic symptoms have returned to baseline), and there is no evidence of new or
enlarging brain metastases
15. Patients who require full-dose anticoagulation (according to local guidelines). No 
Vitamin K antagonist and other anticoagulation allowed; Low Molecular Weight Heparin 
(LMWH) allowed only for prevention not for curative treatment.
16. History (including current) of interstitial lung disease or pneumonitis within the last 5 
years.
17. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial
18. Patients not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled. (e.g. chronic alcohol or drug abuse or any other condition 
that, in the investigator’s opinion, makes the patient an unreliable trial participant).
19. Patients who were previously treated in this trial. 
20. Patients with haematological malignancies.
21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
Female patients of childbearing potential must have a negative urine or serum pregnancy 
test within 3 days prior to taking study medication. If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy 
test must be negative for the patient to be eligible. Women who are nursing can be 
enrolled if they stop nursing. In this case, the patient cannot resume nursing even after 
discontinuation of study treatment.
In this trial, patients with history of anti-PD-1 treatment will not be excluded, as it is 
considered that such patients still have chance to respond. Preclinical data showed 
modulation of immunosuppressive cells by an anti-VEGF treatment and enhancement of 
anti-tumour effect with the combination of VEGF, Ang2 and PD-1 inhibition.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole 
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.
Every effort should be made to keep the patients in the trial: if possible on treatment, or at
least to collect important trial data.
Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and the case report form (CRF). If the reason 

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for discontinuation is death, this should be reported on the serious adverse event (SAE) form 
as well, regardless of causal relationship. If applicable, consider the requirements for Adverse 
Event collection reporting (please see Sections 5.2.9.2.1 and 5.2.9.2).
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:

The patient wants to discontinue trial treatment, without the need to justify the decision.

The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.

The patient needs to use concomitant medication that interferes with the investigational 
medicinal product or trial assessments. Refer to Section 4.2.2.1 for prohibited 
concomitant medications.

The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy). Refer to Section 4.1.6 for AEs that require 
treatment discontinuation.

The patient experiences unequivocal PD by RECIST v1.1 and/or iRECIST (iRECIST 
applies to Part II only). Refer to Section 5.1.1 for details.
Even if the trial treatment is discontinued, the patient remains in the trial and, will undergo 
the procedures for the end of treatment (EoT) visit and follow up as outlined in the Flow 
Chart and Section 6.2.3.
For all patients the reason for withdrawal from trial treatment (e.g. AEs) must be recorded in 
the CRF. These data will be included in the trial database and reported.
During the dose finding part, patients withdrawn for a reason other than having a DLT or 
patients who miss more than one visit during MTD evaluation period may be replaced after 
discussion in the SMC if the information that needed to be collected during that visit is not 
available and makes the patient non-evaluable for the PK analyses or safety parameters
(including evaluation for DLTs).
Patients who come off trial due to a DLT will not be replaced.
If a patient should become pregnant during the trial, the study treatment must be immediately 
stopped. The patient will be followed up until delivery or termination of pregnancy (see 
Section 5.2.9.2.3 for information on pregnancy forms). The data of the patient will be 
collected and reported in the electronic case report form (eCRF) until the last patient’s last 
visit and any events occurring thereafter will be reported in the BI drug safety database.
3.3.4.2
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion 
with the patient and explain the difference between trial treatment discontinuation and 

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withdrawal of consent to trial participation, as well as explain the options for continued 
follow up after trial treatment discontinuation, please see Section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial 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. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct
of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).

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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
Details of the trial medications, BI 836880, and BI 754091, are presented in Tables 4.1.1: 1, 
and 4.1.1: 2. Additional details are presented in the BI 836880 and BI 754091 IB and the 
instruction for pharmacist.
Table 4.1.1: 1
BI 836880
Substance:
BI 836880
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml (vials with 10 ml)
Posology
rate controlled infusion on Day 1 of each 3-week 
cycle
Route of administration:
i.v.
Table 4.1.1: 2
BI 754091
Substance:
BI 754091
Pharmaceutical formulation:
Solution for infusion
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg /mL (15 mL vial)
Posology
rate controlled infusion on Day 1 of each 3-week 
cycle
Route of administration:
i.v.

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4.1.2
Selection of doses in the trial
4.1.2.1
Selection of dose in Part I
BI 836880 will be tested from a starting dose of 360 mg in every 3 week administration
schedule. The dose-finding will be guided by the BLRM, and the final decision will be made 
by the SMC (see Section 8.7)
BI 836880 monotherapy is currently tested in two phase I trials, trial 1336-0001 for every 3 
week administration schedule and trial 1336-0006 for weekly administration schedule, both 
conducted in Europe.
Since the RP2D was already defined in trial 1336-0001 and patient 
convenience, the every 3 week schedule will be used in this trial. The starting dose was 
selected based on the data obtained in trial 1336-0001. 
In trial 1336-0001, 29 patients were treated with BI 836880, at dose levels between 40 mg 
and 1000 mg. Amongst them 17 patients received BI 836880 at the recommended Phase 2 
dose (RP2D) of 720 mg (Table 4.1.2.1: 1). The majority of these patients were females 
(62.1%) with a median age of 57 years. The trial included 6 patients with pancreatic cancer, 4 
patients with breast cancer, 4 patients with colorectal cancer 3 patients with oesophageal
cancer, as well as other cancer types each represented by 1-2 patients. 
BI 836880 was well tolerated in this trial with 1 DLT (pulmonary embolism, CTCAE grade 
3) reported at the highest tested dose of 1000 mg. 
Table 4.1.2.1: 1
Number of evaluable patients and DLTs in trial 1336-0001
Dose level
BI 836880 dose
Number of evaluable patients
Number of DLTs
1
40 mg
2
0
2
120 mg
2
0
3
360 mg
2
0
4
720 mg
17
0
5
1000 mg
5
1
Total
-
28
1
As of August 2018, 47 patients were treated with BI 836880 monotherapy in trial 1336-0001 
or 1336-0006. 
Exploratory PK and Pd analysis was performed. BI 836880 plasma exposure is
dose-proportional over the dose ranges 40-1000 mg based on Cmax and partial AUCs. The 
gmean half-life over all dose groups was 197 hours (cycle 1, n=12), 238 hours (cycle 2, n=7), 
and 343 hours (cycle 4, n=4). The required trough values of 20 mg/L (according to preclinical 
experiments) could be achieved at dosages starting from 720 mg every 3 weeks.

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Biomarker analysis has shown complete systemic VEGF levels blocked at the lowest dose of 
40 mg. Systemic ANG2 levels were blocked dose-dependently showing complete inhibition 
at dosages starting at 360 mg. These inhibition remained before start of next treatment. 
Based on safety data as well as PK and PD analysis, the dose of 720 mg is selected as RP2D. 
The dose level of 360 mg, one level lower than RP2D, was also safe and showed complete 
inhibition of systemic targets, and will be used for the starting dose of the Part I of the current 
trial. 
4.1.2.2
Selection of dose in Part II
BI 836880 will be tested from a starting dose of 120 mg in every 3 week administration
schedule. The escalating dose of BI 836880 will be administered in combination with the 
dose of BI 754091 at 240 mg, which is also administered in every 3 week schedule. 
The starting dose of BI 836880 may be adapted via protocol amendment based on the most 
recent safety information from another ongoing trial, 1336-0011. As of 15 Oct 2018, one 
DLT was reported in the cohort of BI 836880 360 mg and BI 754091 240 mg cohort.
BI 754091 was tested in monotherapy in the dose-escalation part of trials 1381-0001 and 
1381-0004, which were conducted in North America and Japan respectively. 
In trial 1381-0001, a total of 9 patients received BI 754091 at 3 dose levels (80 mg, 240 mg 
and 400 mg) in the dose escalation cohorts. There were no DLTs or drug-related SAEs in any 
cohort. The most common reported AEs were nausea, fatigue, decreased appetite, 
constipation and arthralgia. Eight additional patients have been treated at dose of 240 mg in 
the expansion part of this trial. No grade 4, Grade 5 AE or DLT was reported.
The exploratory analysis of biomarker performed in these 9 patients shows 100% PD-1 
receptor occupancy in peripheral blood in all on-treatment patient samples compared to 
baseline throughout one treatment cycle. 
Plasma concentration of BI 754091 appears to increase in dose proportional manner (based 
on AUC0-504h, Cmax and Cpre). Furthermore, the observed BI 754091 PK was compared with 
model simulated pembrolizumab PK (R17-2460). Observed BI 754091 PK profiles overlap 
with those simulated for pembrolizumab at a dose of 200 mg.
The dose of 240 mg of BI 754091 once every 3 weeks was chosen to be further explored in 
monotherapy trials and is recommended as a starting dose in combination trials. 
In trial 1381-0004, a total of 6 Japanese patients received BI 754091 in the dose-finding part 
at 240 mg dose level, and none of them experienced DLT or drug related SAE.
4.1.3
Dose-finding scheme
The dose is planned to be tested in cohorts at pre-defined provisional dose levels. The 
provisional dose levels to be assigned to different cohorts of patients are listed in Table 4.1.3: 

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1 and 4.1.3: 2. Intermediate or lower dose levels may be investigated if agreed in the SMC, 
depending on the number of DLTs observed in the trial.
In Part II, increasing doses of BI 836880 will be administered in combination with BI 754091 
at 240 mg. The dose of BI 754091 may also be titrated based on DLTs and the overall safety 
profile of the combination.
Table 4.1.3: 1
Example of dose escalation in Part I*
Dose level
Proposed dose of BI 836880
Increment from previous 
dose
0
360 mg
Starting dose
1
720 mg*
100%
*Actual dose assignments for a cohort will be communicated separately as determined by the 
SMC. Intermediate dose level(s) may be investigated depending on the latest DLT rate 
estimate. Dose levels which are higher than the recommended dose in trial 1336-0001 (720 
mg) will not be investigated.
Table 4.1.3: 2
Example of dose escalation in Part II*
Dose level
Proposed dose of 
BI 836880
Proposed dose of 
BI 754091
Increment from 
previous dose
(BI 836880)
0
120 mg*
240 mg*
Starting dose
1
360 mg*
240 mg*
200%
2-a
500 mg*
240 mg*
39% (from 360 mg)
2-b
720 mg*
240 mg*
100% (from 360 mg)
*Actual dose assignments for a cohort will be communicated separately as determined by the 
SMC. Intermediate dose level(s) may be investigated depending on the latest DLT rate 
estimate. Dose levels which are higher than the recommended dose in trial 1336-0011 will 
not be investigated. For dose level 2, level 2-a or 2-b will be investigated based on the 
information from trial 1336-0011.
There will be no dose escalations of BI 836880 or BI 754091 in any one patient.
When the last patient in each cohort completes Cycle 1, the SMC will evaluate the available 
data. The SMC will review all safety data including, but not limited to, DLTs and all CTCAE 
Version 5 Grade ≥2 toxicity data during cycle 1. Updated safety data on other ongoing 
patients, including data beyond cycle 1, will be discussed as well. Based on that, a decision 
on the next dose level to be tested will be made.

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4.1.4
Method of assigning patients to treatment groups
There will be no randomisation in this trial, as it is a single-arm open-label trial. After 
assessment of all inclusion and exclusion criteria, each eligible patient will be assigned a dose 
of medication available at the time of enrolment.
To determine the dose or doses for subsequent cohorts, the available safety data (including
DLTs, AEs that are not DLTs, and AE information), as well as the recommendations from the
BLRM, will be evaluated by the SMC members.
The SMC must reach a consensus on whether to declare the MTD, escalate the dose any
further, or de-escalate and/or expand recruitment into particular cohorts. Dose-finding of BI 
836880 monotherapy in Part I will continue until the MTD is reached and/or RP2D is 
determined whichever occurs earlier. Similarly, dose-finding of BI 836880 and BI 754091 
combination in Part II will continue until the MTD is reached and/or RP2D is determined, 
whichever occurs earlier.
To further characterise the safety (e.g., specific suspected treatment-related AEs) or PK
profiles of BI 836880 monotherapy or BI 836880 plus BI 754091 combination, one or several 
doses may be expanded. Dose-finding may be terminated at any time based on emerging 
safety concerns without establishing the RP2D or the MTD.
4.1.5
Drug assignment and administration of doses for each patient
Patients will be assigned to their doses based on the available toxicity information (including 
DLTs, AEs that are not DLTs, and AE information post MTD evaluation period), PK, and 
anti-tumour activity information, as well as the recommendations from the SMC members 
following the dose decision meeting, please see Section 4.1.2.
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.
The study treatment will be administered by authorized site staffs 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”. Appropriate drugs and 
medical equipment to treat anaphylactic reactions must be immediately available and study 
personnel must be trained to recognize and treat anaphylaxis.
No premedication will be required for BI 836880 infusion or BI 754091 infusion. If a patient
had signs or symptoms 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 per os (p.o. [oral]), or equivalent

Antihistamine p.o. or i.v., equivalent to Diphenhydramine 50 mg i.v.

Glucocorticoid i.v., equivalent to prednisolone 100 mg

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The expected infusion time is about 60 minutes for BI 836880 and the same for BI 754091. In 
case no relevant infusion reactions are observed, the infusion time for BI 836880 can be 
shorten to about 30 minutes, but the infusion time for BI 754091 should be kept at about 60 
minutes. The duration of infusion should not be prolonged to more than 6 hours for BI 
836880, and more than 3 hours for BI 754091.
If symptoms of an infusion-related reaction CTCAE grade ≤2, but not qualifying as DLT 
according to Section 4.1.7 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 cycles should be adapted according to Investigator 
decision.
In the combination treatment, BI 836880 and BI 754091 will be given as two separate 
consecutive intra-venous infusions. BI 754091 should be administered first, and BI 836880 
will be administered approximately 15 minutes after the end of this infusion of BI 754091.
4.1.6
Dose modifications
Before initiating a new treatment cycle, the actual health status will be assessed according to
Flow Chart and described in Section 5.2. To continue treatment with further cycles, all of the 
following retreatment criteria must be met:

No uncontrolled hypertension (according to Exclusion-Criterion #10)

QTcF <=470 ms (according to Exclusion-Criterion #9)

Acceptable tolerability (in case of an adverse event at the planned start of a treatment
cycle 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 the administration of 
study drug(s) should be delayed. Any case of a delay in treatment cycle for more than 2 
weeks should be communicated to the study team at Boehringer Ingelheim. The investigator 
in agreement with the BI study team will decide about further treatment of individual patient, 
based on known risk/benefit of BI 836880 and BI 754091.
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.
Administration of trial drugs has to be stopped temporarily in case of a DLT (see Section
4.1.7). Patients may resume the treatment only after recovery from DLT to at least fulfil 
retreatment criteria. The future dose of BI 836880 must be a tested dose which is one dose 
level below the dose received by the patient. The dose level for treatment resumption should 

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be as prescribed in Table 4.1.6: 1. Treatment has to be discontinued in case the DLT is not 
reversible.
If a patient develops an interstitial lung disease, the treatment has to be discontinued.
Table 4.1.6: 1
Dose reduction recommendations for BI 836880
BI 836880 received dose 
BI 836880 reduced dose 
720 mg
360 mg
360 mg 
120 mg
120 mg
120 mg (no change)
Dose reduction for BI 754091 is not allowed. The dose of BI 754091 may be delayed for a 
patient for one cycle, plus an additional 3 weeks (i.e. for up to 6 weeks), because of AEs 
following discussion with the sponsor.
In combination treatment arms, both drugs (BI 836880 and BI 754091) will be stopped,
paused, or re-exposed together unless an AE can be attributed to either BI 836880 or
BI 754091. Only if a causal relationship to one trial drug can be unequivocally established,
the other trial drug may be continued.
4.1.7
Dose limiting toxicities
DLTs will be recorded throughout the trial, and should be reported to the sponsor (AESIs, see 
Section 5.2.9.1.4) within 24 hours of first knowledge. 
Any of the following AEs will be reported as potential DLTs, and will be classified as DLTs
following review by the Investigators and the sponsor, unless unequivocally due to 
underlying malignancy or an extraneous cause.
DLTs observed during the MTD evaluation period will be considered for MTD 
determination. However, all AEs and SAEs meeting criteria of DLT observed in all treatment 
cycles will be considered for determining a Recommended Phase 2 Dose (RP2D)
Haematologic toxicities:

Any Grade 5 toxicity

Neutropenia Grade 4 lasting for >7 days

Grade ≥3 documented infection with neutropenia

Febrile neutropenia (absolute neutrophil count <1.0 X 109 cells/L and fever ≥38.5°C or a 
sustained temperature of ≥38.0°C for more than 1 hour)

Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding

Thrombocytopenia of any Grade which requires platelet transfusions

Grade 4 anaemia unexplained by underlying disease

Anaemia of any Grade which requires blood transfusions

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Non-haematological toxicities:

AST or ALT >3 times ULN and concurrent total bilirubin >2 times ULN without initial 
findings of cholestasis

≥ Grade 4 AST or ALT of any duration

Any ≥ Grade 3 non-haematologic toxicity with the following exceptions:
o
Grade 3 irAE that resolves to ≤ Grade 1 or to baseline with immunosuppressive 
therapy within 2 weeks
o
Grade 3 fatigue that persists <7 days
o
Grade 3 rash that resolves to ≤ Grade 1 within 2 weeks
o
Grade 3 or 4 elevation in serum amylase and/or lipase that is not associated with 
clinical or radiographic evidence of pancreatitis
o
Grade 3 electrolyte abnormality that lasts <72 hours, is not clinically complicated, 
and resolves spontaneously or responds to conventional medical intervention
o
Grade 3 nausea or vomiting that lasts <48 hours, and resolves to ≤ Grade 1 either 
spontaneously or with conventional medical intervention
o
Alopecia
o
Grade 3 asymptomatic endocrine disorders (thyroid, pituitary, and/or adrenal 
insufficiency) that are sufficiently managed with or without systemic 
corticosteroid therapy and/or hormone replacement therapy.
o
Grade 3 tumour flare

Any Grade 4 or 5 AE other than disease progression

Any Grade 2 pneumonitis of any duration

Any Grade 2 uveitis, eye pain, or blurred vision that does not respond to topical therapy 
and does not improve to Grade 1 severity within 2 weeks or requires systemic treatment

Any ≥ Grade 2 toxicity that persists and results in > 14 days delay of administration of 
study medication (BI 836880 in Part I, BI 836880 and BI 754091 in Part II) on Cycle 2 
Day 1

Hypertension: systolic blood pressure >160 mm Hg or diastolic blood pressure >100 mm 
Hg, confirmed by second measurement of an additional set of 3 BP measurements, or 3 
sequential ambulatory blood pressure measurements when indicated (e.g. white coat 
effect), which cannot be controlled by hypertensive medication and requires a dose 
reduction/discontinuation of trial medication(s). Refer to Section 10.3 for details of the 
assessment of blood pressure

Grade >3 proteinuria (urinary protein >3.5 g/day). Refer to Section 5.2.4.4 for the 
assessment of proteinuria
NOTE: Any laboratory abnormality which is considered not clinically relevant by the 
investigator or resolves spontaneously, or resolves with appropriate treatment is not a DLT. 
Clinically relevant abnormalities must be documented as AEs.
Late immune-related DLTs are irAEs that meet the same grading criteria as DLT criteria, but 
occur after Cycle 1 administration during Part 1. These, as well as all toxicities will be 
monitored throughout the trial. If any late immune-related DLT is reported during 
dose-escalation, the BLRM will be rerun including the late immune-related DLT, and 
updated results will be reviewed in the SMC meeting to recommend the next dose level and 
cohort size.

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4.1.8
Definition of evaluable patient
For decisions on dose escalation, an evaluable patient is defined as a patient who has received 
BI 836880 or BI 836880 plus BI 754091 and either:

has completed cycle 1 without experiencing DLT
OR

has experienced DLT during cycle 1
4.1.9
Blinding and procedures for unblinding
4.1.9.1
Blinding
Not applicable, as this is an open-label, single-arm trial.
4.1.9.2
Unblinding and breaking the code
Not applicable
4.1.10
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI or a designated Contract 
Research Organisation (CRO). They will be packaged and labelled in accordance with the 
principles of Good Manufacturing Practice (GMP). Re-supply to the sites will be managed 
via an Interactive Response Technology (IRT) system, which will also monitor expiry dates 
of supplies available at the sites.
For details of packaging and the description of the label, refer to the ISF.
4.1.11
Storage conditions
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 Clinical Research 
Associate (CRA) must be contacted immediately.
4.1.12
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor 
when the following requirements are fulfilled:

Approval of the clinical trial protocol (CTP) by the Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC),

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site,

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
Approval/notification of the regulatory authority, e.g. competent authority (CA),

Availability of the curriculum vitae of the Principal Investigator,

Availability of a signed and dated CTP
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the CTP and reconcile all investigational 
medicinal products received from the sponsor. At the time of return to the sponsor, the 
investigator or designee must verify that all unused or partially used drug supplies have been 
returned by the clinical trial patient and that no remaining supplies are in the investigator’s 
possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no other mandatory treatments to be used or special emergency procedures to be 
followed.
Potential side effects of BI 836880 or BI 754091 have to be treated symptomatically. 
Symptomatic treatments of side effects or tumour-associated symptoms are allowed.
4.2.1.1
Permitted concomitant medications

If medically feasible, patients taking regular medication should be maintained on it
throughout the trial.

Pre-medication is not required, but may be utilised following the first dose of study 
medication. This includes medications for the management of nausea, diarrhoea, and 
vomiting for which the patient must be treated according to institutional standards.

Supportive care and other medications that are considered necessary for the patient’s
well-being may be given at the discretion of the Investigator.

Blood transfusions are allowed at any time during the trial, except to meet inclusion
criteria.

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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment

No other investigational therapy or anticancer agent should be given to patients. If such
agents are required for a patient, then the patient must first be withdrawn from the trial.

Immunosuppressive medications including, but not limited to systemic corticosteroids at
doses exceeding 10 mg/day of prednisone or equivalent, methotrexate, azathioprine, and
tumour necrosis factor-alpha blockers are prohibited. Use of immunosuppressive
medications for the management of investigational product-related AEs or in patients
with contrast allergies is acceptable, and does not necessarily warrant immediate
treatment discontinuation. In addition, use of inhaled, topical, intranasal corticosteroids 
or local steroid injections (e.g., intra-articular injection) is permitted. Temporary uses of
corticosteroids for concurrent illnesses (e.g., food allergies, computed tomography [CT] 
scan contrast hypersensitivity) are acceptable.

Live attenuated vaccines are prohibited during the trial through 30 days after the last 
dose of investigational product.

Patients already receiving erythropoietin at the time of screening for the trial may
continue it, provided they have been receiving it for more than one month at the time trial
treatment is started. Prophylactic erythropoietin should not be started during the first 3 
weeks of any cohort, but may be started thereafter.
In Japan, no erythropoietin product is approved for anaemia associated with cancer 
chemotherapy.

Prophylactic granulocyte colony stimulating factors, and palliative radiotherapy are not 
allowed during the first 3 weeks.

For symptom control, palliative radiotherapy is permitted for any lesion, except during 
the first cycle as it could interfere with the DLT evaluation for MTD/RP2D 
determination. Lesions that have been exposed to radiotherapy are no longer evaluable, 
and may not be included in the assessment of the non-target lesions and the overall 
assessment. These lesions may also not be used for a trial biopsy.

Full-dose anticoagulation (according to local guidelines) with Vitamin K antagonist and 
other anticoagulation are not allowed during the trial conduct; LMWH is allowed only 
for prevention but 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
There is no restriction on diet and life style.

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4.2.2.3
Contraception requirements
Women of childbearing potential and men able to father a child must use highly effective 
methods of birth control per ICH M3 (R2) 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.
4.3
TREATMENT COMPLIANCE
BI 836880 and BI 754091 will be administered by i.v. infusion at the sites by the Investigator
and/or trained site personnel, and dosing will be recorded in the eCRF. Therefore, actual
dosing is expected to precisely follow the prescribed drug regimen. Missed or interrupted
doses will be recorded in the eCRF with the associated reasons. The method of collecting
dosing information assures that total exposure can be calculated programmatically taking into
account any missing doses.

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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
5.2
ASSESSMENT OF SAFETY
The safety of BI 836880 and BI 754091 will be assessed by a descriptive analysis of 
incidence and severity of AEs graded according to CTCAE (Version 5), the incidence of 
DLTs, laboratory data, and results of physical examinations.
DLTs observed during the MTD evaluation period will be considered for MTD determination. 
However, all DLTs observed in all treatment cycles will be collected and will be considered 
for determining a RP2D. The BLRM will be re-run including the DLT information from all 

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cycles. Based on both estimates, the recommended dose for further development will be 
selected. If there are too few or no DLTs for BLRM guided dose selection, other data will be 
taken into consideration for RP2D determination.
5.2.1
Physical examination
A complete physical examination (including cardiac, neurological, dermatological, 
pulmonological examination) will be performed at the time points specified in the Flow 
Chart. 
The physical examination will include measurement of height (screening only) and of body 
weight.
5.2.2
ECOG performance status
The ECOG performance status will be assessed at the times indicated in the Flow Chart.
5.2.3
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling (if applicable).
This includes systolic and diastolic blood pressure, pulse rate, arterial oxygen saturation 
(SpO2), and body temperature. The results must be included in the source documents 
available at the site.
At days of administration blood pressure and pulse rate will be evaluated at the following
time points:
Part I
1.
pre-dose (-60 min. to -5 min.), before infusion of BI 836880
2.
5 to 10 minutes after infusion of BI 836880.
Part II
1.
pre-dose (-60 min. to -5 min.), before infusion of BI 754091
2.
5 to 10 minutes before infusion of BI 836880,
3.
5 to 10 minutes after infusion of BI 836880.
Blood pressure and pulse rate
Systolic and diastolic blood pressure as well as pulse rate (electronically or by palpation, 
count for 1 minute) should be measured after a 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. The mean value will be used for clinical decision. 
Further details on the procedure for blood pressure measurements are given in Appendix 
10.3.

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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 
common clinical practice. 
Body temperature measurements > 38°C must be re-assessed after 1 hour, especially in cases 
where febrile neutropenia is suspected.
5.2.4
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, and will be analysed by the site's 
local safety laboratories. The laboratory tests should be more frequent in case of relevant 
findings, e.g. in case of grade 4 neutropenia, which will be counted as DLT if not recovered
within 7 days, or proteinurea, for which determination of CTCAE grade 2 or grade 3 need to 
be done by quantitative measurement, or grade 3 electrolyte abnormality, which will be 
counted as DLT if not recovered within 72 hours (see Section 4.1.7). Screening laboratory 
assessments performed within 72 hours of the first trial treatment administration are not 
required to be repeated on Cycle 1 Day 1. In cases where screening laboratory investigations 
have been performed >72 hours prior to the first trial treatment administration, the results of 
the new laboratory investigations performed within 72 hours of the first trial treatment 
administration must be available to confirm eligibility.
5.2.4.1
Hematology
Hemoglobin, white blood cell count with differential, platelets.
5.2.4.2
Biochemistry
Glucose, sodium, potassium, calcium, magnesium, inorganic phosphate, creatinine (and eGFR 
if creatinine is >1.5 x ULN), AST, ALT, alkaline phosphatase, lactate dehydrogenase (LDH), 
bilirubin, urea (or blood urea nitrogen [BUN]), total protein, albumin, uric acid, creatine 
kinase (CK), CK-MB, serum immunoglobulin levels (IgG, IgM, IgA, and IgE).
A thyroid panel (TSH, free T4, and free T3) will be done at the time of each standard 
biochemistry panel.
HBV, HCV, and HIV testing should be performed at screening unless test results obtained in 
routine diagnostics within 14 days before the informed consent date are available
Direct antiglobulin test have to be measured at screening and at occurrence of infusion related 
reactions.
Additionally, amylase and lipase should be analysed in case of symptoms of pancreatitis.

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5.2.4.3
Coagulation
Activated partial thromboplastin time (aPTT), prothrombin time (PT) or international 
normalised ratio (INR) where indicated (e.g. treatment with vitamin K antagonists)
5.2.4.4
Urinalysis
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 grade 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.
5.2.4.5
Pregnancy test
A serum pregnancy test needs to be obtained at the time points indicated in the Flow Chart in 
patients of childbearing potential.
5.2.5
Electrocardiogram
The 12-lead ECGs must be performed at the time points specified in the Flow Chart. The 
investigator or a designee will evaluate whether the ECG is normal or abnormal and assess 
clinical relevance. ECGs may be repeated for quality reasons and a repeated recording used 
for analysis. 
On the days of administration, ECG should be taken at two time points:
1. pre-dose (-60 min. to -5 min.)
2. shortly before the end of the infusion of trial medication.
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. 
Cardiac monitoring for patients presenting a QTc interval prolongation CTCAE grade ≥ 3 
shall be followed as follows: 
-
Continuous ECG monitoring until the QTc interval < 470 ms 
-
Cardiologist opinion for potential treatment of this event as soon as the QTc 
interval prolongation is observed. 
-
Cardiologist recommendation after QTc interval normalisation (< 470 ms) and 
potential follow-up. 
In order not to confuse ECG recording, PK samples should be taken after performing the 
ECG. Decision on patient’s eligibility will be taken based on Investigator medical opinion. 
Pathological ECG results will be recorded as AEs by the investigator.

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5.2.6
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.
5.2.7
Chest X-ray
A chest X-ray must be performed at the timepoints specified in the Flow Chart.
5.2.8
Other safety parameters
No assessment planned.
5.2.9
Assessment of adverse events
5.2.9.1
Definitions of AEs 
5.2.9.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
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.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):
Worsening of pre-existing conditions other than the underlying disease
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.9.1.2
Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe,
-
requires inpatient hospitalisation,
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity, 
-
is a congenital anomaly / birth defect,

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-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
-
AEs which possibly lead to disability will be handled as “deemed serious for any 
other reason”
5.2.9.1.3
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the electronic data capture (eDC)
system. A copy of the latest list of “Always Serious AEs” will be provided upon request. 
These events should always be reported as SAEs as described above.
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the time since the discontinuation of the trial medication and must be reported 
as described in Section 5.2.9.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
5.2.9.1.4
Adverse events of special interest
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.9.2.2.
In this trial, dose limiting toxicities, severe hypertension, immune-related adverse events, 
infusion-related reactions, and hepatic injury are considered as AESIs.
Dose limiting toxicities
All DLTs are considered to be AESIs, and must be reported as such. The definition of DLT is 
presented in Section 4.1.7.
Severe hypertension
A hypertensive episode will be considered an AESI if:

Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg which 
persist longer than 2 days despite either initiation of antihypertensive agent(s) in a 
patient without prior history of hypertension, or intensification / addition of new 
antihypertensive agents in a patient with prior history of hypertension.
Immune-related adverse events (irAEs) (Part II only)

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Immune-related AEs are AEs associated with immunotherapy treatments that appear to be
associated with the immune therapy’s mechanism of action, such as BI 754091 in this study.
These adverse reactions, which can be severe, may involve the gastrointestinal, skin, liver, 
endocrine, respiratory, renal, or other organ systems. The sponsor has defined a list of 
potential irAEs that could occur with BI 754091 (Appendix 10.1). These irAEs must be 
reported as AESIs. If an Investigator determines another event (not on the list) should be a 
potential irAE, the Investigator may also report that event as an AESI. 
Recommendations for the management of irAEs are presented in Appendix 10.2.
Infusion-related reactions
In the event of an infusion-related reaction ≤Grade 2, the infusion should be temporarily 
stopped. Upon recovery, it should be infused at 50% of the initial rate until completion of the 
infusion. In patients experiencing infusion-related reactions ≤ Grade 2, subsequent infusions 
may be administered at 50% of the initial rate.
If a patient experiences an infusion-related reaction, acetaminophen and/or an antihistamine 
(e.g., diphenhydramine) and/or corticosteroid or equivalent medication per institutional 
standard may be administered prior to subsequent infusions at the discretion of the 
Investigator for secondary prophylaxis of infusion-related reactions. If an infusion-related 
reaction is Grade 3 or higher in severity at any point during the study, treatment with BI 
836880 and/or BI 754091 will be permanently discontinued.
As with any mAb, allergic reactions to study medication administration are possible. 
Appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and trial personnel must be trained to recognize and treat anaphylaxis. 
The trial site must have immediate access to emergency resuscitation teams and equipment in 
addition to the ability to admit patients to an intensive care unit if necessary.
The following terms describe those events that are to be considered potential infusion-related 
AEs. Regardless of grade, these events are considered as AESIs and must be reported to the 
sponsor within 24 hours of the event:

Allergic reaction

Anaphylaxis

Cytokine-release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
If the Investigator determines that another event (not on the list) may be a potential infusion 
related AE, the Investigator may also report that event as an AESI.
Hepatic injury
A potential hepatic injury is defined by the following alterations of hepatic laboratory 
parameters in patients with normal aminotransferase levels at baseline: 

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
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3 fold ULN combined with an elevation of total bilirubin ≥2 fold 
ULN measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
A potential hepatic injury is defined by the following alterations of hepatic laboratory 
parameters in patients with abnormal aminotransferase levels of >ULN and ≤2.5 fold ULN at 
baseline: 

an elevation of AST and/or ALT ≥3 fold the baseline value combined with an elevation of 
bilirubin ≥2 fold the baseline value measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥10 fold the baseline value.
A potential hepatic injury is defined by the following alterations of hepatic laboratory 
parameters in patients with abnormal aminotransferase levels of >2.5 fold and ≤5 fold ULN 
at baseline (patients with liver metastases only):

an elevation of AST and/or ALT ≥2 fold the baseline value combined with an elevation of 
bilirubin ≥2 fold the baseline value measured in the same blood draw sample, or

aminotransferase (ALT, and/or AST) elevations ≥3 fold the baseline value.
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” provided in the eDC 
system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed
5.2.9.1.5
Intensity (severity) of AEs
The severity of adverse events should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.
5.2.9.1.6
Causal relationship of AEs
Medical judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, considering all 
relevant factors, including pattern of reaction, temporal relationship, de-challenge or 
re-challenge, confounding factors such as concomitant medication, concomitant diseases and 
relevant history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

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
Evidence that the event is reproducible when the drug is re-introduced.

No medically sound alternative aetiologies that could explain the event (e.g. 
pre-existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.9.2
Adverse event collection and reporting
5.2.9.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual patient’s end of trial: 
All AEs (serious and non-serious) and all AESIs.
•
After the individual patient’s end of trial: 
The investigator does not need to actively monitor the patient for new AEs but should 
only report any occurrence of cancer of new histology and trial treatment related SAEs 
and trial treatment related AESIs of which the investigator may become aware of by any 
means of communication, e.g. phone call. Those AEs should be reported on the BI SAE 
form (see section 5.2.9.2.2), but not on the CRF.
The rules for Adverse Event Reporting exemptions still apply, please see section 5.2.9.2.4.

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5.2.9.2.2
AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.9.2.3
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a patient has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of 
the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Pregnancy until 6 months after the last dose of study medication should be reported as a drug 
exposure during pregnancy.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B) as 
well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.9.2.4
Exemptions to SAE reporting
The outcomes “disease progression” / “progressive disease (PD)” / “relapse” / “resistant 
disease” are used to assess trial endpoints for the analysis of efficacy, and will be recorded on 
the appropriate page of the eCRF. 
If disease progression outcomes do not meet the standard seriousness criteria (see Section 
5.2.9.1.2), then they are exempt from AE reporting, and will only be recorded on the 
appropriate page of the eCRF. For example, asymptomatic disease progression detected on a 
routine scan would be exempt from AE reporting. However, if there is evidence suggesting a 
causal relationship between the study drug or study drugs and the progression of the 
underlying malignancy, the event must be reported as an SAE on the SAE Form and on the 
eCRF.

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If disease progression outcomes meet the standard seriousness criteria (see Section 5.2.9.1.2), 
they will in addition be recorded on the AE page in the eCRF as well as on the BI SAE form,
and the SAE reporting process will be followed.
Clinical symptoms and/or signs of PD will be recorded on the AE page in the eCRF. If signs 
and symptoms of “disease progression” / “progressive disease (PD)” / “relapse” / “resistant 
disease” of the patient's underlying malignancy meet the standard seriousness criteria, they 
will additionally be reported on the BI SAE form and SAE reporting procedures will be 
followed.
Exempted events are reviewed at appropriate intervals by sponsor following a pre-specified 
review plan.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Actual date and clock time of drug administration and exact time points of blood sampling
will be documented in the CRFs by the medical personnel. The actual drug administration
times and sampling times will be used for determination of pharmacokinetic parameters.
5.3.1
Assessment of pharmacokinetics
Pharmacokinetic profiles of BI 836880 (Part I and II) and BI 754091 (Part II) in plasma will 
be investigated after the first, second and fourth infusion cycle in Part I and the first and after 
the fourth infusion cycle in Part II. Standard plasma PK parameters as specified in Sections
2.1.3 and 2.2 will be calculated. Pharmacokinetic data may additionally be analyzed using 
population pharmacokinetic approaches. 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 standard operating procedure (SOP).
Exploratory pharmacokinetic analyses can be performed as necessary for safety review. In 
contrast to the final PK analysis, the exploratory analyses will be based on planned sampling 
times rather than on actual times; no supplementary subject information, e.g. on adverse 
events or concomitant medication, will be used in these analyses, and the outputs will not be 
validated. Minor discrepancies between interim and final results may therefore occur.
5.3.2
Methods of sample collection
The time points for collection of PK samples are given in Appendix 10.4. For quantification 
of analyte concentrations, approximately 3 mL of blood will be taken from a forearm vein 
into a blood drawing tube for each drug administered at the time points listed in the Appendix 
10.4. Details of the sample collection, preparation, storage and shipment are described in the 
laboratory manual.  
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the analyte and/or its 
metabolite(s) including anti-drug antibodies (if applicable) will be generated by these 
additional investigations. The study samples will be discarded after completion of the 

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additional investigations but not later than 5 years upon the final study report has been 
signed.

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5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic and 
pharmacodynamic parameters in an appropriate way. The scheduled measurements will allow 
monitoring of changes in vital signs, standard laboratory values, and ECG parameters that 
might occur as a result of administration of trial medication. The safety assessments are 
standard, are accepted for evaluation of safety and tolerability of an intravenously 
administered drug, and are widely used in clinical trials. The pharmacokinetic parameters and 
measurements outlined in Sections 2.1.3, 2.2, and 5.3 are generally used assessments of drug 
exposure. The biomarkers and pharmacodynamic parameters and measurements outlined in 
Section 5.4 are of exploratory nature only. The determination of the immunogenic response 
before or during treatment with NBEs is generally applied to monitor immunogenicity risks.

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients must comply with all inclusion and exclusion criteria prior to the patient 
participation in 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 cycle 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 cycle. In case the day of treatment administration (visit 1 of a cycle) is delayed, 
all subsequent visits of a cycle will be recalculated based on the actual date of treatment of 
the delayed cycle.
During the treatment phase, patients are required to be hospitalized under close surveillance 
with access to intensive care for at least 48 hours after the first administration of trial 
medication(s) 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 cycle of trial 
medication, 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 may
shorten the duration of surveillance to 8 hours for cycles 2, 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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the Flow Chart will be performed at the respective visits.
Specific details to conduct of physical examination, collection of vital signs (including blood 
pressure measurement), laboratory investigations, assessment of ECG and echocardiography 
can be found in the subsections of Section 5.2.
Procedure for collection of blood samples for PK, 
 are given in Sections 
5.3 and 5.4.
A more detailed overview of collection of blood samples for PK, 
is 
given in Appendix 10.4.

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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 
specified in the Flow Chart. Prior to any other study related procedure, written informed 
consent must be obtained from the patient.
Baseline Conditions
Demographics (sex, birth date, race, and ethnicity where allowed), information on tobacco
and alcohol use, and baseline conditions will be collected during the screening visit.
Medical History of cancer:
History of the patient’s cancer will be obtained. The type of cancer, the date of the first 
histological diagnosis (month and year may be sufficient), and the primary tumour site will 
be reported on the eCRF. The differentiation grade (not specified, undifferentiated, poorly 
differentiated, moderately differentiated, well differentiated) obtained at the time of diagnosis 
and the location of metastatic sites as well as the stage according to the tumour, (lymph) 
node, and metastasis (TNM) classification will be provided as obtained at diagnosis and at 
trial screening. Previous surgeries will be reported.
Previously administered chemotherapy, tyrosine kinase inhibitor treatment, vaccine therapy, 
antibodies therapy, immune therapy, and hormone therapy will be reported, including start 
and end dates (month and year may be sufficient), as well as whether therapy was given as 
neoadjuvant, adjuvant, or palliative therapy. The date of tumour progression after previous 
lines of treatment will be recorded, if known.
Baseline information relevant to the disease history such as PD-L1 expression level, 
microsatellite instability (MSI), and tumour mutation burden (TMB) information will be 
collected in eCRF where available.
Other Medical History:
Past diseases and/or concomitant diagnoses relevant to patient's safety during the trial as 
judged by the Investigator will be recorded in eCRF.
Concomitant Medications:
Past medications relevant to patient's safety during the trial as judged by the Investigator will 
be recorded in eCRF. From the date of signature of the ICF, all concomitant medications will 
be recorded
6.2.2
Treatment period(s)
Please refer to the Flow Chart for a detailed presentation of each visit during the treatment 
period.

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6.2.3
Follow-up period and trial completion
6.2.3.1
End of treatment (EoT) visit 
The EoT visit will be performed as soon as possible but no later than 7 days after permanent 
discontinuation of the trial medication for any reason or e.g. when the Investigator decided 
with the patient to permanently discontinue the trial medication or became aware that the trial 
medication had been terminated.
The assessments of the EoT visit will then be performed instead of at the next planned visit. 
If the patient finishes active treatment without having PD, tumour assessment/imaging must 
be performed at the time of EoT, unless it has been done within the past 4 weeks.
6.2.3.2
Safety follow-up visit
The safety follow-up visit is performed 42 (+3) days after the last administration of trial 
medication(s). The information collected at this visit must include all new AEs that occurred 
after the EoT visit, and a follow-up of AEs ongoing at EoT.
A patient will be considered as having completed the trial when any of the following applies:

Completion of safety follow-up visit

Lost to follow-up

Withdrawal to be followed-up

Death

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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
7.1.1
Statistical design – Part I (BI 836880 monotherapy dose finding part)
Part I of the trial will be designed as an open label study. The objective of the design is to 
determine the MTD defined as the highest dose with less than 25% risk of the true DLT rate 
being equal or above 0.33 (EWOC criterion). The part I dose-finding will be guided by a 
Bayesian 2-parameter logistic regression model with overdose control (R13-4806; 
R13-4803).
The model is formulated as follows:
logit(πd) = log(α) + β*log(d/d*), 
where logit(π) = log(π/(1-π)).
πd represents the probability of having a DLT in the MTD evaluation period at dose d, d* = 
720 mg 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.
The estimated probability of a DLT at each dose level from the model will be summarized 
using the following intervals:
Underdosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over toxicity: [0.33, 1.00]
The BLRM-recommended dose for the next cohort is the level with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33] among the doses 
fulfilling EWOC. Applying the EWOC criterion it should be unlikely (<25% posterior 
probability) that the DLT rate at that dose will exceed 0.33. 
The MTD may be considered reached if one of the following criteria is fulfilled:
1.
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33] of the 
MTD is above 0.5, OR
2.
At least 9 patients have been treated in this part, of which at least 6 at the MTD.
The SMC may recommend stopping the dose finding phase after the criterion for MTD is 
fulfilled. Further patients may be included to confirm this MTD estimate. If no DLT is 
observed at a dose of which the efficacy is considered sufficient, the SMC may decide to 
include additional number of patients at this dose level and to declare this dose as the dose 
recommended for further testing.
Since a Bayesian approach is applied, a prior distribution f(θ) for the unknown parameter 
vector θ needs to be specified.

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The prior distribution for θ will be specified as a mixture of two bivariate normal 
distributions, 
f(θ) = a1f1(θ) + a2f2(θ)
with
ai, i = 1, 2 the prior mixture weights (a1+ a2 = 1)
and
fi(θ) = MVN(μi, Σi)
the multivariate normal distribution of the i-th component with mean vector μi and covariance 
matrix Σi, where 
Σ = 
	
,
 , ,		
 , ,		
	
,		

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust.
Prior derivation:
To determine the prior distribution for θ, a meta-analytic predictive (MAP) approach will be 
used. Toxicity information on BI 836880 from the 1336-0001 is available. Exact details on 
the derivation of the prior distributions and on the evaluation of the model using hypothetical 
data scenarios and operating characteristics are provided in the statistical appendix, i.e., 
Section 10.5.1, a brief description is given here. 
The historical data for 1336-0001 phase I as of 20 July2018 can be found in Table 7.1.1: 1.
Table 7.1.1: 1
Historical data from 1336-0001 as of 20 July2018
Dose BI 836880 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
40
2
0
120
2
0
360
2
0
720
17
0
1000
5
1
The following steps were performed to derive the prior distribution for θ:
-
The MAP prior was derived using the information in Table 7.1.1: 1 allowing for 
moderate to substantial between-trial heterogeneity. This mixture component was 
assigned 90% mixture weight.
-
A second, weakly informative component was added with 10% mixture weight. The 
weakly informative prior was derived to reflect a prior assumption that the median 
DLT rate at the starting dose of 360 mg would equal 10% and median DLT rate at 
720 mg would equal 60%. 

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The prior distributions are given in Table 7.1.1: 2. The corresponding prior probabilities of a
DLT at different doses and the corresponding probability of underdosing, targeted dosing, 
and overdosing are shown in Table 7.1.1: 3.
Table 7.1.1: 2
Prior distribution
Parameter
Means, standard deviations, 
correlation
Mixture weight
θ: component 1
(-2.263,0.116), 
(0.677,0.946), -0.076
0.9
θ: component 2
(0.405, 1.323), (2,1), 0
0.1
Table 7.1.1: 3
Prior probabilities of DLTs
Dose
Probability of true DLT rate in
Quantiles
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
StD
2.5%
50%
97.5%
360 mg
0.925
0.049
0.026
0.069
0.109
0.000
0.041
0.336
720 mg
0.751
0.169
0.080
0.154
0.176
0.027
0.100
0.844
The prior may be updated once the trial has started in case new data that can be used will be 
available. The prior that is used for each BLRM analysis for the SMC meetings will be 
documented in the SMC minutes, the prior used for the final analysis will be documented in 
the Trial Statistical Analysis Plan (TSAP).
7.1.2
Statistical design – Part II (BI 836880 and BI 754091 combination dose 
finding)
Part II of the trial will be performed as an open label single arm study. The primary objective 
of the design is also to determine the MTD in Japanese patients of BI 836880 in combination 
with BI 754091. To determine the MTD, patients are entered sequentially into escalating dose 
cohorts. The dose-finding will be guided by a Bayesian 5-parameter logistic regression model 
with overdose control. The model is defined as follows. Let π1,d1 be the probability of 
having a DLT when giving dose d1 of BI 836880 as monotherapy, and π2,d2 the probability of 
having a DLT when giving dose d2 of the combination partner BI 754091 as monotherapy, 
respectively. A logistic regression model is used to model the dose-toxicity relationship for 
each component individually: 
BI 836880 part: 
logit(π1,d1) =log(α1) + β1log(d1/d1*)
BI 754091 part:
logit(π2,d2) =log(α2) + β2log(d2/d2*)

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where logit(π) = log(π /(1- π)), the reference doses d1*=500 mg and d2*=240 mg are set for 
BI 836880 and BI 754091, respectively.
Assuming no toxicity interaction between the two compounds, the probability of a DLT when 
giving the combination of dose d1, d2 is obtained as 
π0
12,d1,d2 = π1,d1 + π2,d2 - π1,d1π2,d2
with corresponding odds
odds(π0
12,d1,d2)= π0
12,d1,d2 /(1- π0
12,d1,d2)
In order to account for a potential positive (higher toxicity than expected under 
independence) or negative (lower toxicity than expected under independence) interaction 
between BI 836880 and BI 754091, a dose-dependent interaction term -∞<η<∞ is introduced 
to the model by the following definition:
odds(π12,d1,d2) = odds(π0
12,d1,d2) exp(η d1/d1* d2/d2*)
and π12,d1,d2 is used in the likelihood
rd1,d2 ~ Binomial(nd1,d2,π12,d1,d2)
where rd1,d2 denotes the variable describing the observed number of DLTs from nd1,d2 patients 
at the dose combination d1, d2.
Since a Bayesian approach is applied, prior distributions f for each of the parameter vectors 
θ1=(log(α1),log(β1)), θ2=(log(α2),log(β2)) and for the interaction term η need to be specified.
The prior distributions for θ1 and θ2 will be specified as mixtures of two multivariate normal 
distributions, i.e.
f(θk) = a1,k f1(θk) + a2,k f2(θk) 
with
a1,k, a2,k the prior mixture weights, k=1,2 and 
fi(θk) = MVN(μik, Σik) (k=1,2),
the multivariate normal distribution of the i-th component with mean vector μik and 
covariance matrix Σik, where 
Σ = 
2 ,11
 ,11 ,22
 ,11 ,22
2 ,22

Mixture prior distributions have the advantage that they allow for specification of different 
logistic dose-toxicity curves, therefore making the prior more robust. 
A meta-analytic approach will be used for the prior specification of η.
The estimated probability π12,d1,d2 of a DLT at each dose combination d1, d2 from the model 
will be summarised using the following intervals:
Under dosing: [0.00, 0.16)
Targeted toxicity: [0.16, 0.33)
Over dosing: [0.33, 1.00]

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The BLRM-recommended dose for the next cohort is the level with the highest posterior 
probability of the DLT rate falling in the target interval [0.16, 0.33) among the doses 
fulfilling EWOC. Applying the EWOC criterion it should be unlikely (<25% posterior 
probability) that the DLT rate at that dose will exceed 0.33. 
As described The MTD may be considered to be reached if one of the following criteria is 
fulfilled:
1.
The posterior probability of the true DLT rate in the target interval [0.16 – 0.33) of 
the MTD is above 0.5, OR
2.
At least 9 patients have been treated in the study, of which at least 6 at the MTD.
Prior derivation:
To determine the prior distributions for θ1, θ2 and η a meta-analytic predictive (MAP) 
approach will be used. Toxicity information on BI 836880 monotherapy from the study 
1336-0001, and the Part 1 of this study, toxicity information on BI 754091 monotherapy from 
the studies 1381-0001 and 1381-0004, and toxicity information on the combination of BI 
836880 and BI 754091 from study 1336-0011 will be incorporated. Exact details on the 
evaluation of the model using hypothetical data scenarios and operating characteristics are 
provided in the statistical appendix; a brief description is given here. 
The historical data for BI 836880 can be found in Table 7.1.1: 1. For BI 754091, the 
historical data can be found in Tables 7.1.2: 2 and 7.1.2: 3. Expected historical data for the 
combination of BI 836880 and BI 754091 can be found in Table 7.1.2: 4. Since data from 
1336-0012 Part 1 and 1336-0011 were not yet available by the time of finalization of the 
CTP, data as is might be observed in future in these trials will be used as dummy data. This 
dummy data will be replaced by actual data as soon as it becomes available. Whenever 
BLRM calculations are performed for Part 2 of 1336-0012, all available information will be 
used and the resulting prior distribution will be documented.
Table 7.1.2: 1
Hypothetical data expected from 1336-0012 part 1
Dose BI 836880 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
360
6
1
720
3
2
Table 7.1.2: 2
Preliminary data from 1381-0001
Dose BI 754091 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
80
3
0
240
34
0
400
3
0

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Table 7.1.2: 3
Preliminary data from 1381-0004
Dose BI 754091 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
240
6
0
Table 7.1.2: 4
Hypothetical data expected from 1336-0011
Dose BI 836880 (mg) / BI 
754091 (mg)
N of patients treated
N of patients with DLTs 
during MTD evaluation 
period
360 / 240
1
1
500 / 240
0
0
720 / 240
0
0
The following steps were performed to derive the prior distribution for Part 2:
1) The meta-analytic predictive prior was derived for both compounds and for the 
interaction parameter η using the information in Tables 7.1.2: 1 – 7.1.2: 4, allowing 
for moderate to substantial between-trial heterogeneity, tau parameters are assumed 
to be normally distributed with mean log(0.25) and SD log(2)/1.96. See a reference 
(R18-3210) for details on the MAP prior. These prior components were assigned 90% 
mixture weight for both compounds.
2) A second, weakly informative prior component was added with the same mean values 
as the MAP prior, standard deviation (2, 1) and correlation 0. This mixture component 
was assigned 10% mixture weight
The resulting parameters of the prior distributions for four combination levels, i.e., (120/240, 
360/240, 500/240, 720/240), are given in Table 7.1.2: 5. The corresponding prior 
probabilities of a DLT at different dose combinations and the corresponding probabilities of 
under toxicity, targeted toxicity and over toxicity are shown in Table 7.1.2: 6. As can be seen 
from Table 7.1.2: 6, the dose combination 120 mg BI 836880 and 240 mg BI 754091 has 
prior probability of over toxicity below 25%. It fulfils the overdose criterion and is therefore 
a suitable starting dose combination.

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Table 7.1.2: 5
Prior Distribution
Parameter
Prior distributions
Means, standard deviations, 
correlation
Mixture weight
log(α1), log(β1): component 1
(-1.877,-0.574), (0.983, 0.893), 
-0.145
0.9
log(α1), log(β1): component 2
(-1.877,-0.574), (2,1), 0
0.1
log(α2), log(β2): component 1
(-1.500, 1,213), (1.070, 1.034), 0.387
0.9
log(α2), log(β2): component 2
(-1.500, 1,213), (2,1), 0
0.1
η
0.466, 0.989
N/A
Table 7.1.2: 6
Prior probabilities of DLTs
Dose 
(mg)
Dose 
(mg)
Probability of true DLT rate in
Descriptive 
statistics
BI 
836880
BI 
754091
[0,0.16)
[0.16,0.33)
[0.33,1]
Mean
SD
2.5%
50%
97.5%
120
240
0.486
0.327
0.187
0.209
0.162
0.023
0.165
0.637
360
240
0.280
0.311
0.409
0.318
0.213
0.035
0.273
0.814
500
240
0.134
0.213
0.653
0.468
0.255
0.059
0.454
0.933
720
240
0.077
0.100
0.822
0.680
0.299
0.065
0.774
1.000
The prior will be updated once the trial has started in case new data that can be used will be 
available. The prior that is used for each BLRM analysis for the SMC meetings will be 
documented in the SMC minutes, the prior used for the final analysis will be documented in 
the TSAP.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal hypothesis testing is planned in this trial. All analyses in this trial are descriptive 
and exploratory.
7.3
PLANNED ANALYSES
No per protocol set will be used in the analysis. However, important protocol deviations will 
be summarised. The TSAP will specify the important protocol deviations in detail.
For the determination of the MTD, only MTD evaluable patients will be considered. For the 
analysis of secondary and further endpoints, all patients in the treated set (i.e. patients treated 
with at least one dose of trial medication) will be included in the analysis. Any other analysis 
sets will be defined in the TSAP.

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7.3.1
General considerations
Treated set includes all patients who were treated with at least one dose of trial medication. 
The pharmacokinetic parameters listed in Sections 2.1.3 and 2.2.2 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). PK analyses will be performed 
using validated software programs, normally, Phoenix WinNonlin 
 with 
applications validated for the respective purpose. Graphs and tables will be generated using 
validated customised 
macros or appropriate graphic software.
7.3.2
Primary endpoint analyses
In order to identify the MTD, the number of patients with DLTs during the MTD evaluation 
period of Part I and Part II at each dose level must be presented. Patients who discontinue 
during the first treatment course for reasons other than DLTs will be excluded from the 
determination of MTD. 
In addition, the number of patients with DLTs that occurred during the entire treatment 
period will be also summarised.
7.3.3
Secondary endpoint analyses
Please refer to Section 2.1.3 for PK related secondary endpoints. Details on the statistical 
inference for PK parameters, e.g., dose proportionality using Cmax and AUC0-504h of BI 
836880 in case of more than 3 dose level tested, will be specified in the TSAP.
7.3.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities 
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 42 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.

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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 MedDRA
at database lock.
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 summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of patients with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.6
Interim Analyses
No formal interim analysis is foreseen.
The sponsor will continuously monitor the safety. The dose escalation design foresees that 
the sponsor and the SMC perform regular safety evaluations. These evaluations will be 
unblinded to dose.
If considered necessary, an evaluation of the efficacy and 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.
Regarding exploratory PK analysis, please refer Section 5.3.1.
7.4
HANDLING OF MISSING DATA
In general, no imputation will be performed on missing efficacy data. Detailed censoring 
rules will be specified in the TSAP. 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 AEs, 
with particular emphasis on potential DLTs. For partial or missing AE onset and/or end dates, 
BI internal rules will be followed (see Reference Document 001-MCG-156_RD-01
“Handling of missing and incomplete AE dates”).
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor
(001-MCS-36-472_RD-01).
7.5
RANDOMISATION
No randomisation will be performed. 
7.6
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations of sample size were performed. Approximately 9
patients for Part I are expected, and approximately 15 patients for Part II are expected. As 

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more patients might be needed based on the recommendation of the SMC and the actual 
number of cohorts tested.

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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the Japanese 
GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 1997) and 
other relevant regulations. Investigators and site staff must adhere to these principles. 
Deviation from the protocol, the principles of ICH GCP or applicable regulations as will be 
treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 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 patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. 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 finalisation of the Clinical Trial Report. 
In exceptional cases, data may be published before the clinical trial report as long as this is 
discussed and agreed to by the investigators and the sponsor.
The certificate of insurance cover is made available to the investigator and the patients, and is 
stored in the ISF.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB/IEC and CA according to national and international 
regulations. The same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH-GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional 
patient-information form retained by the investigator as part of the trial records. A signed 
copy of the informed consent and any additional patient information must be given to each 
patient or the patient’s legally accepted representative.”
The investigator or delegate must give a full explanation to trial patients based on the patient
information form. A language understandable to the patient should be chosen, technical terms 
and expressions avoided, if possible. 

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The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the patient’s own free will with the 
informed consent form after confirming that the patient understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form.
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual patients will be provided by the sponsor. For drug accountability, refer to 
Section 4.1.12.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make at least one documented attempt to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.

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Copies of source documents necessary for tumour assessment will be provided to an 
authorised vendor. Before sending or uploading those copies, the investigator must ensure 
that all patient identifiers (e.g. patient’s name, initials, address, phone number, social security 
number) have properly been removed or redacted from any copy of the patients’ source 
documents.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:

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The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
Exemptions from expedited reporting are described in Section 5.2.9.2.4.
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organisation (WHO) GCP handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised 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 at the site
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB / IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as 
specified in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”). 

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The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of suspected unexpected 
serious adverse reactions (SUSARs) occurring with the trial medication until 30 days after 
LPLT at their site. Early termination of the trial is defined as the premature termination of 
the trial due to any reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim.
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial. Tasks and responsibilities are defined in a contract. 
A SMC composed of participating investigators and members of the BI trial team will be 
established to review individual and aggregated safety and efficacy data at regular intervals to 
determine the safety profile, risk/benefit ratio, recommend next dose level/does 
escalation/de-escalation/modification/next cohort size, and appropriateness of further 
enrolment.
Details of the SMC responsibilities and procedures are described in the SMC charter.
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers), Clinical Research Associates (CRAs), and investigators of participating 
countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a CRO with which the responsibilities and tasks will have 
been agreed and a written contract filed before initiation of the clinical trial.
Data Management will be done by BI or a vendor according to BI SOPs.
Statistical Evaluation will be done by BI according to BI SOPs.

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Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
A central laboratory service, a central imaging collection service, and an IRT vendor will be 
used in this trial. Details will be provided in the IRT Manual and Central Laboratory Manual, 
available in the ISF.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
R07-4856
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on clinical trials in small populations 
(London, 27 July 2006, doc. ref. CHMP/EWP/83561/2005). London: 
EMEA (2006)
R09-0262 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: revised RECIST
guideline (version 1.1). Eur J Cancer. 2009; 45:228-247.
R12-3593 
Falcon BL, Hashizume H, Koumoutsakos P, Chou J, Bready JV, Coxon A,
Oliner JD, McDonald DM. Contrasting actions of selective inhibitors of
angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood
vessels. Am J Pathol 2009. 175(5):2159-2170.
R12-3834 
Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular
morphogenesis and homeostasis through the angiopoietin-Tie system. Nat
Rev Mol Cell Biol 2009. 10:165-177.
R13-0448 
Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of
angiogenesis. Nature 2011. 473:298-307.
R13-4802
Jaki T, Clive S, Weir CJ. Principles of dose finding studies in cancer: a 
comparison of trial designs. Cancer Chemother Pharmacol. 
2013;71:1107-14.
R13-4803
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the 
Bayesian approach to phase I cancer trials. Stat Med. 2008;27:2420-39.
R13-4804
Rogatko A, Schoeneck D, Jonas W, Tighiouart M, Khuri FR, Porter A. 
Translation of innovative designs into phase I trials. J Clin Oncol.
2007;25(31):4982-6.
R13-4805
Tourneau C le, Gan HK, Razak ARA, Paoletti X. Efficiency of new dose 
escalation designs in dose-finding phase I trials of molecularly targeted 
agents. Plos One. 2012;7(12):e51039.
R13-4806
Babb J, Rogatko A, Azcks S. Cancer phase I clinical trials: efficient dose 
escalation with overdose control. Stat Med. 1998;17:1103-20.

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R13-4881
FDA's critical path initiative. Babb J, Rogatko A, Azcks S. 
http://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/u
cm07668 9.htm (access date: 8 November 2013); Silver Spring: U.S. Food 
and Drug Administration (2018)
R15-1222 
Avastin (bevacizumab) solution for intravenous infusion (Genentech) (U.S.
prescribing information, revised: 11/2014). 2014.
R15-1719 
Hassanzadeh-Ghassabeh G, Devoogdt N, Pauw P de, Vincke 
C,Muyldermands S. Nanobodies and their potential applications.
Nanomedicine (Lond) 2013. 8(6):1013-1026
R15-1720 
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.
R17-0923
Seymour L, Bogaerts J, Perone A, Ford R, Schwartz LH, Mandrekar S, et 
al, RECIST Working Group. iRECIST: guidelines for response criteria for 
use in trials testing immunotherapeutics. Lancet Oncol 2017. 
18(3):e143-e152.
R17-2460
Ahamadi M, Freshwater T, Prohn M, Li CH, Alwis DP de, Greef R de, et 
al. Model-based characterization of the pharmacokinetics of 
pembrolizumab: a humanized anti-PD-1 monoclonal antibody in advanced 
solid tumors. CPT Pharmacometrics Syst Pharmacol 2017. 6(1):49-57
R17-4036
Gabrilovich D, Ishida T, Nadaf S, Ohm JE, Carbone DP. Antibodies to
vascular endothelial growth factor enhance the efficacy of cancer 
immunotherapy by improving endogenous dendritic cell function Clin 
Cancer Res. 1999 Oct;5(10):2963-70.
R17-4037
Osada T, Chong G, Tansik R, Hong T, Spector N, Kumar R, et al. The 
effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in 
cancer patients. Cancer Immunol Immunother 2008. 57(8):1115-1124.
R17-4038
Pan PY, Ma G, Weber KJ, Ozao-Choy J, Wang G, Yin B, et al. Immune 
stimulatory receptor CD40 is required for T-cell suppression and T 
regulatory cell activation mediated by myeloid-derived suppressor cells in 
cancer. Cancer Res 2010. 70(1):99-108
R17-4039
Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo P, Rosenberg SA. 
Antiangiogenic agents can increase lymphocyte infiltration into tumor and 
enhance the effectiveness of adoptive immunotherapy of cancer. Cancer 
Res 2010. 70(15):6171-6180

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R18-3204
Population fact sheets: world fact sheet: world.
https://gco.iarc.fr/today/data/factsheets/populations/900-world-fact-sheets.p
df (access date: 22 October 2018); International Agency for Research on 
Cancer, Global Cancer Observatory (2018)
R18-3210
Neuenschwander B, Roychoudhury S, Schmidli H. On the use of co-data in 
clinical trials. Stat Biopharm Res. 2016 8(3):345-54
R18-3778
McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, 
et al. Clinical activity and molecular correlates of response to atezolizumab 
alone or in combination with bevacizumab versus sunitinib in renal cell 
carcinoma. Nature Med 2018. 24:749-57
9.2
UNPUBLISHED REFERENCES
c02353883
 Investigator’s Brochure BI 836880, current version.
c07895879
. Investigator’s Brochure BI 754091, current version.
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics
001-MCG-156_RD-01
Handling of missing and incomplete AE dates
001-MCS-36-472_RD-01 Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses 
of Clinical Trials

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10.
APPENDICES
10.1
IMMUNE-RELATED ADVERSE EVENTS OF SPECIAL INTEREST
Table 10.1: 1 Immune-related adverse events of special interest
This table defines immune-related AEs that must be reported as AESIs if they occur after 
exposure to BI 754091.
Immune-related adverse events of special interest
Pneumonitis (report as AESI if an irAE is ≥Grade 2)

Acute interstitial pneumonitis

Interstitial lung disease

Pneumonitis
Colitis (report as AESI if an irAE is ≥Grade 2 or any grade resulting in dose modification or use 
of systemic steroids to treat the AE)

Intestinal obstruction

Colitis

Colitis microscopic

Enterocolitis

Enterocolitis haemorrhagic

Gastrointestinal perforation

Necrotizing colitis

Diarrhea
Endocrine (report as AESI if an irAE is ≥Grade 3 or ≥Grade 2 and resulting in dose modification 
or use of systemic steroids to treat the AE)

Adrenal insufficiency

Hyperthyroidism

Hypophysitis

Hypopituitarism

Hypothyroidism

Thyroid disorder

Thyroiditis

Hyperglycaemia, if ≥ Grade 3 and associated with ketosis or metabolic acidosis
Endocrine (report as AESI for any grade)

Type 1 diabetes mellitus (if new onset)

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Immune-related adverse events of special interest
Hematologic (report as AESI if an irAE is ≥Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)

Autoimmune haemolytic anaemia

Aplastic anaemia

Thrombotic thrombocytopenic purpura

Idiopathic (or immune) thrombocytopenia purpura

Disseminated intravascular coagulation

Haemolytic-uraemic syndrome

Any Grade 4 anaemia regardless of underlying mechanism
Hepatic (report as AESI if an irAE is ≥Grade 2, or any grade resulting in dose modification or use 
of systemic steroids to treat the AE)

Hepatitis

Autoimmune hepatitis

Transaminase elevations (ALT and/or AST)
Infusion Reactions (report as AESI for any grade)

Allergic reaction

Anaphylaxis

Cytokine release syndrome

Serum sickness

Infusion reactions

Infusion-like reactions
Neurologic (report as AESI for any grade)

Autoimmune neuropathy

Guillain-Barre syndrome

Demyelinating polyneuropathy

Myasthenic syndrome
Ocular (report as AESI if an irAE is ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE)

Uveitis

Iritis

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Immune-related adverse events of special interest
Renal (report as AESI if an irAE is ≥ Grade 2)

Nephritis

Nephritis autoimmune

Renal failure

Renal failure acute

Creatinine elevations (report as an irAE if ≥ Grade 3 or any grade resulting in dose modification or 
use of systemic steroids to treat the AE)
Skin (report as AESI for any grade)

Dermatitis exfoliative

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis
Skin (report as AESI if an irAE is ≥ Grade 3)

Pruritus

Rash

Rash generalized

Rash maculopapular

Any rash considered clinically significant in the physician’s judgment
Other (report as AESI for any grade)

Myocarditis

Pancreatitis

Pericarditis

Any other Grade 3 event that is considered immune-related by the physician

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10.2
MANAGEMENT OF IMMUNE-RELATED ADVERSE EVENTS (PART 
II ONLY)
Management of immune-related adverse event toxicities associated with anti-PD-1 mAbs are 
presented below. BI 754091 should be permanently discontinued for Grade 3-4 
pneumonitis, Grade 3-4 adrenal insufficiency, Grade 4 diabetes mellitus, any grade 
encephalitis, Grade 4 hypophysitis, Grade 4 rash, Grade 3-4 or recurrent colitis of any 
grade, any recurrent Grade 3-4 AE, transaminase increased >5 times ULN or total 
bilirubin >3 times ULN (unless unequivocally attributably to another cause), inability to 
taper steroids to 10 mg or less prednisone or equivalent within 12 weeks, or persistent 
Grade 2-3 AEs that do not recover to Grade 1 or less within 12 weeks.

Pneumonitis:
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 
28 days.
o
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.
o
For Grade 3-4 events immediately treat with i.v. steroids. Administer additional 
anti-inflammatory measures, as needed.
o
BI 754091 should be permanently discontinued for Grade 3-4 pneumonitis, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2 AEs that do not recover to Grade 1 or less within 
12 weeks.

Diarrhoea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhoea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).
o
All subjects who experience diarrhoea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via i.v. infusion. For Grade 2 or higher 
diarrhoea, consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhoea/colitis that persists greater than 3 days, administer oral 
corticosteroids.
o
For Grade 3 or 4 diarrhoea that persists >1 week, treat with i.v. steroids followed 
by high-dose oral steroids.
o
For Grade 3 or 4 colitis, or recurrent colitis of any grade, permanently discontinue
BI 754091, and immediately treat with i.v. steroids followed by high-dose oral 
steroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 should be permanently discontinued for Grade 3-4 or recurrent colitis 
of any grade, inability to taper steroids to 10 mg or less prednisone or equivalent 
within 12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or 
less within 12 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis) Grade 3, or
≥Grade 3 hyperglycaemia, if associated with ketosis (ketonuria) or metabolic acidosis

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o
For Type 1 diabetes mellitus Grade 3-4 or Grade 3-4 hyperglycaemia
•
Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycaemia associated with metabolic 
acidosis or ketonuria.
•
Evaluate subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated haemoglobin, and C-peptide.
o
BI 754091 should be permanently discontinued for Grade 4 diabetes mellitus, any 
recurrent Grade 3 AE or persistent Grade 2-3 AE that does not recover to Grade 1 
or less within 12 weeks.

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 28 days. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3 events, treat with an initial dose of i.v. corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 28 days. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
o
For Grade 4 events, permanently discontinue BI 754091, and treat with an initial 
dose of i.v. corticosteroids followed by oral corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 28 days. Replacement of appropriate hormones may be required as the 
steroid dose is tapered.
o
BI 754091 should be permanently discontinued for Grade 4 hypophysitis, any 
recurrent Grade 3 AE, inability to taper steroids to 10 mg or less prednisone or 
equivalent within 12 weeks, or persistent Grade 2-3 AEs that do not recover to 
Grade 1 or less within 12 weeks.

Hyperthyroidism or Hypothyroidism:
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
o
For Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism):
•
In hyperthyroidism, nonselective beta-blockers (e.g., propranolol) are 
suggested as initial therapy.
•
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.
o
For Grade 3-4 hyperthyroidism
•
Treat with an initial dose of i.v. corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 28 days. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered.
o
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.

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
Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
•
Treat with i.v. or oral corticosteroids
o
For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 48 hours.
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
transaminase increases >5 times ULN or total bilirubin >3 times ULN (unless 
unequivocally attributably to another cause), inability to taper steroids to 10 mg or 
less prednisone or equivalent within 12 weeks, or persistent Grade 2-3 AEs that do
not recover to Grade 1 or less within 12 weeks.

Renal failure or nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 28 days.
o
BI 754091 should be permanently discontinued for any recurrent Grade 3-4 AE, 
inability to taper steroids to 10 mg or less prednisone or equivalent within 
12 weeks, or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.

Adrenal insufficiency:
o
BI 754091 should be permanently discontinued for Grade 3-4 adrenal 
insufficiency or persistent Grade 2 AEs that do not recover to Grade 1 or less 
within 12 weeks.

Rash:
o
BI 754091 should be permanently discontinued for Grade 4 rash, any recurrent 
Grade 3 AE or persistent Grade 2-3 AEs that do not recover to Grade 1 or less 
within 12 weeks.

Encephalitis:
o
BI 754091 should be permanently discontinued for any grade encephalitis.

Infusion reactions:
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion.

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10.3
BLOOD PRESSURE MEASUREMENT PROCEDURE
Blood pressure measurements should be performed on the same arm and, if possible, by the
same person. The machines or devices to be used for blood pressure measurement should be 
certified. The machines to be used for blood pressure measurement should be certified. 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.
In case of a suspected “white coat effect” it is recommended to repeat the measurement in a
pleasant condition after sufficient rest. Values from self-blood pressure measurement (SBPM)
communicated from patient to investigator is not considered valuable for study related
decisions.

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10.4
TIME SCHEDULE FOR PHARMACOKINETIC (PK), 
 
BLOOD SAMPLING
Table 10.4: 1
Time schedule for PK, 
 blood sampling for Part I
Cycle
Visit
Day
Time Point 
CRF Time / 
planned 
time
(hh:min)
PK:
BI 836880
1, 2
1
1
Before start of BI 836880 
infusion
-0:05
X
Start of BI 836880 infusion
0:00
Immediately after end of 
infusion*
1:00**
X
0.5h after the end of infusion
1:30
X
1.5h after the end of infusion
2:30
X
3.5h after the end of infusion
4:30
X
6.5h after the end of infusion
7:30
X
2a
2
24h after the start of infusion
24:00
X
2b
3
48h after the start of infusion
48:00
X
3
8
7 days after start of infusion
168:00
X
4
15
14 days after start of infusion
336:00
X
3
1
1
Before start of BI 836880 
infusion
-0:05
X
Start of BI 836880 infusion
0:00
Immediately after end of 
infusion*
1:00**
X
2a
2
24h after the start of infusion
24:00
X
4
1
1
Before start of BI 836880 
infusion
-0:05
X
Start of BI 836880 infusion
0:00
Immediately after end of 
infusion*
1:00**
X
0.5h after the end of infusion
1:30
X
1.5h after the end of infusion
2:30
X

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Cycle
Visit
Day
Time Point 
CRF Time / 
planned 
time
(hh:min)
PK:
BI 836880
3.5h after the end of infusion
4:30
X
6.5h after the end of infusion
7:30
X
2a
2
24h after the start of infusion
24:00
X
3
8
7 days after start of infusion
168:00
X
4
15
14 days after start of infusion
336:00
X
5-12
1
1
Before start of BI 836880 
infusion
-0:05
X
Start of BI 836880 infusion
0:00
EoT
X
Safety follow-up
X
*
within 5 min after the end of infusion
**
PTM of 1:00 according to an infusion duration of 60 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.
Table 10.4: 2
Time schedule for PK, 
 blood sampling for Part II
Cycle
Visit
Day
Time Point
CRF 
Time / 
planned 
time
(hh:min)
PK 
BI 
836880
BI 
754091
1
1
1
Before start of 
BI 754091 
infusion
-0:05
X
Start of BI 
754091 
infusion
0:00
After end of 
BI 754091 
infusion
1:00*
X
Start of 
BI 836880 
infusion
1:15
After end of
BI 836880 
infusion
2:15*
X
6 hours after 
start of BI 
754091infusion
(3:45 after end 
of BI 836880 if 
6:00
X

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Cycle
Visit
Day
Time Point
CRF 
Time / 
planned 
time
(hh:min)
PK 
BI 
836880
BI 
754091
no infusion 
delay)
2a
2
24h after start 
of BI 754091 
infusion
24:00
X
3
8
7 days after 
start of BI 
754091 
infusion
168:00
X
4
15 
14 days after 
start of BI 
754091 
infusion
336:00
X
2, 3
1
1
Before start of 
BI 754091 
infusion
-0:05
X
Start of BI 
754091 
infusion
0:00
After end of 
BI 754091 
infusion
1:00*
X
Start of 
BI 836880 
infusion
1:15
After end of BI 
836880 
infusion
2:15*
X
4
1
1
Before start of 
BI 754091 
infusion
-0:05
X
Start of BI 
754091 
infusion
0:00
After end of BI 
754091 
infusion
1:00*
X
Start of BI 
836880 
infusion
1:15
After end of BI 
836880 
infusion
2:15*
X
6 hours after 
start of BI 
754091 
infusion
(3:45 after end 
of BI 836880 if 
no infusion 
delay)
6:00
X
2a
2
24h after start 
of BI 754091 
infusion
24:00
X
3
8
7 days after 
start of BI 
754091 
168:00
X

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Cycle
Visit
Day
Time Point
CRF 
Time / 
planned 
time
(hh:min)
PK 
BI 
836880
BI 
754091
infusion
4
15
14 days after 
start of BI 
754091 
infusion
336:00
X
5, 6
1
1
Before start of 
BI 754091 
infusion
-0:05
X
Start of BI 
754091 
infusion
0:00
After end of BI 
754091 
infusion
1:00*
X
Start of BI 
836880 
infusion
1:15
After end of BI 
836880 
infusion
2:15*
X
7-12
1
1
Before start of 
BI 754091 
infusion
-0:05
X
EoT
X
Safety follow-up
X
*
within 5 min after the end of infusion

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10.5
STATISTICAL APPENDIX INCLUDING MODEL PERFORMANCE AND 
DATA SCENARIOS
The model was assessed by two different metrics: hypothetical on-study data scenarios and 
long-run operating characteristics. The simulations for scenarios and operating characteristics 
were produced using R version 3.4.2.
10.5.1
Part I (BI 836880 monotherapy dose finding part)
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5.1: 1. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model. 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.
For example, scenario 1 represents the case that no DLT is observed in the first three patients 
at the starting dose of 360 mg. In this case, the next optimal dose, i.e. the dose with the 
highest probability of being in the target interval, is 720 mg. Similarly scenario 4 represents 
the case where no DLTs are observed, and the next optimal dose recommended is 720 mg 
according to BLRM since no higher dose is available.
Scenarios 5 illustrates the case where low dose cohorts have no DLT and the highest dose 
level 720 mg/kg has 1 DLT, in such cases, BLRM would continue to assign patients on 
720 mg/kg,
In scenario 6, two DLT is observed already in the patient. In this case, the model 
recommends de-escalation to 360 mg.
Table 10.5.1: 1 
Hypothetical data scenarios
Scenario
Dose 
(mg)
#
DLT
#
Pat
Current
Dose:
P(OD)
Next 
Recommended
Dose
Next Dose
P(UD)
P(TD)
P(OD)
1
360
0
3
0.005
720
0.728
0.213
0.059
2
360
1
3
0.052
720
0.406
0.416
0.179
3
360
2
3
0.241
360
0.350
0.410
0.241
4
360
720
0
0
3
3
0.016
720
0.831
0.152
0.016
5
360
720
0
1
3
3
0.093
720
0.561
0.346
0.093

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6
360
720
0
2
3
3
0.319
360
0.865
0.114
0.021
Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. 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 10.5.1: 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 means

Scenario 2: high-toxicity scenario

Scenario 3: low-toxicity scenario

Scenario 4: non-logistic dose-toxicity scenario

Scenario 5: low-toxicity followed by high-toxicity

Scenario 6: super high-toxicity scenario
Table 10.5.1: 2
Assumed true dose-toxicity scenarios 
Scenario
Dose (mg)
360
720
1 (Prior)
P(DLT)
0.069
0.154
2 (High Tox)
0.321
0.500
3 (Low Tox)
0.039
0.180
4 (Non-Logistic)
0.280
0.360
5 (Low-High)
0.180
0.317
6 (Super High Tox)
0.580
0.769
* Additional dose level 1250mg added (assumed true tox probability of 0.444, 0.603, 0.250, 
0.380 and 0.600 under scenarios 1-5 respectively) to allow R code to run. For scenario 6, 
additional dose level 120mg added (assumed true tox probability of 0.26) to allow R code to 
run.
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 10.5.1: 3.

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Table 10.5.1: 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
72.6
0.0
25.7
1.7
11.4(3-24)
2.3(1-8)
2
0.0
40.5
19.3
40.2
8.3(3-27)
3.4(1-10)
3
10.9
88.4
0.0
0.7
11.7(3-33)
1.8(1-6)
4
0.0
29.7
44.9
25.4
9.3(3-24)
3.0(1-12)
5
0.0
83.3
5.3
11.4
10.3(3-21)
3.1(1-8)
6
0.0
46.4
11.6
42.0
8.7(3-18)
4.1(2-9)
In Scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
72.6% of the simulated trials declared a dose as MTD with true DLT rate under the targeted 
dose range, since there is no dose with assumed true toxicity probability in the target interval, 
therefore it is logical that none of the trials declares a MTD with true tox probability in the 
target interval. In many cases the model chooses that dose as MTD that is closest to the target 
interval, this is 720mg with assumed tox probability of 0.154, since 0.154 is very close to the 
target interval.
Scenario 2 (high-toxicity scenario) shows, that when the true DLT rate is high, i.e. the 
majority dose levels with true DLT rate above the target interval, 40.5% of the simulated 
trials declared a dose as MTD with true DLT rate in the targeted dose range. The starting 
dose has already >32.1% 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 (40.2%) of all 
simulated trials for which the trial is stopped, since none of the doses is considered tolerable 
anymore. This is an expected situation for a high-toxicity scenario.
Scenarios 3 and 5 show that when the true DLT rate is low and low-high, most of the 
simulated trials declared a dose as MTD with true DLT rate in the targeted dose range.
Scenario 4 shows, that when the true DLT rate is non-logistic, then more likely the model 
will declare a overdose as MTD.
Scenario 6 shows that when the true DLT rate is super high, 42% of simulated trials stopped, 
since none of the doses is considered tolerable anymore. This is an expected situation for a
super high-toxicity scenario.
The mean patient numbers range from 8.3 patients (Scenario 2) to 11.7 (Scenario 3) during 
the simulation. This shows that the planned maximum of 9 patients is reasonable. 

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In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.
10.5.2
Part II (BI 836880 and BI 754091 combination dose finding)
Hypothetical data scenarios
Hypothetical data scenarios are shown in Table 10.5.2: 1. These scenarios reflect potential 
on-study data constellations and related escalation as allowed by the model. For each scenario, 
the probability of overdose for the current dose combination, as well as the next potential 
dose combination and related probabilities of under-dosing, target dose, and over-dosing are 
shown.
Table 10.5.2: 1
Hypothetical data scenarios
Scenario
Dose 
(mg)
#
DLT
#
Pat
Current
Dose:
P(OD)
Next 
Recommended
Dose
Next Dose
P(UD)
P(TD)
P(OD)
1
120/240
0
3
0.054
360/240
0.413
0.339
0.248
2
120/240
1
3
0.228
120/240
0.336
0.436
0.228
3
120/240
2
3
0.528
NA
NA
NA
NA
4
120/240
360/240
0
0
3
3
0.085
360/240
0.609
0.306
0.085
5
120/240
360/240
0
1
3
3
0.295
120/240
0.627
0.324
0.049
6
120/240
360/240
0
2
3
3
0.602
120/240
0.408
0.440
0.152
For example, scenario 1 represents the case that no DLT is observed in the first three patients 
at the starting dose combination of 120/240 mg/kg. In this case, the next optimal dose
combination, i.e. the dose combination with the highest probability of being in the target 
interval, is the next dose combination, i.e., 360/240 mg/kg. Scenarios 5 illustrates the case 
where low dose combination cohorts have no DLT and the highest dose combination level 
360/240 mg/kg has 1 DLT, in such cases, BLRM would de-escalate and put patients on 
120/240 mg/kg, In scenarios 3, two DLT is observed already in the patient. In this case, the 
model recommends stopping the trial because of high overdose probabilities.

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Operating characteristics
Operating characteristics are a way to assess the long-run behaviour of a model by illustrating 
the precision of the design in estimating the MTD. Under an assumed true dose-toxicity curve, 
metrics such as the probability of recommending a dose combination with true DLT rate in 
the target interval can be approximated via simulation. Table 10.5.2: 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 means

Scenario 2: high-toxicity scenario

Scenario 3: low-toxicity scenario

Scenario 4: non-logistic dose-toxicity scenario

Scenario 5: low-toxicity followed by high-toxicity

Scenario 6: super high-toxicity scenario
Table 10.5.2: 2
Assumed true dose-toxicity scenarios
Scenario
Dose (mg)
120/240
360/240
720/240
1 (Prior)
P(DLT)
0.209
0.318
0.680
2 (High Tox)
0.291
0.327
0.516
3 (Low Tox)
0.054
0.128
0.190
4 (Non-Logistic)
0.145
0.290
0.505
5 (Low-High)
0.128
0.169
0.550
6 (Super High Tox)
0.489
0.580
0.769
Table 10.5.2: 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
5.9
76.9
3.8
13.4
11.9 (3-30)
3.3 (1-10)
2
0.0
64.6
9.5
25.9
10.3 (3-30)
3.4 (1-11)
3
68.1
29.2
0.0
2.7
14.6 (3-42)
1.8 (0-8)
4
66.3
7.5
20.8
5.4
11.8 (3-27)
2.8 (1-9)
5
62.2
10.6
23.4
3.8
11.9 (3-27)
2.7 (1-7)

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6
0.0
24.4
26.5
49.1
11.0 (3-27)
4.3 (1-10)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with prior means, 
76.9% of the simulated trials declared a dose as MTD with true DLT rate in the targeted dose 
range.
In Scenario 2 (high-toxicity scenario), 64.6% of the simulated trials declared a dose as MTD 
with true DLT rate in the targeted dose range.
In Scenarios 1 and 2, the starting dose has already >12.0% 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 of all simulated trials for which the trial is stopped, since none of the doses is 
considered tolerable anymore. This is an expected situation for assumed dose-toxocity 
scenarios.
In Scenarios 3-5, there is/are one or two dose(s) with assumed true toxicity probability in the 
underdosing interval [0.00, 0.16), in some cases the model chooses that dose as MTD that is 
closest to the target interval, which results in certain percentage of trials with an MTD with 
true DLT rate in underdosing interval.
Scenario 6 shows that when the true DLT rate is super high, 49.1% of simulated trials 
stopped, since none of the doses is considered tolerable anymore. This is an expected 
situation for a super high-toxicity scenario.
The mean patient numbers range from 10.3 patients (Scenario 2) to 14.6 (Scenario 3) during 
simulation. This shows that the planned maximum of 12 patients is reasonable. 
In summary, the considered data scenarios show a reasonable behaviour of the model and the 
operating characteristics demonstrate a good precision of MTD determination.

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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
28 Mar 2019
EudraCT number
EU number
Not applicable
BI Trial number
1336-0012
BI Investigational Medicinal 
Product(s)
BI 836880 and BI 754091
Title of protocol
An open label, Phase I study of BI 836880 
monotherapy and combination therapy of BI 
836880 and BI 754091 in Japanese patients with 
advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
Clinical Trial Protocol Synopsis – Trial site(s)
Description of change
Multi-centre trial conducted in Japan Asia
Rationale for change
Clarification
Section to be changed
Clinical Trial Protocol Synopsis – Total number of 
patients treated
Clinical Trial Protocol Synopsis – Number of 
patients on each treatment
Description of change
Approximately 24 21
Rationale for change
A buffer of 3 patients was added for the possibility 
of adding extra number of patients for DLTs or 
other reasons.
Section to be changed
Flow Chart and Section 5.2.3 Vital signs
Description of change
Arterial oxygen saturation (SpO2) was added as a 
part of vital signs measurements.
Rationale for change
For early detection of potential interstitial lung 
diseases.
Section to be changed
Flow Chart and Section 5.2.7 Chest X-ray
Description of change
Regular Chest X-ray testing was added.
Rationale for change
For early detection of potential interstitial lung 
diseases.
Section to be changed
Flow Chart
Description of change
Footnote b is modified:
Safety laboratory assessments including 
haematology, clinical biochemistry, and urinalysis 

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will be performed locally. If screening laboratory 
assessments, and, pregnancy testing, and chest 
X-ray are performed within 72 hours of 3 days 
before initiation of treatment, they do not need to 
be repeated on Cycle 1 Day 1. Refer to Section 5.2
for additional details.
Rationale for change
Clarification
Section to be changed
1.1 Medical background
Description of change
The following description in the fourth paragraph 
was deleted:
Studies in mice have shown that Ang2, a ligand of 
the Tie2 receptor, controls vascular remodelling 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  tumour vessel plasticity, 
allowing vessels to respond to VEGF and FGF2 
(R12-3834).
Rationale for change
It was found to be redundant.
Section to be changed
1.3
Rationale for performing the trial
Description of change
In order to be able to address future scientific 
questions, patients will be asked to voluntarily 
donate biospecimens for banking (please see 
Section 5.5 5.4)
Rationale for change
Correction of error
Section to be changed
1.4.1   Benefits
Description of change
This trial is for patients with advanced cancer and 
for whom there are no therapy options of proven 
efficacy, or who are not amenable to currently 
available standard therapies. The investigational 
agent BI 836880 is an investigational 
antiangiogenic agent and BI 754091 is an 
investigational immune checkpoint inhibitor. 
There are many antiangiogenic agents already 
approved to treat various types of cancer. and by 
Similarly there are many immune checkpoint 
inhibitors approved in various types of cancers. 
By participating in this trial and receiving study 
medication(s) either as monotherapy or in 
combination, patients with advanced cancer may 
have a better chance to delay in tumour 
progression, compared with no anti-cancer 
treatment.

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Based on the mode of action of BI 836880 and BI
754091, published and internal preclinical data,
and available clinical data, it is anticipated that
treatment with this the combination will 
potentially improve response rate with increase 
the anti tumour efficacy resulting in an increase in 
response rate with prolonged duration of response 
as compared to each monotherapy.
Rationale for change
Clarification
Section to be changed
Table 1.4.2:1 Potential risks, their rationale, and 
mitigation strategy
Description of change
Summary of data, rationale for the risk of 
hypertension in BI 836880:
This is a class effect AE and has been identified as 
a side effect an expected AE in this trial.
Summary of data, rationale for the risk of 
thromboembolic events in BI 836880:
This is a class effect and expected AE with 
antiangiogenics AE.
Mitigation strategy for immune-related adverse 
events (irAEs) in BI 754091:
Recommendations for the management of irAEs 
are provided. Investigators involved in this trial 
have experience in managing irAE and sites 
have facilities. A 48-hour hospitalisation with 
access to intensive care is mandated for all 
patients after the first study drug 
administration to secure the patient safety.
Rationale for change
Clarification
Section to be changed
1.4.3  Discussion
Description of change
Both BI 836880 and BI 754091 are currently tested 
in early phase clinical trials as monotherapy and 
as a combination.
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&::,2*&0/, '.#DB
Rationale for change
Clarification
Section to be changed
3.3.3
Exclusion criteria
Description of change
21.
Women who are pregnant, nursing, or who 
plan to become pregnant while in the trial. Female 
patients of childbearing potential must have a 
negative urine or serum pregnancy test within 72 
hours3 days prior to taking study medication. If the 
urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required. 
The serum pregnancy test must be negative for the 
patient to be eligible. Women who are nursing 
can be enrolled if they stop nursing. In this case, 
the patient cannot resume nursing even after 
discontinuation of study treatment.
Rationale for change
Clarification
Section to be changed
4.1.6 Dose modifications
Description of change
Updated:
Before initiating a new treatment cycle, the actual 
health status will be assessed according to Flow 
Chart and described in Section 5.2. To continue 
treatment with further cycles, all of the following 
retreatment criteria must be met:
Added:
If a patient develops an interstitial lung disease, 
the treatment has to be discontinued
Rationale for change
In response to the PMDA's review, the first 
paragraph was updated for clarification. The 
discontinuation criteria for interstitial lung diseases 
were also added in response to a PMDA's review 
comment.
Section to be changed
4.1.7
Dose limiting toxicities
Description of change
The following exception from a DLT criterion of 
≥G3 non-haematologic toxicities was removed:
o
Grade 3 infusion related reaction which 
can be controlled by appropriate medication 
according to investigator’s decision, and the 
subsequent infusion will not be delayed for more 
than two weeks
Rationale for change
In response to the PMDA's review, BI is going to 
handle G3 Infusion related reactions regardless of 
the controllability

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Section to be changed
5.3.2
Methods of sample collection
Description of change
After completion of the trial the plasma and urine 
samples may be used for further methodological 
investigations, e.g. for stability testing. However, 
only data related to the analyte and/or its 
metabolite(s) including anti-drug antibodies (if 
applicable) will be generated by these additional 
investigations. The study samples will be discarded 
after completion of the additional investigations 
but not later than 5 years upon the final study 
report has been signed.
Rationale for change
Correction of error
Section to be changed
7.1.2
Statistical design – Part II (BI 836880 and 
BI 754091 combination dose finding)
Description of change
A sentence in the 12th paragraph was updated as 
follows:
Since data from 1336-0012 Part 1 and 1336-0011
1336-0012 were not yet available by the time of 
finalization of the CTP, data as is might be 
observed in future in these trials will be used as 
dummy data.
Rationale for change
Correction of error
Section to be changed
7.1.2
Statistical design – Part II (BI 836880 and 
BI 754091 combination dose finding)
Description of change
The title of tables 7.1.2: 2 and 7.1.2: 3 was updated 
as follows:
Table 7.1.2: 2
Preliminary data Hypothetical 
data expected from 1381-0001
Table 7.1.2: 3
Preliminary data Hypothetical 
data expected from 1381-0004
Rationale for change
Clarification
Section to be changed
7.6
Determination of sample size
Description of change
No formal statistical power calculations of sample 
size were performed. Approximately 9 patients for 
Part I are expected, And approximately 1512

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patients for Part II are expected. As Fewer or more 
patients might be needed based on the 
recommendation of the SMC and the actual 
number of cohorts tested.
Rationale for change
A buffer of 3 patients was added for the possibility 
of adding extra number of patients for DLTs or 
other reasons.
Section to be changed
8.3
Records
Description of change
CRFs for individual patients will be provided by 
the sponsor. For drug accountability, refer to 
Section 4.1.12 4.1.13
Rationale for change
Correction of error
11.2
GLOBAL AMENDMENT 2
Date of amendment
21 Aug 2019
EudraCT number
EU number
Not applicable
BI Trial number
1336-0012
BI Investigational Medicinal 
Product(s)
BI 836880 and BI 754091
Title of protocol
An open label, Phase I study of BI 836880 
monotherapy and combination therapy of BI 
836880 and BI 754091 in Japanese patients with 
advanced solid tumours
Global Amendment due to urgent safety reasons
Global Amendment
Section to be changed
4.1.5  Drug assignment and administration of 
doses for each patient
Description of change
The duration of infusion should not be prolonged 
to more than 6 hours for BI 836880, and more than 
32 hours for BI 754091.
Rationale for change
Update according to the latest result of in-use 
stability test for BI 754091.
Section to be changed
4.1.6  Dose modifications
Description of change
Administration of trial drugs has to be stopped 
temporarily in case of a DLT (see Section 4.1.7). 
Patients may resume the treatment only after 
recovery from DLT to at least fulfil retreatment 
criteria. The future dose of BI 836880 must be a 
tested dose which is one dose level below the 
dose received by the patient. The dose level for 

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treatment resumption should be as prescribed in
Table 4.1.6: 1. Treatment has to be discontinued in 
case the DLT is not reversible.
Rationale for change
Clarification
Section to be changed
4.1.6  Dose modifications
Description of change
Dose reduction for BI 754091 is not allowed. 
The dose of BI 754091 may be delayed for a 
patient for one cycle, plus an additional 3 weeks, 
because of AEs following discussion with the 
sponsor.
In combination treatment arms, both drugs (BI 
836880 and BI 754091) will be stopped,
paused, or re-exposed together unless an AE 
can be attributed to either BI 836880 or
BI 754091. Only if a causal relationship to one 
trial drug can be unequivocally established,
the other trial drug may be continued.
In case of irAEs which meets the criteria in Section 
10.2, dose level of BI 754091 can be reduced 
according to Table 4.1.6: 2.
Table 4.1.6:2  Dose reduction recommendations 
for BI 754091
Rationale for change
Correction: Dose reduction recommendation for BI 
754091 is removed to follow the determination at 
the project. Clarification of recommendation on 
combination treatment in Part II.
Section to be changed
5.2.3  Vital signs
Description of change
At days of administration blood pressure and 
pulseheart rate will be evaluated at the following
time points:
Rationale for change
Correction
Section to be changed
5.2.9.1.4  Adverse events of special interest
Description of change
Infusion-related reactions
In the event of an infusion-related reaction ≤Grade 
2, the infusion rate of study drug(s) may be 
decreased by 50% or interrupted until resolution of 
the event and re-initiated the infusion should be 
temporarily stopped. Upon recovery, it should 
be infused at 50% of the initial rate until 
completion of the infusion. In patients 
experiencing infusion-related reactions ≤ Grade 

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2, subsequent infusions may be administered at 
50% of the initial rate.
Rationale for change
Correction to be consistent with descriptions in 
Section 4.1.5.
Section to be changed
7.1.1
Statistical design – Part I (BI 836880 
monotherapy dose finding part)
Description of change
The estimated probability of a DLT at each dose 
level from the model will be summarized using the 
following intervals:
Underdosing: [0.00, 0.16)]
Targeted toxicity: [0.16, 0.33)]
Over toxicity: [0.33, 1.00]
Rationale for change
Correction of typographical error
Section to be changed
7.1.2  Statistical design – Part II (BI 836880 and 
BI 754091 combination dose finding)
Description of change
The resulting parameters of the prior distributions 
for four combination levels, i.e., (120/240, 
360/240, 500/240, 720/240), are given in Table
7.1.2: 5. The corresponding prior probabilities of a 
DLT at different dose combinations (with the 
consideration of BLRM simulation, BI754091 80 
and 400 mg are included and they will not be 
tested in patients. More details about simulation 
are included in Section 10.5.2) and the 
corresponding probabilities of under toxicity, 
targeted toxicity and over toxicity are shown in 
Table 7.1.2: 6.
Rationale for change
Updated according to removal of dose reduction 
recommendation and keep fixed dose for BI 
754091
Section to be changed
7.1.2  Statistical design – Part II (BI 836880 and 
BI 754091 combination dose finding)
Description of change
Removal of the 1st and 3rd tables (tables for BI 
754091 80 mg and 400 mg) from Table 7.1.2: 6
Rationale for change
Updated according to removal of dose reduction 
recommendation and keep fixed dose for BI 
754091
Section to be changed
10.5.2  Part II (BI 836880 and BI 754091 
combination dose finding)
Description of change
Removal of the 1st and 3rd tables (tables for BI 
754091 80 mg and 400 mg) from Table 10.5.2:2

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Rationale for change
Updated according to removal of dose reduction 
recommendation and keep fixed dose for BI 
754091

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
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c25769893
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clinical-trial-protocol-version-03
An open label, Phase I study of BI 836880 monotherapy and combination therapy of
BI 836880 and BI 754091 in Japanese patients with advanced solid tumours
Author-Clinical Trial Leader
21 Aug 2019 14:39 CEST
Approval-Team Member Medicine
21 Aug 2019 14:49 CEST
Approval-Therapeutic Area 
21 Aug 2019 22:32 CEST
Author-Clinical Pharmacokineticist
22 Aug 2019 02:06 CEST
Author-Trial Statistician
22 Aug 2019 03:08 CEST
Verification-Paper Signature
Completion
30 Aug 2019 03:07 CEST

Boehringer Ingelheim 
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